Formation of neuronal pathways in the imaginal discs of Drosophila melanogaster.
We have followed the formation of neuronal pathways in different imaginal discs of Drosophila. The pattern is highly reproducible for a given disc type but distinct for each type of discs: in leg discs, several neurons are present before metamorphosis and provide two major pathways that are joined by later neurons; in the wing and haltere discs, a few pairs of neurons appear after the onset of metamorphosis and pioneer the major pathways; in antenna discs, no pioneers are detected before massive neuronal differentiation begins. The mechanisms used for axonal guidance seem common to all discs, and the differences between discs can be accounted for simply by differences in the arrangement and birth time of pioneer neurons. Different subsets of pioneer neurons are deleted by mutations such as scute and engrailed.


The elusive definition of pandemic influenza.
There has been considerable controversy over the past year, particularly in Europe, over whether the World Health Organization (WHO) changed its definition of pandemic influenza in 2009, after novel H1N1 influenza was identified. Some have argued that not only was the definition changed, but that it was done to pave the way for declaring a pandemic. Others claim that the definition was never changed and that this allegation is completely unfounded. Such polarized views have hampered our ability to draw important conclusions. This impasse, combined with concerns over potential conflicts of interest and doubts about the proportionality of the response to the H1N1 influenza outbreak, has undermined the public trust in health officials and our collective capacity to effectively respond to future disease threats. WHO did not change its definition of pandemic influenza for the simple reason that it has never formally defined pandemic influenza. While WHO has put forth many descriptions of pandemic influenza, it has never established a formal definition and the criteria for declaring a pandemic caused by the H1N1 virus derived from "pandemic phase" definitions, not from a definition of "pandemic influenza". The fact that despite ten years of pandemic preparedness activities no formal definition of pandemic influenza has been formulated reveals important underlying assumptions about the nature of this infectious disease. In particular, the limitations of "virus-centric" approaches merit further attention and should inform ongoing efforts to "learn lessons" that will guide the response to future outbreaks of novel infectious diseases.


Long-Dose Intensive Therapy Is Necessary for Strong, Clinically Significant, Upper Limb Functional Gains and Retained Gains in Severe/Moderate Chronic Stroke.
Background. Effective treatment methods are needed for moderate/severely impairment chronic stroke. Objective. The questions were the following: (1) Is there need for long-dose therapy or is there a mid-treatment plateau? (2) Are the observed gains from the prior-studied protocol retained after treatment? Methods. Single-blind, stratified/randomized design, with 3 applied technology treatment groups, combined with motor learning, for long-duration treatment (300 hours of treatment). Measures were Arm Motor Ability Test time and coordination-function (AMAT-T, AMAT-F, respectively), acquired pre-/posttreatment and 3-month follow-up (3moF/U); Fugl-Meyer (FM), acquired similarly with addition of mid-treatment. Findings. There was no group difference in treatment response (P ≥ .16), therefore data were combined for remaining analyses (n = 31; except for FM pre/mid/post, n = 36). Pre-to-Mid-treatment and Mid-to-Posttreatment gains of FM were statistically and clinically significant (P < .0001; 4.7 points and P < .001; 5.1 points, respectively), indicating no plateau at 150 hours and benefit of second half of treatment. From baseline to 3moF/U: (1) FM gains were twice the clinically significant benchmark, (2) AMAT-F gains were greater than clinically significant benchmark, and (3) there was statistically significant improvement in FM (P < .0001); AMAT-F (P < .0001); AMAT-T (P < .0001). These gains indicate retained clinically and statistically significant gains at 3moFU. From posttreatment to 3moF/U, gains on FM were maintained. There were statistically significant gains in AMAT-F (P = .0379) and AMAT-T P = .003.


Mitochondria in complex psychiatric disorders: Lessons from mouse models of 22q11.2 deletion syndrome: Hemizygous deletion of several mitochondrial genes in the 22q11.2 genomic region can lead to symptoms associated with neuropsychiatric disease.
Mitochondrial ATP synthesis, calcium buffering, and trafficking affect neuronal function and survival. Several genes implicated in mitochondrial functions map within the genomic region associated with 22q11.2 deletion syndrome (22q11DS), which is a key genetic cause of neuropsychiatric diseases. Although neuropsychiatric diseases impose a serious health and economic burden, their etiology and pathogenesis remain largely unknown because of the dearth of valid animal models and the challenges in investigating the pathophysiology in neuronal circuits. Mouse models of 22q11DS are becoming valid tools for studying human psychiatric diseases, because they have hemizygous deletions of the genes that are deleted in patients and exhibit neuronal and behavioral abnormalities consistent with neuropsychiatric disease. The deletion of some 22q11DS genes implicated in mitochondrial function leads to abnormal neuronal and synaptic function. Herein, we summarize recent findings on mitochondrial dysfunction in 22q11DS and extend those findings to the larger context of schizophrenia and other neuropsychiatric diseases.


The cost of data collection for performance monitoring in hospitals: protocol for a systematic review.
Key performance indicators (KPIs) are used to identify where organisational performance is meeting desired standards and where performance requires improvement. Valid and reliable KPIs depend on the availability of high-quality data, specifically, the relevant minimum data set (MDS; the core data identified as the minimum required to measure performance for a KPI) elements. However, the feasibility of collecting the relevant MDS elements is always a limitation of performance monitoring using KPIs. Preferably, data should be integrated into service delivery, and where additional data are required that are not currently collected as part of routine service delivery, there should be an economic evaluation to determine the cost of data collection. The aim of this systematic review is to synthesise the evidence base concerning the costs of data collection in hospitals for performance monitoring using KPIs, and to identify hospital data collection systems that have proven to be cost minimising. Electronic databases will be systematically searched for publications in English that examine the cost of data collection within a hospital context. The database searches will be supplemented by searching through citations and references. Screening of both titles and abstracts will be done by two independent reviewers. All disagreements will be resolved by an independent third reviewer. Data analysis will be completed and reported in a narrative review. This review will cohere the evidence base regarding cost-minimising hospital data collections systems for performance monitoring and if these are associated with potential benefits for patients. PROSPERO CRD42014007450.


Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations.
Innate immunity to viral infection involves induction of the type I IFN response; however, dysfunctional regulation of this pathway leads to inappropriate inflammation. Here, we evaluated a nonconsanguineous family of mixed European descent, with 4 members affected by systemic inflammatory and autoimmune conditions, including lupus, with variable clinical expression. We identified a germline dominant gain-of-function mutation in TMEM173, which encodes stimulator of type I IFN gene (STING), in the affected individuals. STING is a key signaling molecule in cytosolic DNA-sensing pathways, and STING activation normally requires dimerization, which is induced by 2'3' cyclic GMP-AMP (cGAMP) produced by the cGAMP synthase in response to cytosolic DNA. Structural modeling supported constitutive activation of the mutant STING protein based on stabilized dimerization. In agreement with the model predictions, we found that the STING mutant spontaneously localizes in the Golgi of patient fibroblasts and is constitutively active in the absence of exogenous 2'3'-cGAMP in vitro. Accordingly, we observed elevated serum IFN activity and a type I IFN signature in peripheral blood from affected family members. These findings highlight the key role of STING in activating both the innate and adaptive immune responses and implicate aberrant STING activation in features of human lupus.


Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models.
Two types of mutations of a transcription factor CCAAT-enhancer binding protein α (C/EBPα) are found in leukemic cells of 5%-14% of acute myeloid leukemia (AML) patients: N-terminal mutations expressing dominant negative p30 and C-terminal mutations in the basic leucine zipper domain. Our results showed that a mutation of C/EBPα in one allele was observed in AML after myelodysplastic syndrome, while the 2 alleles are mutated in de novo AML. Unlike an N-terminal frame-shift mutant (C/EBPα-N(m))-transduced cells, a C-terminal mutant (C/EBPα-C(m))-transduced cells alone induced AML with leukopenia in mice 4-12 months after bone marrow transplantation. Coexpression of both mutants induced AML with marked leukocytosis with shorter latencies. Interestingly, C/EBPα-C(m) collaborated with an Flt3-activating mutant Flt3-ITD in inducing AML. Moreover, C/EBPα-C(m) strongly blocked myeloid differentiation of 32Dcl3 cells, suggesting its class II mutation-like role in leukemogenesis. Although C/EBPα-C(m) failed to inhibit transcriptional activity of wild-type C/EBPα, it suppressed the synergistic effect between C/EBPα and PU.1. On the other hand, C/EBPα-N(m) inhibited C/EBPα activation in the absence of PU.1, despite low expression levels of p30 protein generated by C/EBPα-N(m). Thus, 2 types of C/EBPα mutations are implicated in leukemo-genesis, involving different and cooperating molecular mechanisms.


The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox.
The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the "Autophagy Paradox". We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism" or "Battery-Operated Tumor Growth". In this sense, autophagy in the tumor stroma serves as a "battery" to fuel tumor growth, progression and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients-both effectively "starving" cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy, by the upregulation of natural endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy, by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an anti-cancer therapy that combines the alternating use of both autophagy promoters and autophagy inhibitors would be expected to prevent the onset of drug resistance. We also discuss why anti-angiogenic therapy has been found to promote tumor recurrence, progression and metastasis. More specifically, anti-angiogenic therapy would induce autophagy in the tumor stroma via the induction of stromal hypoxia, thereby converting a non-aggressive tumor type to a "lethal" aggressive tumor phenotype. Thus, uncoupling the metabolic parasitic relationship between cancer cells and an autophagic tumor stroma may hold great promise for anti-cancer therapy. Finally, we believe that autophagy in the tumor stroma is the local microscopic counterpart of systemic wasting (cancer-associated cachexia), which is associated with advanced and metastatic cancers. Cachexia in cancer patients is not due to decreased energy intake, but instead involves an increased basal metabolic rate and increased energy expenditures, resulting in a negative energy balance. Importantly, when tumors were surgically excised, this increased metabolic rate returned to normal levels. This view of cachexia, resulting in energy transfer to the tumor, is consistent with our hypothesis. So, cancer-associated cachexia may start locally as stromal autophagy, and then spread systemically. As such, stromal autophagy may be the requisite precursor of systemic cancer-associated cachexia.


Hyperacute direct thrombus imaging using computed tomography and gold nanoparticles.
Advancing the understanding and management of thromboembolic stroke requires simple and robust new methods that would be useful for the in vivo assessment of thrombus burden/distribution and for characterizing its evolution in a prompt and quantitative manner. Animals (n=127) with experimental models of thrombosis were imaged with microcomputed tomography 5 minutes (and/or ~3 weeks) after intravenous injection of glycol chitosan (GC) gold nanoparticles (AuNPs). Nanoparticles accumulated in the thrombus, allowing computed tomography visualization of both the presence and extent of primary and recurrent thrombi in mouse carotid arteries without a single failure of detection. Nanoparticle thrombus imaging was also effective in monitoring the therapeutic efficacy of thrombolysis (n=118 tissue plasminogen activator [tPA] therapies). Thrombus evolution (either spontaneous or post-tPA) could be mapped at high resolution in both space and time. Due to a long circulating half-life, GC-AuNPs remain available for entrapment into fibrin matrix for an extended period of time (up to 3 weeks), allowing repetition or ongoing monitoring of thrombogenesis and thrombolysis. This is the first report on a hyperacute direct thrombus imaging technique using thrombus-seeking AuNPs and computed tomography. When translated into stroke practice, the thrombus imaging may allow us to advance to personalized thrombolytic therapy by demonstrating thrombus burden, distribution, and character in a prompt and quantitative manner. Further study into this area is indicated.


Biosynthesis of Menaquinone (Vitamin K2) and Ubiquinone (Coenzyme Q).
Escherichia coli and Salmonella contain the naphthoquinones menaquinone (MK; vitamin K2) and demethylmenaquinone and the benzoquinone ubiquinone (coenzyme Q; Q). Both quinones are derived from the shikimate pathway, which has been called a "metabolic tree with many branches." There are two different pathways for the biosynthesis of the naphthoquinones. The vast majority of prokaryotes, including E. coli and Salmonella, and the plants use the o-succinylbenzoate pathway, while a minority uses the futalosine pathway. The quinone nucleus of Q is derived directly from chorismate, while that of MK is derived from chorismate via isochorismate. The prenyl side chains of both quinones are from isopentenyl diphosphate formed by the 2-C-methyl-D-erythritol 4-phosphate (non-mevalonate) pathway and the methyl groups are from S-adenosylmethionine. In addition, MK biosynthesis requires 2-ketoglutarate and cofactors ATP, coenzyme A, and thiamine pyrophosphate. Despite the fact that both quinones originate from the shikimate pathway, there are important differences in their biosyntheses. The prenyl side chain in MK biosynthesis is introduced at the penultimate step, accompanied by decarboxylation, whereas in Q biosynthesis it is introduced at the second step, with retention of the carboxyl group. In MK biosynthesis, all the reactions of the pathway up to prenylation are carried out by soluble enzymes, whereas all the enzymes involved in Q biosynthesis except the first are membrane bound. In MK biosynthesis, the last step is a C-methylation; in Q biosynthesis, the last step is an O-methylation. In Q biosynthesis a second C-methylation and O-methylation take place in the middle part of the pathway. Despite the fact that Q and MK biosyntheses diverge at chorismate, the C-methylations in both pathways are carried out by the same methyltransferase.


Ubiquitous overexpression of CXCL12 confers radiation protection and enhances mobilization of hematopoietic stem and progenitor cells.
C-X-C motif chemokine ligand 12 (CXCL12; aka SDF1α) is a major regulator of a number of cellular systems, including hematopoiesis, where it influences hematopoietic cell trafficking, proliferation, and survival during homeostasis and upon stress and disease. A variety of constitutive, temporal, ubiquitous, and cell-specific loss-of-function models have documented the functional consequences on hematopoiesis upon deletion of Cxcl12. Here, in contrast to loss-of-function experiments, we implemented a gain-of-function approach by generating a doxycycline-inducible transgenic mouse model that enables spatial and temporal overexpression of Cxcl12. We demonstrated that ubiquitous CXCL12 overexpression led to an increase in multipotent progenitors in the bone marrow and spleen. The CXCL12+ mice displayed reduced reconstitution potential as either donors or recipients in transplantation experiments. Additionally, we discovered that Cxcl12 overexpression improved hematopoietic stem and progenitor cell mobilization into the blood, and conferred radioprotection by promoting quiescence. Thus, this new CXCL12+ mouse model provided new insights into major facets of hematopoiesis and serves as a versatile resource for studying CXCL12 function in a variety of contexts.


Effect of crop residues on interception and activity of prosulfocarb, pyroxasulfone, and trifluralin.
Crop residue retention on the soil surface in no-tillage system can intercept pre-emergent herbicides and reduce their efficacy. Three experiments were conducted to investigate the effect of crop residue amount (0, 1, 2 and 4 t ha-1), moisture (wet versus dry), type (wheat, barley, canola, chickpea and lupin) and age (fresh or aged for one year) on the interception and subsequent leaching of prosulfocarb, pyroxasulfone, and trifluralin from the residue into soil. Bioassays, using cucumber and annual ryegrass as indicator plants, were used to assess herbicide activity/availability in the soil and on the residue. Herbicide interception increased considerably as residue quantity increased from 2 to 4 t ha-1. After simulated rainfall, which washed herbicide into the soil, complete control of ryegrass occurred for trifluralin with 0 t ha-1 residue, for prosulfocarb with 0 and 1 t ha-1 residue, and for pyroxasulfone with all residue rates. Therefore, with rain or irrigation, pyroxasulfone was the herbicide least affected by high residue loads. Less chemical leached from the crop residue into the soil after rainfall, when prosulfocarb and trifluralin were applied to wet residue compared with dry residue, but the initial moisture condition had no effect on the leaching of pyroxasulfone from residue. If practically possible, farmers should minimise spraying prosulfocarb and trifluralin onto wet crop residue. Barley and wheat residues intercepted more herbicide than an equivalent mass of canola, chickpea or lupin residue, which was largely due to the increased ground cover with cereal residues. The effect of residue age on herbicide interception and leaching was relatively small and variable. Overall, more herbicide reached the soil when sprayed on one-year old residue than new residue, which was largely due to reduced ground cover with aged residue. A strong positive linear relationship existed between ground cover percentage and growth of bioassay species (r2 = 0.75). This means that there was little difference in the ability of residue to adsorb and retain herbicide between crop residue types and ages, such that farmers can simply use the ground cover of the crop residue to assess interception.


The state of the science of health and wellness for adults with intellectual and developmental disabilities.
Historically, people with intellectual and developmental disabilities (IDD) have experienced health disparities related to several factors including: a lack of access to high quality medical care, inadequate preparation of health care providers to meet their needs, the social determinants of health (e.g., poverty, race and gender), and the failure to include people with IDD in public health efforts and other prevention activities. Over the past decade, a greater effort has been made to both identify and begin to address myriad health disparities experienced by people with IDD through a variety of activities including programs that address health lifestyles and greater attention to the training of health care providers. Gaps in the literature include the lack of intervention trials, replications of successful approaches, and data that allow for better comparisons between people with IDD and without IDD living in the same communities. Implications for future research needed to reduce health disparities for people with IDD include: better monitoring and treatment for chronic conditions common in the general population that are also experienced by people with IDD, an enhanced understanding of how to promote health among those in the IDD population who are aging, addressing the health needs of people with IDD who are not part of the disability service system, developing a better understanding of how to include people with IDD in health and wellness programs, and improving methods for addressing the health care needs of members of this group in an efficient and cost-effective manner, either through better access to general medical care or specialized programs.


The mRNP remodeling mediated by UPF1 promotes rapid degradation of replication-dependent histone mRNA.
Histone biogenesis is tightly controlled at multiple steps to maintain the balance between the amounts of DNA and histone protein during the cell cycle. In particular, translation and degradation of replication-dependent histone mRNAs are coordinately regulated. However, the underlying molecular mechanisms remain elusive. Here, we investigate remodeling of stem-loop binding protein (SLBP)-containing histone mRNPs occurring during the switch from the actively translating mode to the degradation mode. The interaction between a CBP80/20-dependent translation initiation factor (CTIF) and SLBP, which is important for efficient histone mRNA translation, is disrupted upon the inhibition of DNA replication or at the end of S phase. This disruption is mediated by competition between CTIF and UPF1 for SLBP binding. Further characterizations reveal hyperphosphorylation of UPF1 by activated ATR and DNA-dependent protein kinase upon the inhibition of DNA replication interacts with SLBP more strongly, promoting the release of CTIF and eIF3 from SLBP-containing histone mRNP. In addition, hyperphosphorylated UPF1 recruits PNRC2 and SMG5, triggering decapping followed by 5'-to-3' degradation of histone mRNAs. The collective observations suggest that both inhibition of translation and recruitment of mRNA degradation machinery during histone mRNA degradation are tightly coupled and coordinately regulated by UPF1 phosphorylation.


A longitudinal study of fear of hypoglycaemia in adults with type 1 diabetes.
To investigate fear of hypoglycaemia (FoH) longitudinally in a cross-sectional study of adult patients with type 1 diabetes. Specifically, we investigated two subgroups of patients who over 4 years either showed a substantial increase or decrease in level of FoH to identify factors associated with changes in FoH. The Swedish version of the Hypoglycaemia Fear Survey (HFS) along with a questionnaire to assess hypoglycaemia history was sent by mail to 764 patients in 2010. The responders in 2010 (n = 469) received another set of the same two questionnaires in 2014. HbA1c, insulin regimen, weight and creatinine from 2010 and 2014 were obtained from medical records. Those with an absolute difference in HFS scores ≥ 75th percentile were included in the subgroup analyses. Statistical analyses included one-sample t tests, chi-square and McNemar's test. The absolute difference in the HFS total score (n = 347) between 2010 and 2014 was m = ±7.6, SD ± 6. In the increased FoH group, more patients reported a high level of moderate hypoglycaemic episodes as well as impaired awareness of hypoglycaemia in 2014 compared with the decreased FoH group. There were more subjects in the increased FoH group with insulin pumps in 2014 and in 2010. In the decreased FoH group, more patients had a high frequency of daily self-monitoring of blood glucose (SMBG) in 2010 and in 2014. Fear of hypoglycaemia is stable across time for most patients. Changes in fear level are associated with changes in hypoglycaemia frequency. Thus, asking patients about changes in hypoglycaemia experiences is of great importance.


Evaluation of the effects of temporomandibular joint disk displacement and its progression on dentocraniofacial morphology in symptomatic patients using lateral cephalometric analysis.
The aim of this study was to evaluate the effects of disk displacement (DD) and its progression on dentocraniofacial morphology in symptomatic patients and compare the results with asymptomatic volunteers. Skeletal and dental Class I female patients with DD, diagnosed using magnetic resonance imaging (MRI) and lateral cephalometric analysis were included in the study. Subjects were grouped as follows: control group with bilateral normal disk position (group 1, n=12), unilateral DD with reduction (group 2, n=16), bilateral DD with reduction (group 3, n=26), unilateral DD without reduction (group 4, n=12), and bilateral DD without reduction (group 5, n=8). Thirty-two (32) cephalometric variables were measured, and statistically significant differences were found in 11. Dental and soft tissue measurements did not reveal any differences, but variables related to the mandible showed statistically significant differences. Progression of DD was associated with an increase in all angular measurements related to vertical skeletal relationships and articular angle and a decrease in the ratio of posterior face height to anterior face height indicating clockwise rotation of the mandible. Similarly, the height of ramus was decreased with the progression of DD. The results of this study demonstrated that the presence of DD in skeletal Class I female patients effects facial morphology, and its progression makes the differences more significant and remarkable. These results emphasize the importance of early diagnosis and treatment in the management of DD.


[Immunological aspects of infection of 6 inbred strains of mice by 3 different strains of Trypanosoma cruzi].
We evaluated humoral and cellular immune responses in 6 inbred mouse strains (BALB/c, B-10, C3H, A/J, AKR and DBA) infected with 3 Trypanosoma cruzi strains (Peruvian, 21 SF and Colombian), which are the standards for the 3 strains Types of Andrade's classification. Negative delayed-type hipersensitivity reactions to parasite antigens were evidence of suppressed cell-mediated immunity. An early drop of IgG1 and rise of IgM levels were observed in almost all mouse strains infected by any T. cruzi strain. Elevation of IgG2a and/or IgG2b levels was higher in resistant mouse strains. Anti-T. cruzi antibody levels (Indirect immunofluorescence and ELISA) did not correlate with survival. Despite some differences among mouse strains there was a definition of an overall pattern of host response and the maintenance of biological standards which characterize the basic types of T. cruzi strains.


Cost-optimization in the treatment of multidrug resistant tuberculosis in Nigeria.
To compare the cost of facility-based MDR TB care (F) to home-based care (H) from the perspective of the Nigerian national health system. We assessed the expected costs of the two MDR TB treatment approaches using a decision-analytic model with a follow-up of 6 months. MDR TB treatment outcomes were obtained from a systematic review of randomised clinical trials. The outcomes of interest included treatment success, treatment failure, treatment default and mortality and did not vary significantly between the two alternatives. Treatment costs included the cost of the following: drug therapy (F, H), hospital stay (F), nurse care (F, H), physician care (F), nursing facility (F) and transport to the healthcare provider (H). Finally, we estimated the potential cost savings associated with home-based treatment for all patients starting MDR TB treatment in Nigeria. The average expected total treatment cost for a Nigerian patient treated for MDR TB was estimated at US2095 for facility - based care and 1535 for home-based care, a potential saving of 25%. One of the major drivers of this difference is significantly more intensive, and therefore more costly, nursing care in hospitals. In 2013, a total of 426 patients were initiated on facility-based MDR TB treatment in Nigeria. Thus, the potential savings through home-based care are US$ 223 204 per year. In Nigeria, treatment of MDR TB using home-based care is expected to result in similar patient outcomes at markedly reduced public health costs as facility-based care.


Electrodialysis-based zero liquid discharge in industrial wastewater treatment.
Over the past few decades, reverse osmosis (RO) has been the dominant technology employed in zero liquid discharge (ZLD) systems for industrial wastewater treatment (WWT). However, RO is limited to a maximum operating salinity of about 75 g kg-1. Electrodialysis (ED) is a potentially attractive option as it can achieve much higher concentrations, thereby reducing the capacity and energy demand of the subsequent evaporation step. Feed-and-bleed experiments were undertaken on a laboratory-scale ED stack using a series of model solutions based on the most common inorganic salts with the aim of determining maximum achievable concentrations. The maximum salt concentration achievable via ED ranged between 104.2 and 267.6 g kg-1, with levels predominantly limited by water transport. In addition, a straightforward review of how ED incorporation can affect ZLD process economics is presented. The operational cost of an ED-based ZLD system for processing RO retentate was almost 20% lower than comparable processes employing high-efficiency RO and disc tubular RO. As the ED-based ZLD system appears economically preferable, and as maximum achievable concentrations greatly exceeded RO operating limits, it would appear to be a promising approach for bridging the gap between RO and evaporation, and may even eliminate the evaporation step altogether.


Validity and reliability of the Setswana translation of the Short Form-8 health-related quality of life health survey in adults.
The absence of culturally relevant measures in indigenous languages could pose a challenge to epidemiological studies on health-related quality of life (HRQoL) in developing nations. To explore the feasibility and determine the validity and reliability of the Setswana translation of the HRQoL Short Form-8 (SF-8) among Setswana-speaking adults. Potchefstroom in the North West province. Sixty healthy men (n = 26) and women (n = 34), aged 45.5 ± 9.3 years, completed a Setswana translation of the SF-8 questionnaire and the original English version twice, with a 4-week interval between completions. The Setswana SF-8 presented good concurrent validity with the Spearman's correlation coefficients (ρ) of 0.72 for role physical to 0.91 for social functioning. The Cronbach's alpha coefficients for the first and second measurements were 0.87 and 0.87, respectively, for the Setswana-translated SF-8 and 0.86 and 0.89 for the original English SF-8. The reliability coefficients were moderate for the mental health (ρ = 0.60), social functioning (ρ = 0.56) and role emotional (ρ = 0.50) domains, as well as the mental component summary (ρ = 0.50) and physical component summary (ρ = 0.45), but fair for the role physical (ρ = 0.43), body pain (ρ = 0.43), general health (ρ = 0.42), physical functioning (ρ = 0.41) and vitality (ρ = 0.38) domains on the translated Setswana version of the SF-8. The Setswana SF-8 version was feasible, acceptable and had acceptable concurrent validity and fair to moderate evidence of test-retest reliability for assessing HRQoL among adult Setswana-speaking community dwellers.


Reduction of hard-tissue debris accumulation during rotary root canal instrumentation by etidronic acid in a sodium hypochlorite irrigant.
Hard-tissue debris is accumulated during rotary instrumentation. This study investigated to what extent a calcium-complexing agent that has good short-term compatibility with sodium hypochlorite (NaOCl) could reduce debris accumulation when applied in an all-in-one irrigant during root canal instrumentation. Sixty extracted mandibular molars with isthmuses in the mesial root canal system were selected based on prescans using a micro-computed tomography system. Thirty teeth each were randomly assigned to be instrumented with a rotary system and irrigated with either 2.5% NaOCl or 2.5% NaOCl containing 9% (wt/vol) etidronic acid (HEBP). Using a side-vented irrigating tip, 2 mL of irrigant was applied by 1 blinded investigator to the mesial canals after each instrument. Five milliliters of irrigant was applied per canal as the final rinse. Mesial root canal systems were scanned at high resolution before and after treatment, and accumulated hard-tissue debris was calculated as vol% of the original canal anatomy. Values between groups were compared using the Student's t test (α < .05). Irrigation with 2.5% NaOCl resulted in 5.5 ± 3.6 vol% accumulated hard-tissue debris compared with 3.8 ± 1.8 vol% when HEBP was contained in the irrigant (P < .05). A hypochlorite-compatible chelator can reduce but not completely prevent hard-tissue debris accumulation during rotary root canal instrumentation.


Plantar tactile perturbations enhance transfer of split-belt locomotor adaptation.
Patterns of human locomotion are highly adaptive and flexible and depend on the environmental context. Locomotor adaptation requires the use of multisensory information to perceive altered environmental dynamics and generate an appropriate movement pattern. In this study, we investigated the use of multisensory information during locomotor learning. Proprioceptive perturbations were induced by vibrating tactors, placed bilaterally over the plantar surfaces. Under these altered sensory conditions, participants were asked to perform a split-belt locomotor task representative of motor learning. Twenty healthy young participants were separated into two groups: no-tactors (NT) and tactors (TC). All participants performed an overground walking trial, followed by treadmill walking including 18 min of split-belt adaptation and an overground trial to determine transfer effects. Interlimb coordination was quantified by symmetry indices and analyzed using mixed repeated-measures ANOVAs. Both groups adapted to the locomotor task, indicated by significant reductions in gait symmetry during the split-belt task. No significant group differences in spatiotemporal and kinetic parameters were observed on the treadmill. However, significant group differences were observed overground. Step and swing time asymmetries learned on the split-belt treadmill were retained and decayed more slowly overground in the TC group whereas in NT, asymmetries were rapidly lost. These results suggest that tactile stimulation contributed to increased lower limb proprioceptive gain. High proprioceptive gain allows for more persistent overground after effects, at the cost of reduced adaptability. Such persistence may be utilized in populations displaying pathologic asymmetric gait by retraining a more symmetric pattern.


Neural transposition in the Drosophila brain: is it all bad news?
Transposition of mobile genetic elements can radically alter genome structure and sequence. In doing so, they can alter gene expression and cellular function. Perhaps unsurprisingly, this potentially catastrophic process is heavily constrained, especially in the germ line where aberrations lead to sterility or could be passed onto the next generation. However, recent studies in mammals and fruit flies suggest that transposition happens at measurable levels in the brain, and possibly more so in some cell types than in others. This has led to the suggestion that certain cell types may utilize transposable elements to diversify cellular properties. In this review, we discuss these findings and ideas in light of our current understanding of transposons and their control in the fly, and the growing evidence for an involvement of transposition in neurological disease in humans.


Correlations between the equine metacarpophalangeal joint angulation and toe conformation in statics.
The angulation of the equine fetlock determines the load of associated tendons and probably their predisposition for injuries. However, it is questionable how the individual toe conformation and tendon properties interact with the dorsal metacarpophalangeal joint angle (DMPJ). Data are needed for a tangible evaluation of the equine limb conformation for more specific orthopaedic treatment. The aim was to evaluate the correlation between the DMPJ, toe conformation and cross-sectional area (CSA) of both flexor tendons; the superficial digital flexor tendon (SDFT) and deep digital flexor tendon (DDFT). Thirty Warmblood horses were available for the study. Lateromedial radiographs of the toe and fetlock and transverse ultrasound images of both flexor tendons were obtained from three zones. The DMPJ, length and angle of the phalanges and CSA SDFT/DDFT were measured. In addition, hoof angle, wither height, age, and sex were documented. Correlations were calculated using Pearson's test. A paired t-test was used to evaluate left-right differences. Length and angle of the proximal and middle phalanx were significantly associated with the DMPJ (r = -0.28 - -0.45, p<0.001-0.04). Neither the angle of the hoof and distal phalanx nor the CSA SDFT/DDFT, showed a noticeable correlation with the DMPJ. Significant left-right differences occurred for the DMPJ (p<0.002) and the angle of the proximal and middle phalanx (p<0.01 - 0.002). A moderate negative correlation was shown between the DMPJ and wither height (r = - 0.31, p=0.04). Results represent only a specific population. The study provides only a static evaluation of a dynamic situation. In a clinical context, it might be useful to focus on the angulation and length of the pastern to evaluate the individual load affecting the DMPJ and its associated structures. These findings might be relevant for orthopaedic treatments and shoeing recommendations.


Coronal and root caries in Southern Chinese adults.
Southern China is the most prosperous part of China, but information useful for oral care planning is very limited. A large-scale epidemiological survey was conducted in 1996-97. The objectives of this report were to describe the coronal and root caries of the adult Southern Chinese and to analyze the influence of selected demographic and socio-economic factors on the disease pattern. A total sample of 1,573 35- to 44-year-olds and 1,515 65- to 74-year-olds from 8 urban and 8 rural survey sites in Guangdong Province participated in an oral health interview and underwent clinical examination. World Health Organization examination procedures and diagnostic criteria were used. The weighted mean DMFT scores of the middle-aged and the elderly subjects were 4.8 and 16.1, respectively. People living in rural areas had a higher DMFT score than those living in urban areas (4.9 vs. 4.3 in the 35- to 44-year-olds and 16.5 vs. 14.7 in the 65- to 74-year-olds). In both age groups, MT was the major component of the DMFT score. Analysis of covariance showed that women and those who were economically less well off had higher DMFT scores in both age groups. The weighted prevalence rates of decayed/filled roots were 12% and 37%, with a mean of 0.2 and 0.7 teeth affected, in the middle-aged and the elderly, respectively. In conclusion, socio-economic factors had a considerable effect on the dental caries status of adults in Southern China.


An integrated transcriptomics and proteomics analysis of the secretome of the helminth pathogen Fasciola hepatica: proteins associated with invasion and infection of the mammalian host.
To infect their mammalian hosts, Fasciola hepatica larvae must penetrate and traverse the intestinal wall of the duodenum, move through the peritoneum, and penetrate the liver. After migrating through and feeding on the liver, causing extensive tissue damage, the parasites move to their final niche in the bile ducts where they mature and produce eggs. Here we integrated a transcriptomics and proteomics approach to profile Fasciola secretory proteins that are involved in host-pathogen interactions and to correlate changes in their expression with the migration of the parasite. Prediction of F. hepatica secretory proteins from 14,031 expressed sequence tags (ESTs) available from the Wellcome Trust Sanger Centre using the semiautomated EST2Secretome pipeline showed that the major components of adult parasite secretions are proteolytic enzymes including cathepsin L, cathepsin B, and asparaginyl endopeptidase cysteine proteases as well as novel trypsin-like serine proteases and carboxypeptidases. Proteomics analysis of proteins secreted by infective larvae, immature flukes, and adult F. hepatica showed that these proteases are developmentally regulated and correlate with the passage of the parasite through host tissues and its encounters with different host macromolecules. Proteases such as FhCL3 and cathepsin B have specific functions in larvae activation and intestinal wall penetration, whereas FhCL1, FhCL2, and FhCL5 are required for liver penetration and tissue and blood feeding. Besides proteases, the parasites secrete an array of antioxidants that are also highly regulated according to their migration through host tissues. However, whereas the proteases of F. hepatica are secreted into the parasite gut via a classical endoplasmic reticulum/Golgi pathway, we speculate that the antioxidants, which all lack a signal sequence, are released via a non-classical trans-tegumental pathway.


Microsporidians in penaeid shrimp along the west coast of Madagascar.
Three species of penaeid shrimp, Fenneropenaeus indicus, Penaeus monodon and P. semisulcatus, found in trawler catches off the west coast of Madagascar were infected with microsporidian parasites. The infections were evident as muscular lesions with a cottony appearance when abundant. Spore size (2.6 x 1.6 microm) and morphology (ovoid) for the parasites infecting both F. indicus and P. semisulcatus were not significantly different, suggesting that they might be the same microsporidian species. Spore size (1.4 x 1.1 microm) and morphology (sub-globose to ovoid) in P. monodon infections were significantly different from those in the other 2 shrimp species, suggesting that it was a different parasite. The presence of microsporidians in this biogeographical zone means that there is a potential risk of infections of cultured shrimp in farms situated in the vicinity. This must be assessed by increasing current knowledge of the parasites.


Landscape connectivity for bobcat (Lynx rufus) and lynx (Lynx canadensis) in the Northeastern United States.
Landscape connectivity is integral to the persistence of metapopulations of wide ranging carnivores and other terrestrial species. The objectives of this research were to investigate the landscape characteristics essential to use of areas by lynx and bobcats in northern New England, map a habitat availability model for each species, and explore connectivity across areas of the region likely to experience future development pressure. A Mahalanobis distance analysis was conducted on location data collected between 2005 and 2010 from 16 bobcats in western Vermont and 31 lynx in northern Maine to determine which variables were most consistent across all locations for each species using three scales based on average 1) local (15 minute) movement, 2) linear distance between daily locations, and 3) female home range size. The bobcat model providing the widest separation between used locations and random study area locations suggests that they cue into landscape features such as edge, availability of cover, and development density at different scales. The lynx model with the widest separation between random and used locations contained five variables including natural habitat, cover, and elevation-all at different scales. Shrub scrub habitat-where lynx's preferred prey is most abundant-was represented at the daily distance moved scale. Cross validation indicated that outliers had little effect on models for either species. A habitat suitability value was calculated for each 30 m2 pixel across Vermont, New Hampshire, and Maine for each species and used to map connectivity between conserved lands within selected areas across the region. Projections of future landscape change illustrated potential impacts of anthropogenic development on areas lynx and bobcat may use, and indicated where connectivity for bobcats and lynx may be lost. These projections provided a guide for conservation of landscape permeability for lynx, bobcat, and species relying on similar habitats in the region.


Altered expression and localization of creatine kinase B, heterogeneous nuclear ribonucleoprotein F, and high mobility group box 1 protein in the nuclear matrix associated with colon cancer.
Identification of biomarkers could lead to the development of effective screening tests for colorectal cancer. A previous study from our laboratory showed specific alterations of nuclear structure in colon cancer. In an effort to characterize these biomarkers, protein spots were selected from separations made by two-dimensional gel electrophoresis, which were analyzed by mass spectrometry. The sequences obtained from the isolated spots revealed that they have close similarity to creatine kinase B (CKB) isoforms, heterogeneous nuclear ribonucleoprotein F (hnRNP F) and high mobility group box 1 protein (HMGB1) isoforms. To determine the expression of these proteins in colon cancer, expression was studied in 9 tumor and matched adjacent normal pairs, 5 donor colons, 16 polyps, 4 metastatic liver lesions and matched adjacent normal pairs, and 3 liver donors. CKB and hnRNP F were expressed in 78% and 89% of colon tumors, respectively. hnRNP F had a higher frequency of expression than CKB in premalignant polyps. With the establishment of differential expression of the proteins in colon cancer, their subcellular localization was analyzed. The subcellular fractions studied both showed high protein levels of hnRNP F in colon tumors compared with normal colon tissues. Surprisingly, subcellular levels of CKB were decreased in colon tumors, suggesting that the observed high CKB levels in nuclear matrix extracts are caused by the enhanced localization of CKB to the nuclear matrix during colon tumorigenesis. These results suggest an involvement of hnRNP F and CKB in colorectal cancer. Additionally, they suggest that hnRNP F is a potential marker for colorectal cancer progression.


Studying integrin-mediated cell adhesion at the single-molecule level using AFM force spectroscopy.
The establishment of cell adhesion involves specific recognition events between individual cell-surface receptors and molecules of the cellular environment. However, characterizing single-molecule adhesion events in the context of a living cell presents an experimental challenge. The atomic force microscope (AFM) operated in force spectroscopy mode provides an ultrasensitive method to investigate cell adhesion forces at the level of single receptor-ligand bonds. With a living cell attached to the AFM cantilever, the number of cell-substrate interactions can be controlled and limited to the formation of single receptor-ligand bonds. From force-distance (F-D) curves recorded during cell detachment, the strength of single receptor-ligand bonds can be determined. Furthermore, by varying the rate of force application during bond rupture, a dynamic force spectrum (DFS) can be generated from which additional parameters that describe the energy landscape of the interaction, such as dissociation rate and energy barrier width, can be obtained. Using the example of alpha(2)beta(1) integrin-mediated adhesion to type I collagen, we provide a detailed description of how dynamic AFM single-cell force spectroscopy (SCFS) adhesion measurements can be performed with single-molecule sensitivity, and how specific energy landscape parameters of the integrin-collagen bond can be extracted from the DFS.


Behavioral dissection of the Drosophila circadian multioscillator system that regulates locomotor rhythms.
The fruit fly, Drosophila melanogaster , shows a bimodal circadian activity rhythm with peaks around light-on and before light-off. This rhythm is driven by seven groups of so-called clock neurons in the brain. To dissect the multioscillatory nature of the Drosophila clock system, the process of reentrainment to a reversed light cycle was examined by using wild-type flies and cry(b) mutant flies that carry a strong loss-of-function mutation in cryptochrome (cry) gene. The wild-type flies showed that the morning peak dissociated into two components, while a substantial fraction of cry(b) flies exhibited dissociation of the evening peak into two components that shifted in different directions. When the temperature cycle was given in constant darkness in such a manner that the thermophase corresponded to the previous night phase, the morning peak also split into two components in wild-type flies. These results suggest that both morning and evening peaks are driven by two separate oscillators that have different entrainability to light and temperature cycles. Examination of the process of reentrainment to a reversed LD in mutant flies that lack some of the four known circadian photoreceptors (compound eyes, ocelli, CRYPTOCHROME [CRY], and Hofbauer-Buchner [H-B] eyelets) revealed that these four photoreceptors play different roles in photic entrainment of the four putative oscillators.


Birth weight and diazoxide unresponsiveness strongly predict the likelihood of congenital hyperinsulinism due to a mutation in ABCC8 or KCNJ11.
Mutations in the KATP channel genes, ABCC8 and KCNJ11, are the most common cause of congenital hyperinsulinism. The diagnosis of KATP-hyperinsulinism is important for the clinical management of the condition. We aimed to determine the clinical features that help to identify KATP-hyperinsulinism at diagnosis. We studied 761 individuals with KATP-hyperinsulinism and 862 probands with hyperinsulinism of unknown aetiology diagnosed before 6 months of age. All were referred as part of routine clinical care. We compared the clinical features of KATP-hyperinsulinism and unknown hyperinsulinism cases. We performed logistic regression and receiver operator characteristic (ROC) analysis to identify the features that predict KATP-hyperinsulinism. Higher birth weight, diazoxide unresponsiveness and diagnosis in the first week of life were independently associated with KATP-hyperinsulinism (adjusted odds ratio: 4.5 (95% CI: 3.4-5.9), 0.09 (0.06-0.13) and 3.3 (2.0-5.0) respectively). Birth weight and diazoxide unresponsiveness were additive and highly discriminatory for identifying KATP-hyperinsulinism (ROC area under the curve for birth weight 0.80, diazoxide responsiveness 0.77, and together 0.88, 95% CI: 0.85-0.90). In this study, 86% born large for gestation and 78% born appropriate for gestation and who did not respond to diazoxide treatment had KATP-hyperinsulinism. In contrast, of those individuals born small for gestation, none who were diazoxide responsive and only 4% of those who were diazoxide unresponsive had KATP-hyperinsulinism. Individuals with hyperinsulinism born appropriate or large for gestation and unresponsive to diazoxide treatment are most likely to have an ABCC8 or KCNJ11 mutation. These patients should be prioritised for genetic testing of KATP channel genes.


Using Aiptasia as a Model to Study Metabolic Interactions in Cnidarian-Symbiodinium Symbioses.
The symbiosis between cnidarian hosts and microalgae of the genus Symbiodinium provides the foundation of coral reefs in oligotrophic waters. Understanding the nutrient-exchange between these partners is key to identifying the fundamental mechanisms behind this symbiosis, yet has proven difficult given the endosymbiotic nature of this relationship. In this study, we investigated the respective contribution of host and symbiont to carbon and nitrogen assimilation in the coral model anemone Aiptaisa. For this, we combined traditional measurements with nanoscale secondary ion mass spectrometry (NanoSIMS) and stable isotope labeling to investigate patterns of nutrient uptake and translocation both at the organismal scale and at the cellular scale. Our results show that the rate of carbon and nitrogen assimilation in Aiptasia depends on the identity of the host and the symbiont. NanoSIMS analysis confirmed that both host and symbiont incorporated carbon and nitrogen into their cells, implying a rapid uptake and cycling of nutrients in this symbiotic relationship. Gross carbon fixation was highest in Aiptasia associated with their native Symbiodinium communities. However, differences in fixation rates were only reflected in the δ13C enrichment of the cnidarian host, whereas the algal symbiont showed stable enrichment levels regardless of host identity. Thereby, our results point toward a "selfish" character of the cnidarian-Symbiodinium association in which both partners directly compete for available resources. Consequently, this symbiosis may be inherently instable and highly susceptible to environmental change. While questions remain regarding the underlying cellular controls of nutrient exchange and the nature of metabolites involved, the approach outlined in this study constitutes a powerful toolset to address these questions.


BID Mediates Oxygen-Glucose Deprivation-Induced Neuronal Injury in Organotypic Hippocampal Slice Cultures and Modulates Tissue Inflammation in a Transient Focal Cerebral Ischemia Model without Changing Lesion Volume.
The BH3 interacting-domain death agonist (BID) is a pro-apoptotic protein involved in death receptor-induced and mitochondria-mediated apoptosis. Recently, it has also been suggested that BID is involved in the regulation of inflammatory responses in the central nervous system. We found that BID deficiency protected organotypic hippocampal slice cultures in vitro from neuronal injury induced by oxygen-glucose deprivation. In vivo, BID-knockout (KO) mice and wild type (WT) mice were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO) to induce focal cerebral ischemia, and allowed to recover for 24 h. Infarct volumes and functional outcome were assessed and the inflammatory response was evaluated using immunofluorescence, Western blotting, quantitative PCR (qPCR) and Mesoscale multiplex analysis. We observed no difference in the infarct volume or neurological outcome between BID-KO and WT mice. The inflammatory response was reduced by BID deficiency as indicated by a change in microglial/leukocyte response. In conclusion, our data suggest that BID deficiency is neuroprotective in an in vitro model and modulates the inflammatory response to focal cerebral ischemia in vivo. However, this is not translated into a robust neuroprotection in vivo.


Is Local Infiltration Analgesia Superior to Peripheral Nerve Blockade for Pain Management After THA: A Network Meta-analysis.
Local infiltration analgesia and peripheral nerve blocks are common methods for pain management in patients after THA but direct head-to-head, randomized controlled trials (RCTs) have not been performed. A network meta-analysis allows indirect comparison of individual treatments relative to a common comparator; in this case placebo (or no intervention), epidural analgesia, and intrathecal morphine, yielding an estimate of comparative efficacy. We asked, when compared with a placebo, (1) does use of local infiltration analgesia reduce patient pain scores and opioid consumption, (2) does use of peripheral nerve blocks reduce patient pain scores and opioid consumption, and (3) is local infiltration analgesia favored over peripheral nerve blocks for postoperative pain management after THA? We searched six databases, from inception through June 30, 2014, to identify RCTs comparing local infiltration analgesia or peripheral nerve block use in patients after THA. A total of 35 RCTs at low risk of bias based on the recommended Cochrane Collaboration risk assessment tool were included in the network meta-analysis (2296 patients). Primary outcomes for this review were patient pain scores at rest and cumulative opioid consumption, both assessed at 24 hours after THA. Because of substantial heterogeneity (variation of outcomes between studies) across included trials, a random effect model for meta-analysis was used to estimate the weighted mean difference (WMD) and 95% CI. The gray literature was searched with the same inclusion criteria as published trials. Only one unpublished trial (published abstract) fulfilled our criteria and was included in this review. All other studies included in this systematic review were full published articles. Bayesian network meta-analysis included all RCTs that compared local infiltration analgesia or peripheral nerve blocks with placebo (or no intervention), epidural analgesia, and intrathecal morphine. Compared with placebo, local infiltration analgesia reduced patient pain scores (WMD, -0.61; 95% CI, -0.97 to -0.24; p = 0.001) and opioid consumption (WMD, -7.16 mg; 95% CI, -11.98 to -2.35; p = 0.004). Peripheral nerve blocks did not result in lower pain scores or reduced opioid consumption compared with placebo (WMD, -0.43; 95% CI, -0.99 to 0.12; p = 0.12 and WMD, -3.14 mg, 95% CI, -11.30 to 5.02; p = 0.45). However, network meta-analysis comparing local infiltration analgesia with peripheral nerve blocks through common comparators showed no differences between postoperative pain scores (WMD, -0.36; 95% CI, -1.06 to 0.31) and opioid consumption (WMD, -4.59 mg; 95% CI, -9.35 to 0.17), although rank-order analysis found local infiltration analgesia to be ranked first in more simulations than peripheral nerve blocks, suggesting that it may be more effective. Using the novel statistical network meta-analysis approach, we found no differences between local infiltration analgesia and peripheral nerve blocks in terms of analgesia or opioid consumption 24 hours after THA; there was a suggestion of a slight advantage to peripheral nerve blocks based on rank-order analysis, but the effect size in question is likely not large. Given the slight difference between interventions, clinicians may choose to focus on other factors such as cost and intervention-related complications when debating which analgesic treatment to use after THA. Level I, therapeutic study.


Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS.
The RNA-binding proteins TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) play central roles in neurodegeneration associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Normally localized in the nucleus, in sites affected by ALS and FTLD-U they are mislocalized to the cytoplasm and form cytoplasmic inclusions. TDP-43 and FUS are transported to the nucleus in a Ran-GTPase-dependent manner via nuclear import receptors, but they also contribute to the formation of stress granules (SGs), which are intracytoplasmic structures incorporating RNA. C-terminal truncations of TDP-43 eliminate the nuclear transport signal and cause mislocalization of the protein to the cytoplasm, where it accumulates and forms SGs. ALS-associated FUS mutations impair nuclear transport and cause mislocalization of FUS to the cytoplasm, where it also contributes to assembly of SGs. Furthermore, the ALS susceptibility factor ataxin-2, recently identified as a potent modifier of TDP-43 toxicity, is also a predicted cytoplasmic RNA-binding protein and a constituent protein of SGs, suggesting that it is a part of the common pathologic cascade formed by TDP-43 and FUS. Thus, we propose that excessive mislocalization of the RNA-binding proteins TDP-43, FUS, and ataxin-2 into the cytoplasm leads to impairment of the RNA quality control system, forming the core of the ALS/FTLD-U degenerative cascade. In this review, we discuss the molecular basis of the novel disease spectrum of ALS/FTLD-U, including the neurodegenerative mechanism of the cytoplasmic RNA-binding proteins TDP-43 and FUS and the possibility of a novel therapeutic strategy.


The influence of sex and pre-operative obesity on biomechanics two years after total knee arthroplasty: A longitudinal cohort study.
Sex and obesity may influence knee biomechanics associated with poor outcomes following primary total knee arthroplasty (TKA) however their long-term impact has not been investigated. Does sex and/or pre-operative obesity influence change in gait biomechanics from pre-TKA to two-years after TKA, and do knee biomechanics return to normal two-years after TKA? In this longitudinal study, gait analysis was performed on 78 patients undergoing TKA for knee osteoarthritis prior to surgery (baseline), and on 66 (85 %) of these who returned at the two year follow-up. Gait biomechanics were also collected on a reference sample of 40 asymptomatic participants. Knee variables were analyzed according to time (pre- and post-TKA), sex (men and women), pre-operative obesity (obese vs non-obese), and group (TKA vs reference). Mixed linear regression models were used to examine the effects of TKA, obesity status, gender and all interactions. There were two-year reductions in peak knee frontal plane angle (mean difference -7.21°; 95% confidence intervals -9.37 to -5.05), peak knee adduction moment (KAM) (-17.64Nm; -23.04 to -12.24) and KAM impulse (-9.40Nm.s; -12.04 to -6.77) in males. These and other variables were unchanged in women. At two years, men exhibited a greater varus-valgus thrust excursion (4.9°; 2.7-7.2), and a lower peak knee frontal plane angle (-4.4°; -7.1 to -1.7) and peak KAM (-13.1Nm; -20.9 to -5.4), compared to the reference sample. Biomechanics at two years did not differ between pre-operative obesity subgroups, or between female TKA patients and the reference sample. Changes in gait biomechanics two years after TKA are influenced by sex but not obesity. Men but not women showed altered knee biomechanics two years following TKR and compared to a reference sample. It is unknown whether these altered biomechanics in men impact longer term clinical outcomes and satisfaction following surgery.


Female arsonists: a clinical study.
This paper is a detailed study of a sample of 15 female arsonists. A review of the literature suggests that arson is seen more frequently in males with female firesetters usually comprising 10 to 18% of the samples of firesetters studied. As a result, female arsonists have been studied less often, and only a few authors have reported on their clinical features. This retrospective study demonstrates that female arsonists do not fall in any particular age group and are mostly either single or separated. Some psychosexual aspects of their behavior also appear to be clinically relevant. In contrast to previous studies, they were more often diagnosed as personality disordered and an association with suicidal behavior was found. Their motivations for the firesetting behavior were also considered. Finally, this paper compares some demographic, clinical, and other differences between male and female arsonists. The study also suggests that poor impulse control may be a prerequisite to this type of criminal behavior. The identification of psychopathic traits in the arsonist has important medico-legal implications.


A biophysical study with carbohydrate derivatives explains the molecular basis of monosaccharide selectivity of the Pseudomonas aeruginosa lectin LecB.
The rise of resistances against antibiotics in bacteria is a major threat for public health and demands the development of novel antibacterial therapies. Infections with Pseudomonas aeruginosa are a severe problem for hospitalized patients and for patients suffering from cystic fibrosis. These bacteria can form biofilms and thereby increase their resistance towards antibiotics. The bacterial lectin LecB was shown to be necessary for biofilm formation and the inhibition with its carbohydrate ligands resulted in reduced amounts of biofilm. The natural ligands for LecB are glycosides of D-mannose and L-fucose, the latter displaying an unusual strong affinity. Interestingly, although mannosides are much weaker ligands for LecB, they do form an additional hydrogen bond with the protein in the crystal structure. To analyze the individual contributions of the methyl group in fucosides and the hydroxymethyl group in mannosides to the binding, we designed and synthesized derivatives of these saccharides. We report glycomimetic inhibitors that dissect the individual interactions of their saccharide precursors with LecB and give insight into the biophysics of binding by LecB. Furthermore, theoretical calculations supported by experimental thermodynamic data suggest a perturbed hydrogen bonding network for mannose derivatives as molecular basis for the selectivity of LecB for fucosides. Knowledge gained on the mode of interaction of LecB with its ligands at ambient conditions will be useful for future drug design.


Definitions and outcome measures of clinical trials regarding opioid-induced constipation: a systematic review.
Opioid-induced constipation (OIC) is a frequent symptom in patients treated with opioids and impacts the patients' quality of life. However, there is no generally accepted definition for OIC. The aims of this study were to identify definitions for OIC in clinical trials and Cochrane Reviews and to compile assessment tools and outcome measures that were used in clinical trials. In a systematic review, 5 databases (MEDLINE, PubMed, The Cochrane Library, Web of Science, and EMBASE) were searched to identify clinical trials assessing OIC in adult patients or healthy volunteers. Studies published between 1993 and August 2013 were included. A total of 1488 studies were retrieved and 47 publications were included in the analysis. A minority of the publications (n=16, 34%) provided a clear definition for OIC. The definitions were highly variable and the present or recent history of opioid therapy was frequently (n=6, 38%) not included in these definitions. Of 46 clinical trials, 17 (37%) relied exclusively on objective measures such as bowel movement frequency, whereas another 17 studies additionally included patient-reported outcome measures such as, "feeling of incomplete bowel evacuation." Few trials (n=7, 15%) assessed the patient-reported global burden of OIC. Standard definitions and outcome measures are necessary (i) for consistency in OIC diagnosis in clinical practice and clinical trials; and (ii) to assure comparability of trial findings (eg, in meta-analyses). An OIC definition and outcome measures are proposed.


The prognosis of ankle fractures: a systematic review.
The aim of this study was to update the scientific evidence for ankle fracture prognosis by addressing radiographic osteoarthritis, time course and prognostic factors. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were included if they were randomized controlled trials, controlled trials or observational studies, including case series and case-control studies investigating radiologically confirmed osteoarthritis in adults with a classified ankle fracture, treated with or without surgery, with a minimum follow-up of 1 year. Also included were studies examining prognostic factors predicting radiologically confirmed osteoarthritis. Tibial plafond and talus fractures were excluded. Thirty-four studies were included examining 3447 patients. Extracted data included study type, inclusion and exclusion criteria, age, number of patients, number of fractures according to the author-reported classification method, radiological osteoarthritis, follow-up period, prognostic factors, and treatment. Severe heterogeneity was visible in the analyses (I2 > 90%), reflecting clinical heterogeneity possibly arising from the presence of osteoarthritis at baseline, the classifications used for the fractures and for osteoarthritis. The incidence of osteoarthritis was 25% (95% CI: 18-32) and 34% (95% CI: 23-45) for more severe fractures with involvement of the posterior malleolus. The severity of the trauma, as reflected by the fracture classification, was the most important prognostic factor for the development of radiographic osteoarthritis, but there is also a risk with simpler injuries. The period within which osteoarthritis develops or becomes symptomatic with an indication for treatment could not be specified.


Neonatal mortality within 24 hours of birth in six low- and lower-middle-income countries.
To estimate neonatal mortality, particularly within 24 hours of birth, in six low- and lower-middle-income countries. We analysed epidemiological data on a total of 149 570 live births collected between 2007 and 2013 in six prospective randomized trials and a cohort study from predominantly rural areas of Bangladesh, Ghana, India, Pakistan, the United Republic of Tanzania and Zambia. The neonatal mortality rate and mortality within 24 hours of birth were estimated for all countries and mortality within 6 hours was estimated for four countries with available data. The findings were compared with published model-based estimates of neonatal mortality. Overall, the neonatal mortality rate observed at study sites in the six countries was 30.5 per 1000 live births (range: 13.6 in Zambia to 47.4 in Pakistan). Mortality within 24 hours was 14.1 per 1000 live births overall (range: 5.1 in Zambia to 20.1 in India) and 46.3% of all neonatal deaths occurred within 24 hours (range: 36.2% in Pakistan to 65.5% in the United Republic of Tanzania). Mortality in the first 6 hours was 8.3 per 1000 live births, i.e. 31.9% of neonatal mortality. Neonatal mortality within 24 hours of birth in predominantly rural areas of six low- and lower-middle-income countries was higher than model-based estimates for these countries. A little under half of all neonatal deaths occurred within 24 hours of birth and around one third occurred within 6 hours. Implementation of high-quality, effective obstetric and early newborn care should be a priority in these settings.


Women with abnormal Pap smear result: a qualitative study of Swedish healthcare professionals' experiences.
A Papanicolaou (Pap) smear can be used to detect pre-cancerous cellular changes, so that they can be treated before they develop into cervical cancer. When the results of a Pap smear test are abnormal, women need further investigation, treatment and follow-up. Healthcare professionals (HCPs) are in a position to care for these women with abnormalities. The aim of this study was to explore the experiences of HCPs in caring for women with abnormal Pap smear results. In total, 20 HCPs from two counties in south-eastern Sweden participated in individual interviews, based on two open-ended questions. Interviews were recorded, transcribed verbatim and analysed using content analysis. The results showed that HCPs experienced that abnormal Pap smear results created anxiety in women, who often sought information from the Internet as a way to cope. Furthermore, the HCPs thought that it was a problem that women chose not to attend investigation, treatment and follow-ups. However, information about the seriousness of abnormal Pap smear results causes women to participate. It is a challenge for HCPs to inform in a reassuring manner. Finally, HCPs should collaborate with women to meet their information needs and to also provide support regarding finding and filtering reliable information on the Internet.


The influence of menthol, e-cigarettes and other tobacco products on young adults' self-reported changes in past year smoking.
Progression to regular smoking often occurs during young adulthood. This study examines self-reported changes in past year smoking among young adults and the potential influence of tobacco products on these trajectories. Respondents to the 2011 National Young Adult Health Survey who smoked 100 cigarettes in their lifetime (n=909) described smoking behaviour at the time of the survey and 1 year prior. Cigarette smoking trajectories were categorised as: no change, quit, decreased smoking or increased smoking. Participants were also asked about current use of menthol cigarettes and other tobacco products (ie, cigars, smokeless tobacco, hookah) and ever use of e-cigarettes. Most young adults (73.1%) reported stable cigarette smoking behaviours, while 8.2% reported having quit, 5.8% reported that they smoke on fewer days, 5% progressed from someday to daily smoking and 8% increased from not at all to current smoking. The youngest smokers (18-20) had significantly higher odds (adjusted OR (AOR) =2.6) of increasing cigarette use over the past year compared to those aged 30-34, as did blacks versus whites (AOR=2.35). Menthol cigarette use nearly doubled (AOR=1.87) the odds of increased smoking behaviour. E-cigarette and other tobacco product (OTP) use were not associated with increasing smoking but OTP use was negatively associated with remaining quit from cigarettes. Young adulthood is a critical period for smoking interventions, particularly among those most vulnerable to increasing smoking behaviours (ie, black and younger young adults). Policy efforts to restrict menthol cigarettes may reduce young adult smoking progression.


Guideline on the management of psoriasis in South Africa.
BACKGROUND; Psoriasis vulgaris is a chronic, relapsing, immune-mediated, potentially devastating disease, influenced by genetic and environmental factors, that can cause substantial morbidity and psychological stress and have a profound negative impact on patient quality of life. These guidelines for the management of psoriasis have been developed in an attempt to improve the outcomes of treatment of this condition in South Africa. Psoriasis has a major impact on the quality of life of sufferers, and it is expected that these guidelines, if implemented, will play a role in achieving improved outcome. These guidelines were developed to address the diagnosis and treatment of psoriasis, of differing degrees of severity and in patients of all ages, by all health care professionals involved with its management. All health care workers involved in the management of psoriasis should take note of these guidelines and try to implement them in clinical practice as far as possible. All treatment methods and procedures not substantiated by evidence from the literature should be discontinued and avoided to decrease the financial burden of psoriasis treatment. These guidelines were developed through general consensus by a group of 8 South African dermatologists (the 'Working Group') sanctioned by the Dermatological Society of South Africa (DSSA), by adaptation for the South African situation of the current guidelines used in the USA, the UK, Germany, Canada and Finland. Draft documents were made available for comment to the dermatological community as a whole via the official website of the DSSA, and the guidelines were presented and discussed at the annual congress of the DSSA in 2008. All input from these sources, where appropriate, were then incorporated into these guidelines. GUIDELINES SPONSOR: Schering-Plough initiated the project and sponsored the meetings of the working group and all costs generated by these meetings. PLANS FOR GUIDELINE REVISION: The field of biologicals and cytokine modulators is in a rapid phase of development, and revision of the scope and content of these guidelines will be ongoing as longer-term data emerge.


Biomimetic autoseparation of leukocytes from whole blood in a microfluidic device.
Leukocytes comprise less than 1% of all blood cells. Enrichment of their number, starting from a sample of whole blood, is the required first step of many clinical and basic research assays. We created a microfluidic device that takes advantage of the intrinsic features of blood flow in the microcirculation, such as plasma skimming and leukocyte margination, to separate leukocytes directly from whole blood. It consists of a simple network of rectangular microchannels designed to enhance lateral migration of leukocytes and their subsequent extraction from the erythrocyte-depleted region near the sidewalls. A single pass through the device produces a 34-fold enrichment of the leukocyte-to-erythrocyte ratio. It operates on microliter samples of whole blood, provides positive, continuous flow selection of leukocytes, and requires neither preliminary labeling of cells nor input of energy (except for a small pressure gradient to support the flow of blood). This effortless, efficient, and inexpensive technology can be used as a lab-on-a-chip component for initial whole blood sample preparation. Its integration into microanalytical devices that require leukocyte enrichment will enable accelerated transition of these devices into the field for point-of-care clinical testing.


Technology, Privacy, and User Opinions of COVID-19 Mobile Apps for Contact Tracing: Systematic Search and Content Analysis.
Many countries across the globe have released their own COVID-19 contact tracing apps. This has resulted in the proliferation of several apps that used a variety of technologies. With the absence of a standardized approach used by the authorities, policy makers, and developers, many of these apps were unique. Therefore, they varied by function and the underlying technology used for contact tracing and infection reporting. The goal of this study was to analyze most of the COVID-19 contact tracing apps in use today. Beyond investigating the privacy features, design, and implications of these apps, this research examined the underlying technologies used in contact tracing apps. It also attempted to provide some insights into their level of penetration and to gauge their public reception. This research also investigated the data collection, reporting, retention, and destruction procedures used by each of the apps under review. This research study evaluated 13 apps corresponding to 10 countries based on the underlying technology used. The inclusion criteria ensured that most COVID-19-declared epicenters (ie, countries) were included in the sample, such as Italy. The evaluated apps also included countries that did relatively well in controlling the outbreak of COVID-19, such as Singapore. Informational and unofficial contact tracing apps were excluded from this study. A total of 30,000 reviews corresponding to the 13 apps were scraped from app store webpages and analyzed. This study identified seven distinct technologies used by COVID-19 tracing apps and 13 distinct apps. The United States was reported to have released the most contact tracing apps, followed by Italy. Bluetooth was the most frequently used underlying technology, employed by seven apps, whereas three apps used GPS. The Norwegian, Singaporean, Georgian, and New Zealand apps were among those that collected the most personal information from users, whereas some apps, such as the Swiss app and the Italian (Immuni) app, did not collect any user information. The observed minimum amount of time implemented for most of the apps with regard to data destruction was 14 days, while the Georgian app retained records for 3 years. No significant battery drainage issue was reported for most of the apps. Interestingly, only about 2% of the reviewers expressed concerns about their privacy across all apps. The number and frequency of technical issues reported on the Apple App Store were significantly more than those reported on Google Play; the highest was with the New Zealand app, with 27% of the reviewers reporting technical difficulties (ie, 10% out of 27% scraped reviews reported that the app did not work). The Norwegian, Swiss, and US (PathCheck) apps had the least reported technical issues, sitting at just below 10%. In terms of usability, many apps, such as those from Singapore, Australia, and Switzerland, did not provide the users with an option to sign out from their apps. This article highlighted the fact that COVID-19 contact tracing apps are still facing many obstacles toward their widespread and public acceptance. The main challenges are related to the technical, usability, and privacy issues or to the requirements reported by some users.


Psychosocial factors at work and in every day life are associated with irritable bowel syndrome.
The etiology of irritable bowel syndrome (IBS) tends to be complex and multi-factorial and there is still a lack of understanding of how different psychosocial factors are associated with the syndrome. Our aim was to examine the occurrence of psychosocial and behavioural factors among patients diagnosed with IBS in primary care. The study had an epidemiological population-based case-control design comparing 347 IBS cases to 1041 age and sex matched controls from the general population. A survey was directed to cases and controls based on validated questions asking for mood status, job strain, family history of IBS, and sleeping habits as well as education, nutritional and exercise habits and medication. In multivariate analyses, independent associations were found between IBS and lack of influence on work planning, a family history of IBS, anxiety, and sleeping disturbances. Important factors associated with IBS diagnosis among females were anxiety as well as family history of IBS and lack of co-determination at work. For males, only lack of influence on working pace and family history of IBS remained independently associated with an IBS diagnosis. The causal associations of the complex risk factor panorama for IBS warrants further study. This study indicates that there should be a special focus on investigating the psychosocial working conditions and their associations to IBS.


Association Between Human Telomerase Reverse Transcriptase Gene Variations and Risk of Developing Breast Cancer.
Despite a reduction in the number of deaths from cancers made possible by the development of early detection tests, improvements in treatment, changes in the age distribution of the population, and changes of personal behaviors as a result of awareness, breast cancer remains a major health problem worldwide. Breast cancer is the most common cancer and second leading cause of cancer death in women. Several genetic and environmental factors are known to be involved in breast cancer pathogenesis, but its exact etiology is complicated and is not clearly identified. The structure and integrity of telomeres are pivotal for genome stability, and telomere length is maintained by the expression of the telomerase enzyme. The human telomerase reverse transcriptase (hTERT) gene is a principal functional subunit of the telomerase. Several recent studies have provided evidence that hTERT gene variants may have an important role in cancer development. Three hTERT variants (rs2736100, rs2736098, and rs2853669) were genotyped for 107 breast cancer patients and 110 healthy controls to determine their effect on breast cancer susceptibility. It was observed that hTERT rs2736098 was associated with breast cancer risk (odds ratio [OR] = 1.88; p = 0.034), while rs2736100 and rs2853669 did not significantly differ between the groups. These findings are the first description of hTERT allele distributions in the Turkish population and may contribute to our understanding of breast cancer development. Nevertheless, further large-scale population studies are needed to understand the role of the hTERT polymorphisms and haplotypes in the development of breast cancer.


A Qualitative Study of Serious Illness Conversations in Patients with Advanced Cancer.
Background: Conversations with seriously ill patients about their values and goals have been associated with reduced distress, a better quality of life, and goal-concordant care near the end of life. Yet, little is known about how such conversations are conducted. Objective: To characterize the content of serious illness conversations and identify opportunities for improvement. Design: Qualitative analysis of audio-recorded, serious illness conversations using an evidence-based guide and obtained through a cluster randomized controlled trial in an outpatient oncology setting. Setting/Measurements: Clinicians assigned to the intervention arm received training to use the "Serious Illness Conversation Guide" to have a serious illness conversation about values and goals with advanced cancer patients. Conversations were de-identified, transcribed verbatim, and independently coded by two researchers. Key themes were analyzed. Results: A total of 25 conversations conducted by 16 clinicians were evaluated. The median conversation duration was 14 minutes (range 4-37), with clinicians speaking half of the time. Thematic analyses demonstrated five key themes: (1) supportive dialogue between patients and clinicians; (2) patients' openness to discuss emotionally challenging topics; (3) patients' willingness to articulate preferences regarding life-sustaining treatments; (4) clinicians' difficulty in responding to emotional or ambiguous patient statements; and (5) challenges in discussing prognosis. Conclusions: Data from this exploratory study suggest that seriously ill patients are open to discussing values and goals with their clinician. Yet, clinicians may struggle when disclosing a time-based prognosis and in responding to patients' emotions. Such skills should be a focus for additional training for clinicians caring for seriously ill patients.


In situ observations of the reversible vacancy ordering process in van der Waals-bonded Ge-Sb-Te thin films and GeTe-Sb2Te3 superlattices.
Chalcogenide-based thin films are employed in data storage and memory technology whereas van der Waals-bonded layered chalcogenide heterostructures are considered to be a main contender for memory devices with low power consumption. The reduction of switching energy is due to the lowering of entropic losses governed by the restricted motion of atoms in one dimension within the crystalline states. The investigations of switching mechanisms in such superlattices have recently attracted much attention and the proposed models are still under debate. This is partially due to the lack of direct observation of atomic scale processes, which might occur in these chalcogenide systems. This work reports direct, nanoscale observations of the order-disorder processes in van der Waals bonded Ge-Sb-Te thin films and GeTe-Sb2Te3-based superlattices using in situ experiments inside an aberration-corrected transmission electron microscope. The findings reveal a reversible self-assembled reconfiguration of the structural order in these materials. This process is associated with the ordering of randomly distributed vacancies within the studied materials into ordered vacancy layers and with readjustment of the lattice plane distances within the newly formed layered structures, indicating the high flexibility of these layered chalcogenide-based systems. Thus, the ordering process results in the formation of vacancy-bonded building blocks intercalated within van der Waals-bonded units. Moreover, vacancy-bonded building blocks can be reconfigured to the initial structure under the influence of an electron beam, while in situ exposure of the recovered layers to a targeted electron beam leads to the reverse process. Overall, the outcomes provide new insights into local structure and switching mechanism in chalcogenide superlattices.


Relationships between global motion and global form processing, practice, cognitive and visual processing in adults with dyslexia or visual discomfort.
The aim of the first of two experiments was to investigate the effect of practice on sensitivity to global motion and global form in a group of adults with dyslexia, a group of normal readers with visual discomfort, a group with dyslexia and visual discomfort, and a control group. In comparison to the control group, and regardless of the effect of practice, the group with dyslexia was significantly less sensitive to global motion. No differences in global motion sensitivity were found when individuals with dyslexia, with or without visual discomfort, were compared. The normal reading group with visual discomfort was less sensitive to global motion than the control group at baseline, but not when a second estimate of motion sensitivity was obtained. About 30% of the group with dyslexia had a global motion deficit on each threshold estimate. In contrast, there were no significant effects of practice or group on sensitivity to global form. In Experiment 2, performance on a number of cognitive and visual processing tasks was measured in four groups: two with dyslexia; one with and one without a global motion deficit, a normal reading group with visual discomfort, and a control group. The group with visual discomfort had reduced visual processing speed only. Regardless of whether a global motion processing deficit was present or absent in individuals with dyslexia, reduced accuracy was found on the language and visual processing measures, and on a rapid temporal sequencing task. Individuals with dyslexia and a global motion deficit had poorer accuracy than individuals with dyslexia and no motion deficit on the phonological processing and verbal short term memory tasks. We concluded that some adults with dyslexia have a persistent deficit when processing global motion but not global form. This is consistent with reports of a magnocellular pathway deficit in this group. Individuals with visual discomfort do not have a magnocellular processing deficit, but have perceptual difficulties when performing complex visual processing tasks.


Comparative genomics shows differences in the electron transport and carbon metabolic pathways of Mycobacterium africanum relative to Mycobacterium tuberculosis and suggests an adaptation to low oxygen tension.
The geographically restricted Mycobacterium africanum lineages (MAF) are primarily found in West Africa, where they account for a significant proportion of tuberculosis. Despite this phenomenon, little is known about the co-evolution of these ancient lineages with West Africans. MAF and M. tuberculosis sensu stricto lineages (MTB) differ in their clinical, in vitro and in vivo characteristics for reasons not fully understood. Therefore, we compared genomes of 289 MAF and 205 MTB clinical isolates from the 6 main human-adapted M. tuberculosis complex lineages, for mutations in their Electron Transport Chain and Central Carbon Metabolic pathway in order to explain these metabolic differences. Furthermore, we determined, in silico, whether each mutation could affect the function of genes encoding enzymes in these pathways. We found more mutations with the potential to affect enzymes in these pathways in MAF lineages compared to MTB lineages. We also found that similar mutations occurred in these pathways between MAF and some MTB lineages. Generally, our findings show further differences between MAF and MTB lineages that may have contributed to the MAF clinical and growth phenotype and indicate potential adaptation of MAF lineages to a distinct ecological niche, which we suggest includes areas characterized by low oxygen tension.


Circumcision and its effects in Africa.
Male circumcision is one of the most commonly performed procedures in Africa, with a wide variation between the different regions on the practice. This is because circumcision is often done for religious and cultural or traditional reasons, which includes being part of rituals or rite of passage to adulthood. There had been few medical indications for the procedure until the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) pandemic, which is prevalent in many of the countries in the region. Evidence from randomized controlled trials conducted in the continent had shown that male circumcision could be instrumental to reducing the transmission of HIV/AIDS in heterosexual couples in high disease prevalent and low circumcision prevalent areas. This had led to the roll-out of large population-based adult male circumcisions as well as the development of tools to facilitate the procedure. Circumcision, however, is not without complications and the incidence appears related to the age of the patient, where the procedure was done, technique used and level of proficiency of the practitioners. This article reviews the practice of circumcision in Africa and highlights the impact of the procedure on the continent.


Annotation of the Staphylococcus aureus Metabolome Using Liquid Chromatography Coupled to High-Resolution Mass Spectrometry and Application to the Study of Methicillin Resistance.
Staphylococcus aureus can cause a variety of severe disease patterns and can readily acquire antibiotic resistance; however, the mechanisms by which this commensal becomes a pathogen or develops antibiotic resistance are still poorly understood. Here we asked whether metabolomics can be used to distinguish bacterial strains with different antibiotic susceptibilities. Thus, an efficient and robust method was first thoroughly implemented to measure the intracellular metabolites of S. aureus in an unbiased and reproducible manner. We also placed special emphasis on metabolome coverage and annotation and used both hydrophilic interaction liquid chromatography and pentafluorophenyl-propyl columns coupled to high-resolution mass spectrometry in conjunction with our spectral database developed in-house to identify with high confidence as many meaningful S. aureus metabolites as possible. Overall, we were able to characterize up to 210 metabolites in S. aureus, which represents a substantial ∼50% improvement over previously published data. We then preliminarily compared the metabolic profiles of 10 clinically relevant methicillin-resistant and susceptible strains harvested at different time points during the exponential growth phase (without any antibiotic exposure). Interestingly, the resulting data revealed a distinct behavior of "slow-growing" resistant strains, which show modified levels of several precursors of peptidoglycan and capsular polysaccharide biosynthesis.


The human parahippocampal region: I. Temporal pole cytoarchitectonic and MRI correlation.
The temporal pole (TP) is the rostralmost portion of the human temporal lobe. Characteristically, it is only present in human and nonhuman primates. TP has been implicated in different cognitive functions such as emotion, attention, behavior, and memory, based on functional studies performed in healthy controls and patients with neurodegenerative diseases through its anatomical connections (amygdala, pulvinar, orbitofrontal cortex). TP was originally described as a single uniform area by Brodmann area 38, and von Economo (area TG of von Economo and Koskinas), and little information on its cytoarchitectonics is known in humans. We hypothesize that 1) TP is not a homogenous area and we aim first at fixating the precise extent and limits of temporopolar cortex (TPC) with adjacent fields and 2) its structure can be correlated with structural magnetic resonance images. We describe here the macroscopic characteristics and cytoarchitecture as two subfields, a medial and a lateral area, that constitute TPC also noticeable in 2D and 3D reconstructions. Our findings suggest that the human TP is a heterogeneous region formed exclusively by TPC for about 7 mm of the temporal tip, and that becomes progressively restricted to the medial and ventral sides of the TP. This cortical area presents topographical and structural features in common with nonhuman primates, which suggests an evolutionary development in human species.