Effects of community health worker interventions on socioeconomic inequities in maternal and newborn health in low-income and middle-income countries: a mixed-methods systematic review.
Community health worker (CHW) interventions are promoted to improve maternal and newborn health in low-income and middle-income countries. We reviewed the evidence on their effectiveness in reducing socioeconomic inequities in maternal and newborn health outcomes, how they achieve these effects, and contextual processes that shape these effects. We conducted a mixed-methods systematic review of quantitative and qualitative studies published between 1996 and 2017 in Medline, Embase, Web of Science and Scopus databases. We included studies examining the effects of CHW interventions in low-income and middle-income countries on maternal and newborn health outcomes across socioeconomic groups (wealth, occupation, education, class, caste or tribe and religion). We then conducted a narrative synthesis of evidence. We identified 1919 articles, of which 22 met the inclusion criteria. CHWs facilitated four types of interventions: home visits, community-based groups, cash transfers or combinations of these. Four studies found that CHWs providing home visits or facilitating women's groups had equitable coverage. Four others found that home visits and cash transfer interventions had inequitable coverage. Five studies reported equitable effects of CHW interventions on antenatal care, skilled birth attendance and/or essential newborn care. One study found that a CHW home visit intervention did not reduce wealth inequities in skilled birth attendance. A study of women's groups reported greater reductions in neonatal mortality among lower compared with higher socioeconomic groups. Equity was most improved when CHWs had relevant support for assisting women to improve health practices and access health care within community contexts. While current evidence remains limited, particularly for mortality, existing studies suggest that CHW interventions involving home visits, cash transfers, participatory women's groups or multiple components can improve equity in maternal and newborn health. Future mixed-methods research should explore intervention strategies and contextual processes shaping such effects on equity to optimise these efforts.


Validity of fluorescent microspheres method for bone blood flow measurement during intentional arterial hypotension.
In this study, we compared bone blood flow values obtained by simultaneously injected fluorescent (FM) and radiolabeled microspheres (RM) at stepwise reduced arterial blood pressure. Ten anesthetized female New Zealand White rabbits received simultaneous left ventricular injections of FM and RM at 90, 70, and 50 mmHg mean arterial blood pressure (MAP). After the experiments, both kidneys and long bones of all four limbs were removed and dissected in a standardized manner. Radioactivity (corrected for decay, background, and spillover) and fluorescence were determined, and blood flow values were calculated. Relative blood flow values estimated for each bone sample by RM and FM were significantly correlated (r = 0.98, slope = 0.99, and intercept = 0.04 for 90 mmHg; r = 0.98, slope = 0.94, and intercept = 0.09 for 70 mmHg; r = 0.98, slope = 0.96, and intercept = 0.07 for 50 mmHg). Blood flow values (ml x min-1 x 100 g-1) of right and left bone samples determined at the different arterial blood pressures were identical. During moderate hypotension (70 mmHg MAP), blood flow in all bone samples remained unchanged compared with 90 mmHg MAP, whereas a significant decrease of bone blood flow was observed at severe hypotension (50 mmHg MAP). Our results demonstrate that the FM technique is valid for measuring bone blood flow. Differences in bone blood flow during altered hemodynamic conditions can be detected reliably. In addition, changes in bone blood flow during hypotension indicate that vasomotor control mechanisms, as well as cardiac output, play a role in setting bone blood flow.


Use of sodium dodecyl sulfate pretreatment and 2-stage curing for improved quality of salted duck eggs.
The effects of use of sodium dodecyl sulfate (SDS) pretreatment and 2-stage curing on the microbial, physicochemical, and microstructural qualities of salted duck eggs were studied. After pretreatment in 0.5% (w/v) SDS solution at room conditions for 15 min, no discolorations were observed and no microorganisms were detected on the egg shells. In the 2-stage curing process, 25% (w/v) and 30% (w/v) saline solutions were evaluated in the 1st step (Stage I, approximately 18 d), whereas 4% (w/v) saline solution was applied in the 2nd step (Stage II, approximately 15 d). Along with increased curing time, water content decreased and NaCl content increased in the egg yolks from approximately 0.40% to 0.86%, whereas the water content of egg albumen remained at approximately 85% during the 2-stage curing. More importantly, the NaCl content of albumen maintained at approximately 4.0% at Stage II curing. Yolk index as a sign of maturity for salted duck eggs reached 1 at the end of Stage I (18 d) and retained the same value during Stage II curing regardless of the NaCl concentration in the Stage I saline solution. Oil exudation in egg yolks increased as the time of curing increased. As seen from scanning electron microscopy, oil was released from yolk granules. This study indicated that SDS pretreatment is effective to reduce microbial load on the shells of fresh duck eggs and the 2-stage curing can improve physicochemical qualities of the salted duck eggs and shortened curing time to about 7 to 17 d as compared to the traditional 1-step curing method. Spoiled saline solution and uneven distribution of salt are the 2 major problems in producing salted duck eggs. Sodium dodecyl sulfate (SDS) pretreatment and 2-stage curing process have shown effective to solve these problems, respectively. The SDS pretreatment was able to remove microorganisms and soil from the surface of fresh egg shells, thus preventing the spoilage of the saline solution. The 2-stage curing process successfully controlled the NaCl content of egg albumen and yolk in the final product, and shortened the curing time compared to the traditional 1-step curing method.


Functional magnetic resonance imaging studies of emotional processing in normal and depressed patients: effects of venlafaxine.
Functional magnetic resonance imaging (fMRI) techniques were used to identify the neural circuitry underlying emotional processing in control and depressed subjects. Depressed subjects were studied before and after treatment with venlafaxine. This new technique provides a method to noninvasively image regional brain function with unprecedented spatial and temporal resolution. Echo-planar imaging was used to acquire whole brain images while subjects viewed positively and negatively valenced visual stimuli. Two control subjects and two depressed subjects who met DSM-IV criteria for major depression were scanned at baseline and 2 weeks later. Depressed subjects were treated with venlafaxine after the baseline scan. Preliminary results from this ongoing study revealed three interesting trends in the data. Both depressed patients demonstrated considerable symptomatic improvement at the time of the second scan. Across control and depressed subjects, the negative compared with the positive pictures elicited greater global activation. In both groups, activation induced by the negative pictures decreased from the baseline scan to the 2-week scan. This decrease in activation was also present in the control subjects when they were exposed to the positive pictures. In contrast, when the depressed subjects were presented with the positive pictures they showed no activation at baseline, whereas after 2 weeks of treatment an area of activation emerged in right secondary visual cortex. While preliminary, these results demonstrate the power of using fMRI to study emotional processes in normal and depressed subjects and to examine mechanisms of action of antidepressant drugs.


Effect of royal jelly ingestion for six months on healthy volunteers.
Royal jelly is a widely ingested supplement for health, but its effects on humans are not well known. The objective was to evaluate the effects of long-term royal jelly ingestion on humans. We conducted a randomized placebo-controlled, double-blind trial. A total of 61 healthy volunteers aged 42-83 years were enrolled and were randomly divided into a royal jelly group (n = 31) and a control group (n = 30). Three thousand mg of royal jelly (RJ) or a placebo in 100 ml liquid/day were ingested for 6 months. The primary outcomes were changes in anthropometric measurements and biochemical indexes from baseline to 6 months after intervention. Thirty subjects in the RJ group and 26 in the control group were included in the analysis of endpoints. In an adjusted mean change of the variables from the baseline, significant differences between the two groups could be found in red blood cell counts (+0.16x10⁶/μL for the RJ group vs. -0.01x10⁶/μL for the control group, P = 0.0134), hematocrit (+0.9% vs. -0.8%, P = 0.0251), log (fasting plasma glucose) (+0.01 ± 0.01 log mg/dL vs. +0.05 ± 0.01 log mg/dL, P = 0.0297), log (insulinogenic index) (+0.25 vs. -0.13, P = 0.0319), log dehydroepiandrosterone sulfate (DHEA-S) (+0.08 log μg/dL vs. +0.20 log μg/dL, P = 0.0483), log testosterone (T) (+0.12 ± 0.04 log ng/mL vs. -0.02 ± 0.05 log ng/mL, P = 0.0416), log T/DHEA-S ratio (+0.05 ± 0.05 vs. -0.23 ± 0.59, P = 0.0015), and in one of the SF-36 subscale scores, mental health (MH) (+4 vs. -7, P = 0.0276). Six-month ingestion of RJ in humans improved erythropoiesis, glucose tolerance and mental health. Acceleration of conversion from DHEA-S to T by RJ may have been observed among these favorable effects.


Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production.
Estrogen appears to play a central role in the immune response and immune-mediated diseases. Estrogen receptors are expressed in a variety of immunocompetent cells, including CD4(+) and CD8(+) T cells and macrophages. Clinical observations indicate that some autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, frequently remit during pregnancy but exacerbate, or have their onset during the postpartum period. Pharmacological levels of estrogen also appear to ameliorate certain autoimmune diseases. In addition, estrogen is known to suppress certain infectious diseases, as well as T cell-mediated responses toward oxazolone, keyhol lympet hemocyanin, Listeria soluble protein and purified protein derivatives. The immune basis for these phenomena is poorly understood. Based on a distinctive profile of cytokine production, data accumulated thus far have revealed modulatory effects for estrogen on the TH1-type and TH2-type cells, which represent two polarized forms of the effector specific immune response. Recent evidence indicates that estrogens inhibit the production of TH1 proinflammatory cytokines, such as IL-12, TNF-alpha and IFN-gamma, whereas they stimulate the production of TH2 anti-inflammatory cytokines, such as IL-10, IL-4, and TGF-beta. This can explain why estrogen suppresses and potentiates TH1- and TH2-mediated diseases, respectively. We hypothesize that exacerbation or suppression of inflammatory diseases by estrogen is mediated by skewing TH1-type to TH2-type response. This view represents a novel mechanism for the modulatory effect of estrogen on certain inflammatory diseases that can lead to beneficial or detrimental impacts depending on the type of immune involved. Such a concept is valuable when considering the application of combination therapies that include estrogen.


Practical genetics of colorectal cancer.
Hereditary colorectal cancer (CRC) is highly heterogeneous, both genotypically and phenotypically. The most frequently occurring hereditary colorectal cancer syndrome is Lynch syndrome, accounting for approximately 3% of the total colorectal cancer burden. Polyposis syndromes, such as familial adenomatous polyposis, account for a lesser percentage. Familial colorectal cancer, defined by family history, occurs in an estimated 20% of all colorectal cancer cases. With a worldwide annual colorectal cancer incidence of over one million, and annual mortality of over 600,000, hereditary and familial forms of colorectal cancer are a major public health problem. Lynch syndrome is attributable to DNA mismatch repair germline mutations, with the MSH2, MLH1, MSH6, and PMS2 genes being implicated. The characteristics of Lynch syndrome-associated colorectal tumors, including early age of onset and predilection to the proximal colon, mandate surveillance by colonoscopy beginning by age 20 to 25 and repeated every other year through age 40 and annually thereafter. Besides colorectal cancer, Lynch syndrome also predisposes to a litany of extracolonic cancers, foremost of which is endometrial cancer, followed by cancer of the ovary, stomach, renal pelvis and ureter, small bowel, hepatobiliary tract, pancreas, glioblastoma multiforme in the Turcot's variant, and sebaceous skin tumors in the Muir-Torre variant and, more recently identified, cancers of the breast and prostate. The most common polyposis syndrome is familial adenomatous polyposis, caused by mutations in the APC gene. Affected individuals have multiple colonic adenomas and, without treatment invariably develop colorectal cancer. Colonic surveillance with polypectomy may be pursued until the appearance of multiple colonic adenomas, at which time prophylactic colectomy should be considered. Extra-intestinal manifestations include desmoid tumor, hepatoblastoma, thyroid carcinoma, and medulloblastoma. Other polyposis syndromes include the hamartomatous polyp syndromes, including juvenile polyposis syndrome, Peutz-Jeghers syndrome, Cowden syndrome, and Bannayan-Ruvalcaba-Riley syndrome.


17-Acet-oxy-mulinic acid.
THE TITLE COMPOUND, [SYSTEMATIC NAME: 5a-acet-oxy-methyl-3-isopropyl-8-methyl-1,2,3,3a,4,5,5a,6,7,10,10a,10b-dodeca-hydro-7,10-endo-epidi-oxy-cyclo-hepta-[e]indene-3a-carb-oxy-lic acid], C(22)H(32)O(6) (I), is closely related to methyl 5a-acet-oxy-methyl-3-isopropyl-8-methyl-1,2,3,3a,4,5,5a,6,7,10,10a,10b-dodeca-hydro-7,10-endo-epidi-oxy-cyclo-hepta-[e]indene-3a-carboxyl-ate, (II) [Brito et al., (2008 ▶). Acta Cryst. E64, o1209]. There are two mol-ecules in the asymmetric unit, which are linked by two strong intra-molecular O-H⋯O hydrogen bonds with graph-set motif R(2) (2)(8). In both (I) and (II), the conformation of the three fused rings are almost identical. The five-membered ring has an envelope conformation, the six-membered ring has a chair conformation and the seven-membered ring has a boat conformation. The most obvious differences between the two compounds is the observed disorder of the acet-oxy-methyl fragments in both mol-ecules of the asymmetric unit of (I). This disorder is not observed in (II). The crystal structure and the molecular conformation is stabilized by intermolecular C-H⋯O hydrogen bonds. The ability to form hydrogen bonds is different in the two compounds. The crystal studied was a non-merohedral twin, the ratio of the twin components being 0.28 (1):0.72 (1).


Stimulation of groups III and IV phrenic afferents reflexly decreases total lung resistance in dogs.
Little is known about the reflex effect on airway caliber evoked by stimulation of phrenic afferents. Therefore, in chloralose-anesthetized, paralyzed dogs, we recorded airflow, airway pressure, arterial pressure, and heart rate while electrically stimulating a phrenic nerve. Total lung resistance was calculated breath by breath. The phrenic nerve was stimulated at 3, 5, 20, 70, 140, and 200 times motor threshold and the compound action potential was recorded. Stimulation of the phrenic nerve at three and five times threshold, which activated groups I, II, and a few group III fibers, had no effect on any of the variables measured. Stimulation at 20 times threshold, which activated many group III fibers and groups I and II fibers, reflexly decreased resistance. Stimulation at 70, 140, and 200 times threshold, which activated groups I-IV fibers, evoked progressively greater decreases in lung resistance. The reflex bronchodilation evoked by phrenic nerve stimulation was unaffected by propranolol or phentolamine but was abolished by atropine. We conclude that activation of groups III and IV phrenic nerve afferents reflexly decreased total lung resistance by withdrawing cholinergic tone to airway smooth muscle.


Borrelia burgdorferi-Induced Changes in the Class II Self-Immunopeptidome Displayed on HLA-DR Molecules Expressed by Dendritic Cells.
The MHC class II antigen processing and presentation pathway has evolved to derive short amino acid peptides from proteins that enter the endocytic pathway, load them onto MHC class II molecules and display them on the surface of antigen presenting cells for recognition by CD4+ T cells. Under normal circumstances, peptides bound to MHC class II molecules are derived from host (self) proteins and not recognized by T cells due to tolerance mechanisms. Pathogens induce significant changes in the biology of antigen presenting cells, including upregulation of MHC processing and presentation. We therefore hypothesized that exposure to pathogens may alter the repertoire of self-peptides bound to MHC class II molecules. To test this hypothesis, we isolated monocyte-derived dendritic cells from healthy subjects, exposed them to the TLR-2 agonist lipoteichoic acid or live Borrelia burgdorferi, the causative agent of Lyme disease, and isolated and characterized HLA-DR associated peptides using mass spectrometry. Our results show that lipoteichoic acid-stimulated, B. burgdorferi-stimulated and unstimulated monocyte-derived dendritic cells largely derive their self-peptides from similar overlapping sets of host proteins. However, lipoteichoic acid and B. burgdorferi stimulation promote the processing and presentation of new sets of HLA-DR associated self-peptides derived from unique protein sources. Examination of processes and compartments these proteins reside in, indicate that activation of monocyte-derived dendritic cells changes the range of host self-proteins available for processing and presentation on MHC class II molecules. These findings reveal that the HLA-DR-bound self-immunopeptidome presented by mo-DCs is dynamic in nature and changes with activation state reflective of cellular function. In addition, among the repertoire of self-peptides bound to HLA-DR are several epitopes known to be recognized by autoreactive T cells. These studies are relevant to our basic understanding of pathogen-induced changes in monocyte-derived dendritic cell function, and the mechanisms involved in infection-induced autoimmune illnesses such as Lyme arthritis.


Mathematical modeling and application of removal functions during deterministic ion beam figuring of optical surfaces. Part 1: Mathematical modeling.
Ion beam figuring (IBF) is established for the final precision figuring of high-performance optical components, where the figuring accuracy is guaranteed by the stability of the removal function and the solution accuracy of the dwell time. In this deterministic method, the figuring process can be represented by a two-dimensional (2D) convolution operation of a constant removal function and the dwell time. However, we have found that the current 2D convolution operation cannot factually describe the IBF process of curved surfaces, which neglects the influences of the projection distortion and the workpiece geometry on the removal function. Consequently, the current 2D convolution algorithm would influence the solution accuracy for the dwell time and reduce the convergence of the figuring process. In this part, based on the material removal characteristics of IBF, a mathematical model of the removal function is developed theoretically and verified experimentally. Research results show that the removal function during IBF of a curved surface is actually a dynamic function in the 2D convolution algorithm. The mathematical modeling of the dynamic removal function provides theoretical foundations for our proposed new algorithm in the next part, and final verification experiments indicate that this algorithm can effectively improve the accuracy of the dwell time solution for the IBF of curved surfaces.


Neural correlates of individual differences in pain-related fear and anxiety.
Although individual differences in fear and anxiety modulate the pain response and may even cause more suffering than the initiating physical stimulus, little is known about the neural systems mediating this relationship. The present study provided the first examination of the neural correlates of individual differences in the tendency to (1) feel anxious about the potentially negative implications of physical sensations, as measured by the anxiety sensitivity index (ASI), and (2) fear various types of physical pain, as indexed by the fear of pain questionnaire (FPQ). In separate sessions, participants completed these questionnaires and experienced alternating blocks of noxious thermal stimulation (45-50 degrees C) and neutral thermal stimulation (38 degrees C) during the collection of whole-brain fMRI data. Regression analyses demonstrated that during the experience of pain, ASI scores predicted activation of a medial prefrontal region associated with self-focused attention, whereas FPQ scores predicted activation of a ventral lateral frontal region associated with response regulation and anterior and posterior cingulate regions associated with monitoring and evaluation of affective responses. These functional relationships cannot be wholly explained by generalized anxiety (indexed by STAI-T scores), which did not significantly correlate with activation of any regions. The present findings may help clarify both the impact of individual differences in emotion on the neural correlates of pain, and the roles in anxiety, fear, and pain processing played by medial and orbitofrontal systems.


Further immunochemical and biocatalytic characterization of CYP1A1 from feral leaping mullet liver (Liza saliens) microsomes.
CYP1A is known to play important roles in the metabolism, detoxification and bioactivation of carcinogens and other xenobiotics in animals including fish. In our laboratory, CYP1A1 was obtained in a highly purified form with a specific content of 15-17 nmol P450 per mg protein from liver microsomes of feral fish, leaping mullet (Liza saliens). Purified mullet CYP1A1 showed a very high substrate specificities for 7-ethoxyresorufin and 7-methoxyresorufin in a reconstituted system containing purified fish P450 reductase and lipid. In addition, effects of each individual components of the reconstituted system, i.e., CYP1A1 and P450 reductase on 7-methoxyresorufin O-demethylase (MROD) activity were studied. 7-ethoxyresorufin O-deethylase (EROD) activity was strongly inhibited by alpha-naphthoflavone (ANF). At 0.5 and 2.5 microM. ANF inhibited EROD activity by 90 and 98%, respectively. Mullet CYP1A1 did not catalyze monooxygenations of other substrates such as aniline, ethylmorphine, N-nitrosodimethylamine and p-nitrophenol. Antibodies produced against CYP1A1 orthologues in fish such as trout and scup showed strong cross-reactivity with the purified mullet CYP1A1. In addition, anti-L. saliens liver CYP1A1 produced in our laboratory inhibited both the EROD and MROD activities catalyzed by L. saliens liver microsomes but stronger inhibition was observed with EROD activity. On the other hand, anti-mullet CYP1A1 antibodies showed very weak cross-reactivity with two proteins (presumably CYP1A1 and CYP1A2) in 3MC-treated rat liver microsomes. Moreover, 3MC-treated rat liver microsomal EROD activity was weakly inhibited by the anti-L. saliens liver CYP1A1. These results strongly suggested that the purified mullet CYP1A1 is structurally, functionally and immunochemically similar to the CYP1A1 homologues purified from other teleost species but functionally and immunochemically distinct from mammalian CYP1A1.


Hybridization of PNA to structured DNA targets: quadruplex invasion and the overhang effect.
Peptide nucleic acid (PNA) probes have been synthesized and targeted to quadruplex DNA. UV-vis and CD spectroscopy reveal that the quadruplex structure of the thrombin binding aptamer (TBA) is disrupted at 37 degrees C by a short PNA probe. The corresponding DNA probe fails to bind to the stable secondary structure at this temperature. Thermal denaturation experiments indicate surprisingly high thermal and thermodynamic stabilities for the PNA-TBA hybrid. Our results point to the nonbonded nucleobase overhangs on the DNA as being responsible for this stability. This "overhang effect" is found for two different PNA-DNA sequences and a variety of different overhang lengths and sequences. The stabilization offered by the overhangs assists the PNA in overcoming the stable secondary structure of the DNA target, an effect which may be significant in the targeting of biological nucleic acids, which will always be much longer than the PNA probe. The ability of PNA to invade a structured DNA target expands its potential utility as an antigene agent or hybridization probe.


How We Transmit Memories to Other Brains: Constructing Shared Neural Representations Via Communication.
Humans are able to mentally construct an episode when listening to another person's recollection, even though they themselves did not experience the events. However, it is unknown how strongly the neural patterns elicited by mental construction resemble those found in the brain of the individual who experienced the original events. Using fMRI and a verbal communication task, we traced how neural patterns associated with viewing specific scenes in a movie are encoded, recalled, and then transferred to a group of naïve listeners. By comparing neural patterns across the 3 conditions, we report, for the first time, that event-specific neural patterns observed in the default mode network are shared across the encoding, recall, and construction of the same real-life episode. This study uncovers the intimate correspondences between memory encoding and event construction, and highlights the essential role our common language plays in the process of transmitting one's memories to other brains.


KNOWLEDGE DRIVEN BINNING AND PHEWAS ANALYSIS IN MARSHFIELD PERSONALIZED MEDICINE RESEARCH PROJECT USING BIOBIN.
Next-generation sequencing technology has presented an opportunity for rare variant discovery and association of these variants with disease. To address the challenges of rare variant analysis, multiple statistical methods have been developed for combining rare variants to increase statistical power for detecting associations. BioBin is an automated tool that expands on collapsing/binning methods by performing multi-level variant aggregation with a flexible, biologically informed binning strategy using an internal biorepository, the Library of Knowledge (LOKI). The databases within LOKI provide variant details, regional annotations and pathway interactions which can be used to generate bins of biologically-related variants, thereby increasing the power of any subsequent statistical test. In this study, we expand the framework of BioBin to incorporate statistical tests, including a dispersion-based test, SKAT, thereby providing the option of performing a unified collapsing and statistical rare variant analysis in one tool. Extensive simulation studies performed on gene-coding regions showed a Bin-KAT analysis to have greater power than BioBin-regression in all simulated conditions, including variants influencing the phenotype in the same direction, a scenario where burden tests often retain greater power. The use of Madsen- Browning variant weighting increased power in the burden analysis to that equitable with Bin-KAT; but overall Bin-KAT retained equivalent or higher power under all conditions. Bin-KAT was applied to a study of 82 pharmacogenes sequenced in the Marshfield Personalized Medicine Research Project (PMRP). We looked for association of these genes with 9 different phenotypes extracted from the electronic health record. This study demonstrates that Bin-KAT is a powerful tool for the identification of genes harboring low frequency variants for complex phenotypes.


Adherence to guidelines and its effects on hospitalizations with complications of type 2 diabetes.
To study the discrepancy between actual and recommended rates of use among several measures of screening for complications of diabetes in a national longitudinal sample, the correlations among measures of adherence, and whether or not higher rates of adherence reduce hospitalizations for complications of diabetes. The key study hypothesis was that lack of adherence to professional recommendations for diabetes care leads to adverse health outcomes for elderly persons. Administrative claims and survey data for 1994-1999 on a nationally representative sample of Medicare beneficiaries age 65+. Principal components analysis and instrumental variables probit regression methods were used. Most Medicare beneficiaries diagnosed with type 2 diabetes had at least one physician visit per year, but rates of screening (eye examinations and HbA1c, lipid, microalbumin and urine tests) fell far short of recommendations. Correlations among use rates for various types of screening were positive but far less than one, suggesting that failure to screen reflects a complex set of underlying factors. Increased rates of adherence were observed for HbA1c and lipid testing over the observation period. Higher use was associated with lower rates of hospitalization for complications of diabetes (vascular (p=0.007), renal (p=0.002), and other complication (p=0.005)). Adherence to guidelines was associated with significantly reduced rates of hospitalization. Continued analysis of the trends in clinical practice is needed to demonstrate the effectiveness of standardized guidelines for the care of patients with diabetes.


Aging influences cardiac mitochondrial gene expression and cardiovascular function following hemorrhage injury.
Cardiac dysfunction and mortality associated with trauma and sepsis increase with age. Mitochondria play a critical role in the energy demand of cardiac muscles, and thereby on the function of the heart. Specific molecular pathways responsible for mitochondrial functional alterations after injury in relation to aging are largely unknown. To further investigate this, 6- and 22-month-old rats were subjected to trauma-hemorrhage (T-H) or sham operation and euthanized following resuscitation. Left ventricular tissue was profiled using our custom rodent mitochondrial gene chip (RoMitochip). Our experiments demonstrated a declined left ventricular performance and decreased alteration in mitochondrial gene expression with age following T-H and we have identified c-Myc, a pleotropic transcription factor, to be the most upregulated gene in 6- and 22-month-old rats after T-H. Following T-H, while 142 probe sets were altered significantly (39 up and 103 down) in 6-month-old rats, only 66 were altered (30 up and 36 down) in 22-month-old rats; 36 probe sets (11 up and 25 down) showed the same trend in both groups. The expression of c-Myc and cardiac death promoting gene Bnip3 were increased, and Pgc1-α and Ppar-α a decreased following T-H. Eleven tRNA transcripts on mtDNA were upregulated following T-H in the aged animals, compared with the sham group. Our observations suggest a c-myc-regulated mitochondrial dysfunction following T-H injury and marked decrease in age-dependent changes in the transcriptional profile of mitochondrial genes following T-H, possibly indicating cellular senescence. To our knowledge, this is the first report on mitochondrial gene expression profile following T-H in relation to aging.


STORMSeq: an open-source, user-friendly pipeline for processing personal genomics data in the cloud.
The increasing public availability of personal complete genome sequencing data has ushered in an era of democratized genomics. However, read mapping and variant calling software is constantly improving and individuals with personal genomic data may prefer to customize and update their variant calls. Here, we describe STORMSeq (Scalable Tools for Open-Source Read Mapping), a graphical interface cloud computing solution that does not require a parallel computing environment or extensive technical experience. This customizable and modular system performs read mapping, read cleaning, and variant calling and annotation. At present, STORMSeq costs approximately $2 and 5-10 hours to process a full exome sequence and $30 and 3-8 days to process a whole genome sequence. We provide this open-access and open-source resource as a user-friendly interface in Amazon EC2.


Trypanosoma cruzi and Trypanosoma rangeli: interplay with hemolymph components of Rhodnius prolixus.
Studies were carried out on the course of infection of Trypanosoma cruzi (clone Dm28c) and Trypanosoma rangeli (clone San Agustin) and their interactions with hemolymph components of Rhodnius prolixus. These parasites when inoculated into the hemocoel of adult R. prolixus (i) had different courses of infection (T. rangeli had high rates of both multiplication and infection and T. cruzi had no division and disappeared soon from the hemolymph); (ii) induced high but no differential increases in lysozyme levels; (iii) failed to induce any other antibacterial activity; (iv) showed similar patterns of hemolymph agglutination activity for erythrocytes and parasites, although there was evidence of limited, unquantifiable, agglutination of T. cruzi; (v) elicited different hemocyte responses with only the T. rangeli infection resulting in significantly increased hemocyte counts; and (vi) did not induce trypanolytic activity. These experiments, unlike previous studies, also showed (i) an interaction of these trypanosomes with the prophenoloxidase-activating system [phenoloxidase (PO) production was spontaneously activated by both parasites but the number of T. cruzi in the hemolymph was directly correlated with PO levels] and (ii) that the elimination of T. cruzi also corresponded to the formation of nodules in the hemolymph. The significance of these results is discussed in relation to the hypothesis that T. rangeli but not T. cruzi has the ability to escape from and perhaps utilize the vector immune system in order to successfully colonize the R. prolixus hemolymph.


Reactive oxygen species and male reproductive hormones.
Reports of the increasing incidence of male infertility paired with decreasing semen quality have triggered studies on the effects of lifestyle and environmental factors on the male reproductive potential. There are numerous exogenous and endogenous factors that are able to induce excessive production of reactive oxygen species (ROS) beyond that of cellular antioxidant capacity, thus causing oxidative stress. In turn, oxidative stress negatively affects male reproductive functions and may induce infertility either directly or indirectly by affecting the hypothalamus-pituitary-gonadal (HPG) axis and/or disrupting its crosstalk with other hormonal axes. This review discusses the important exogenous and endogenous factors leading to the generation of ROS in different parts of the male reproductive tract. It also highlights the negative impact of oxidative stress on the regulation and cross-talk between the reproductive hormones. It further describes the mechanism of ROS-induced derangement of male reproductive hormonal profiles that could ultimately lead to male infertility. An understanding of the disruptive effects of ROS on male reproductive hormones would encourage further investigations directed towards the prevention of ROS-mediated hormonal imbalances, which in turn could help in the management of male infertility.


Automation in single-particle electron microscopy connecting the pieces.
Throughout the history of single-particle electron microscopy (EM), automated technologies have seen varying degrees of emphasis and development, usually depending upon the contemporary demands of the field. We are currently faced with increasingly sophisticated devices for specimen preparation, vast increases in the size of collected data sets, comprehensive algorithms for image processing, sophisticated tools for quality assessment, and an influx of interested scientists from outside the field who might lack the skills of experienced microscopists. This situation places automated techniques in high demand. In this chapter, we provide a generic definition of and discuss some of the most important advances in automated approaches to specimen preparation, grid handling, robotic screening, microscope calibrations, data acquisition, image processing, and computational infrastructure. Each section describes the general problem and then provides examples of how that problem has been addressed through automation, highlighting available processing packages, and sometimes describing the particular approach at the National Resource for Automated Molecular Microscopy (NRAMM). We contrast the more familiar manual procedures with automated approaches, emphasizing breakthroughs as well as current limitations. Finally, we speculate on future directions and improvements in automated technologies. Our overall goal is to present automation as more than simply a tool to save time. Rather, we aim to illustrate that automation is a comprehensive and versatile strategy that can deliver biological information on an unprecedented scale beyond the scope available with classical manual approaches.


Temporal overexpression of IL-22 and Reg3γ differentially impacts the severity of experimental autoimmune encephalomyelitis.
IL-22 is an alpha-helical cytokine which belongs to the IL-10 family of cytokines. IL-22 is produced by RORγt+ innate and adaptive lymphocytes, including ILC3, γδ T, iNKT, Th17 and Th22 cells and some granulocytes. IL-22 receptor is expressed primarily by non-haematopoietic cells. IL-22 is critical for barrier immunity at the mucosal surfaces in the steady state and during infection. Although IL-22 knockout mice were previously shown to develop experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), how temporal IL-22 manipulation in adult mice would affect EAE course has not been studied previously. In this study, we overexpressed IL-22 via hydrodynamic gene delivery or blocked it via neutralizing antibodies in C57BL/6 mice to explore the therapeutic impact of IL-22 modulation on the EAE course. IL-22 overexpression significantly decreased EAE scores and demyelination, and reduced infiltration of IFN-γ+IL-17A+Th17 cells into the central nervous system (CNS). The neutralization of IL-22 did not alter the EAE pathology significantly. We show that IL-22-mediated protection is independent of Reg3γ, an epithelial cell-derived antimicrobial peptide induced by IL-22. Thus, overexpression of Reg3γ significantly exacerbated EAE scores, demyelination and infiltration of IFN-γ+IL-17A+ and IL-17A+GM-CSF+Th17 cells to CNS. We also show that Reg3γ may inhibit IL-2-mediated STAT5 signalling and impair expansion of Treg cells in vivo and in vitro. Finally, Reg3γ overexpression dramatically impacted intestinal microbiota during EAE. Our results provide novel insight into the role of IL-22 and IL-22-induced antimicrobial peptide Reg3γ in the pathogenesis of CNS inflammation in a murine model of MS.


A novel topological centrality measure capturing biologically important proteins.
Topological centrality in protein interaction networks and its biological implications have widely been investigated in the past. In the present study, a novel metric of centrality-weighted sum of loads eigenvector centrality (WSL-EC)-based on graph spectra is defined and its performance in identifying topologically and biologically important nodes is comparatively investigated with common metrics of centrality in a human protein-protein interaction network. The metric can capture nodes from peripherals of the network differently from conventional eigenvector centrality. Different metrics were found to selectively identify hub sets that are significantly associated with different biological processes. The widely accepted metrics degree centrality, betweenness centrality, subgraph centrality and eigenvector centrality are subject to a bias towards super-hubs, whereas WSL-EC is not affected by the presence of super-hubs. WSL-EC outperforms other metrics of centrality in detecting biologically central nodes such as pathogen-interacting, cancer, ageing, HIV-1 or disease-related proteins and proteins involved in immune system processes and autoimmune diseases in the human interactome.


Population growth of Mexican free-tailed bats (Tadarida brasiliensis mexicana) predates human agricultural activity.
Human activities, such as agriculture, hunting, and habitat modification, exert a significant effect on native species. Although many species have suffered population declines, increased population fragmentation, or even extinction in connection with these human impacts, others seem to have benefitted from human modification of their habitat. Here we examine whether population growth in an insectivorous bat (Tadarida brasiliensis mexicana) can be attributed to the widespread expansion of agriculture in North America following European settlement. Colonies of T. b. mexicana are extremely large (~10(6) individuals) and, in the modern era, major agricultural insect pests form an important component of their food resource. It is thus hypothesized that the growth of these insectivorous bat populations was coupled to the expansion of agricultural land use in North America over the last few centuries. We sequenced one haploid and one autosomal locus to determine the rate and time of onset of population growth in T. b. mexicana. Using an approximate Maximum Likelihood method, we have determined that T. b. mexicana populations began to grow ~220 kya from a relatively small ancestral effective population size before reaching the large effective population size observed today. Our analyses reject the hypothesis that T. b. mexicana populations grew in connection with the expansion of human agriculture in North America, and instead suggest that this growth commenced long before the arrival of humans. As T. brasiliensis is a subtropical species, we hypothesize that the observed signals of population growth may instead reflect range expansions of ancestral bat populations from southern glacial refugia during the tail end of the Pleistocene.


Prevalence of female genital mutilation among female infants in Kano, Northern Nigeria.
To determine the prevalence and type of female genital mutilation (FGM) among female infants, reasons and attitude of the mothers to the practice. A cross sectional descriptive study. Tertiary centre in Kano Northern Nigeria. A Pretested questionnaire was administered for mothers of female infants presenting for routine immunization in Aminu Kano Teaching Hospital (AKTH). A total of 250 questionnaires were administered, but only 200 were properly filled and this was used for the analysis. Prevalence and type of FGM, reason for and attitude of mothers towards FGM. Twenty-six infants had FGM during the period of study, giving a prevalence rate of 13 %. The mean age at cutting was 8 days ± 7.3. The commonest type of FGM was type I accounting for 96.2 % of the cases. Tradition/culture was the commonest reason for mutilation accounting for 73.1 %, other reasons included; religious in 11.5 %, hygienic in 11.5 % and to preserve virginity in 3.8 %. Traditional barbers were the commonest operators in 80.8 % of cases, followed by the nurse/midwife in 15.4 % of cases. The fathers were the main decision makers in 46.2 %, followed by both parents in 26.9 % and grandparents in 15.4 % of the cases. 84 % of mothers were not in support of the practice. Thirteen percent of the clients would circumcise all their daughters. Forty-eight percent of the clients were of the opinion that FGM cause harm to the victims. Four percent of those whose daughters were yet to be circumcised will do so later. Female genital cutting is still practiced in our environment. Educational enlightenment is fundamental in changing public opinion as well as in offering reasonable alternative to FGM. Campaign against the practice of FGM should be encouraged to eradicate its practice.


Reformulated Kemeny optimal aggregation with application in consensus ranking of microRNA targets.
MicroRNAs are very recently discovered small noncoding RNAs, responsible for negative regulation of gene expression. Members of this endogenous family of small RNA molecules have been found implicated in many genetic disorders. Each microRNA targets tens to hundreds of genes. Experimental validation of target genes is a time- and cost-intensive procedure. Therefore, prediction of microRNA targets is a very important problem in computational biology. Though, dozens of target prediction algorithms have been reported in the past decade, they disagree significantly in terms of target gene ranking (based on predicted scores). Rank aggregation is often used to combine multiple target orderings suggested by different algorithms. This technique has been used in diverse fields including social choice theory, meta search in web, and most recently, in bioinformatics. Kemeny optimal aggregation (KOA) is considered the more profound objective for rank aggregation. The consensus ordering obtained through Kemeny optimal aggregation incurs minimum pairwise disagreement with the input orderings. Because of its computational intractability, heuristics are often formulated to obtain a near optimal consensus ranking. Unlike its real time use in meta search, there are a number of scenarios in bioinformatics (e.g., combining microRNA target rankings, combining disease-related gene rankings obtained from microarray experiments) where evolutionary approaches can be afforded with the ambition of better optimization. We conjecture that an ideal consensus ordering should have its total disagreement shared, as equally as possible, with the input orderings. This is also important to refrain the evolutionary processes from getting stuck to local extremes. In the current work, we reformulate Kemeny optimal aggregation while introducing a trade-off between the total pairwise disagreement and its distribution. A simulated annealing-based implementation of the proposed objective has been found effective in context of microRNA target ranking. Supplementary data and source code link are available at: >http://www.isical.ac.in/bioinfo_miu/ieee_tcbb_kemeny.rar.


A history of abuse and negative life events in patients with a sexually transmitted disease and in a community sample.
Our aim was to investigate the psychological impact of abuse and negative life events during childhood, adolescence and adulthood in patients recruited from a sexual health clinic. Sixty-two patients with a sexually transmitted disease (STD) were matched on age and gender with a community sample. Forty-two patients without an STD formed another control group. Subjects self-reported their trauma histories and current psychological distress. Compared to controls, categories of abuse and negative life events were more prevalent in STD patients, particularly Physical/Sexual Abuse in adolescence and adulthood. Both within the STD and community samples, a negative life event category that measured illness/death of loved ones during childhood and adolescence predicted current psychological distress. In addition, Control Abuse (a subtype of psychological abuse involving selfish manipulation and deprivation) in childhood and adolescence strongly predicted current psychological distress in STD patients. In general, effects were stronger in females than in males. Psychological/Verbal Abuse did not independently predict current psychological distress, but accompanied other abuse types and possibly amplified their adverse effects. Our findings suggest that multiple types of abuse and negative life events increase the risk of STD infection, perhaps by increasing the likelihood of multiple sexual partners. These patients may ignore social conventions of sexual behaviour because they are bitter about past life experiences. Alternatively, they may persistently search for affection to compensate for a lack of affection in the past.


Dietary thiols in exercise: oxidative stress defence, exercise performance, and adaptation.
Endurance athletes are susceptible to cellular damage initiated by excessive levels of aerobic exercise-produced reactive oxygen species (ROS). Whilst ROS can contribute to the onset of fatigue, there is increasing evidence that they play a crucial role in exercise adaptations. The use of antioxidant supplements such as vitamin C and E in athletes is common; however, their ability to enhance performance and facilitate recovery is controversial, with many studies suggesting a blunting of training adaptations with supplementation. The up-regulation of endogenous antioxidant systems brought about by exercise training allows for greater tolerance to subsequent ROS, thus, athletes may benefit from increasing these systems through dietary thiol donors. Recent work has shown supplementation with a cysteine donor (N-acetylcysteine; NAC) improves antioxidant capacity by augmenting glutathione levels and reducing markers of oxidative stress, as well as ergogenic potential through association with delayed fatigue in numerous experimental models. However, the use of this, and other thiol donors may have adverse physiological effects. A recent discovery for the use of a thiol donor food source, keratin, to potentially enhance endogenous antioxidants may have important implications for endurance athletes hoping to enhance performance and recovery without blunting training adaptations.


Genetic evidence that Neisseria gonorrhoeae produces specific receptors for transferrin and lactoferrin.
Transferrin (TF) and lactoferrin (LF) are probably the major sources of iron (Fe) for Neisseria gonorrhoeae in vivo. We isolated mutants of N. gonorrhoeae FA19 that were unable to grow with Fe bound to either TF (TF-) or LF (LF-) or to both TF and LF ([TF LF]-). The amount of Fe internalized by each of the mutants was reduced to background levels from the relevant iron source(s). The wild-type parent strain exhibited saturable specific binding of TF and LF; receptor activity was induced by Fe starvation. The TF(-)-specific or LF(-)-specific mutants were almost completely lacking in receptor activity for TF or LF, respectively, whereas the [TF LF]- mutants bound both TF and LF as well as the wild-type strain. All mutants utilized citrate and heme normally as Fe sources. These results demonstrate that ability to bind TF or LF is essential for gonococci to scavenge appreciable amounts of Fe from these sources in vitro. In addition, the TF and LF Fe acquisition pathways are linked by the mutual use of a nonreceptor gene product that is essential to Fe scavenging from both of these sources; this gene product is not required for Fe acquisition from other sources.


[Louis XIV's Ginseng: Shaping of Knowledge on an Herbal Medicine in the Late 17th and the Early 18th Century France].
This article aims to investigate the shaping of knowledge and discourse on ginseng, especially among physicians and botanists, since its introduction to France from the 17th century until the early 18th century. In France, knowledge on herbal medicine, including that of ginseng, was shaped under the influence of the modern state's policy and institution: mercantilism and the Académie royale des sciences. The knowledge of herbal medicine developed as an important part of the mercantilist policy supported systematically by the Académie. The East Asian ginseng, renowned as a panacea, was first introduced into France in the 17th century, initially in a roundabout way through transportation and English and Dutch publications of travel tales from various foreign countries. The publication activity was mainly conducted by Thévenot company with the intention to meet the needs of French mercantilism promoted by Colbert. It also implied interests on medicine in order to bolster the people's health. The Thévenot company's activity thus offered vital information on plants and herbs abroad, one of which was ginseng. Furthermore, with Louis XIV's dispatching of the Jesuit missionaries to East Asia, the Frenchmen were able to directly gather information on ginseng. These information became a basis for research of the Académie. In the Académie, founded in 1666 by Colbert, the king's physicians and botanists systematically and collectively studied on exotic plants and medical herbs including ginseng. They were also key figures of the Jardin du Roi. These institutions bore a striking contrast to the faculty of medicine at the University of Paris which has been a center of the traditional Galenic medicine. The research of the Académie on ginseng was greatly advanced, owing much to the reports and samples sent from China and Canada by Jartoux, Sarrazin, and Lapitau. From the early 18th century, the conservative attitude of the University of Paris, which was a stronghold of conservative Galenic Medicine, began to change with its new interest on foreign medicine herbs, including Chinese medicine. In our opinion, this change is exemplified in a paper, that is to say in a thése de licence or thése quolibétique in French, submitted to the Faculty of Medicine in 1736 by Folliot de Saint-Vast under the direction of Jacques-François Vendermonde. During this period, the knowledge of Chinese Materia Medica was introduced, despite of textual adaptation and interpolation, through the "translation" of Chinese medicale books such as Bencao Gangmu. The Chinese medical books were presented to the French academic public by doctors and Jesuit missionaries active in China. The assessment of the ginseng was generally favorable yet, although physicians and doctors began to take more caution on considering it as a panacea.


Thyroid hormone enhanced human hepatoma cell motility involves brain-specific serine protease 4 activation via ERK signaling.
The thyroid hormone, 3, 3', 5-triiodo-L-thyronine (T3), has been shown to modulate cellular processes via interactions with thyroid hormone receptors (TRs), but the secretory proteins that are regulated to exert these effects remain to be characterized. Brain-specific serine protease 4 (BSSP4), a member of the human serine protease family, participates in extracellular matrix remodeling. However, the physiological role and underlying mechanism of T3-mediated regulation of BSSP4 in hepatocellular carcinogenesis are yet to be established. The thyroid hormone response element was identified by reporter and chromatin immunoprecipitation assays. The cell motility was analyzed via transwell and SCID mice. The BSSP4 expression in clinical specimens was examined by Western blot and quantitative reverse transcription polymerase chain reaction. Upregulation of BSSP4 at mRNA and protein levels after T3 stimulation is a time- and dose-dependent manner in hepatoma cell lines. Additionally, the regulatory region of the BSSP4 promoter stimulated by T3 was identified at positions -609/-594. BSSP4 overexpression enhanced tumor cell migration and invasion, both in vitro and in vivo. Subsequently, BSSP4-induced migration occurs through the ERK 1/2-C/EBPβ-VEGF cascade, similar to that observed in HepG2-TRα1 and J7-TRα1 cells. BSSP4 was overexpressed in clinical hepatocellular carcinoma (HCC) patients, compared with normal subjects, and positively associated with TRα1 and VEGF to a significant extent. Importantly, a mild association between BSSP4 expression and distant metastasis was observed. Our findings collectively support a potential role of T3 in cancer cell progression through regulation of the BSSP4 protease via the ERK 1/2-C/EBPβ-VEGF cascade. BSSP4 may thus be effectively utilized as a novel marker and anti-cancer therapeutic target in HCC.


A couple-based HIV prevention intervention for Latino men who have sex with men: study protocol for a randomized controlled trial.
Latino men who have sex with men (MSM) experienced a 13% increase in HIV diagnoses from 2010 to 2014, more than any other racial/ethnic subgroup of MSM in the United States. If current HIV diagnoses rates persist, about one in four Latino MSM in the United States will be diagnosed with HIV during their lifetime. Although some efficacious HIV prevention interventions for Latino MSM exist, none have focused on couples. This paper describes the protocol of a randomized controlled trial (RCT) to test the preliminary efficacy of a couple-based HIV prevention intervention that is culturally tailored for Latino men and their same-sex partners. The RCT will determine the preliminary efficacy of Connecting Latinos en Pareja (CLP) to increase the proportion of anal sex acts that are HIV protected (i.e., anal sex acts in which condoms, pre-exposure prophylaxis (PrEP), treatment as prevention (TasP), or a combination thereof, are used to reduce risk of HIV transmission). CLP builds upon previous couple-based interventions with white and black MSM by incorporating biomedical prevention techniques, such as PrEP and TasP, implementing a framework responsive to the couple's serostatus, and addressing the socio-cultural factors that influence HIV risk among Latino MSM. We also include input from community stakeholders, members of the target population, and a community advisory board as part of intervention development. Assessments will be conducted at baseline, and 3- and 6-months post-intervention to examine the intervention effects on outcomes (HIV-protected sex acts), and factors potentially mediating or moderating intervention effects. This paper describes an innovative RCT that incorporates multiple HIV prevention techniques for Latino MSM in couples, regardless of serostatus. The ongoing involvement of community stakeholders, members of the target population, and a community advisory board is emphasized, and plans for widespread dissemination and application of findings into practice are discussed. Trial registration: NCT03048838 . Registered on 3 February 2017.


Single-scale spectroscopy of structurally colored butterflies: measurements of quantified reflectance and transmittance.
Butterfly scales generally have very elaborate structures in submicrometer size, and some of them show distinctive optical effects through interaction with light. We describe two methods to quantitatively characterize the optical properties of the individual scales in those structurally colored butterflies. Owing to the small dimensions of the scale and to the fact that the reflection and transmission are very diffuse, it is generally difficult to accurately measure the reflectance and transmittance. To overcome these difficulties, we have carefully constructed an optical system including an integrating sphere and investigated variously colored nine kinds of scale. It is shown that the obtained spectra clearly characterize the optical differences among those structurally colored scales and also the differences between structural and pigmentary colors. Further, we have performed the angle-resolved measurement of the reflected light to characterize the spatial pattern of reflection, which is closely related to the mechanism of reflection.


Paradoxical regulation of hypoxia inducible factor-1α (HIF-1α) by histone deacetylase inhibitor in diffuse large B-cell lymphoma.
Hypoxia inducible factor (HIF) is important in cancer, as it regulates various oncogenic genes as well as genes involved in cell survival, proliferation, and migration. Elevated HIF-1 protein promotes a more aggressive tumor phenotype, and greater HIF-1 expression has been demonstrated to correlate with poorer prognosis, increased risk of metastasis and increased mortality. Recent reports suggest that HIF-1 activates autophagy, a lysosomal degradation pathway which may promote tumor cell survival. We show here that HIF-1α expression is constitutively active in multiple diffuse large B cell lymphoma (DLBCL) cell lines under normoxia and it is regulated by the PI3K/AKT pathway. PCI-24781, a pan histone deacetylase inhibitor (HDACI), enhanced accumulation of HIF-1α and induced autophagy initially, while extended incubation with the drug resulted in inhibition of HIF-1α. We tested the hypothesis that PCI-24781- induced autophagy is mediated by HIF-1α and that inhibition of HIF-1α in these cells results in attenuation of autophagy and decreased survival. We also provide evidence that autophagy serves as a survival pathway in DLBCL cells treated with PCI-24781 which suggests that the use of autophagy inhibitors such as chloroquine or 3-methyl adenine in combination with PCI-24781 may enhance apoptosis in lymphoma cells.


Effectiveness of the Alfredson protocol compared with a lower repetition-volume protocol for midportion Achilles tendinopathy: a randomized controlled trial.
Randomized clinical trial. To compare the effectiveness of the Alfredson eccentric heel-drop protocol with a "do-as-tolerated" protocol for nonathletic individuals with midportion Achilles tendinopathy. The Alfredson protocol recommends the completion of 180 eccentric heel drops a day. However, completing this large number of repetitions is time consuming and potentially uncomfortable. There is a need to investigate varying exercise dosages that minimize the discomfort yet retain the clinical benefits. Twenty-eight individuals from outpatient physiotherapy departments were randomized to either the standard (n = 15) or the do-as-tolerated (n = 13) 6-week intervention protocol. Apart from repetition volume, all other aspects of management were standardized between groups. Tendinopathy clinical severity was assessed with the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire. Pain intensity was assessed using a visual analog scale (VAS). Both were assessed at baseline, 3 weeks, and 6 weeks. Treatment satisfaction was assessed at week 6. Adverse effects were also monitored. There was a statistically significant within-group improvement in VISA-A score for both groups (standard, P = .03; do as tolerated, P<.001) and VAS pain for the do-as-tolerated group (P = .001) at week 6, based on the intention-to-treat analysis. There was a statistically significant between-group difference in VISA-A scores at week 3, based on both the intention-to-treat (P = .004) and per-protocol analyses (P = .007), partly due to a within-group deterioration at week 3 in the standard group. There were no statistically significant between-group differences for VISA-A and VAS pain scores at week 6, the completion of the intervention. There was no significant association between satisfaction and treatment groups at week 6. No adverse effects were reported. Performing a 6-week do-as-tolerated program of eccentric heel-drop exercises, compared to the recommended 180 repetitions per day, did not lead to lesser improvement for individuals with midportion Achilles tendinopathy, based on VISA-A and VAS scores.


Evidence-based medicine in bovine, equine and canine reproduction: quality of current literature.
The objective was to evaluate deficits and differences of published literature on reproduction in cattle, horses, and dogs. A literature search was conducted in the databases Medline and Veterinary Science. Approximately five times more articles on clinical bovine reproduction (n = 25 910) were found compared to canine (n = 5 015) and equine (n = 5 090) reproduction. For the evaluation of the literature, a checklist was used. A subset of 600 articles published between 1999 and 2008 was randomly selected. After applying exclusion criteria, a total of 268 trials (86 for cattle, 99 for horses, and 83 for dogs) were evaluated and used for further analysis. For the field of canine and equine reproduction, there were fewer clinical trials with a control group compared to bovine reproduction (cattle 66%, horses 41%, and dogs 41%). For all three species investigated, few publications were identified (4%) with the highest level of evidence, i.e., controlled, randomized, and blinded trials, or meta-analyses. In cattle 33% of the publications were graded adequate to draw sound conclusions; however, only 7 and 11% were graded adequate in dogs and horses, respectively. Therefore, the veterinarian should always assess the quality of information before implementing results into practice to provide best available care for the animals. In conclusion, improvement of the quality of well-designed, conducted and reported clinical trails in animal reproduction is required.


Progression of diet-induced diabetes in C57BL6J mice involves functional dissociation of Ca2(+) channels from secretory vesicles.
The aim of the study was to elucidate the cellular mechanism underlying the suppression of glucose-induced insulin secretion in mice fed a high-fat diet (HFD) for 15 weeks. C57BL6J mice were fed a HFD or a normal diet (ND) for 3 or 15 weeks. Plasma insulin and glucose levels in vivo were assessed by intraperitoneal glucose tolerance test. Insulin secretion in vitro was studied using static incubations and a perfused pancreas preparation. Membrane currents, electrical activity, and exocytosis were examined by patch-clamp technique measurements. Intracellular calcium concentration ([Ca(2+)](i)) was measured by microfluorimetry. Total internal reflection fluorescence microscope (TIRFM) was used for optical imaging of exocytosis and submembrane depolarization-evoked [Ca(2+)](i). The functional data were complemented by analyses of histology and gene transcription. After 15 weeks, but not 3 weeks, mice on HFD exhibited hyperglycemia and hypoinsulinemia. Pancreatic islet content and beta-cell area increased 2- and 1.5-fold, respectively. These changes correlated with a 20-50% reduction of glucose-induced insulin secretion (normalized to insulin content). The latter effect was not associated with impaired electrical activity or [Ca(2+)](i) signaling. Single-cell capacitance and TIRFM measurements of exocytosis revealed a selective suppression (>70%) of exocytosis elicited by short (50 ms) depolarization, whereas the responses to longer depolarizations were (500 ms) less affected. The loss of rapid exocytosis correlated with dispersion of Ca(2+) entry in HFD beta-cells. No changes in gene transcription of key exocytotic protein were observed. HFD results in reduced insulin secretion by causing the functional dissociation of voltage-gated Ca(2+) entry from exocytosis. These observations suggest a novel explanation to the well-established link between obesity and diabetes.


The production and detoxification of a potent cytotoxin, nitric oxide, by pathogenic enteric bacteria.
The nitrogen cycle is based on several redox reactions that are mainly accomplished by prokaryotic organisms, some archaea and a few eukaryotes, which use these reactions for assimilatory, dissimilatory or respiratory purposes. One group is the Enterobacteriaceae family of Gammaproteobacteria, which have their natural habitats in soil, marine environments or the intestines of humans and other warm-blooded animals. Some of the genera are pathogenic and usually associated with intestinal infections. Our body possesses several physical and chemical defence mechanisms to prevent pathogenic enteric bacteria from invading the gastrointestinal tract. One response of the innate immune system is to activate macrophages, which produce the potent cytotoxin nitric oxide (NO). However, some pathogens have evolved the ability to detoxify NO to less toxic compounds, such as the neuropharmacological agent and greenhouse gas nitrous oxide (N₂O), which enables them to overcome the host's attack. The same mechanisms may be used by bacteria producing NO endogenously as a by-product of anaerobic nitrate respiration. In the present review, we provide a brief introduction into the NO detoxification mechanisms of two members of the Enterobacteriaceae family: Escherichia coli and Salmonella enterica serovar Typhimurium. These are discussed as comparative non-pathogenic and pathogenic model systems in order to investigate the importance of detoxifying NO and producing N₂O for the pathogenicity of enteric bacteria.


Synthetic genetic polymers capable of heredity and evolution.
Genetic information storage and processing rely on just two polymers, DNA and RNA, yet whether their role reflects evolutionary history or fundamental functional constraints is currently unknown. With the use of polymerase evolution and design, we show that genetic information can be stored in and recovered from six alternative genetic polymers based on simple nucleic acid architectures not found in nature [xeno-nucleic acids (XNAs)]. We also select XNA aptamers, which bind their targets with high affinity and specificity, demonstrating that beyond heredity, specific XNAs have the capacity for Darwinian evolution and folding into defined structures. Thus, heredity and evolution, two hallmarks of life, are not limited to DNA and RNA but are likely to be emergent properties of polymers capable of information storage.


PrcR, a PucR-type transcriptional activator, is essential for proline utilization and mediates proline-responsive expression of the proline utilization operon putBCP in Bacillus subtilis.
The soil bacterium Bacillus subtilis can utilize exogenous proline as a sole nitrogen or carbon source. The proline-inducible putBCP (formerly ycgMNO) operon encodes proteins responsible for proline uptake and two-step oxidation of proline to glutamate. We now report that a gene (formerly ycgP, now designated prcR) located downstream of the putBCP operon is essential for B. subtilis cells to utilize proline as a sole nitrogen or carbon source. Disruption of the prcR gene also abolished proline induction of putB transcription. prcR expression is not subject to autoregulation and proline induction. The PrcR protein shows no significant amino acid sequence similarity to the known transcriptional activators for proline utilization genes of other bacteria, but it does show partial amino acid sequence similarity to the transcriptional regulator PucR for the purine degradation genes of B. subtilis. PrcR orthologues of unknown function are present in some other Bacillus species. Primer-extension analysis suggests that both putB and prcR are transcribed by a σ(A)-dependent promoter. Deletion and mutation analysis revealed that an inverted repeat (5'-TTGTGG-N5-CCACAA-3') centred at position -76 relative to the transcriptional initiation site of putB is essential for putB expression. Electrophoretic mobility shift assays showed that the purified His-tagged PrcR was capable of binding specifically to this inverted repeat. Altogether, these results suggest that PrcR is a PucR-type transcriptional activator that mediates expression of the B. subtilis putBCP operon in response to proline availability.


Risk factors for Colles' fracture in men and women: results from the European Prospective Osteoporosis Study.
The aim of this study was to determine the contribution of constitutional and lifestyle variables on the subsequent risk of distal forearm (Colles') fracture in a multinational, multicenter, population-prospective study. A total of 15,745 subjects from the European Vertebral Osteoporosis Study, who had completed a baseline questionnaire on lifestyle and constitutional factors, were followed up annually using a validated questionnaire to ascertain the occurrence of new fractures. Risks are expressed as hazard ratios (with 95% confidence intervals) derived from a Cox proportional hazards regression model. The incidence of Colles' fracture was 1.7 and 7.3 per 1000 person years in men and women, respectively. In women delayed menarche, over the age of 15 years, was associated with a modest increased risk [HR 1.5 (range 1.1-2.0)]. Regular walking in that group also increased the risk [HR 1.6 (1.2-2.2)] perhaps reflecting the increased exposure to risk of falling. None of the other factors examined revealed any important influences. The results are broadly in line with the few other published prospective studies suggesting only a modest role for these factors in influencing susceptibility to fracture.


Pathogenesis of early atherosclerotic lesions in infants.
High serologic lipid levels, infections, and genetic susceptibility have been proposed as possible etiologic factors of initial atherosclerotic lesions of the coronary arteries in infancy. At a recent WHO annual meeting, it was stated that breast milk substitutes cause irreparable damage in infants. This prompted us to verify whether formula feeding and parental cigarette smoking might play a role in the pathogenesis of early atherosclerotic alterations in infancy. The major epicardial coronary arteries from 36 infants dying suddenly and unexpectedly (sudden infant death syndrome) were embedded in paraffin and serially cut for histologic examination. In 67% of the cases, multifocal coronary early atherosclerotic lesions of varying entities were detected. The alterations ranged from focal plaques with mild myointimal thickening to juvenile soft plaques reducing the arterial lumen. A significant correlation was observed between the early atherosclerotic lesions and the risk factors considered. In particular, we noted different morphologic patterns related to formula feeding and cigarette smoking. Baby formula feeding and parental cigarette smoking might have an atherogenic effect on the coronary walls as from the first months of life. The lesions appear to be larger and more diffuse when both these atherogenic factors are present.


Glucocorticoids reduce inflammation in cystic fibrosis bronchial epithelial cells.
Reduction of lung inflammation is one of the goals of cystic fibrosis (CF) therapy. Among anti-inflammatory molecules, glucocorticoids (GC) are one of the most prescribed. However, CF patients seem to be resistant to glucocorticoid treatment. Several molecular mechanisms that contribute to decrease anti-inflammatory effects of glucocorticoids have been identified in pulmonary diseases, but the molecular actions of glucocorticoids have never been studied in CF. In the cytoplasm, glucocorticoids bind to glucocorticoid receptor (GR) and then, control NF-κB and MAPK pathways through direct interaction with AP-1 and NF-κB in the nucleus. Conversely, MAPK can regulate glucocorticoid activation by targeting GR phosphorylation. Together these pathways regulate IL-8 release in the lung. Using bronchial epithelial cell lines derived from non CF and CF patients, we analyzed GR-based effects of glucocorticoids on NF-κB and MAPK pathways, after stimulation with TNF-α. We demonstrate that the synthetic glucocorticoid dexamethasone (Dex) significantly decreases IL-8 secretion, AP-1 and NF-κB activity in CF cells in a pro-inflammatory context. Moreover, we show that p38 MAPK controls IL-8 release by determining GR activation through specific phosphorylation on serine 211. Finally, we demonstrate a synergistic effect of dexamethasone treatment and inhibition of p38 MAPK inducing more than 90% inhibition of IL-8 production in CF cells. All together, these results demonstrate the good responsiveness to glucocorticoids of CF bronchial epithelial cells and the reciprocal link between glucocorticoids and p38 MAPK in the control of CF lung inflammation.


Digital health: a new dimension in rheumatology patient care.
The new digital health innovations have opened up several opportunities to help the clinicians, patients and other caregivers of rheumatology healthcare system in maximizing efficiencies resulting in better patient outcomes. In the global context, digital health technology has the potential to bridge the distance gap between all the key stakeholders involved in rheumatology health care. In this review, we update on the recent advances in the field of digital health and highlight unique features of these technologies which would help in routine care. Application of technology in any form to enable, facilitate or enhance the quality of care is the foundation of digitised care. The components could be smartphone apps, sensors, video, social media platforms or messenger platforms, wearables or a combination of these enabling healthcare delivery and overcoming the constraints of distance, location and time. Digital therapeutics have started evolving and an important step in this direction is the involvement of FDA in the approval process. Speciality specific apps, personalised patient education as per disease status, remote specialist consultations or virtual health coach to guide on lifestyle modifications are some of the developments which have been facilitated by increased digitization in all walks of life. Assisted care with the help of robots rendering care in the hospitals or an intelligent robot guiding a patient by voice and visual sense at home are already at the threshold of entering the mainstream of patient care. Wearable devices equipped with powerful sensors are coming handy in keeping a watch on patient symptoms all the time and providing useful insights on disease progression, clinical response or complications. In chronic care such as rheumatology the implications, possibilities and benefits seem unprecedented. Real time data analytics and artificial intelligence are helping the clinicians, healthcare systems and policy makers optimise the resources and improve patient outcomes. Digitization of healthcare has gained momentum in the recent years and it is envisaged that it could be a catalyst to change, bridge the quality of care and most important democratise the healthcare access across the globe. However, more data, efficacy and objective results are needed which would be fulfilled by ongoing observational studies, clinical trials, systematic review and meta-analysis to further establish the role of digital health in the realms of patient care.


Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuasca.
Harmine, harmaline, tetrahydroharmine (THH), and N,N-dimethyltryptamine (DMT) were quantitated in plasma from 15 healthy male volunteers after the ingestion of ayahuasca, a beverage that has been used for religious purposes in Brazil since pre-Columbian times. A growing awareness of the interest in this ancient shamanistic practice in modern urban cultures and the widespread popular dissemination of the inebriant effects and type and sources of the plant admixtures used to prepare the beverage have provided additional impetus for this study. The three harmala alkaloids were quantitated from protein-precipitated plasma by high-performance liquid chromatography using fluorescence detection. Recovery from blank human plasma was quantitative, and the limit of quantitation (LOQ) was below 2 ng/mL of plasma for each of the harmala alkaloids. Standard concentrations ranged from 10 to 250 ng/mL for harmine and THH and from 1.0 to 25.0 ng/mL for harmaline, respectively. Linearity was observed for harmine, harmaline, and THH within these respective ranges. The highest concentrations of harmala alkaloids in human plasma were found to be 222.3 ng/mL for harmine, 134.5 ng/mL for THH, and 9.4 ng/mL for harmaline. DMT was quantitated by gas chromatography using nitrogen-phosphorus detection after liquid-liquid extraction with diphenhydramine as an internal standard. DMT recovery was quantitative, and the limit of detection and LOQ were 0.5 and 5 ng/mL, respectively. Linearity for DMT was observed from 5 to 1000 ng/mL. The one-step extraction method for DMT and the protein precipitation method for the three harmala alkaloids afford rapid, sensitive, and quantitative analyses of these alkaloids with minimal analyte loss. The analytical methods also may be applicable to other matrices, including whole blood and urine samples and homogenized tissue specimens. These are the first reported observations of DMT and harmala alkaloids in plasma after ritual ingestion of ayahuasca.


Uncemented jumbo cups for revision total hip arthroplasty: a concise follow-up, at a mean of twenty years, of a previous report.
Uncemented jumbo cups are commonly used for acetabular revision because they are technically straightforward to implant and provide good intermediate-term results. Understanding long-term survival is particularly important because this method is common and because jumbo cups do not provide notable bone stock restoration. The purpose of the present study was to determine the twenty-year results of jumbo cup use during revision total hip arthroplasty. In the original publication, we reported on eighty-nine patients who underwent revision with an uncemented jumbo cup with a single design (Harris-Galante) prior to 1993. The Harris Hip Score (HHS), radiographic results, and Kaplan-Meier survivorship curves were evaluated. Mean follow-up was twenty years. The mean postoperative HHS was 71 compared with 56 preoperatively (p=0.001). A total of five jumbo cups were revised for aseptic loosening; one, for infection; and one, for recurrent dislocation. Eight liners were revised with retention of the metal acetabular component: six during femoral component revision, one for wear, and one for recurrent dislocations. Twenty-year survivorship was 88% free from aseptic loosening of the metal acetabular component, 85% free from aseptic loosening or radiographic evidence of definite loosening of the metal acetabular component, and 83% free from revision of the metal acetabular component for any reason. The twenty-year results of revision with uncemented jumbo acetabular components demonstrated acceptable clinical outcomes and radiographic stability. These results justify the use of jumbo cups as a common method of acetabular revision.


Adaptation of Complete Denture Base Fabricated by Conventional, Milling, and 3-D Printing Techniques: An In Vitro Study.
The aim of this study was to compare the adaptation of complete denture base (CDB) manufactured by three different techniques: conventional, milling, and three-dimensional (3-D) printing. A master cast was duplicated to create 60 gypsum casts. Twenty casts (n = 20) were attributed to each group. In the computer-aided design and computer-aided manufacturing (CAD/CAM) groups (milling and 3-D printing), the 40 gypsum casts reserved for these two groups were scanned. An STL file was obtained and a master CDB was designed and then fabricated according to each technique. In the conventional group, a polyvinyl siloxane putty mold was obtained from the milled CDB, and this mold was used to fabricate 20 conventional denture bases by compression molding using the silicon-gypsum technique in a bronze flask. The inner surfaces of the obtained 60 CDB were scanned and superimposed over their corresponding master cast. Deviation analyses were calculated using digital subtraction technique. Five functional areas (posterior palatal seal, anterior border seal, crest of the ridge, maxillary tuberosities, and palate) were selected to evaluate the variations in CBD adaptation. Based on the results and color maps of all selected regions, milling technique offers the best adaptation. The crest of ridge in the conventional technique showed the least adaptation and the posterior palatal seal in the 3-D printing technique showed the best adaptation. Within the limitations of this study, the CAD/CAM fabrication techniques seem to offer better adaptation of CDB compared to the conventional fabrication technique. Milled CDBs presented the most homogeneous distribution of adaptation, yet the 3-D printing process seems a promising techniques that needs to be addressed and perfected. The CAD/CAM technologies can help overcome many limitations related to conventional impressions and therefore should be well investigated to improve the edentulous patient's quality of life.


A 3D human lung-on-a-chip model for nanotoxicity testing.
The prevalent application of nanoparticles (NPs) has drawn intense concerns about their impact on the environment and human health. Inhalation of NPs is the major route of NP exposure and has led to adverse effects on the lung. It is of great concern to evaluate the potential hazards of nanoparticles for human health during pulmonary exposure. Here, we proposed a novel 3D human lung-on-a-chip model to recreate the organ-level structure and functions of the human lung that allow to us evaluate the pulmonary toxicity of nanoparticles. The lung-on-a-chip consists of three parallel channels for the co-culture of human vascular endothelial cells and human alveolar epithelial cells sandwiching a layer of Matrigel membrane, which recapitulate the key features of the alveolar capillary barrier in the human lung. Cell-cell interaction, cell-matrix interaction and vascular mechanical cues work synergistically to promote the barrier function of the lung-on-a-chip model. TiO2 nanoparticles and ZnO nanoparticles were applied on the lung-on-a-chip to assay their nanotoxicity on both epithelial cells and endothelial cells. Junction protein expression, increased permeability to macromolecules, dose dependent cytotoxicity, ROS production and apoptosis were assayed and compared on the chip. This lung-on-a-chip model indicated its versatile application in human pulmonary health and safety assessment for nanoparticles, environment, food and drugs.


Cyberknife for brain metastases of malignant melanoma and renal cell carcinoma.
To evaluate the efficacy of CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiosurgery (SRS) for patients with brain metastases of malignant melanoma and renal cell carcinoma. We conducted a retrospective review of all patients treated by image-guided radiosurgery at our institution between March 1999 and December 2005. Sixty-two patients with 145 brain metastases of renal cell carcinoma or melanoma were identified. The median follow-up period was 10.5 months. Forty-four patients had malignant melanoma, and 18 patients had renal cell carcinoma. The median age was 57 years, and patients were classified as recursive partitioning analysis Class 1 (6 patients), 2 (52 patients) or 3 (4 patients). Thirty-three patients had been treated systemically with either chemotherapy or immunotherapy, and 33 patients were taking corticosteroids at the time of treatment. The mean tumor volume was 1.47 mL (range, 0.02-35.7 mL), and the mean prescribed dose was 20 Gy (range, 14-24 Gy). The median survival after SRS was 8.3 months. Actuarial survival at 6 and 12 months was 57 and 37%, respectively. On multivariate analysis, Karnofsky Performance Scale score (P < 0.01) and previous immunotherapy/clinical trial (P = 0.01) significantly affected overall survival. One-year intracranial progression-free survival was 38%, and local control was 87%. Intracranial control was impacted by whole-brain radiotherapy (P = 0.01), previous chemotherapy (P = 0.01), and control of the primary at the time of SRS (P = 0.02). Surgical resection had no effect on intracranial or local control. Radiographic evidence of radiation necrosis developed in 4 patients (6%). CyberKnife radiosurgery provided excellent local control with acceptable toxicity in patients with melanoma or renal cell brain metastases. Initial SRS alone appeared to be a reasonable option, as survival was dictated by systemic disease.


Near real-time VOCs analysis using an aspiration ion mobility spectrometer.
The ChemPro 100i chemical detector (aspiration-type ion mobility spectrometer) was used for the detection of selected volatile organic compounds known to be potential indicators of human presence. The targeted group of compounds mainly comprised ketones (acetone, 2-butanone, 2-pentanone, 3-methyl-2-butanone, 4-heptanone), aldehydes (propanal, pentanal, hexanal, octanal), dimethyl disulfide (DMDS), isoprene and ethanol. Gaseous standards of these compounds were produced from pure substances and analysed using the aspiration ion mobility spectrometry (AIMS) chemical detector. The chemical fingerprints obtained (patterns) were compared to evaluate possible differences in responses. The limits of detection ranged from 5 ppbv for 4-heptanone to 87 ppbv for DMDS, whereas relative standard deviations varied from 1.5% to 5%. Additionally, quantitative AIMS measurements of acetone levels in human breath samples were carried out. The breath acetone levels measured with AIMS ranged from 290 to 540 ppbv and correlated quite well with the SPME-GC-MS results, showing limited potential of AIMS for the detection of breath acetone; however, deviations were observed for concentrations above 500 ppbv. The further success of AIMS in breath analysis depends on improvements of the analytical power (e.g. selectivity, sensitivity, resolution) and the implementation of multivariate data analysis techniques.


Working hard to belong: a qualitative study exploring students from black, Asian and minority ethnic backgrounds experiences of pre-registration physiotherapy education.
Previous research has demonstrated that attainment inequalities exist for students from Black Asian and Minority Ethnic (BAME) groups in pre-registration physiotherapy education. While previous research has explored students from BAME backgrounds experience of university, the context of physiotherapy is unique and is under researched. Therefore the purpose of this study was to explore BAME student experiences during their physiotherapy training. Using a phenomenological approach pre-registration BSc and MSc students from BAME backgrounds from two universities who had completed both academic and clinical modules were invited to participate. Focus groups followed a topic guide developed from the literature and were facilitated by physiotherapy educators from outside the host institution. They were digitally recorded, transcribed verbatim and analysed thematically. Analytical triangulation was adopted throughout the research process as a mechanism to enhance rigour. Seventeen students participated from a range of self-identified BAME backgrounds that were also representative of age, gender and course. Themes derived from the data included: feeling an outsider in reflections of belonging, behaviours by others that marginalise BAME and personal strategies to integrate in physiotherapy despite the lack of power and influence. Collectively these themes demonstrate a range of challenges which students from BAME backgrounds face within both an academic and practice learning environment. While this may not be surprising based on other disciplines, this study demonstrates that studying physiotherapy as a student from BAME background requires persistence to overcome a series of many implicit challenges. Understanding the experiences of students from BAME backgrounds presents unique opportunities to educate the profession and co-create opportunities for a more diverse profession with practitioners and educators as role models. There is a need for greater training for educators to listen to these students' voices and their stories, and understand where institutional structures and practices could be modified to enable BAME student inclusion in physiotherapy education and practice.


Method to determine the speckle characteristics of front projection screens.
We present a method to determine the speckle properties of front projection screens. Seven different screens are investigated in a backscattering geometry for 808 nm light. The speckle contrast reduction that results from polarization scrambling and reduced temporal coherence is modeled for the case of volume scattering in the screens. For this purpose, the screen's volume scattering path length distributions and depolarization characteristics are determined. This is done via a streak camera setup to measure the temporal broadening of ultrashort 50 fs light pulses scattered in the screens. We show that it is essential to properly select a projection screen with large volume roughness in order to achieve low speckle contrast values for moderate illumination bandwidths.


STUDIES ON CILIA. THE FIXATION OF THE METACHRONAL WAVE.
Upon excision into spring water, the lateral cilia of the gill of the freshwater mussel Elliptio complanatus (Solander) stop beating, but 0.04 M potassium ion can activate the gill so that these cilia again beat with metachronal rhythm. One per cent osmium tetroxide quickly pipetted onto a fully activated gill fixes the lateral cilia in a pattern that preserves the form and arrangement of the metachronal wave, and permits the cilia to be studied with the electron microscope in all stages of their beat cycle. Changes are seen in the fixed active preparation that are not present in the inactive control, i.e., in the packing of the cilia, the position of the axis of the ciliary cross-section, and the diameter of the ring of peripheral filaments. Analysis of these parameters may lead to new correlations between ciliary fine structure and function.


Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis.
Hereditary hemochromatosis (HH) is a common genetic disorder characterized by excess absorption of dietary iron and progressive iron deposition in several tissues, particularly liver. The vast majority of individuals with HH are homozygous for mutations in the HFE gene. Recently a second transferrin receptor (TFR2) was discovered, and a previously uncharacterized type of hemochromatosis (HH type 3) was identified in humans carrying mutations in the TFR2 gene. To characterize the role for TFR2 in iron homeostasis, we generated mice in which a premature stop codon (Y245X) was introduced by targeted mutagenesis in the murine Tfr2 coding sequence. This mutation is orthologous to the Y250X mutation identified in some patients with HH type 3. The homozygous Tfr2(Y245X) mutant mice showed profound abnormalities in parameters of iron homeostasis. Even on a standard diet, hepatic iron concentration was several-fold higher in the homozygous Tfr2(Y245X) mutant mice than in wild-type littermates by 4 weeks of age. The iron deposition in the mutant mice was predominantly hepatocellular and periportal. The mean splenic iron concentration in the homozygous Tfr2(Y245X) mutant mice was significantly less than that observed in the wild-type mice. The homozygous Tfr2(Y245X) mutant mice also demonstrated elevated transferrin saturations. There were no significant differences in parameters of erythrocyte production including hemoglobin levels, hematocrits, erythrocyte indices, and reticulocyte counts. Heterozygous Tfr2(Y245X) mice did not differ in any measured parameter from wild-type mice. This study confirms the important role for TFR2 in iron homeostasis and provides a tool for investigating the excess iron absorption and abnormal iron distribution in iron-overload disorders.


The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma.
Assessment of eosinophilic airway inflammation may be helpful in the management of asthma. Nitric oxide (NO) has potential advantages as a tool to monitor airway inflammation although little is known about the relationship between NO and eosinophilic airway inflammation and the factors which influence it. We set out to define the relationship between exhaled NO and the sputum eosinophil count, identify the exhaled NO concentration that best identified a sputum eosinophil count >3% and investigate the impact of several potential confounding factors in 566 consecutive patients with varying severity of asthma. Finally we examined the ability of exhaled NO concentrations measured at differing exhalation flows to identify the presence of a sputum eosinophilia. We found a significant positive relationship between exhaled NO and sputum eosinophil count (R(2)=0.26, P<0.001) which was best described using a non-linear model. There were no clinically important confounding factors to this model. In non-smokers an exhaled NO concentration of >8.3 p.p.b. at 250 mL/s gave 71% sensitivity and 72% specificity for identifying a sputum eosinophil count of >3%. This value of exhaled NO would seem to be the best for identifying significant eosinophilic airway inflammation. It is applicable to a wide range of non-smoking patients with asthma; exhalation flow does not alter the ability of exhaled NO concentration to detect a sputum eosinophilia.


Protein ranking by semi-supervised network propagation.
Biologists regularly search DNA or protein databases for sequences that share an evolutionary or functional relationship with a given query sequence. Traditional search methods, such as BLAST and PSI-BLAST, focus on detecting statistically significant pairwise sequence alignments and often miss more subtle sequence similarity. Recent work in the machine learning community has shown that exploiting the global structure of the network defined by these pairwise similarities can help detect more remote relationships than a purely local measure. We review RankProp, a ranking algorithm that exploits the global network structure of similarity relationships among proteins in a database by performing a diffusion operation on a protein similarity network with weighted edges. The original RankProp algorithm is unsupervised. Here, we describe a semi-supervised version of the algorithm that uses labeled examples. Three possible ways of incorporating label information are considered: (i) as a validation set for model selection, (ii) to learn a new network, by choosing which transfer function to use for a given query, and (iii) to estimate edge weights, which measure the probability of inferring structural similarity. Benchmarked on a human-curated database of protein structures, the original RankProp algorithm provides significant improvement over local network search algorithms such as PSI-BLAST. Furthermore, we show here that labeled data can be used to learn a network without any need for estimating parameters of the transfer function, and that diffusion on this learned network produces better results than the original RankProp algorithm with a fixed network. In order to gain maximal information from a network, labeled and unlabeled data should be used to extract both local and global structure.