Morbimortality in adult patients with septic arthritis: a three-year hospital-based study.
The objective of this ambispective study was to determine outcomes and associated factors for adult patients with confirmed septic arthritis (SA). All adult patients admitted to Amiens University Hospital between November 2010 and December 2013 with confirmed SA were included in the study. Patients with prosthetic joint infections were excluded. A statistical analysis was performed in order to identify risk factors associated with a poor outcome (including mortality directly attributable to SA). A total of 109 patients (mean ± SD age: 60.1 ± 20.1; 74 male/35 females) were diagnosed with SA during the study period. The most commonly involved sites were the small joints (n = 34, 31.2 %) and the knee (n = 25, 22.9 %). The most frequent concomitant conditions were cardiovascular disease (n = 45, 41.3 %) and rheumatic disease (n = 39, 35.8 %). One hundred patients (91.7 %) had a positive microbiological culture test, with Staphylococcus aureus as the most commonly detected pathogen (n = 59, 54.1 %). Mortality directly attributable to SA was relatively infrequent (n = 6, 5.6 %) and occurred soon after the onset of SA (median [range]: 24 days [1-42]). Major risk factors associated with death directly attributable to SA were older age (p = 0.023), high C-reactive protein levels (p = 0.002), diabetes mellitus (p = 0.028), rheumatoid arthritis and other inflammatory rheumatic diseases (p = 0.021), confusion on admission (p = 0.012), bacteraemia (p = 0.015), a low creatinine clearance rate (p = 0.009) and the presence of leg ulcers/eschars (p = 0.003). The median duration of follow-up (in patients who survived for more than 6 months) was 17 months [6-43]. The proportion of poor functional outcomes was high (31.8 %). Major risk factors associated with a poor functional outcome were older age (0.049), hip joint involvement (p = 0.003), the presence of leg ulcers/eschars (p = 0.012), longer time to presentation (0.034) and a low creatinine clearance rate (p = 0.013). In a university hospital setting, SA is still associated with high morbidity and mortality rates.


Deposition of mannan binding protein and mannan binding protein-mediated complement activation in the glomeruli of patients with IgA nephropathy.
Mannan binding protein (MBP) is a C-type lectin and has a high affinity to mannose and N-acetyl glucosamine. It is also known to activate C4 and C2 without C1 component, which is called 'lectin pathway'. We now report the presence of MBP and MBP-mediated complement activation in renal glomeruli of IgA nephropathy patients using an immunohistochemical method. In 7 of 42 cases with IgA nephropathy, MBP was detected in the glomerular mesangial area and colocalized with IgA1. In 19 cases with other types of IC-mediated glomerulonephritis including lupus nephritis and membranous nephropathy or without nephritis, MBP was not detected in the glomerulus. The C2- and/or C4-positive rate was 87.5% in the MBP-positive group and 20% in the MBP-negative group of IgA nephropathy. In addition, MBP-positive cases showed marked mesangial cell proliferation, lower creatinine clearance (53.4 +/- 10.0 vs. 77. 8 +/- 4.7 ml/min) and higher urinary protein excretion (2.5 +/- 0.9 vs. 0.9 +/- 0.2 g/day) compared with MBP-negative cases. These findings suggested that MBP was involved in glomerular complement activation through the lectin pathway and thus induced glomerular injury of IgA nephropathy. Since oligosaccharide chain alterations such as reduced sialic acid and galactose of IgA1 molecule have been reported in IgA nephropathy patients, MBP might bind to the IgA1 molecule via interaction between MBP and sugar chain.


ABCB1 is predominantly expressed in human fetal neural stem/progenitor cells at an early development stage.
ABCB1 is a human ABC transporter originally characterized by its ability to cause resistance to chemotherapy drugs in cancer cells, and later found to be functionally expressed in human neural stem/progenitor cells (NSPCs) in vitro. Here, we performed a detailed examination of ABCB1's expression on human NSPCs in vitro and in human fetal brain tissues, and analyzed the cellular properties of the human NSPCs expressing ABCB1. We confirmed that ABCB1 was expressed on the surface of human NSPCs, and its level correlated well with those of Nestin and CD133. The population of fluorescence-activated cell sorter-sorted human NSPCs expressing high levels of ABCB1 showed enrichment of proliferating cells, higher expression of 246 genes (e.g., RGS6, IGFBP7, GFAP, TNC, Hes1), and lower expression of 71 genes (e.g., STMN2, DLX5, BASP1, DCX, CD24) compared with human NSPCs expressing low or no ABCB1. In situ, ABCB1 was selectively expressed in cells in the ventricular or subventricular regions of lateral ventricles that expressed Nestin in human development. These findings suggest that ABCB1 is predominantly expressed in immature human fetal NSPCs in vitro and at early developmental stages in vivo, and that it may be a useful marker for human NSPCs.


Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis.
As a paradigm for chronic infectious diseases, tuberculosis exhibits a variety of clinical presentations, ranging from primary pulmonary tuberculosis to reactivation tuberculosis and cavitary disease. To date, the animal models used in evaluating chemotherapy of tuberculosis have been high-dose intravenous models that mimic the disseminated forms of the disease. In the present study, we have used a low-dose aerosol exposure model which we feel better reflects newly diagnosed tuberculosis in patients converting to tuberculin positivity. As appropriate examples of chemotherapy, four rifamycins (rifampin, rifabutin, rifapentine, and KRM-1648) were tested, first in an in vitro murine macrophage model and then in the low-dose aerosol infection model, for their activity against Mycobacterium tuberculosis. In both models, KRM-1648 had the highest level of activity of the four compounds. In the infected-lung model, rifabutin, rifapentine, and KRM-1648 all had sterilizing activity when given orally at 5 mg/kg of body weight per day. When given at 2.5 mg/kg/day, KRM-1648 had the highest level of activity of the four drugs, reducing the bacterial load by 2.7 logs over 35 days of therapy.


Working memory retention systems: a state of activated long-term memory.
High temporal resolution event-related brain potential and electroencephalographic coherence studies of the neural substrate of short-term storage in working memory indicate that the sustained coactivation of both prefrontal cortex and the posterior cortical systems that participate in the initial perception and comprehension of the retained information are involved in its storage. These studies further show that short-term storage mechanisms involve an increase in neural synchrony between prefrontal cortex and posterior cortex and the enhanced activation of long-term memory representations of material held in short-term memory. This activation begins during the encoding/comprehension phase and evidently is prolonged into the retention phase by attentional drive from prefrontal cortex control systems. A parsimonious interpretation of these findings is that the long-term memory systems associated with the posterior cortical processors provide the necessary representational basis for working memory, with the property of short-term memory decay being primarily due to the posterior system. In this view, there is no reason to posit specialized neural systems whose functions are limited to those of short-term storage buffers. Prefrontal cortex provides the attentional pointer system for maintaining activation in the appropriate posterior processing systems. Short-term memory capacity and phenomena such as displacement of information in short-term memory are determined by limitations on the number of pointers that can be sustained by the prefrontal control systems.


Complementary inhibition of synoviocyte, smooth muscle cell or mouse lymphoma cell proliferation by a vanadyl curcumin complex compared to curcumin alone.
A novel vanadyl curcumin complex (VO(cur)2) has been synthesized and and its physicochemical properties characterized. Biological characterization included in vitro testing for anti-rheumatic activity in synoviocytes, angiogenesis inhibition in smooth muscle cells and anti-cancer potential in mouse lymphoma cells; as well as in vivo testing for hypoglycemic activity by oral gavage in streptozotocin (STZ)-diabetic rats. VO(cur)2 was more effective as an anti-cancer agent, compared to uncomplexed curcumin or vanadyl ion alone, was more than twice as effective as curcumin alone as an anti-arthritic agent, and was more than four times as effective as curcumin alone in inhibiting smooth muscle cell proliferation. In both acute and chronic screening tests, VO(cur)2 was ineffective as an insulin mimetic agent; however, it also proved to be exceptionally non-toxic, with no evidence of negative symptomatology during a month-long treatment period, at doses up to and including 2.0 mmol kg(-1) day(-1).


The growing role of noninvasive ventilation in patients requiring prolonged mechanical ventilation.
For many patients with chronic respiratory failure requiring ventilator support, noninvasive ventilation (NIV) is preferable to invasive support by tracheostomy. Currently available evidence does not support the use of nocturnal NIV in unselected patients with stable COPD. Several European studies have reported benefit for high intensity NIV, in which setting of inspiratory pressure and respiratory rate are selected to achieve normocapnia. There have also been studies reporting benefit for the use of NIV as an adjunct to exercise training. NIV may be useful as an adjunct to airway clearance techniques in patients with cystic fibrosis. Accumulating evidence supports the use of NIV in patients with obesity hypoventilation syndrome. There is considerable observational evidence supporting the use of NIV in patients with chronic respiratory failure related to neuromuscular disease, and one randomized controlled trial reported that the use of NIV was life-prolonging in patients with amyotrophic lateral sclerosis. A variety of interfaces can be used to provide NIV in patients with stable chronic respiratory failure. The mouthpiece is an interface that is unique in this patient population, and has been used with success in patients with neuromuscular disease. Bi-level pressure ventilators are commonly used for NIV, although there are now a new generation of intermediate ventilators that are portable, have a long battery life, and can be used for NIV and invasive applications. Pressure support ventilation, pressure controlled ventilation, and volume controlled ventilation have been used successfully for chronic applications of NIV. New modes have recently become available, but their benefits await evidence to support their widespread use. The success of NIV in a given patient population depends on selection of an appropriate patient, selection of an appropriate interface, selection of an appropriate ventilator and ventilator settings, the skills of the clinician, the motivation of the patient, and the support of the family.


Guilt by association: the arginine case revisited.
If the genetic code arose in an RNA world, present codon assignments may reflect primordial RNA-amino acid affinities. Whether aptamers selected from random pools to bind free amino acids do so using the cognate codons at their binding sites has been controversial. Here we defend and extend our previous analysis of arginine binding sites, and propose a model for the maintenance of codon-amino acid interactions through the evolution of amino acids from ribozyme cofactors into the building blocks of proteins.


Large scale mitochondrial sequencing in Mexican Americans suggests a reappraisal of Native American origins.
The Asian origin of Native Americans is largely accepted. However uncertainties persist regarding the source population(s) within Asia, the divergence and arrival time(s) of the founder groups, the number of expansion events, and migration routes into the New World. mtDNA data, presented over the past two decades, have been used to suggest a single-migration model for which the Beringian land mass plays an important role. In our analysis of 568 mitochondrial genomes, the coalescent age estimates of shared roots between Native American and Siberian-Asian lineages, calculated using two different mutation rates, are A4 (27.5 ± 6.8 kya/22.7 ± 7.4 kya), C1 (21.4 ± 2.7 kya/16.4 ± 1.5 kya), C4 (21.0 ± 4.6 kya/20.0 ± 6.4 kya), and D4e1 (24.1 ± 9.0 kya/17.9 ± 10.0 kya). The coalescent age estimates of pan-American haplogroups calculated using the same two mutation rates (A2:19.5 ± 1.3 kya/16.1 ± 1.5 kya, B2:20.8 ± 2.0 kya/18.1 ± 2.4 kya, C1:21.4 ± 2.7 kya/16.4 ± 1.5 kya and D1:17.2 ± 2.0 kya/14.9 ± 2.2 kya) and estimates of population expansions within America (~21-16 kya), support the pre-Clovis occupation of the New World. The phylogeography of sublineages within American haplogroups A2, B2, D1 and the C1b, C1c and C1d subhaplogroups of C1 are complex and largely specific to geographical North, Central and South America. However some sub-branches (B2b, C1b, C1c, C1d and D1f) already existed in American founder haplogroups before expansion into the America. Our results suggest that Native American founders diverged from their Siberian-Asian progenitors sometime during the last glacial maximum (LGM) and expanded into America soon after the LGM peak (~20-16 kya). The phylogeography of haplogroup C1 suggest that this American founder haplogroup differentiated in Siberia-Asia. The situation is less clear for haplogroup B2, however haplogroups A2 and D1 may have differentiated soon after the Native American founders divergence. A moderate population bottle neck in American founder populations just before the expansion most plausibly resulted in few founder types in America. The similar estimates of the diversity indices and Bayesian skyline analysis in North America, Central America and South America suggest almost simultaneous (~ 2.0 ky from South to North America) colonization of these geographical regions with rapid population expansion differentiating into more or less regional branches across the pan-American haplogroups.


Localization, dynamics, and protein interactions reveal distinct roles for ER and Golgi SNAREs.
ER-to-Golgi transport, and perhaps intraGolgi transport involves a set of interacting soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins including syntaxin 5, GOS-28, membrin, rsec22b, and rbet1. By immunoelectron microscopy we find that rsec22b and rbet1 are enriched in COPII-coated vesicles that bud from the ER and presumably fuse with nearby vesicular tubular clusters (VTCs). However, all of the SNAREs were found on both COPII- and COPI-coated membranes, indicating that similar SNARE machinery directs both vesicle pathways. rsec22b and rbet1 do not appear beyond the first Golgi cisterna, whereas syntaxin 5 and membrin penetrate deeply into the Golgi stacks. Temperature shifts reveal that membrin, rsec22b, rbet1, and syntaxin 5 are present together on membranes that rapidly recycle between peripheral and Golgi-centric locations. GOS-28, on the other hand, maintains a fixed localization in the Golgi. By immunoprecipitation analysis, syntaxin 5 exists in at least two major subcomplexes: one containing syntaxin 5 (34-kD isoform) and GOS-28, and another containing syntaxin 5 (41- and 34-kD isoforms), membrin, rsec22b, and rbet1. Both subcomplexes appear to involve direct interactions of each SNARE with syntaxin 5. Our results indicate a central role for complexes among rbet1, rsec22b, membrin, and syntaxin 5 (34 and 41 kD) at two membrane fusion interfaces: the fusion of ER-derived vesicles with VTCs, and the assembly of VTCs to form cis-Golgi elements. The 34-kD syntaxin 5 isoform, membrin, and GOS-28 may function in intraGolgi transport.


Spinning Carbon Nanotube Nanothread under a Scanning Electron Microscope.
Nanothread with a diameter as small as one hundred nanometers was manufactured under a scanning electron microscope. Made directly from carbon nanotubes, and inheriting their superior electrical and mechanical properties, nanothread may be the world's smallest man-made fiber. The smallest thread that can be spun using a bench-top spinning machine is about 5 microns in diameter. Nanothread is a new material building block that can be used at the nanoscale or plied to form yarn for applications at the micro and macro scales. Preliminary electrical and mechanical properties of nanothread were measured. The resistivity of nanothread is less than 10-5 Ω∙m. The strength of nanothread is greater than 0.5 GPa. This strength was obtained from measurements using special glue that cures in an electron microscope. The glue weakened the thread, thus further work is needed to obtain more accurate measurements. Nanothread will have broad applications in enabling electrical components, circuits, sensors, and tiny machines. Yarn can be used for various macroscale applications including lightweight antennas, composites, and cables.


En bloc spondylectomy in patients older than 60 years: indications, results and complications in a series of 37 patients.
To review a series of patients > 60 years affected by primary spine bone tumors, who have undergone surgery, and to describe their clinical presentation, results and complications associated with surgical treatment. A review of all patients > 60 years affected by primary spine bone tumor surgically treated with en bloc spondylectomy from 1993 to 2015 was performed. Thirty-seven cases were identified, and clinical and radiological characteristics, therapy, complications and survival were evaluated. Only 14/37 cases were not previously treated. Complications were quite frequent: 64% of patients experienced almost one early complication; 48% and 27% experienced 2 and ≥ 3 early complications, respectively; 37% of patients experienced almost one late complication; and 10% and 8% experienced 2 and ≥ 3 late complications, respectively. Massive blood loss and dural tear were the more frequent surgical complications; no deaths were reported during surgeries; one patient died during the first postoperative day due to hemorrhage and cardiac complications, one during the third postoperative day for the same cause despite of a savage surgery, and another one died at 7 days from index surgery due to myocardial infarction. The 5-year disease-related survival and global survival were 62.8% and 52.1%, respectively. Nineteen patients are still alive, 15 of whom without any evidence of disease. Primary malignant or locally aggressive bone tumors of the spine should be treated with wide surgery also in the older age, although the complications rate and the risk of patient survival can be considered high. These slides can be retrieved under Electronic Supplementary Material.


Acupuncture: role in comprehensive cancer care--a primer for the oncologist and review of the literature.
In recent studies, patients have reported an increased use of complementary and alternative medicine (CAM). Acupuncture is a popular complementary therapy for patients with cancer. This article will provide current cancer treatment providers with information on acupuncture as well as the research conducted on cancer symptoms and side effects of cancer treatments. Antiemetic studies are the most prevalent and contain the most promising results. Several studies have found that acupuncture significantly reduces the number of emesis (vomiting) episodes for patients receiving chemotherapy. While studies on pain control vary due to the heterogeneity of pain, there are few studies investigating pain caused from cancer and the removal of cancerous tumors. These studies, while promising, provide basic results that need further investigation for more definitive results. Although relatively few studies have been done on anxiety and depression, several researchers have found acupuncture to be just as effective as or more effective than antidepressants for patients without cancer. Studies on breathlessness, while small, have shown acupuncture to have a significant positive effect on chronic obstructive pulmonary disease, breathlessness associated with end-stage cancer, and asthma. Researchers studying xerostomic individuals who have received salivary gland irradiation found significant positive results in salivary flow rates compared to baseline. Patients with hot flashes due to hormonal imbalance may benefit from the use of acupuncture. A recent pilot study showed improvement of chronic postchemotherapy fatigue following acupuncture treatments. Many individuals with cancer have turned to acupuncture because their symptoms persisted with conventional treatments or as an alternative or complement to their ongoing treatments. Despite the immense popularity in the community, few large randomized trials have been conducted to determine the effects acupuncture has on cancer symptoms and side effects of treatments. A majority of the current studies have shown beneficial effects that warrant further investigation with large trial sizes.


Simplifying Exosuits: Kinematic Couplings in the Upper Extremity during Daily Living Tasks.
In the past few years, several light-weight soft wearable robots, so called exosuits, for upper extremity assistance have been developed. The design of exosuits is often based on a bio-mimetic design approach, mimicking the human biomechanics. However, in the design process, the interactions of movement directions during daily living tasks have not yet been analyzed comprehensively. Therefore, the designs of exosuits might be overly complex, as movement directions that are coupled during daily life tasks were implemented independently; or lack functionality, as relevant movement directions were disregarded. In the meta-analysis presented in this paper, the maximum angles occurring during daily living tasks in the upper extremity of unimpaired individuals were examined. To identify the kinematic couplings between joint axes, the interactions between movement directions that act against gravity were analyzed. The strongest correlations were found between rotation in the plane of elevation and humeral axial rotation ($R^{2} = 0.82$, p < 0.001), and between humeral elevation and humeral axial rotation $(R^{2}\ =\ 0.16,\ p=\ 0.001)$. Shoulder rotations and elbow flexion were not correlated. We conclude that humeral axial rotation is a relevant movement direction in the upper extremity, which, so far, has often been neglected in the design of exosuits. To simplify the design of exosuits, we propose a one degree of freedom support trajectory in which rotation in the plane of elevation (at -70° and 80°) and humeral axial rotation (at 110° and -60°) are coupled to humeral elevation (continuously from -40° to -110°).


Natural Phyto-Bioactive Compounds for the Treatment of Type 2 Diabetes: Inflammation as a Target.
Diabetes is a metabolic, endocrine disorder which is characterized by hyperglycemia and glucose intolerance due to insulin resistance. Extensive research has confirmed that inflammation is closely involved in the pathogenesis of diabetes and its complications. Patients with diabetes display typical features of an inflammatory process characterized by the presence of cytokines, immune cell infiltration, impaired function and tissue destruction. Numerous anti-diabetic drugs are often prescribed to diabetic patients, to reduce the risk of diabetes through modulation of inflammation. However, those anti-diabetic drugs are often not successful as a result of side effects; therefore, researchers are searching for efficient natural therapeutic targets with less or no side effects. Natural products' derived bioactive molecules have been proven to improve insulin resistance and associated complications through suppression of inflammatory signaling pathways. In this review article, we described the extraction, isolation and identification of bioactive compounds and its molecular mechanisms in the prevention of diabetes associated complications.


The Proteome of the Murine Presynaptic Active Zone.
The proteome of the presynaptic active zone controls neurotransmitter release and the short- and long-term structural and functional dynamics of the nerve terminal. The proteinaceous inventory of the presynaptic active zone has recently been reported. This review will evaluate the subcellular fractionation protocols and the proteomic approaches employed. A breakthrough for the identification of the proteome of the presynaptic active zone was the successful employment of antibodies directed against a cytosolic epitope of membrane integral synaptic vesicle proteins for the immunopurification of synaptic vesicles docked to the presynaptic plasma membrane. Combining immunopurification and subsequent analytical mass spectrometry, hundreds of proteins, including synaptic vesicle proteins, components of the presynaptic fusion and retrieval machinery, proteins involved in intracellular and extracellular signaling and a large variety of adhesion molecules, were identified. Numerous proteins regulating the rearrangement of the cytoskeleton are indicative of the functional and structural dynamics of the presynapse. This review will critically discuss both the experimental approaches and prominent protein candidates identified. Many proteins have not previously been assigned to the presynaptic release sites and may be directly involved in the short- and long-term structural modulation of the presynaptic compartment. The identification of proteinaceous constituents of the presynaptic active zone provides the basis for further analyzing the interaction of presynaptic proteins with their targets and opens novel insights into the functional role of these proteins in neuronal communication.


The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
The PRISMA statement is a reporting guideline designed to improve the completeness of reporting of systematic reviews and meta-analyses. Authors have used this guideline worldwide to prepare their reviews for publication. In the past, these reports typically compared 2 treatment alternatives. With the evolution of systematic reviews that compare multiple treatments, some of them only indirectly, authors face novel challenges for conducting and reporting their reviews. This extension of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement was developed specifically to improve the reporting of systematic reviews incorporating network meta-analyses. A group of experts participated in a systematic review, Delphi survey, and face-to-face discussion and consensus meeting to establish new checklist items for this extension statement. Current PRISMA items were also clarified. A modified, 32-item PRISMA extension checklist was developed to address what the group considered to be immediately relevant to the reporting of network meta-analyses. This document presents the extension and provides examples of good reporting, as well as elaborations regarding the rationale for new checklist items and the modification of previously existing items from the PRISMA statement. It also highlights educational information related to key considerations in the practice of network meta-analysis. The target audience includes authors and readers of network meta-analyses, as well as journal editors and peer reviewers.


HIV Prevalence Correlates with High-Risk Sexual Behavior in Ethiopia's Regions.
HIV prevalence varies between 0.9 and 6.5% in Ethiopia's eleven regions. Little has been published examining the reasons for this variation. We evaluated the relationship between HIV prevalence by region and a range of risk factors in the 2005 and 2011 Ethiopian Demographic Health Surveys. Pearson's correlation was used to assess the relationship between HIV prevalence and each variable. There was a strong association between HIV prevalence and three markers of sexual risk: mean lifetime number of partners (men: r = 0.87; P < 0.001; women: r = 0.60; P = 0.05); reporting sex with a non-married, non-cohabiting partner (men: r = 0.92; P < 0.001, women r = 0.93; P < 0.001); and premarital sex. Condom usage and HIV testing were positively associated with HIV prevalence, while the prevalence of circumcision, polygamy, age at sexual debut and male migration were not associated with HIV prevalence. Variation in sexual behavior may contribute to the large variations in HIV prevalence by region in Ethiopia. Population-level interventions to reduce risky sexual behavior in high HIV incidence regions should be considered.


Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ.
Recent advances in the study of the tumor microenvironment have revealed significant interaction between tumor cells and their surrounding stroma in model systems. We have previously shown that two distinct stromal signatures derived from a macrophage (CSF1) response and a fibroblastic (DTF-like) response are present in subsets of invasive breast cancers and show a correlation with clinical outcome. In the present study we explore whether these signatures also exist in the stroma of ductal carcinoma in situ (DCIS). We studied the signatures by both gene expression profile analysis of a publically available data set of DCIS and by immunohistochemistry (IHC) on a tissue microarray of DCIS and invasive breast cancer cases. Both the gene expression and immunohistochemical data show that the macrophage response and fibroblast expression signatures are present in the stroma of subsets of DCIS cases. The incidence of the stromal signatures in DCIS is similar to the incidence in invasive breast cancer that we have previously reported. We also find that the macrophage response signature is associated with higher grade DCIS and cases which are ER and PR negative, whereas the fibroblast signature was not associated with any clinicopathologic features in DCIS. A comparison of 115 matched cases of DCIS and invasive breast cancer found a correlation between the type of stromal response in DCIS and invasive ductal carcinoma (IDC) within the same patient for both the macrophage response and the fibroblast stromal signatures (P = 0.03 and 0.08, respectively). This study is a first characterization of these signatures in DCIS. These signatures have significant clinicopathologic associations and tend to be conserved as the tumor progresses from DCIS to invasive breast cancer.


Cellular and synaptic adaptations of neural circuits processing skylight polarization in the fly.
Specialized ommatidia harboring polarization-sensitive photoreceptors exist in the 'dorsal rim area' (DRA) of virtually all insects. Although downstream elements have been described both anatomically and physiologically throughout the optic lobes and the central brain of different species, little is known about their cellular and synaptic adaptations and how these shape their functional role in polarization vision. We have previously shown that in the DRA of Drosophila melanogaster, two distinct types of modality-specific 'distal medulla' cell types (Dm-DRA1 and Dm-DRA2) are post-synaptic to long visual fiber photoreceptors R7 and R8, respectively. Here we describe additional neuronal elements in the medulla neuropil that manifest modality-specific differences in the DRA region, including DRA-specific neuronal morphology, as well as differences in the structure of pre- or post-synaptic membranes. Furthermore, we show that certain cell types (medulla tangential cells and octopaminergic neuromodulatory cells) specifically avoid contacts with polarization-sensitive photoreceptors. Finally, while certain transmedullary cells are specifically absent from DRA medulla columns, other subtypes show specific wiring differences while still connecting the DRA to the lobula complex, as has previously been described in larger insects. This hints towards a complex circuit architecture with more than one pathway connecting polarization-sensitive DRA photoreceptors with the central brain.


The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1.
Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a complex genetic disorder with a high predisposition of numerous skeletal dysplasias including short stature, osteoporosis, kyphoscoliosis, and fracture non-union (pseudoarthrosis). We have developed murine models that phenocopy many of the skeletal dysplasias observed in NF1 patients, including reduced bone mass and fracture non-union. We also show that the development of these skeletal manifestations requires an Nf1 haploinsufficient background in addition to nullizygous loss of Nf1 in mesenchymal stem/progenitor cells (MSCs) and/or their progenies. This is replicated in two animal models of NF1, PeriCre(+);Nf1(flox/-) and Col2.3Cre(+);Nf1(flox/-) mice. Adoptive transfer experiments demonstrate a critical role of the Nf1+/- marrow microenvironment in the impaired fracture healing in both models and adoptive transfer of WT bone marrow cells improves fracture healing in these mice. To our knowledge, this is the first demonstration of a non-cell autonomous mechanism in non-malignant NF1 manifestations. Collectively, these data provide evidence of a combinatory effect between nullizygous loss of Nf1 in osteoblast progenitors and haploinsufficiency in hematopoietic cells in the development of non-malignant NF1 manifestations.


Microstructure Refinement in W-Y2O3 Alloy Fabricated by Wet Chemical Method with Surfactant Addition and Subsequent Spark Plasma Sintering.
With the aim of preparing high performance oxide-dispersion-strengthened tungsten based alloys by powder metallurgy, the W-Y2O3 composite nanopowder precursor was fabricated by an improved wet chemical method with anion surfactant sodium dodecyl sulfate (SDS) addition. It is found that the employment of SDS can dramatically decrease W grain size (about 40 nm) and improve the size uniformity. What's more, SDS addition can also remarkably improve the uniform dispersion of Y2O3 particles during the synthesis process. For the alloy whose powder precursor was fabricated by traditional wet chemical method without SDS addition, only a few Y2O3 dispersoids with size of approximate 10-50 nm distribute unevenly within tungsten grains. Nevertheless, for the sintered alloy whose powder precursor was produced by improved wet chemical method, the Y2O3 dispersoids (about 2-10 nm in size) with near spherical shape are dispersed well within tungsten grains. Additionally, compared with the former, the alloy possesses smaller grain size (approximate 700 nm) and higher relative density (99.00%). And a Vickers microhardness value up to 600 Hv was also obtained for this alloy. Based on these results, the employment of SDS in traditional wet chemical method is a feasible way to fabricate high performance yttria-dispersion-strengthened tungsten based alloys.


ERRα protein is stabilized by LSD1 in a demethylation-independent manner.
The LSD1 histone demethylase is highly expressed in breast tumors where it constitutes a factor of poor prognosis and promotes traits of cancer aggressiveness such as cell invasiveness. Recent work has shown that the Estrogen-Related Receptor α (ERRα) induces LSD1 to demethylate the Lys 9 of histone H3. This results in the transcriptional activation of a number of common target genes, several of which being involved in cellular invasion. High expression of ERRα protein is also a factor of poor prognosis in breast tumors. Here we show that, independently of its demethylase activities, LSD1 protects ERRα from ubiquitination, resulting in overexpression of the latter protein. Our data also suggests that the elevation of LSD1 mRNA and protein in breast cancer (as compared to normal tissue) may be a key event to increase ERRα protein, independently of its corresponding mRNA.


Physical activity intervention: a transtheoretical model-based intervention designed to help sedentary young adults become active.
Physical activity levels in young adults are low. Research supports the use of the Transtheoretical Model of behaviour change (TM) in designing physical activity interventions. This study used a pre-post randomized control design to investigate the effectiveness of a self-instructional intervention for helping sedentary young adults to initiate physical activity. Post-intervention, significantly more of the experimental group (80%), in comparison to the control group (68%), improved their exercise stage of change (SOC) from baseline (P < 0.05). Discriminant analyses revealed that discrimination between stage improvement/non-improvement was possible using the processes of change data. Stage improvers scored significantly higher on all of the behavioral and four out of five of the cognitive processes of change. For stage improvers, the processes of self-re-evaluation and self-liberation were most frequently used, whilst social liberation was used significantly more by the experimental than the control group. This inexpensive, self-instructional intervention, based on the TM and the 'active living message', is an effective method of assisting sedentary young adults to progress through the exercise SOC.


Tuning in to the voices: a multisite FMRI study of auditory hallucinations.
Auditory hallucinations or voices are experienced by 75% of people diagnosed with schizophrenia. We presumed that auditory cortex of schizophrenia patients who experience hallucinations is tonically "tuned" to internal auditory channels, at the cost of processing external sounds, both speech and nonspeech. Accordingly, we predicted that patients who hallucinate would show less auditory cortical activation to external acoustic stimuli than patients who did not. At 9 Functional Imaging Biomedical Informatics Research Network (FBIRN) sites, whole-brain images from 106 patients and 111 healthy comparison subjects were collected while subjects performed an auditory target detection task. Data were processed with the FBIRN processing stream. A region of interest analysis extracted activation values from primary (BA41) and secondary auditory cortex (BA42), auditory association cortex (BA22), and middle temporal gyrus (BA21). Patients were sorted into hallucinators (n = 66) and nonhallucinators (n = 40) based on symptom ratings done during the previous week. Hallucinators had less activation to probe tones in left primary auditory cortex (BA41) than nonhallucinators. This effect was not seen on the right. Although "voices" are the anticipated sensory experience, it appears that even primary auditory cortex is "turned on" and "tuned in" to process internal acoustic information at the cost of processing external sounds. Although this study was not designed to probe cortical competition for auditory resources, we were able to take advantage of the data and find significant effects, perhaps because of the power afforded by such a large sample.


Patterns of resident health workforce turnover and retention in remote communities of the Northern Territory of Australia, 2013-2015.
The geographical maldistribution of the health workforce is a persisting global issue linked to inequitable access to health services and poorer health outcomes for rural and remote populations. In the Northern Territory (NT), anecdotal reports suggest that the primary care workforce in remote Aboriginal communities is characterised by high turnover, low stability and high use of temporary staffing; however, there is a lack of reliable information to guide workforce policy improvements. This study quantifies current turnover and retention in remote NT communities and investigates correlations between turnover and retention metrics and health service/community characteristics. This study used the NT Department of Health 2013-2015 payroll and financial datasets for resident health workforce in 53 remote primary care clinics. Main outcome measures include annual turnover rates, annual stability rates, 12-month survival probabilities and median survival. At any time point, the clinics had a median of 2.0 nurses, 0.6 Aboriginal health practitioners (AHPs), 2.2 other employees and 0.4 additional agency-employed nurses. Mean annual turnover rates for nurses and AHPs combined were extremely high, irrespective of whether turnover was defined as no longer working in any remote clinic (66%) or no longer working at a specific remote clinic (128%). Stability rates were low, and only 20% of nurses and AHPs remain working at a specific remote clinic 12 months after commencing. Half left within 4 months. Nurse and AHP turnover correlated with other workforce measures. However, there was little correlation between most workforce metrics and health service characteristics. NT Government-funded remote clinics are small, experience very high staff turnover and make considerable use of agency nurses. These staffing patterns, also found in remote settings elsewhere in Australia and globally, not only incur higher direct costs for service provision-and therefore may compromise long-term sustainability-but also are almost certainly contributing to sub-optimal continuity of care, compromised health outcomes and poorer levels of staff safety. To address these deficiencies, it is imperative that investments in implementing, adequately resourcing and evaluating staffing models which stabilise the remote primary care workforce occur as a matter of priority.


Structural remodeling in hypertensive heart disease and the role of hormones.
In hypertension, the risk of adverse cardiovascular events, including heart failure, is increased in the presence of left ventricular hypertrophy. Morphological studies suggest that it is not the quantity but rather the quality, or structure, of myocardium that confers such risk. Iterations in tissue structure that appear in hypertensive heart disease include a remodeling of intramyocardial coronary arterioles, similar to that found in systemic organs, and a disproportionate accumulation of fibrillar collagen within their adventitia and neighboring interstitial space. Microscopic scars replacing necrotic cardiac myocytes are also evident. These expressions of fibrosis appear in the normotensive, nonhypertrophied right and hypertensive, hypertrophied left ventricles and are linked to the renin-angiotensin-aldosterone system. Cardiac myocyte growth, the major determinant of myocardial mass, is related to ventricular loading. Mechanisms responsible for the reactive and reparative fibrosis with renin-angiotensin-aldosterone system activation are under investigation. In vitro quantitative autoradiography has identified angiotensin II, aldosterone, endothelin, and bradykinin receptors in the myocardium. A nonendothelial tissue angiotensin-converting enzyme, whose binding density is marked in the matrix of heart valves, adventitia, and sites of fibrosis, irrespective of its pathogenic basis, has also been found. This angiotensin-converting enzyme may be responsible for regulating local concentrations of angiotensin II and bradykinin that govern fibroblast collagen turnover. Based on a paradigm of discordant reciprocal regulation, in which a relative abundance of stimulators (eg, angiotensin II, aldosterone, and endothelins) of collagen synthesis exceeds inhibitors (eg, bradykinin, prostaglandins, and glucocorticoids), fibrous tissue appears.(ABSTRACT TRUNCATED AT 250 WORDS)


23.4% Hypertonic Saline: A Tactical Option for the Management of Severe Traumatic Brain Injury With Impending or Ongoing Herniation.
There are limited options available to the combat medic for management of traumatic brain injury (TBI) with impending or ongoing herniation. Current pararescue and Tactical Combat Casualty Care (TCCC) guidelines prescribe a bolus of 3% or 5% hypertonic saline. However, this fluid bears a tactical burden of weight (~570g) and pack volume (~500cm3). Thus, 23.4% hypertonic saline is an attractive option, because it has a lighter weight (80g) and pack volume (55cm3), and it provides a similar osmotic load per dose. Current literature supports the use of 23.4% hypertonic saline in the management of acute TBI, and evidence indicates that it is safe to administer via peripheral and intraosseous cannulas. Current combat medic TBI treatment algorithms should be updated to include the use of 23.4% hypertonic saline as an alternative to 3% and 5% solutions, given its effectiveness and tactical advantages.


Efficiency of static and computer adaptive short forms compared to full-length measures of depressive symptoms.
Short-form patient-reported outcome measures are popular because they minimize patient burden. We assessed the efficiency of static short forms and computer adaptive testing (CAT) using data from the Patient-Reported Outcomes Measurement Information System (PROMIS) project. We evaluated the 28-item PROMIS depressive symptoms bank. We used post hoc simulations based on the PROMIS calibration sample to compare several short-form selection strategies and the PROMIS CAT to the total item bank score. Compared with full-bank scores, all short forms and CAT produced highly correlated scores, but CAT outperformed each static short form in almost all criteria. However, short-form selection strategies performed only marginally worse than CAT. The performance gap observed in static forms was reduced by using a two-stage branching test format. Using several polytomous items in a calibrated unidimensional bank to measure depressive symptoms yielded a CAT that provided marginally superior efficiency compared to static short forms. The efficiency of a two-stage semi-adaptive testing strategy was so close to CAT that it warrants further consideration and study.


Validating the Capability for Measuring Age-Related Changes in Grip-Force Strength Using a Digital Hand-Held Dynamometer in Healthy Young and Elderly Adults.
Grip-force performance can be affected by aging, and hand-grip weakness is associated with functional limitations of dasily living. However, using an appropriate digital hand-held dynamometer with continuous hand-grip force data collection shows age-related changes in the quality of hand-grip force control may provide more valuable information for clinical diagnoses rather than merely recording instantaneous maximal hand-grip force in frail elderly adults or people with a disability. Therefore, the purpose of this study was to indicate the construct validity of the digital MicroFET3 dynamometer with Jamar values for maximal grip-force assessments in elderly and young adults and confirmed age-related changes in the maximal and the quality of grip-force performance using the MicroFET3 dynamometer in elderly people. Sixty-five healthy young (23.3 ± 4.5 years) and 50 elderly (69.5 ± 5.8 years) adults were recruited and asked to perform a validity test of the grip-force maximum voluntary contraction (MVC) using both the dominant and nondominant hands with a Jamar dynamometer and a MicroFET3 dynamometer. A strong correlation of maximal grip-force measurements was found between the MicroFET3 dynamometer and Jamar standard dynamometer for both hands in all participants (p < 0.05). Although, the results showed that a lower grip force was measured in both hands by the MicroFET3 dynamometer than with the Jamar dynamometer by 49.9%~57% (p < 0.05), but confidently conversion formulae were also developed to convert MicroFET3 dynamometer values to equivalent Jamar values for both hands. Both dynamometers indicated age-related declines in the maximum grip-force performance by 36.7%~44.3% (p < 0.05). We also found that the maximal hand-grip force values generated in both hand by the elderly adults were slower and more inconsistent than those of the young adults when using the MicroFET3 dynamometer. This study demonstrated that the digital MicroFET3 dynamometer has good validity when used to measure the maximal grip force of both hands, and conversion formulae were also developed to convert MicroFET3 dynamometer force values to Jamar values in both hands. Comparing with the Jamar dynamometer for measuring grip force, the MicroFET3 dynamometer not only indicated age-related declines in the maximum grip-force performance but also showed slower and more inconsistent maximal hand-grip strength generation by the elderly.


Mechanisms of CO2/H+ Sensitivity of Astrocytes.
Ventral regions of the medulla oblongata of the brainstem are populated by astrocytes sensitive to physiological changes in PCO2/[H+]. These astrocytes respond to decreases in pH with elevations in intracellular Ca2+ and facilitated exocytosis of ATP-containing vesicles. Released ATP propagates Ca2+ excitation among neighboring astrocytes and activates neurons of the brainstem respiratory network triggering adaptive increases in breathing. The mechanisms linking increases in extracellular and/or intracellular PCO2/[H+] with Ca2+ responses in chemosensitive astrocytes remain unknown. Fluorescent imaging of changes in [Na+]i and/or [Ca2+]i in individual astrocytes was performed in organotypic brainstem slice cultures and acute brainstem slices of adult rats. It was found that astroglial [Ca2+]i responses triggered by decreases in pH are preceded by Na+ entry, markedly reduced by inhibition of Na+/HCO3- cotransport (NBC) or Na+/Ca2+ exchange (NCX), and abolished in Na+-free medium or by combined NBC/NCX blockade. Acidification-induced [Ca2+]i responses were also dramatically reduced in brainstem astrocytes of mice deficient in the electrogenic Na+/HCO3- cotransporter NBCe1. Sensitivity of astrocytes to changes in pH was not affected by inhibition of Na+/H+ exchange or blockade of phospholipase C. These results suggest that in pH-sensitive astrocytes, acidification activates NBCe1, which brings Na+ inside the cell. Raising [Na+]i activates NCX to operate in a reverse mode, leading to Ca2+ entry followed by activation of downstream signaling pathways. Coupled NBC and NCX activities are, therefore, suggested to be responsible for functional CO2/H+ sensitivity of astrocytes that contribute to homeostatic regulation of brain parenchymal pH and control of breathing. Brainstem astrocytes detect physiological changes in pH, activate neurons of the neighboring respiratory network, and contribute to the development of adaptive respiratory responses to the increases in the level of blood and brain PCO2/[H+]. The mechanisms underlying astroglial pH sensitivity remained unknown and here we show that in brainstem astrocytes acidification activates Na+/HCO3- cotransport, which brings Na+ inside the cell. Raising [Na+]i activates the Na+/Ca2+ exchanger to operate in a reverse mode leading to Ca2+ entry. This identifies a plausible mechanism of functional CO2/H+ sensitivity of brainstem astrocytes, which play an important role in homeostatic regulation of brain pH and control of breathing.


Arp2 links autophagic machinery with the actin cytoskeleton.
Macroautophagy involves lysosomal/vacuolar elimination of long-lived proteins and entire organelles from the cytosol. The process begins with formation of a double-membrane vesicle that sequesters bulk cytoplasm, or a specific cargo destined for lysosomal/vacuolar delivery. The completed vesicle fuses with the lysosome/vacuole limiting membrane, releasing its content into the organelle lumen for subsequent degradation and recycling of the resulting macromolecules. A majority of the autophagy-related (Atg) proteins are required at the step of vesicle formation. The integral membrane protein Atg9 cycles between certain intracellular compartments and the vesicle nucleation site, presumably to supply membranes necessary for macroautophagic vesicle formation. In this study we have tracked the movement of Atg9 over time in living cells by using real-time fluorescence microscopy. Our results reveal that an actin-related protein, Arp2, briefly colocalizes with Atg9 and directly regulates the dynamics of Atg9 movement. We propose that proteins of the Arp2/3 complex regulate Atg9 transport for specific types of autophagy.


Incidental Identification of Possible Delta-Beta Thalassemia Trait in a Family: A Rare Cause of Elevated Hb F.
Delta-Beta thalassaemia is an unusual variant of thalassaemia with elevated level of foetal haemoglobin (HbF). The clinical presentation of delta-beta thalassaemia is mild in both heterozygote and homozygote cases. We hereby describe a rare cause of elevated Hb F in a father and his two daughters. A 52-year-old diabetic male patient, on evaluation of chromatogram of cation exchange HPLC for HbA1c, we incidentally identified elevated Hb F of approximately 20%. Haematological investigation of the patient revealed decreased haemoglobin, normal RBC, leucocyte and platelet count, decreased MCV and MCH. Red cell morphology showed predominantly normocytic normochromic cells with mild anisopoikilocytosis, few microcytes and hypochromic cells seen. His liver function test was normal. Haemoglobin variant analysis revealed decreased Hb A (79.4%), normal Hb A2 (2%) and increased Hb F (19.75%). A possible diagnosis of heterozygous δ β-thalassaemia was considered. Since most laboratories perform HbA1c by cation exchange HPLC method, a careful evaluation of the chromatogram yields useful information. In our case, the elevated Hb F in a father and further careful evaluation of clinical and haematological parameters in the family members made us to possibly think of rare disorders like heterozygous Delta-Beta thalassaemia in the family and provide valuable genetic counseling.


A study of onchocerciasis with severe skin and eye lesions in a hyperendemic zone in the forest of southwestern Cameroon: clinical, parasitologic, and entomologic findings.
Prior to the initiation of an onchocerciasis control program based on the mass administration of ivermectin in the rain forest of southwestern Cameroon, a preliminary baseline study of the area was conducted. The results of this study showed that onchocerciasis was hyperendemic in the area. Skin symptoms and signs were observed including pruritus (67.4% of the population examined), onchocerca nodules (51.6%), skin depigmentation (18.5%), and hanging groins (5.7%). Except for pruritus, the prevalence of these symptoms increased with age. Of the eyes examined, 44.9% had microfilariae in the anterior chamber, 33.5% had choroidoretinitis, 28.0% had punctate keratitis, 8.3% had papillary abnormalities, and 3.6% had sclerosing keratitis. Vision in 10.5% of the eyes examined was classified as blind or very poor (visual acuity = 0-0.10), in 15.7% as poor (visual acuity = 0.11-0.39), and in 73.8% as good (visual acuity = 0.4-1.00). Unlike previous reports that have linked serious ocular damage mainly to savanna onchocerciasis, the present study showed that forest onchocerciasis also caused significant ocular pathology, including blindness. Parasitologically, positive skin snips were recorded for 92.7% of the persons examined, with both sexes being equally infected. The parasite load, expressed as the geometric mean number of microfilariae per skin snip, was 53.6, and was much higher in males than in females. The flv vector, Simulium squamosum, had a high infection rate of 7.5% infective females in Bakumba and 6.8% infective females in Ngbandi, the two fly-catching points. The transmission potential was 266 infective larvae per person per month in Bakumba and 189 in Ngbandi.


Bovine tuberculosis at the human-livestock-wildlife interface: is it a public health problem in Tanzania? A review.
Despite the apparent public health concern about Bovine tuberculosis (BTB) in Tanzania, little has been done regarding the zoonotic importance of the disease and raising awareness of the community to prevent the disease. Bovine tuberculosis is a potential zoonotic disease that can infect a variety of hosts, including humans. The presence of multiple hosts including wild animals, inefficient diagnostic techniques, absence of defined national controls and eradication programs could impede the control of bovine TB. In Tanzania, the diagnosis of Mycobacterium bovis in animals is mostly carried out by tuberculin skin testing, meat inspection in abattoirs and only rarely using bacteriological techniques. The estimated prevalence of BTB in animals in Tanzania varies and ranges across regions from 0.2% to 13.3%, which is likely to be an underestimate if not confirmed by bacteriology or molecular techniques. Mycobacterium bovis has been detected and isolated from different animal species and has been recovered in 10% of apparently healthy wildebeest that did not show lesions at post-mortem. The transmission of the disease from animals to humans can occur directly through the aerosol route and indirectly by consumption of raw milk. This poses an emerging disease threat in the current era of HIV confection in Tanzania and elsewhere. Mycobacterium bovis is one of the causative agents of human extra pulmonary tuberculosis. In Tanzania there was a significant increase (116.6%) of extrapulmonary cases reported between 1995 and 2009, suggesting the possibility of widespread M. bovis and Mycobacterium tuberculosis infection due to general rise of Human Immunodeficiency virus (HIV). This paper aims to review the potential health and economic impact of bovine tuberculosis and challenges to its control in order to safeguard human and animal population in Tanzania.


Association of polyandry and sex-ratio drive prevalence in natural populations of Drosophila neotestacea.
Selfish genetic elements bias their own transmission to the next generation, even at the expense of the fitness of their carrier. Sex-ratio (SR) meiotic drive occurs when an X-chromosome causes Y-bearing sperm to die during male spermatogenesis, so that it is passed on to all of the male's offspring, which are all daughters. How SR is maintained as a stable polymorphism in the absence of genetic suppressors of drive is unknown. Here, we investigate the potential for the female remating rate to affect SR dynamics in natural populations, using the fly Drosophila neotestacea. In controlled laboratory conditions, females from populations where SR is rare mate more often than females from populations where SR is common. Furthermore, only when males mate multiply does the average fertility of SR males relative to wild-type males decrease to a level that can prevent SR from spreading. Our results suggest that differences in the female mating rate among populations may contribute to SR dynamics in the wild, and thus also affect the outcome of this intragenomic conflict. In line with this, we also present evidence of a localized population crash due to SR that may have resulted from habitat fragmentation along with a reduced mating rate.


Human vaginal fluid contains exosomes that have an inhibitory effect on an early step of the HIV-1 life cycle.
Vaginal transmission is crucial to the spread of HIV-1 around the world. It is not yet clear what type (s) of innate defenses against HIV-1 infection are present in the vagina. Here, we aimed to determine whether human vaginal fluid contains exosomes that may possess anti-HIV-1 activity. The exosomal fraction was isolated from samples of vaginal fluids. The presence of exosomes was confirmed by flow cytometry and western blotting. The newly discovered exosomes were tested for their ability to block early steps of HIV-1 infection in vitro using established cell culture systems and real time PCR-based methods. Vaginal fluid contains exosomes expressing CD9, CD63, and CD81 exosomal markers. The exosomal fraction of the fluid-reduced transmission of HIV-1 vectors by 60%, the efficiency of reverse transcription step by 58.4%, and the efficiency of integration by 47%. Exosomes had no effect on the entry of HIV-1 vectors. Human vaginal fluid exosomes are newly discovered female innate defenses that may protect women against HIV-1 infection.


Evaluation of PET/MRI for Tumor Volume Delineation for Head and Neck Cancer.
Computed tomography (CT), combined positron emitted tomography and CT (PET/CT), and magnetic resonance imaging (MRI) are commonly used in head and neck radiation planning. Hybrid PET/MRI has garnered attention for potential added value in cancer staging and treatment planning. Herein, we compare PET/MRI vs. planning CT for head and neck cancer gross tumor volume (GTV) delineation. We prospectively enrolled patients with head and neck cancer treated with definitive chemoradiation to 60-70 Gy using IMRT. We performed pretreatment contrast-enhanced planning CT and gadolinium-enhanced PET/MRI. Primary and nodal volumes were delineated on planning CT (GTV-CT) prospectively before treatment and PET/MRI (GTV-PET/MRI) retrospectively after treatment. GTV-PET/MRI was compared to GTV-CT using separate rigid registrations for each tumor volume. The Dice similarity coefficient (DSC) metric evaluating spatial overlap and modified Hausdorff distance (mHD) evaluating mean orthogonal distance difference were calculated. Minimum dose to 95% of GTVs (D95) was compared. Eleven patients were evaluable (10 oropharynx, 1 larynx). Nine patients had evaluable primary tumor GTVs and seven patients had evaluable nodal GTVs. Mean primary GTV-CT and GTV-PET/MRI size were 13.2 and 14.3 cc, with mean intersection 8.7 cc, DSC 0.63, and mHD 1.6 mm. D95 was 65.3 Gy for primary GTV-CT vs. 65.2 Gy for primary GTV-PET/MRI. Mean nodal GTV-CT and GTV-PET/MRI size were 19.0 and 23.0 cc, with mean intersection 14.4 cc, DSC 0.69, and mHD 2.3 mm. D95 was 62.3 Gy for both nodal GTV-CT and GTV-PET/MRI. In this series of patients with head and neck (primarily oropharynx) cancer, PET/MRI and CT-GTVs had similar volumes (though there were individual cases with larger differences) with overall small discrepancies in spatial overlap, small mean orthogonal distance differences, and similar radiation doses.


Treatment-seeking behaviour for malaria: a typology based on endemicity and gender.
A main component of current malaria control strategies to reduce malaria-related mortality and severe morbidity is early diagnosis and treatment at peripheral health services such as village health posts and dispensaries. This strategy has been promoted mainly by sensitising the population with regard to the available service offered and by providing classical biomedical descriptions of symptoms and signs of malaria. This strategy represents important challenges for successful implementation and maintenance. Early treatment depends upon prompt recognition of symptoms and signs of malaria in the household, i.e. mainly by women. Early treatment also requires that appropriate health services and medication are accessible and used. In this paper we argue that the success of malaria control depends upon an approach that is gender-sensitive and takes into account the level of endemicity in a given setting. The level of endemicity determines which group of the population is at highest risk for infection, morbidity and mortality, and is strongly related to gender considerations. The paper develops a typology that combines the key factors of gender variables with epidemiological features. It consequently outlines an approach to community-based, effective malaria control tailored to a given endemic setting. Finally, we suggest that the proposed framework could be validated for its potential application to the control of other communicable diseases.


Content and psychometric evaluations of questionnaires for assessing physical function in people with neck disorders: a systematic review of the literature.
The purpose was to investigate how physical function is assessed in people with musculoskeletal disorders (MSD) in the neck. Specifically, we aimed to determine: (1) Which questionnaires are used to assess physical function in people with MSD in the neck? (2) What do those questionnaires measure? (3) What are the measurement properties of the questionnaires? A systematic review was performed to identify questionnaires and psychometric evaluations. The content of the questionnaires was categorized according to the International Classification of Function, Disability and Health, and the psychometric properties were quality-rated using the COnsensus-based Standards for the selection of health Measurement INstruments checklist. Ten questionnaires and 32 articles evaluating measurement properties were analyzed. Most questionnaires covered only the components body functions and activity and participation, more often activity participation than body function. Internal consistency was adequate in most questionnaires, whereas responsiveness was generally low. Neck Disability Index was most evaluated, but the evaluations of all questionnaires tended to cover most properties in the checklist. The questionnaires differed substantially in items and extent to which their psychometric properties had been evaluated. Focus of measurement was on activities in daily life rather than physical function as such. Implications for Rehabilitation To provide early diagnostics and effective treatment for patients with neck disorders, valid and reliable instruments that measure relevant aspects of the disorders are needed. This paper presents an overview of content and quality of questionnaires used to assess physical function in neck disorders, which may facilitate informed decisions about which measurement instruments to use when evaluating the course of neck disorders. Most of the questionnaires need more testing to judge the quality, however the NDI was the most frequently tested questionnaire. The COnsensus-based Standards for the selection of health Measurement INstruments checklist is a useful tool in relation to psychometric testing of questionnaires, but clear definitions of interpretation of the quality criteria in each study would enhance comparability of results.


Surgical morbidities and outcomes of major salivary gland neoplasms treated at a tertiary cancer center.
Salivary gland neoplasms are relatively uncommon. They have a wide variety of histopathological types with diverse biological behavior. It involves all the major and minor salivary glands in the head and neck. This article focuses on the various types of major salivary gland tumors treated at a tertiary cancer center along with their surgical morbidities and outcomes. Data of all the salivary gland neoplasms operated in the head and neck services between January 2012 and December 2013 were retrieved from a prospectively collected database. The clinical, demographic data and types of surgeries along with the morbidities were collated from the database and the details regarding the follow-up were collected from the electronic medical record. Out of 235. cases registered, 107. patients were treated at our institute. The parotid gland was most commonly involved; majority were malignant lesions. Sixty-two patients were treatment naive at presentation. Majority presented with advanced disease. Superficial parotidectomy was the most common surgery performed and neck dissection was done in 27. patients. Facial nerve palsy was the most common complication following surgery. (16%). Sixty patients received adjuvant treatment. All patients on follow-up were alive at their last visit, with 10. patients having recurrence. Factors influencing the disease-free survival were extracapsular spread, tumor grade, and perineural invasion. The postoperative morbidities and outcomes for major salivary gland neoplasms in our series were acceptable and comparable to the results available in the literature. Appropriate treatment of the salivary gland neoplasm will yield good outcomes with acceptable morbidity.


Digital restoration of defocused images in the wavelet domain.
Many cameras nowadays are equipped with an autofocus mechanism that attempts to take pictures at the best possible focus. However, there are situations in which the pictures are still out of focus, such as when the photographer has mistakenly focused at a wrong position or when the focusing region consists of objects of different depths and therefore confuses the autofocus system. With a digital camera, we can attempt to use digital image-restoration techniques to bring the pictures back into focus. We design an algorithm that restores the image by digitally enhancing the corresponding frequency bands. We employ the restoration in the wavelet domain so that this restoration scheme can be compliant with JPEG 2000, which is positioned to succeed JPEG as the next image-compression standard and has the potential to be widely adopted by the digital photography industry owing to its many advanced features.


Procedural pain and oral glucose in preterm neonates: brain development and sex-specific effects.
Our objectives were to determine whether procedural pain and glucose exposure are associated with altered structural and functional brain development differently in preterm males and females, and neurodevelopment at 18-month corrected age. Fifty-one very preterm neonates (22 males; median [interquartile range] gestational age 27.6 [2.0] weeks) underwent 3 serial scans including T1-weighted and resting-state functional magnetic resonance imaging (MRI) at median postmenstrual weeks: 29.4, 31.9, and 41.1. Thalamus, basal ganglia, and total brain volumes were segmented. Functional resting-state MRI data were extracted from the independent-components maps. Pain was operationalized as the total number of neonatal intensive care unit-administered invasive procedures. Neurodevelopmental outcomes at 18-month corrected age were assessed with the Bayley Scales of Infant Development, second edition. Generalized estimating equations assessed the association of pain and glucose exposure with brain structural and functional development. More invasive procedures were independently associated with slower growth of thalamic (P < 0.001), basal ganglia (P = 0.028), and total brain volumes (P = 0.001), particularly in females. Similar relationships were observed between glucose exposure and brain volumes. Functional connectivity between thalamus and sensorimotor cortices was negatively associated with number of invasive procedures. Greater procedural pain and higher glucose exposure were related to poorer neurodevelopmental outcomes. These findings suggest that structural and functional brain development is vulnerable to procedural pain. Glucose used for analgesia does not appear to mitigate the adverse impact of pain on brain development. The vulnerability of brain development in females towards early pain is distinct from other neonatal morbidities. The link between pain and glucose with neurodevelopment suggests that these factors have long-lasting impact.


The Novelty of Inhalable Medications: Interest, Use, and Impact of Inhalant Medications in Low-Resource Settings.
Postpartum haemorrhage (PPH) claims more than 100,000 maternal lives annually worldwide, most of them in low-resource settings. To address morbidity and mortality from PPH, the global health community is exploring novel drug formulations, such as inhalable medicine, to improve treatment availability and use, especially in community settings with limited access to skilled birth attendants. A major limitation in the ability to prevent or treat PPH in resource-limited settings is that the most effective medications for prevention and treatment are injectables, which require administration by skilled birth attendants. We conducted formative research, including online surveys and in-person interviews, with a range of providers across a variety of health-care settings in Guatemala, Indonesia, Kenya, and Nigeria, to better understand the standard of care for mothers and newborns in low-resource settings, including care practices related to PPH. It is estimated that up to 40% of PPH deaths could be averted if an inhalable prevention and treatment were available. However, survey and interview respondents noted a desire for more intravenous and oral medicinal formulations over inhalable formulations. Lack of knowledge and use of inhalable medicines among these health workers illuminates key challenges to introducing novel formulations in low-resource settings.


High [Ca2+]o-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium. Phase 2 reentry.
Elevated intracellular calcium activity is thought to play an important role in arrhythmia induction, particularly during ischemia and reperfusion. Delayed after-depolarization-induced triggered activity and intracellular communication problems are thought to be responsible. Increased extracellular calcium levels and rapid pacing are interventions known to elevate intracellular calcium activity. The present study, conducted using standard microelectrode techniques, was designed to compare the effects of increased [Ca2+]o (1.8 to 5.4 mmol/L) in isolated canine ventricular epicardial and endocardial tissues and to test the hypothesis that elevated intracellular calcium activity contributes to arrhythmogenesis in working ventricular myocardial tissues by promoting electrical heterogeneity. High [Ca2+]o caused a slight abbreviation of action potential duration (APD90) in endocardium but more dramatic rate-dependent and dynamic changes in epicardium. Under steady-state conditions, epicardium displayed a marked abbreviation of APD90 at fast rates but no significant changes at slow rates. A significant augmentation of phase 1 was evident at the faster stimulation rates. Vmax and conduction velocity were only slightly reduced. The marked abbreviation of the epicardial response at the factor rates was due to loss of the action potential dome. Recovery of the dome after deceleration was not synchronous throughout the preparation. As a consequence, a sudden slowing of rate caused marked dispersion of repolarization among neighboring epicardial sites, giving rise to ectopic activity via a phase 2 reentry mechanism. These effects of high [Ca2+]o were mimicked by exposure of the preparations to low [Na+]o. Electrical homogeneity was restored and arrhythmias were abolished after addition of the Ito blocker 4-aminopyridine 1 mmol/L. 4-Aminopyridine also eliminated the differential response of epicardium and endocardium to high [Ca2+]o. Our data demonstrate the induction of marked electrical heterogeneity and reentrant activity by high [Ca2+]o and rapid stimulation, conditions known to elevate [Ca2+]i. The results suggest that increased intracellular calcium activity, as occurs during ischemia and reperfusion, may contribute to the development of electrical inhomogeneity in the ventricle and thus to the genesis of ventricular arrhythmias through a mechanism other than triggered activity, namely, phase 2 reentry. Our data point to an increase in net outward current as the underlying mechanism for the calcium-induced changes. Our results also suggest that the presence of a prominent transient outward current (Ito) in epicardium sensitizes that tissue to the effects of high calcium. Finally, the results suggest that Ito blockers can reverse high calcium-induced electrical heterogeneity and thus can exert antiarrhythmic actions.


Reliability, Validity, and Factor Structure of the Hopkins Symptom Checklist-25: Population-Based Study of Persons Living with HIV in Rural Uganda.
Depression and anxiety are highly comorbid among people living with HIV (PLHIV), but few instruments for screening or measurement have been validated for use in sub-Saharan Africa. The objective of this study was to determine the reliability, validity, and factor structure of the 25-item Hopkins Symptom Checklist (HSCL) in a population-based sample of PLHIV in rural Uganda. This study was nested within an ongoing population-based cohort of all residents living in Nyakabare Parish, Mbarara District, Uganda. All participants who identified as HIV-positive by self-report were included in this analysis. We performed parallel analysis on the scale items and estimated the internal consistency of the identified sub-scales using ordinal alpha. To assess construct validity we correlated the sub-scales with related constructs, including subjective well being (happiness), food insecurity, and health status. Of 1814 eligible adults in the population, 158 (8.7%) self-reported being HIV positive. The mean age was 41 years, and 68% were women. Mean HSCL-25 scores were higher among women compared with men (1.71 vs. 1.44; t = 3.6, P < 0.001). Parallel analysis revealed a three-factor structure that explained 83% of the variance: depression (7 items), anxiety (5 items), and somatic symptoms (7 items). The ordinal alpha statistics for the sub-scales ranged from 0.83 to 0.91. Depending on the sub-scale, between 27 and 41% of the sample met criteria for caseness. Strong evidence of construct validity was shown in the estimated correlations between sub-scale scores and happiness, food insecurity, and self-reported overall health. The HSCL-25 is a reliable and valid measure of mental health among PLHIV in rural Uganda. In cultural contexts where somatic complaints are commonly elicited when screening for symptoms of depression, it may be undesirable to exclude somatic items from depression symptom checklists administered to PLHIV.


Attentional and cognitive monitoring brain networks in long-term meditators depend on meditation states and expertise.
Meditation practice is suggested to engage training of cognitive control systems in the brain. To evaluate the functional involvement of attentional and cognitive monitoring processes during meditation, the present study analysed the electroencephalographic synchronization of fronto-parietal (FP) and medial-frontal (MF) brain networks in highly experienced meditators during different meditation states (focused attention, open monitoring and loving kindness meditation). The aim was to assess whether and how the connectivity patterns of FP and MF networks are modulated by meditation style and expertise. Compared to novice meditators, (1) highly experienced meditators exhibited a strong theta synchronization of both FP and MF networks in left parietal regions in all mediation styles, and (2) only the connectivity of lateralized beta MF networks differentiated meditation styles. The connectivity of intra-hemispheric theta FP networks depended non-linearly on meditation expertise, with opposite expertise-dependent patterns found in the left and the right hemisphere. In contrast, inter-hemispheric FP connectivity in faster frequency bands (fast alpha and beta) increased linearly as a function of expertise. The results confirm that executive control systems play a major role in maintaining states of meditation. The distinctive lateralized involvement of FP and MF networks appears to represent a major functional mechanism that supports both generic and style-specific meditation states. The observed expertise-dependent effects suggest that functional plasticity within executive control networks may underpin the emergence of unique meditation states in expert meditators.


Study of transient deformations with pulsed TV holography: application to crack detection.
We report the measurement of reproducible transient deformations with single-pulsed-subtraction and double-pulsed-addition TV holography with both in-plane and out-of-plane optical configurations. An original synchronization system (controlling mechanical excitation of the object, firing the laser pulses, and image acquisition) used to obtain the subtraction and the addition correlation fringes is described. Experimental results are presented for the propagation of mechanical shock waves in a cantilever specimen and their subsequent diffraction by a crack in the specimen. These preliminary results show that the technique may be used for crack detection.


Serum Levels of Melatonin and Oxidative Stress Markers and Correlation between Them in Infertile Men.
Infertility is the problem of 15% of young couples in different societies. One of the factors that could affect fertility is oxidative stress. Therefore, the aim of the present study is to investigate the level of Melatonin, a free radical scavenger, and its correlation with oxidative biomarkers in infertile men. For this purpose, fertile and infertile men in 2 groups, 30 people in each group, were studied. The fertile men were selected from husbands of patients admitted to Alzahra obstetric and gynecology hospital, according to WHO standards. The infertile men were selected from patients referred to infertility ward. Blood sampling from the participants carried out at a specific time, sera collected and the levels of malondialdehyde, total antioxidant capacity and Melatonin were detected in the sera. The data were analyzed using t-test and Sperman's correlation method. Melatonin level in the sera from fertile men were 522 (39.32) ng/L and in infertile men were 511.78 (34.6) ng/L. MDA level in fertile and infertile men were 2.26 (0.34) vs 2.99 (0.44) nmol/ml which was significantly different. The level of TAC in the sera from fertile men were significantly higher than in infertile men. The result obtained for correlation coefficient Spearman's test revealed a significant, strong and direct correlation between Melatonin and TAC and a significant and reverse correlation between melatonin and MDA. It is concluded that melatonin could be involved in infertility. In other word, melatonin treatment and antioxidant-rich nutrition could help fertility by combating oxidative stress.


Single-cell analysis of population context advances RNAi screening at multiple levels.
Isogenic cells in culture show strong variability, which arises from dynamic adaptations to the microenvironment of individual cells. Here we study the influence of the cell population context, which determines a single cell's microenvironment, in image-based RNAi screens. We developed a comprehensive computational approach that employs Bayesian and multivariate methods at the single-cell level. We applied these methods to 45 RNA interference screens of various sizes, including 7 druggable genome and 2 genome-wide screens, analysing 17 different mammalian virus infections and four related cell physiological processes. Analysing cell-based screens at this depth reveals widespread RNAi-induced changes in the population context of individual cells leading to indirect RNAi effects, as well as perturbations of cell-to-cell variability regulators. We find that accounting for indirect effects improves the consistency between siRNAs targeted against the same gene, and between replicate RNAi screens performed in different cell lines, in different labs, and with different siRNA libraries. In an era where large-scale RNAi screens are increasingly performed to reach a systems-level understanding of cellular processes, we show that this is often improved by analyses that account for and incorporate the single-cell microenvironment.


Extracting gene expression patterns and identifying co-expressed genes from microarray data reveals biologically responsive processes.
A common observation in the analysis of gene expression data is that many genes display similarity in their expression patterns and therefore appear to be co-regulated. However, the variation associated with microarray data and the complexity of the experimental designs make the acquisition of co-expressed genes a challenge. We developed a novel method for Extracting microarray gene expression Patterns and Identifying co-expressed Genes, designated as EPIG. The approach utilizes the underlying structure of gene expression data to extract patterns and identify co-expressed genes that are responsive to experimental conditions. Through evaluation of the correlations among profiles, the magnitude of variation in gene expression profiles, and profile signal-to-noise ratio's, EPIG extracts a set of patterns representing co-expressed genes. The method is shown to work well with a simulated data set and microarray data obtained from time-series studies of dauer recovery and L1 starvation in C. elegans and after ultraviolet (UV) or ionizing radiation (IR)-induced DNA damage in diploid human fibroblasts. With the simulated data set, EPIG extracted the appropriate number of patterns which were more stable and homogeneous than the set of patterns that were determined using the CLICK or CAST clustering algorithms. However, CLICK performed better than EPIG and CAST with respect to the average correlation between clusters/patterns of the simulated data. With real biological data, EPIG extracted more dauer-specific patterns than CLICK. Furthermore, analysis of the IR/UV data revealed 18 unique patterns and 2661 genes out of approximately 17,000 that were identified as significantly expressed and categorized to the patterns by EPIG. The time-dependent patterns displayed similar and dissimilar responses between IR and UV treatments. Gene Ontology analysis applied to each pattern-related subset of co-expressed genes revealed underlying biological processes affected by IR- and/or UV- induced DNA damage. EPIG competed with CLICK and performed better than CAST in extracting patterns from simulated data. EPIG extracted more biological informative patterns and co-expressed genes from both C. elegans and IR/UV-treated human fibroblasts. Using Gene Ontology analysis of the genes in the patterns extracted by EPIG, several key biological categories related to p53-dependent cell cycle control were revealed from the IR/UV data. Among them were mitotic cell cycle, DNA replication, DNA repair, cell cycle checkpoint, and G0-like status transition. EPIG can be applied to data sets from a variety of experimental designs.


Novel technique for three-dimensional visualisation and quantification of deformable, moving soft-tissue body parts.
Three-dimensional (3D) imaging of delicate, moving soft-tissue body parts is very difficult. Our understanding of the muscles that control lip movements is based largely on histological and cadaveric studies, which provide scant information about dynamic morphology. Our aim was to develop an innovative scanning technique for the imaging and reconstruction of dynamic orofacial morphology by use of 3D and four-dimensional (4D, ie, 3D plus time) ultrasonography. Four volunteers (including one patient) underwent ultrasonography with 3D/4D imaging systems. To avoid deformation of the delicate orofacial structures, a water bath with an acoustic window was devised. The orofacial part was immersed in the bath throughout scanning, and a timer was used to synchronize lip movements with the 4D scan. 4D views showed the functional differences in superficial and deep muscle groups of the lips, and clearly showed the changes occurring with movement of the lips and mouth. In the patient, a pathological layer and its extension corresponding to surface malformation were clearly identified. We have developed a prototype device that has made possible 3D and 4D examination of orofacial anatomy and function. With further refinement of the device and improvement in 4D acquisition timing, this technique may offer a new way of dynamically imaging and quantifying many soft-tissue parts in 3D without deforming structure or disturbing function.


DOG1 regulates growth and IGFBP5 in gastrointestinal stromal tumors.
Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor α(PDGFRA), which can be therapeutically targeted by tyrosine kinase inhibitors (TKI) such as imatinib. Despite long-lasting responses, most patients eventually progress after TKI therapy. The calcium-dependent chloride channel DOG1 (ANO1/TMEM16A), which is strongly and specifically expressed in GIST, is used as a diagnostic marker to differentiate GIST from other sarcomas. Here, we report that loss of DOG1 expression occurs together with loss of KIT expression in a subset of GIST resistant to KIT inhibitors, and we illustrate the functional role of DOG1 in tumor growth, KIT expression, and imatinib response. Although DOG1 is a crucial regulator of chloride balance in GIST cells, we found that RNAi-mediated silencing or pharmacologic inhibition of DOG1 did not alter cell growth or KIT signaling in vitro. In contrast, DOG1 silencing delayed the growth of GIST xenografts in vivo. Expression profiling of explanted tumors after DOG1 blockade revealed a strong upregulation in the expression of insulin-like growth factor-binding protein 5 (IGFBP5), a potent antiangiogenic factor implicated in tumor suppression. Similar results were obtained after selection of imatinib-resistant DOG1- and KIT-negative cells derived from parental DOG1 and KIT-positive GIST cells, where a 5,000-fold increase in IGFBP5 mRNA transcripts were documented. In summary, our findings establish the oncogenic activity of DOG1 in GIST involving modulation of IGF/IGF receptor signaling in the tumor microenvironment through the antiangiogenic factor IGFBP5.


Noninvasive, accurate assessment of the behavior of representative populations of motor units in targeted reinnervated muscles.
Targeted muscle reinnervation (TMR) redirects nerves that have lost their target, due to amputation, to remaining muscles in the region of the stump with the intent of establishing intuitive myosignals to control a complex prosthetic device. In order to directly recover the neural code underlying an attempted limb movement, in this paper, we present the decomposition of high-density surface electromyographic (EMG) signals detected from three TMR patients into the individual motor unit spike trains. The aim was to prove, for the first time, the feasibility of decoding the neural drive that would reach muscles of the missing limb in TMR patients, to show the accuracy of the decoding, and to demonstrate the representativeness of the pool of extracted motor units. Six to seven flexible EMG electrode grids of 64 electrodes each were mounted over the reinnervated muscles of each patient, resulting in up to 448 EMG signals. The subjects were asked to attempt elbow extension and flexion, hand open and close, wrist extension and flexion, wrist pronation and supination, of their missing limb. The EMG signals were decomposed using the Convolution Kernel Compensation technique and the decomposition accuracy was evaluated with a signal-based index of accuracy, called pulse-to-noise ratio (PNR). The results showed that the spike trains of 3 to 27 motor units could be identified for each task, with a sensitivity of the decomposition > 90%, as revealed by PNR. The motor unit discharge rates were within physiological values of normally innervated muscles. Moreover, the detected motor units showed a high degree of common drive so that the set of extracted units per task was representative of the behavior of the population of active units. The results open a path for a new generation of human-machine interfaces in which the control signals are extracted from noninvasive recordings and the obtained neural information is based directly on the spike trains of motor neurons.


Impact of positive positron emission tomography on prediction of freedom from progression after Stanford V chemotherapy in Hodgkin's disease.
To correlate [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) status after chemotherapy, but before radiation, with outcome in patients treated with the Stanford V regimen. We analyzed retrospectively 81 patients with Hodgkin's disease who had serial [(18)F]FDG-PET scans performed at baseline and again at the completion of Stanford V chemotherapy, before planned radiotherapy. Patients with favorable stage I/II (nonbulky mediastinal disease) and those with bulky mediastinal disease or stage III/IV were scanned after 8 and 12 weeks of chemotherapy, respectively. Radiotherapy fields were determined before starting chemotherapy based on baseline computed tomography scans. After chemotherapy, six of 81 patients had residual [(18)F]FDG-PET-positive sites, all in sites for which radiotherapy was planned. Four of the six patients with positive [(18)F]FDG-PET scans after chemotherapy experienced relapse compared with just three of 75 patients with negative [(18)F]FDG-PET scans. At a median follow-up of 4 years, the freedom from progression (FFP) was 96% in postchemotherapy [(18)F]FDG-PET-negative patients versus 33% in [(18)F]FDG-PET-positive patients (P < .0003). In a bivariate Cox model, [(18)F]FDG-PET positivity after chemotherapy remained a highly significant predictor of progression-free survival even after controlling for bulky disease and International Prognostic Score more than 2. These data indicate that PET status after chemotherapy is strongly predictive of FFP with the Stanford V regimen despite the use of consolidative radiotherapy. These results have implications for the design of clinical trials adapted to functional imaging.


Length of Stay After Childbirth in 92 Countries and Associated Factors in 30 Low- and Middle-Income Countries: Compilation of Reported Data and a Cross-sectional Analysis from Nationally Representative Surveys.
Following childbirth, women need to stay sufficiently long in health facilities to receive adequate care. Little is known about length of stay following childbirth in low- and middle-income countries or its determinants. We described length of stay after facility delivery in 92 countries. We then created a conceptual framework of the main drivers of length of stay, and explored factors associated with length of stay in 30 countries using multivariable linear regression. Finally, we used multivariable logistic regression to examine the factors associated with stays that were "too short" (<24 h for vaginal deliveries and <72 h for cesarean-section deliveries). Across countries, the mean length of stay ranged from 1.3 to 6.6 d: 0.5 to 6.2 d for singleton vaginal deliveries and 2.5 to 9.3 d for cesarean-section deliveries. The percentage of women staying too short ranged from 0.2% to 83% for vaginal deliveries and from 1% to 75% for cesarean-section deliveries. Our conceptual framework identified three broad categories of factors that influenced length of stay: need-related determinants that required an indicated extension of stay, and health-system and woman/family dimensions that were drivers of inappropriately short or long stays. The factors identified as independently important in our regression analyses included cesarean-section delivery, birthweight, multiple birth, and infant survival status. Older women and women whose infants were delivered by doctors had extended lengths of stay, as did poorer women. Reliance on factors captured in secondary data that were self-reported by women up to 5 y after a live birth was the main limitation. Length of stay after childbirth is very variable between countries. Substantial proportions of women stay too short to receive adequate postnatal care. We need to ensure that facilities have skilled birth attendants and effective elements of care, but also that women stay long enough to benefit from these. The challenge is to commit to achieving adequate lengths of stay in low- and middle-income countries, while ensuring any additional time is used to provide high-quality and respectful care.


ENDOPLASMIC RETICULUM STRESS IN SEPSIS.
Sepsis is an enormous public health issue and the leading cause of death in critically ill patients in intensive care units. Overwhelming inflammation, characterized by cytokine storm, oxidative threats, and neutrophil sequestration, is an underlying component of sepsis-associated organ failure. Despite recent advances in sepsis research, there is still no effective treatment available beyond the standard of care and supportive therapy. To reduce sepsis-related mortality, a better understanding of the biological mechanism associated with sepsis is essential. Endoplasmic reticulum (ER), a subcellular organelle, is responsible for the facilitation of protein folding and assembly and involved in several other physiological activities. Under stress and inflammatory conditions, ER loses homeostasis in its function, which is termed ER stress. During ER stress, unfolded protein response (UPR) is activated to restore ER function to its normal balance. However, once stress is beyond the compensatory capacity of UPR or protracted, apoptosis would be initiated by triggering cell injuries, even cell death. As such, ER stress and UPR are reported to be implicated in several pathological and inflammatory conditions. Although the detrimental role of ER stress during infections has been demonstrated, there is growing evidence that ER stress participates in the pathogenesis of sepsis. In this review, we summarize current research in the context of ER stress and UPR signaling associated with sepsis and its related clinical conditions, such as trauma-hemorrhage and ischemia/reperfusion injury. We also discuss the potential implications of ER stress as a novel therapeutic target and prognostic marker in patients with sepsis.


Design analysis of a fiber-bundle-based mobile free-space optical link with wavelength diversity.
This paper reports on a simulation-based investigation of a wavelength diverse free-space optical link with an emphasis on identifying design choices that optimize the performance of the system under different operating scenarios. The simulation incorporates experimental data into the theoretical calculations for optical propagation to better describe the performance of the physical designs. The performance is evaluated in terms of the coverage area at the receiver, which is a measure of misalignment tolerance and is dependent not only on wavelength but on other key parameters, such as link length, transmitted power, the pattern of transmitters, beam divergence, and the receiver construction. The investigation finds that the coverage area of the receiver can be optimized for a given wavelength by proper choices of these parameters, and that parameter choices exist that minimize the change in performance when switching between wavelengths or for variations in link parameters. The interrelationships among key parameters and their impact on the potential system performance are investigated. The results provide guidance on the further development of the overall system.