Streptococcus pneumoniae drives specific and lasting Natural Killer cell memory.
NK cells are important mediators of innate immunity and play an essential role for host protection against infection, although their responses to bacteria are poorly understood. Recently NK cells were shown to display memory properties, as characterized by an epigenetic signature leading to a stronger secondary response. Although NK cell memory could be a promising mechanism to fight against infection, it has not been described upon bacterial infection. Using a mouse model, we reveal that NK cells develop specific and long-term memory following sub-lethal infection with the extracellular pathogen Streptococcus pneumoniae. Memory NK cells display intrinsic sensing and response to bacteria in vitro, in a manner that is enhanced post-bacterial infection. In addition, their transfer into naïve mice confers protection from lethal infection for at least 12 weeks. Interestingly, NK cells display enhanced cytotoxic molecule production upon secondary stimulation and their protective role is dependent on Perforin and independent of IFNγ. Thus, our study identifies a new role for NK cells during bacterial infection, opening the possibility to harness innate immune memory for therapeutic purposes.


Wireless control of intraspinal microstimulation in a rodent model of paralysis.
Despite a promising outlook, existing intraspinal microstimulation (ISMS) techniques for restoring functional motor control after spinal cord injury are not yet suitable for use outside a controlled laboratory environment. Thus, successful application of ISMS therapy in humans will require the use of versatile chronic neurostimulation systems. The objective of this study was to establish proof of principle for wireless control of ISMS to evoke controlled motor function in a rodent model of complete spinal cord injury. The lumbar spinal cord in each of 17 fully anesthetized Sprague-Dawley rats was stimulated via ISMS electrodes to evoke hindlimb function. Nine subjects underwent complete surgical transection of the spinal cord at the T-4 level 7 days before stimulation. Targeting for both groups (spinalized and control) was performed under visual inspection via dorsal spinal cord landmarks such as the dorsal root entry zone and the dorsal median fissure. Teflon-insulated stimulating platinum-iridium microwire electrodes (50 μm in diameter, with a 30- to 60-μm exposed tip) were implanted within the ventral gray matter to an approximate depth of 1.8 mm. Electrode implantation was performed using a free-hand delivery technique (n = 12) or a Kopf spinal frame system (n = 5) to compare the efficacy of these 2 commonly used targeting techniques. Stimulation was controlled remotely using a wireless neurostimulation control system. Hindlimb movements evoked by stimulation were tracked via kinematic markers placed on the hips, knees, ankles, and paws. Postmortem fixation and staining of the spinal cord tissue were conducted to determine the final positions of the stimulating electrodes within the spinal cord tissue. The results show that wireless ISMS was capable of evoking controlled and sustained activation of ankle, knee, and hip muscles in 90% of the spinalized rats (n = 9) and 100% of the healthy control rats (n = 8). No functional differences between movements evoked by either of the 2 targeting techniques were revealed. However, frame-based targeting required fewer electrode penetrations to evoke target movements. Clinical restoration of functional movement via ISMS remains a distant goal. However, the technology presented herein represents the first step toward restoring functional independence for individuals with chronic spinal cord injury.


Parents' Perspectives: An Expanded View of Occupational and Co-Occupational Performance in the Neonatal Intensive Care Unit.
One limitation of occupation-based neonatal practice is the lack of clarity surrounding what parent and infant occupations exist in the neonatal intensive care unit (NICU). Without clear definitions and examples of these constructs, occupational therapists may not recognize or value them as part of practice. To explore concepts of occupational and co-occupational performance in the NICU and provide richly expanded descriptions of parent and infant occupations in this setting. Phenomenological study with convenience sampling. Participants engaged in semistructured interviews. Inductive content analysis, in vivo and process coding methods, and cross-case analysis were used. Member checking and expert review of emergent themes were used to ensure authenticity. A metropolitan 48-bed Level 3 NICU with single-family rooms in the midwestern United States. Fourteen parents (mean age = 29.7 yr; range = 19-37 yr) volunteered for the study. Five themes of active occupational engagement emerged: (1) perceiving "they" versus "I"; (2) maintaining proximity; (3) expressing emotions, values, and beliefs; (4) addressing health issues; and (5) analyzing. A matrix framework displayed emergent themes with definitions of parent occupations, infant occupations, and parent-infant co-occupations. Examples of both directly observable and hidden occupations were found at matrix intersections. Occupational performance prevalently reflected attempts to balance power differentials and pursue meaningful engagement through observable and hidden participation in caregiving. Findings suggest that beyond typical occupations (e.g., feeding, socializing), neonatal therapists can address the doing, being, and becoming occupations expressed by parents in this study. Parents described five broad thematic categories of NICU-based occupation and co-occupation, which may be valuable to therapists seeking to strengthen the occupational focus of neonatal intervention. Neonatal therapists may need to advocate for service provision policy change to fully address the observable and nonobservable doing, being, and becoming occupational and co-occupational needs of parents and infants.


Analysis of multiple restriction fragment length polymorphisms of the gene for the human complement receptor type I. Duplication of genomic sequences occurs in association with a high molecular mass receptor allotype.
Human CR1 exhibits an unusual form of polymorphism in which allotypic variants differ in the molecular weight of their respective polypeptide chains. To address mechanisms involved in the generation of the CR1 allotypes, DNA from individuals having the F allotype (250,000 Mr), the S allotype (290,000 Mr), and the F' allotype (210,000 Mr) was digested by restriction enzymes, and Southern blots were hybridized with CR1 cDNA and genomic probes. With the use of Bam HI and Sac I, an additional restriction fragment was observed in 20 of 21 individuals having the S allotype with no associated loss of other restriction fragments. Southern blot analysis with a noncoding genomic probe derived from the S allotype-specific Bam HI fragment showed hybridization to this fragment and to two other fragments that were also present in FF individuals. Thus, an intervening sequence may be repeated twice in the F allele and three times in the S allele. A restriction fragment length polymorphism (RFLP) unique to two individuals expressing the F' allotype was seen with Eco RV, but the absence of persons homozygous for this rare allotype prevented further comparisons with the F and S allotypes. Analysis of the CR1 transcripts associated with the three CR1 allotypes indicated that these differed by 1.3-1.5 kb and had the same rank order as the corresponding allotypes. Taken together, these findings suggest that the S allele was generated from the F allele by the acquisition of additional sequences, the coding portion of which may correspond to a long homologous repeat of approximately 1.4 kb that has been identified in CR1 cDNA. We saw two other RFLPs with Hind III and Pvu II that were in linkage dysequilibrium with the Bam HI-Sac I RFLPs associated with the S allotype, and a third polymorphism was seen with Eco RI that was not in linkage dysequilibrium with the other polymorphisms. Thus, 10 commonly occurring CR1 alleles can be defined, making this locus a useful marker for the long arm of chromosome 1 to which the CR1 gene maps.


Chromogranin B: intra- and extra-cellular mechanisms to regulate catecholamine storage and release, in catecholaminergic cells and organisms.
Chromogranin B (CHGB) is the major matrix protein in human catecholamine storage vesicles. CHGB genetic variation alters catecholamine secretion and blood pressure. Here, effective Chgb protein under-expression was achieved by siRNA in PC12 cells, resulting in ~ 48% fewer secretory granules on electron microscopy, diminished capacity for catecholamine uptake (by ~ 79%), and a ~ 73% decline in stores available for nicotinic cholinergic-stimulated secretion. In vivo, loss of Chgb in knockout mice resulted in a ~ 35% decline in chromaffin granule abundance and ~ 44% decline in granule diameter, accompanied by unregulated catecholamine release into plasma. Over-expression of CHGB was achieved by transduction of a CHGB-expressing lentivirus, resulting in ~ 127% elevation in CHGB protein, with ~ 122% greater abundance of secretory granules, but only ~ 14% increased uptake of catecholamines, and no effect on nicotinic-triggered secretion. Human CHGB protein and its proteolytic fragments inhibited nicotinic-stimulated catecholamine release by ~ 72%. One conserved-region CHGB peptide inhibited nicotinic-triggered secretion by up to ~ 41%, with partial blockade of cationic signal transduction. We conclude that bi-directional quantitative derangements in CHGB abundance result in profound changes in vesicular storage and release of catecholamines. When processed and released extra-cellularly, CHGB proteolytic fragments exert a feedback effect to inhibit catecholamine secretion, especially during nicotinic cholinergic stimulation.


Efficacy of two praziquantel treatments among primary school children in an area of high Schistosoma mansoni endemicity, Nile Delta, Egypt.
Praziquantel is the cornerstone of schistosomiasis control. A number of reports from endemic areas suggest that resistance or tolerance to praziquantel might exist in Schistosoma mansoni. Several explanations were postulated. The present work was designed to test the hypothesis that a low praziquantel (pzq) cure rate in Egypt is due to survival and maturation of immature stages that escaped pzq, which is effective against mature S. mansoni worms only. The study sample included 1351 children attending El Rouse primary school located in El Rouse village, Nile Delta, Egypt. All children received 2 pzq doses (40 mg/kg) 4 weeks apart. Diagnosis of S. mansoni infection and cure assessment were based on examination of 2 Kato slides prepared from a single stool sample collected before and 4 weeks after the first and second treatments. The cure rate was 78·8% after the first treatment and increased significantly to 90·8% after the second treatment. Egg reduction rates were 71·2% and 77·2% after 1 and 2 treatments respectively. Pre-treatment intensity of infection has a great influence on cure and egg reduction rates. Our results confirmed that low praziquantel cure rate, in Egypt, might be attributed, even partially, to survival and maturation of the immature S. mansoni stages that escaped pzq that is effective against mature worms only.


Plaque fluoride concentrations in a community without water fluoridation: effects of calcium and use of a fluoride or placebo dentifrice.
The results of a recent study by Whitford et al. [Caries Res 2002;36:256-265] with subjects whose drinking water was fluoridated led to two major conclusions: (1) Compared to the use of a placebo dentifrice, plaque fluoride concentrations ([F]) throughout much of the day are not significantly increased by the use of an F dentifrice but (2) they are positively related to plaque [Ca] (p = 0.0001). The present double-blind, double-crossover study with 16 subjects used the same protocol and was done to: (1) determine the effects of the use of an F dentifrice on salivary and plaque [F] in a community without water fluoridation and (2) further examine the relationship between plaque [Ca] and [F]. Following the use of an F dentifrice or placebo for one week, whole saliva and plaque were collected 1.0 and 12 h after the last use of the products. The study was repeated to include rinsing with a 20 mmol/l CaCl(2) solution immediately before the use of the dentifrices. The CaCl(2) rinse had only minor effects on salivary [Ca] and [F] and none on the plaque concentrations. Unlike the results found in the fluoridated community, all salivary and plaque [F] associated with the use of the F dentifrice were significantly higher than those associated with the use of the placebo. The results suggest that the cariostatic effectiveness of an F dentifrice should be greater in areas without water fluoridation. As noted previously, plaque [F] were positively related to plaque [Ca] (p = 0.0001).


PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3Kα Inhibitors.
Purpose: We describe herein a novel P447_L455 deletion in the C2 domain of PIK3CA in a patient with an ER+ breast cancer with an excellent response to the PI3Kα inhibitor alpelisib. Although PIK3CA deletions are relatively rare, a significant portion of deletions cluster within amino acids 446-460 of the C2 domain, suggesting these residues are critical for p110α function.Experimental Design: A computational structural model of PIK3CAdelP447-L455 in complex with the p85 regulatory subunit and MCF10A cells expressing PIK3CAdelP447-L455 and PIK3CAH450_P458del were used to understand the phenotype of C2 domain deletions.Results: Computational modeling revealed specific favorable inter-residue contacts that would be lost as a result of the deletion, predicting a significant decrease in binding energy. Coimmunoprecipitation experiments showed reduced binding of the C2 deletion mutants with p85 compared with wild-type p110α. The MCF10A cells expressing PIK3CA C2 deletions exhibited growth factor-independent growth, an invasive phenotype, and higher phosphorylation of AKT, ERK, and S6 compared with parental MCF10A cells. All these changes were ablated by alpelisib treatment.Conclusions: C2 domain deletions in PIK3CA generate PI3K dependence and should be considered biomarkers of sensitivity to PI3K inhibitors. Clin Cancer Res; 24(6); 1426-35. ©2017 AACR.


Acute motor axonal neuropathy: a frequent cause of acute flaccid paralysis in China.
In northern China, annual epidemics of acute-onset flaccid paralysis diagnosed clinically as Guillain-Barré syndrome have been recognized for at least 20 years. On the basis of an historical analysis of more than 3,200 patients, distinctive features include most cases occurring during the summer months among children and young adults, most of whom reside in rural areas. Of 90 patients with acute flaccid paralysis, 88 had a distinctive pattern that shares clinical and cerebrospinal fluid findings with demyelinating Guillain-Barré syndrome, but that differs from Guillain-Barré syndrome physiologically and pathologically. The clinical course is marked by rapidly progressive ascending tetraparesis, often with respiratory failure, but without fever, systemic illness, or sensory involvement. Cerebrospinal fluid is acellular, and elevations of protein content occur in the second or third week of illness. Electrodiagnostic studies show normal motor distal latencies and limb conduction velocities, but reduced compound muscle action potential amplitudes. Sensory nerve action potentials and, when elicitable, F waves are within the range of normal. Recovery is usually good. Autopsy studies have shown Wallerian-like degeneration of motor fibers. These studies establish that this is a distinctive syndrome, distinguishable from poliomyelitis and demyelinating Guillain-Barré syndrome.


Differential splicing generates a nervous system-specific form of Drosophila neuroglian.
We recently described the characterization and cloning of Drosophila neuroglian, a member of the immunoglobulin superfamily. Neuroglian contains six immunoglobulin-like domains and five fibronectin type III domains and shows strong sequence homology to the mouse neural cell adhesion molecule L1. Here we show that the neuroglian gene generates at least two different protein products by tissue-specific alternative splicing. The two protein forms differ in their cytoplasmic domains. The long form is restricted to the surface of neurons in the CNS and neurons and some support cells in the PNS; in contrast, the short form is expressed on a wide range of other cells and tissues. Thus, whereas the mouse L1 gene appears to encode only one protein that functions largely as a neural cell adhesion molecule, its Drosophila homolog, the neuroglian gene, encodes at least two protein forms that may play two different roles, one as a neural cell adhesion molecule and the other as a more general cell adhesion molecule involved in other tissues and imaginal disc morphogenesis.


Human myo-inositol monophosphatase 2 rescues the nematode thermotaxis mutant ttx-7 more efficiently than IMPA1: functional and evolutionary considerations of the two mammalian myo-inositol monophosphatase genes.
Mammals express two myo-inositol monophosphatase (IMPase) genes, IMPA1/Impa1 and IMPA2/Impa2. In this study, we compared the spatial expression patterns of the two IMPase gene transcripts and proteins in mouse tissues. Results indicated discrete expression of the two IMPase genes and their protein products in various organs, including the brain. In Caenorhabditis elegans, loss of the IMPase gene, ttx-7, disrupts cellular polarity in RIA neurons, eliciting abnormal thermotaxis behavior. We performed a rescue experiment in mutant nematodes using mammalian IMPases. Human IMPA2 rescued the abnormal behavioral phenotype in the ttx-7 mutants more efficiently than IMPA1. These results raise a question about the phylogenetic origin of IMPases and the biological roles of mammalian IMPase 2 in mammals. Impa2 knockout mice generated in our laboratory, exhibited neither behavioral abnormalities nor a significant reduction in myo-inositol content in the brain and other examined tissues. Given the ability of human IMPA2 to rescue the ttx-7 mutant, and its genetic association with multiple neuropsychiatric disorders, close scrutiny of IMPA2 function and the evolutionary origin of IMPase genes is warranted.


Structural and Biochemical Analyses Reveal the Mechanism of Glutathione S-Transferase Pi 1 Inhibition by the Anti-cancer Compound Piperlongumine.
Glutathione S-transferase pi 1 (GSTP1) is frequently overexpressed in cancerous tumors and is a putative target of the plant compound piperlongumine (PL), which contains two reactive olefins and inhibits proliferation in cancer cells but not normal cells. PL exposure of cancer cells results in increased reactive oxygen species and decreased GSH. These data in tandem with other information led to the conclusion that PL inhibits GSTP1, which forms covalent bonds between GSH and various electrophilic compounds, through covalent adduct formation at the C7-C8 olefin of PL, whereas the C2-C3 olefin of PL was postulated to react with GSH. However, direct evidence for this mechanism has been lacking. To investigate, we solved the X-ray crystal structure of GSTP1 bound to PL and GSH at 1.1 Å resolution to rationalize previously reported structure activity relationship studies. Surprisingly, the structure showed that a hydrolysis product of PL (hPL) was conjugated to glutathione at the C7-C8 olefin, and this complex was bound to the active site of GSTP1; no covalent bond formation between hPL and GSTP1 was observed. Mass spectrometry (MS) analysis of the reactions between PL and GSTP1 confirmed that PL does not label GSTP1. Moreover, MS data also indicated that nucleophilic attack on PL at the C2-C3 olefin led to PL hydrolysis. Although hPL inhibits GSTP1 enzymatic activity in vitro, treatment of cells susceptible to PL with hPL did not have significant anti-proliferative effects, suggesting that hPL is not membrane-permeable. Altogether, our data suggest a model wherein PL is a prodrug whose intracellular hydrolysis initiates the formation of the hPL-GSH conjugate, which blocks the active site of and inhibits GSTP1 and thereby cancer cell proliferation.


Cation-pi interaction in model alpha-helical peptides.
Cation-pi interactions are increasingly recognized as important in chemistry and biology. Here we investigate the cation-pi interaction by determining its effect on the helicity of model peptides using a combination of CD and NMR spectroscopy. The data show that a single Trp/Arg interaction on the surface of a peptide can make a significant net favorable free energy contribution to helix stability if the two residues are positioned with appropriate spacing and orientation. The solvent-exposed Trp-->Arg (i, i + 4) interaction in helices can contribute -0.4 kcal/mol to the helix stability, while no free energy gain is detected if the two residues have the reversed orientation, Arg-->Trp (i, i + 4). The derived free energy is consistent with other experimental results studied in proteins or model peptides on cation-pi interactions. However in the same system the postulated Phe/Arg (i, i + 4) cation-pi interaction provides no net free energy to helix stability. Thus the Trp-->Arg interaction is stronger than Phe-->Arg. The cation-pi interactions are not sensitive to the screening effect by adding neutral salt as indicated by salt titration. Our results are in qualitative agreement with theoretical calculations emphasizing that cation-pi interactions can contribute significantly to protein stability with the order Trp > Phe. However, our and other experimental values are significantly smaller than estimates from theoretical calculations.


Serum leptin and short-term regulation of eating in obese women.
1. Leptin is generally thought to play a key role in the regulation of eating. However, its real role in human eating behaviour is still poorly known. Therefore, the role of leptin in the regulation of eating was examined in obese binge- and non-binge-eating women during exposure to food and food-related stimuli. 2. Eleven binge- and ten non-binge-eating obese women took part in the study. In addition to serum leptin, serum insulin, non-esterified fatty acids, plasma glucose, salivation, the feeling of hunger and the desire to eat were repeatedly measured during the experiment. 3. Serum leptin levels did not differ between the binge- and non-binge-eating women. Neither were leptin levels associated with the feeling of hunger or the desire to eat food, nor with the amount or composition of food eaten. During food exposure leptin levels did not change, whereas at the same time serum insulin levels increased and serum non-esterified fatty acid levels decreased. The change in salivation during food exposure was inversely associated with the fasting leptin level. 4. This study indicates that serum leptin does not play a role in the regulation of eating in obese women, at least not in the short term. Furthermore, leptin levels are not different in obese binge-eating women as compared with obese non-binge-eating women. Interestingly, high fasting leptin levels may be associated with a decreased salivation response in the presence of food and food-related stimuli.


Predictors of HVTN 503 MRK-AD5 HIV-1 gag/pol/nef vaccine induced immune responses.
Phambili, the Merck (MRK)-Adenovirus Type 5 (Ad5) HIV-1 gag/pol/nef subtype B vaccine study, conducted in South Africa, suspended enrollment and vaccination when companion study, Step, was found non-efficacious. Although the vaccine did not prevent HIV-1 infection or lower viral-load setpoint, immune responses recognized clades B and C HIV-1 subtypes. We investigated predictors of the vaccine-induced antigen-specific immune responses. Vaccine-induced immunogenicity was ascertained by interferon-γ ELISpot assays on the first 186 enrolled participants receiving two vaccinations. Analyses, stratified by study arm/sex, were performed on baseline demographics [sex, age, Body Mass Index (BMI), site, Adenovirus Type-5 (Ad5) titer, Herpes Simplex Virus Type-2 (HSV2) status, heavy drinking]. Multivariate logistic regression determined predictors. Of the 186 participants, 53.7% (n = 100) were female, median BMI was 22.5 [IQR: 20.4-27.0], 85.5% (n = 159) were Ad5 seropositive, and 18.8% (n = 35) drank heavily. All vaccine recipients responded to both clade B (n = 87; 47%) and/or C (n = 74; 40%), p = 0.17. In multivariate analysis, female sex [Adjusted Odds Ratio (AOR): 6.478; p = 0.0159], overweight/obese BMI (AOR: 0.186; p = 0.0452), and heavy drinking (AOR: 0.270; p = 0.048) significantly predicted immune response to clade C for any antigens. A marginally significant predictor of clade C-pol antigen was female sex (AOR: 3.182; p = 0.0500). Sex, BMI, and heavy drinking affected vaccine-induced HIV-1 specific immune responses to clade C antigens. The role of female sex and overweight/obese BMI boosting and suppressing vaccine-induced HIV-1 specific immune responses, respectively, requires elucidation, including any effect on HIV vaccine efficacy, especially in the era of colliding epidemics (HIV and obesity).


Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.
We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.


Vitamin D supplementation and serum levels of magnesium and selenium in type 2 diabetes mellitus patients: gender dimorphic changes.
The aim of our study was to evaluate the effects of vitamin D supplementation on circulating levels of magnesium and selenium in patients with type 2 diabetes mellitus (T2DM). A total of 126 adult Saudi patients (55 men and 71 women, mean age 53.6±10.7 years) with controlled T2DM were randomly recruited for the study. All subjects were given vitamin D3 tablets (2000 IU/day) for six months. Follow-up mean concentrations of serum 25-hydroxyvitamin D [25-(OH) vitamin D] significantly increased in both men (34.1±12.4 to 57.8±17.0 nmol/L) and women (35.7±13.5 to 60.1±18.5 nmol/L, p<0.001), while levels of parathyroid hormone (PTH) decreased significantly in both men (1.6±0.17 to 0.96±0.10 pmol/L, p=0.003) and women (1.6±0.17 to 1.0±0.14 pmol/L, p=0.02). In addition, there was a significant increase in serum levels of selenium and magnesium in men and women (p-values<0.001 and 0.04, respectively) after follow-up. In women, a significant correlation was observed between delta change (variables at six months-variable at baseline) of serum magnesium versus high-density lipoprotein (HDL)-cholesterol (r=0.36, p=0.006) and fasting glucose (r=-0.33, p=0.01). In men, there was a significant correlation between serum selenium and triglycerides (r=0.32, p=0.04). Vitamin D supplementation improves serum concentrations of magnesium and selenium in a gender-dependent manner, which in turn could affect several cardiometabolic parameters such as glucose and lipids.


Outcomes of gluteus maximus and tensor fascia lata transfer for primary deficiency of the abductors of the hip.
This study aims to present 3 patients' results after undergoing gluteus maximus and tensor fascia lata (TFL) transfer for chronic abductor tears unable to be repaired primarily. 3 patients were identified intraoperatively as having an abductor tear unable to be repaired primarily. The anterior 1/3 of the gluteus maximus and the posterior 1/3 of the TFL were mobilised and transferred to the greater trochanter in order to reproduce the normal force vector of the gluteus medius and minimus. Data was prospectively collected for changes in gait, abductor strength, and the following patient reported outcomes (PROs): modified Harris Hip Score (mHHS), Nonarthritic Hip Score (NAHS), Hip Outcome Score-Sports Specific Subscale (HOS-SSS), Hip Outcome Score-Activities of Daily Living (HOS-ADL), visual analogue scale (VAS), and satisfaction. The patients were female, 63-75 years old, with BMIs of 23-28. All patients had follow-up at mean 2.1 years (1.25-2.5) with positive Trendelenburg signs preoperatively; 2 patients normalised postoperatively. For 2 patients, abductor strength improved by 2 grades postoperatively; the other patient maintained grade four. 2 patients' PROs all improved; the other patient's PROs all improved except mHHS. Postoperative VAS scores were 0, 0, 1. 2 patients reported maximum satisfaction. This case series suggests that gluteus maximus and TFL transfer for irreparable abductor deficiency may be effective for pain relief, improving abductor strength, and reconstructing abductor function. Although this is a small series, it is to our knowledge the first report of clinical outcomes of this procedure.


Advances in Distinguishing Groundwater Influenced by Oil Sands Process-Affected Water (OSPW) from Natural Bitumen-Influenced Groundwaters.
The objective of this study was to advance analytical methods for detecting oil sands process-affected water (OSPW) seepage from mining containments and discriminating any such seepage from the natural bitumen background in groundwaters influenced by the Alberta McMurray formation. Improved sampling methods and quantitative analyses of two groups of monoaromatic acids were employed to analyze OSPW and bitumen-affected natural background groundwaters for source discrimination. Both groups of monoaromatic acids showed significant enrichment in OSPW, while ratios of O2/O4 containing heteroatomic ion classes of acid extractable organics (AEOs) did not exhibit diagnostic differences. Evaluating the monoaromatic acids to track a known plume of OSPW-affected groundwater confirmed their diagnostic abilities. A secondary objective was to assess anthropogenically derived artificial sweeteners and per- and polyfluoroalkyl substances (PFAS) as potential tracers for OSPW. Despite the discovery of acesulfame and PFAS in most OSPW samples, trace levels in groundwaters influenced by general anthropogenic activities preclude them as individual robust tracers. However, their inclusion with the other metrics employed in this study served to augment the tiered, weight of evidence methodology developed. This methodology was then used to confirm earlier findings of OSPW migrations into groundwater reaching the Athabasca River system adjacent to the reclaimed pond at Tar Island Dyke.


The varus ankle and instability.
Varus ankle associated with instability can be simple or complex. Multiple underlying diseases may contribute to this complex pathologic entity. These conditions should be recognized when attempting proper decision-making. Treatment options range from conservative measures to surgical reconstruction. Whereas conservative treatment might be a possible approach for patients with simple varus ankle instability, more complex instabilities require extensive surgical reconstructions. However, adequate diagnostic workup and accurate analysis of varus ankle instability provide a base for the successful treatment outcome.


Is there a blood-brain barrier at the optic nerve head?
The retina and optic nerve have been demonstrated to possess a blood-brain barrier that prevents the passive passage of protein and certain dyes from the blood vessels into the extracellular space. Our observations suggest that an exception is present at the normal optic disc. Using horseradish peroxidase as a tracer for electron microscopy and the normal rhesus monkey as the experimental animal, we have demonstrated that in certain regions of the optic nerve head, horseradish peroxidase from the blood stream reaches the axons of the optic nerve through the border tissue of Elschnig from the adjacent choridal tissues. A barrier formed by a series of cell junctions between glial cells at the edge of the optic disc prevented spread of the tracer from the optic disc into the subretinal space.


Natural language processing and String Metric-assisted Assessment of Semantic Heterogeneity method for capturing and standardizing unstructured nursing activities in a hospital setting: a retrospective study.
Nurses record data in electronic health records (EHRs) using different terminologies and coding systems. The purpose of this study was to identify unstructured free-text nursing activities recorded by nurses in EHRs with natural language processing (NLP) techniques and to map these nursing activities into standard nursing activities using the SMASH method. A retrospective study using NLP techniques with a unidirectional mapping strategy called SMASH. The unstructured free-text nursing activities recorded in the Medicine, Neurology and Gastroenterology inpatient units of the Agostino Gemelli IRCCS University Hospital Foundation, Rome, Italy were collected for 6 months in 2018. Data were analyzed by three phases: a) text summarization component with NLP techniques, b) a consensus analysis by four experts to detect the category of word stems, and c) cross-mapping with SMASH. The SMASH method calculated the string comparison, similarity and distance of words through the Levenshtein distance (LD), Jaro-Winker distance and the cross-mapping's cut-offs: map [0.80-1.00] with < 13 LD, partial-map [0.50-0.79] with <13 LD and no map [0.0-0.49] with >13 LD. During the study period, 491 patient records were assessed. 548 different unstructured free-text nursing activities were recorded by nurses. 451 unstructured free-text nursing activities (82.3%) were mapped to standard PAI nursing activities, 47 (8.7%) were partial mapped, while 50 (9.0%) were not mapped. This automated mapping yielded recall of 0.95%, precision of 0.94%, accuracy of 0.91%, F-measure of 0.96. The F-measure indicates good reliability of this automated procedure in cross-mapping. Lexical similarities between unstructured free-text nursing activities and standard nursing activities were found, NLP with the SMASH method is a feasible approach to extract data related to nursing concepts that are not recorded through structured data entry.


Bringing together evolution on serpentine and polyploidy: spatiotemporal history of the diploid-tetraploid complex of Knautia arvensis (Dipsacaceae).
Polyploidization is one of the leading forces in the evolution of land plants, providing opportunities for instant speciation and rapid gain of evolutionary novelties. Highly selective conditions of serpentine environments act as an important evolutionary trigger that can be involved in various speciation processes. Whereas the significance of both edaphic speciation on serpentine and polyploidy is widely acknowledged in plant evolution, the links between polyploid evolution and serpentine differentiation have not yet been examined. To fill this gap, we investigated the evolutionary history of the perennial herb Knautia arvensis (Dipsacaceae), a diploid-tetraploid complex that exhibits an intriguing pattern of eco-geographic differentiation. Using plastid DNA sequencing and AFLP genotyping of 336 previously cytotyped individuals from 40 populations from central Europe, we unravelled the patterns of genetic variation among the cytotypes and the edaphic types. Diploids showed the highest levels of genetic differentiation, likely as a result of long term persistence of several lineages in ecologically distinct refugia and/or independent immigration. Recurrent polyploidization, recorded in one serpentine island, seems to have opened new possibilities for the local serpentine genotype. Unlike diploids, the serpentine tetraploids were able to escape from the serpentine refugium and spread further; this was also attributable to hybridization with the neighbouring non-serpentine tetraploid lineages. The spatiotemporal history of K. arvensis allows tracing the interplay of polyploid evolution and ecological divergence on serpentine, resulting in a complex evolutionary pattern. Isolated serpentine outcrops can act as evolutionary capacitors, preserving distinct karyological and genetic diversity. The serpentine lineages, however, may not represent evolutionary 'dead-ends' but rather dynamic systems with a potential to further influence the surrounding populations, e.g., via independent polyplodization and hybridization. The complex eco-geographical pattern together with the incidence of both primary and secondary diploid-tetraploid contact zones makes K. arvensis a unique system for addressing general questions of polyploid research.


Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin.
Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease that prominently features brain malformations (tubers) with many patients suffering from epilepsy and autism. These malformations typically exhibit neuronal as well as glial cell abnormalities and likely underlie much of the neurological morbidity seen in TSC. Tuber pathogenesis remains poorly understood though upregulation of the mTORC1 signaling pathway in TSC has been consistently demonstrated. Here we address abnormal brain development in TSC by inactivating the mouse Tsc1 gene in embryonic neural progenitor cells. This strategy permits evaluation of the role of the Tsc1 gene in both neuronal as well as glial cell lineages. Tsc1(Emx1-Cre) conditional knockout (CKO) animals die by 25 days of life. Their brains have increased size and contain prominent large cells within the cerebral cortex that have greatly increased mTORC1 signaling and decreased mTORC2 signaling. Severe defects of cortical lamination, enlarged dysmorphic astrocytes and decreased myelination were also found. Tsc1(Emx1-Cre) CKO mice were then treated with rapamycin to see if the premature death and brain abnormalities can be rescued. Postnatal rapamycin treatment completely prevented premature death and largely reversed the glia pathology but not abnormal neuronal lamination. These findings support a model that loss of function of the TSC genes in embryonic neural progenitor cells causes cortical malformations in patients with TSC. The dramatic effect of rapamycin suggests that even with extensive multi-lineage abnormalities, a postnatal therapeutic window may exist for patients with TSC.


India's Largest Hospital Insurance Program Faces Challenges In Using Claims Data To Measure Quality.
The routine data generated by India's universal coverage programs offer an important opportunity to evaluate and track the quality of health care systematically and on a large scale. We examined the potential and challenges of measuring the quality of hospital care through claims data from India's hospital insurance program for the poor, Rashtriya Swasthya Bima Yojana (RSBY). Using data from one district in India, we illustrate how these data already provide useful insights and show that simple efforts to enhance data quality and an effort to expand the data captured could facilitate RSBY's ability to track quality of care. The data collected by RSBY has significant potential to characterize and uncover the provision of low-quality care and help inform much-needed efforts to raise the quality of hospital care.


Emotional experiences.
This article pleads for a history of emotional experiences that allows for the understanding of complex emotional phenomena in the past that are not easily accommodated within the history of emotions framework. Following the avenues opened by the anthropology of experience, the article considers different ways in which the history of emotional experiences should allow transhistorical and cross-cultural comparisons. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Understanding rivers and their social relations: A critical step to advance environmental water management.
River flows connect people, places, and other forms of life, inspiring and sustaining diverse cultural beliefs, values, and ways of life. The concept of environmental flows provides a framework for improving understanding of relationships between river flows and people, and for supporting those that are mutually beneficial. Nevertheless, most approaches to determining environmental flows remain grounded in the biophysical sciences. The newly revised Brisbane Declaration and Global Action Agenda on Environmental Flows (2018) represents a new phase in environmental flow science and an opportunity to better consider the co-constitution of river flows, ecosystems, and society, and to more explicitly incorporate these relationships into river management. We synthesize understanding of relationships between people and rivers as conceived under the renewed definition of environmental flows. We present case studies from Honduras, India, Canada, New Zealand, and Australia that illustrate multidisciplinary, collaborative efforts where recognizing and meeting diverse flow needs of human populations was central to establishing environmental flow recommendations. We also review a small body of literature to highlight examples of the diversity and interdependencies of human-flow relationships-such as the linkages between river flow and human well-being, spiritual needs, cultural identity, and sense of place-that are typically overlooked when environmental flows are assessed and negotiated. Finally, we call for scientists and water managers to recognize the diversity of ways of knowing, relating to, and utilizing rivers, and to place this recognition at the center of future environmental flow assessments. This article is categorized under: Water and Life > Conservation, Management, and Awareness Human Water > Water Governance Human Water > Water as Imagined and Represented.


Autobiographical memory specificity and affect regulation: coping with a negative life event.
Two decades of research have shown that depressed patients experience significant difficulties retrieving specific autobiographical memories. Importantly, reduced autobiographical memory (AM) specificity is a known vulnerability factor for depression and is predictive of a more chronic course. One of the models that has been put forward to explain the origin of this reduced specificity is the affect-regulation model, which assumes that being less specific might help to prevent negative or painful emotions by recalling events in a less specific way. This avoidant memory style might have beneficial effects in the short run (less emotional impact of stressful events) but is detrimental in the long run. The affect-regulation model, and more in particular the beneficial short-term effect of reduced memory specificity, was investigated in a prospective study. Students were followed over a period of 9 weeks after they failed at their first exams at university. In line with the affect-regulation model, memory specificity predicted the course of symptoms that were experienced as a result of failing these exams. The less specific the student, the less durable the emotional distress over this 9-week period. The correlational nature of this study limits to some extent the conclusions that can be drawn. The results offer support for the affect-regulation account of reduced autobiographical memory specificity.


Social prediction modulates activity of macaque superior temporal cortex.
The ability to attribute thoughts to others, also called theory of mind (TOM), has been extensively studied in humans; however, its evolutionary origins have been challenged. Computationally, the basis of TOM has been interpreted within the predictive coding framework and associated with activity in the temporoparietal junction (TPJ). Here, we revealed, using a nonlinguistic task and functional magnetic resonance imaging, that activity in a region of the macaque middle superior temporal cortex was specifically modulated by the predictability of social situations. As in human TPJ, this region could be distinguished from other temporal regions involved in face processing. Our result suggests the existence of a precursor for the TOM ability in the last common ancestor of human and Old World monkeys.


Solid and gaseous cerebral microembolization after biologic and mechanical aortic valve replacement: investigation with multirange and multifrequency transcranial Doppler ultrasound.
Cerebral microembolization is a well-recognized phenomenon after cardiac valve replacement, but the relative proportion of solid and gaseous emboli is uncertain. Particulate microemboli are thought to be the most damaging. With the use of multifrequency transcranial Doppler ultrasound, we compared the number and nature of microemboli in recipients of biologic and mechanical aortic valve prostheses. The middle cerebral arteries of 60 patients were monitored bilaterally with a new-generation transcranial Doppler ultrasound (Embo-Dop, DWL Elektronische Systeme GmbH, Singen, Germany) that rejects artefacts online and automatically discriminates between solid and gaseous microemboli. All recordings were performed during a 30-minute period 1 day before and at a mean of 5 days and 3 months after isolated aortic valve replacement with a biologic (30, group B) or mechanical (30, group M) prosthesis. The patients in group B were older, with a mean age of 70.6 +/- 9.7 years versus 55.4 +/- 9.4 years (P < .005) in the patients in group M. Biologic prosthesis recipients were all taking aspirin (no warfarin); patients with mechanical valves were well anticoagulated with warfarin both 5 days and 3 months after surgery. None of the patients had solid microemboli preoperatively. Five days postoperatively, the absolute number of cerebral microemboli was 145 and 594 for total microemboli (P = .001) and 41 and 182 for solid microemboli (P = .002) in groups B and M, respectively. At 3 months, the absolute number was 65 and 608 for total microemboli (P < .001) and 10 and 188 for solid microemboli (P < .001) in groups B and M, respectively. Solid microemboli accounted for 16% of the total microembolic load in group B compared with 31% in group M (P = .05) at 3 months. Solid cerebral microemboli represent approximately one third of the total cerebral microembolic load after mechanical aortic valve replacement and are detectable in the majority of such patients both 5 days and 3 months after surgery. The neurofunctional consequences of this phenomenon should be carefully assessed.


Exploring the acceptability and usability of a novel social innovation to encourage physical activity: The iStep prototype.
This study explored the acceptability and usability of the iStep prototype a novel social innovation to encourage intergenerational physical activity (PA) to help reduce obesity levels in older age. Obesity is a major public health issue and physical inactivity is one of the many factors that influence this, especially in childhood and later life. iStep (a pedometer and interactive website) sought to increase PA levels across the life course through intergenerational partnerships participating in walking challenges together. This was a qualitative mixed methods study involving 130 participants from two different settings. Pupils and teachers from a local secondary school (n = 120) tested the iStep prototype over two separate 2-week periods. Pupil and teacher partnerships engaged in a walking challenge using pedometers and the website platform. In addition, 10 retirement age women were involved in a modified co-operative evaluation of the prototype. Two focus groups with pupils (n = 9 and 20), semistructured interviews with teachers (n = 5), and one dyadic interview (pupil/teacher) were undertaken. Data were analysed using an iterative thematic approach. Five themes were identified: perceptions of the technology, attitudes towards the walking challenge, attitudes to the intergenerational partnership, competition versus collaboration and promoting PA. The pedometer was a useful motivational tool which raised awareness of PA levels. The website was thought to be simple and easy to use. Walking was deemed inclusive and accessible to all age groups and setting a target goal was considered beneficial. Engaging in PA with a partner was regarded as a good way to provide support and encouragement. Overall, this early prototype evaluation showed that iStep has potential to be an innovative and engaging way to encourage increased PA across generations. It may positively contribute towards reducing obesity levels in older age but outcomes that effectively measure this need to be incorporated in any future iStep testing.


Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.
We employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female mice lacking LDL receptors (LDLR-/- mice) were viable and fertile. Total plasma cholesterol levels were twofold higher than those of wild-type litter-mates, owing to a seven- to ninefold increase in intermediate density lipoproteins (IDL) and LDL without a significant change in HDL. Plasma triglyceride levels were normal. The half-lives for intravenously administered 125I-VLDL and 125I-LDL were prolonged by 30-fold and 2.5-fold, respectively, but the clearance of 125I-HDL was normal in the LDLR-/- mice. Unlike wild-type mice, LDLR-/- mice responded to moderate amounts of dietary cholesterol (0.2% cholesterol/10% coconut oil) with a major increase in the cholesterol content of IDL and LDL particles. The elevated IDL/LDL level of LDLR-/- mice was reduced to normal 4 d after the intravenous injection of a recombinant replication-defective adenovirus encoding the human LDL receptor driven by the cytomegalovirus promoter. The virus restored expression of LDL receptor protein in the liver and increased the clearance of 125I-VLDL. We conclude that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirus-encoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.


Structure and function of G protein-coupled receptor oligomers: implications for drug discovery.
G protein-coupled receptor (GPCR) oligomers are promising targets for the design of new highly selective therapeutics. GPCRs have historically been attractive drug targets for their role in nearly all cellular processes, and their localization at the cell surface makes them easily accessible to most small molecule therapeutics. However, GPCRs have traditionally been considered a monomeric entity, a notion that greatly oversimplifies their function. As evidence accumulates that GPCRs tune function through oligomer formation and protein-protein interactions, we see a greater demand for structural information about these oligomers to facilitate oligomer-specific drug design. These efforts are slowed by difficulties inherent to studying membrane proteins, such as low expression yield, in vitro stability and activity. Such obstacles are amplified for the study of specific oligomers, as there are limited tools to directly isolate and characterize these receptor complexes. Thus, there is a need to develop new interdisciplinary approaches, combining biochemical and biophysical techniques, to address these challenges and elucidate structural details about the oligomer and ligand binding interfaces. In this review, we provide an overview of mechanistic models that have been proposed to underlie the function of GPCR oligomers, and perspectives on emerging techniques to characterize GPCR oligomers for structure-based drug design.


Apigenin induced MCF-7 cell apoptosis-associated reactive oxygen species.
Apigenin is a flavonoid, which has been proved to possess effective anti-cancer bioactivities against variety of cell lines. However, little is known about its effect on the cell-surface and the interaction between cell-surface and the reacting drug. In this study, human breast cancer line (MCF-7) was selected to be as a cell model to investigate the effects of apigenin on cell growth, proliferation, apoptosis, cellular morphology, etc. MTT assay showed that the growth inhibition induced by apigenin was in a dose-dependent manner when treated with different concentrations of apigenin while had little cytotoxic effects on human normal cells (MCF-10A). Fluorescence-based flow cytometry was used to detect cellular apoptosis and ROS production. The results showed that 80 µM apigenin could effectively induce apoptosis and overproduction of ROS in MCF-7 cells. Here, atomic force microscopy (AFM) was utilized to detect the shapes and membrane structures of MCF-7 cells at cellular or subcellular level. The results showed that the control MCF-7 cells presented typical elongated-spindle shapes with abundant pseudopodia, while after treated with apigenin, the cells shrunk and became round, the pseudopodia diminished. Moreover, the images of ultrastructure indicated that the cell membrane was composed of nanoparticles of 49 nm, but with the treated concentrations of apigenin increasing, the sizes of membrane particles significantly increased to 400 nm. These results can improve our understanding of apigenin, which can be potentially developed as a new agent for treatment of cancers.


Social integration in global mental health: what is it and how can it be measured?
Purpose. Global mental health movements increasingly highlight social integration as a key outcome for mental health services. This creates a pressing need to better articulate and measure this outcome. Much of the work in social integration thus far has been in high-income countries (HIC), and is not directly applicable across diverse socio-cultural environments. We discuss promising concepts and measures of social integration with potential for global cross-cultural application. Then, we present some of the challenges of developing measures for global and cross-cultural use, and suggest ways to confront these challenges. Although we focus primarily on adults with severe mental disorders in low- and middle-income countries (LMIC), the questions we raise are also relevant to children, other mental disorders and HIC. Findings. We identify and describe four distinct conceptual frameworks for social integration that have emerged over the past decade. Then, we discuss the challenge of developing corresponding measures, and the further challenge of developing global cross-cultural measures. We suggest that a key concept shared across much previous and emerging work is active participation in community and civic life. As a platform for future development of global cross-cultural measures of this and other concepts, we propose guidelines and present examples of feasible, previously used strategies. Summary. Emerging concepts of social integration hold great promise, but as yet, there are no corresponding measures suitable for global cross-cultural use. We propose that it is feasible to develop such measures, and that their development will facilitate the advance of community mental health services and the science of global mental health.


[Pituitary adenoma associated with neurofibromatosis type 1: case report].
A case of pituitary adenoma associated is neurofibromatosis type 1 is reported. On June 6, 2000, a 49-year-old man was admitted to the Department of Neurological Surgery, Okayama University Hospital, for bitemporal hemianopsia. Twenty-nine years previously, he had been operated on for a left inguinal tumor that proved to be a neurofibroma. Based on the presence of other manifestations, such as café-au-lait spots and subcutaneous nodules, he had been diagnosed with neurofibromatosis type 1, the same as his father, sister, and daughter. Computed tomography and magnetic resonance imaging demonstrated an intrasellar mass lesion with a cystic portion in the suprasellar region. Endocrinologically, almost all of his basic hormone levels were normal. A right front-temporal craniotomy was performed for a preoperative diagnosis of craniopharyngioma, and total intracapsular tumor extirpation was achieved. The histological diagnosis was clinically silent corticotroph pituitary adenoma. Neurofibromatosis is sometimes associated with neoplasms of the central nervous system, usually optic gliomas. Associations between pituitary adenomas and NF 1 are very rare and have been reported in only four cases, including the present case.


FIFA World Cup 2006 in Germany: enhanced surveillance improved timeliness and detection.
Enhanced surveillance for infectious disease events, with accelerated routine reporting and daily supplementary reports, was undertaken during the 2006 FIFA World Cup in Germany. We evaluated the surveillance outputs, reporting intervals and detection of World Cup-relevant events for the enhanced system. Outbreak numbers for measles, Norovirus and Campylobacter were significantly higher than in previous years, but all increases were explained by prior trends. The median interval (disease onset to receipt at national centre) fell from 17 days in 2005 to 12 days in 2006. Detection of World Cup-relevant events was 44% (8/18) in the routine system and 77% (14/18) in supplementary reports. We did not identify any significant effect on infectious disease epidemiology relating to the FIFA 2006 World Cup. Daily reporting improved timeliness, and supplementary reporting improved relevant event detection. Enhancing existing systems, without the addition of syndromic surveillance, can be an effective approach to mass-event surveillance.


Receptor-induced death in human natural killer cells: involvement of CD16.
Propriocidal regulation of T cells refers to apoptosis induced by interleukin 2 (IL-2) activation with subsequent antigen receptor stimulation. We examined whether natural killer (NK) cells exhibited cytokine- and ligand-induced death similar to activated T cells. Peripheral NK cells were examined for ligand-induced death using antibodies to surface moieties (CD2, CD3, CD8, CD16, CD56), with and without prior activation of IL-2. Only those NK cells stimulated first with IL-2 and then with CD16 exhibited ligand-induced death; none of the other antibody stimuli induced this phenomenon. Next we examined various cytokines (IL-2, IL-4, IL-6, IL-7, IL-12, IL-13, interferon alpha and gamma) that can activate NK cells and determined if CD16-induced killing occurred. Only IL-2 and IL-12 induced NK cell death after occupancy of this receptor by aggregated immunoglobulin or by cross-linking with antireceptor antibody. The CD16-induced death was inhibited by herbimycin A, indicating that cell death was dependent upon protein tyrosine kinases. Identical to T cells, the form of cell death for NK cells was demonstrated to be receptor-induced apoptosis. Overall these data indicate that highly activated NK cells mediate ligand-induced apoptosis via signaling molecules like CD16. Whereas the propriocidal regulation of T cells is antigen specific, this is not the case for NK cells due to the nature of the receptor. The clinical implications of this finding are considered.


Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients.
Adequate surgery still remains the only curative treatment of chordoma. Interesting clinical data on advanced disease with molecularly targeted therapies were reported. We described the clinical outcome of a series of chordoma patients followed at Regina Elena National Cancer Centre of Rome from 2004 to 2008. Twenty-five consecutive patients with sacral (11 patients), spine (13 patients), and skull base (1 patient) chordoma went to our observation. Six patients (24%) had primary disease, 14(56%) a recurrent disease, and 5(20%) a metastatic spreading. Surgery was the primary option for treatment in 22 out of 25 patients. Surgical margins were wide in 5 (23%) and intralesional in 17(77%) patients; 3 out of 4 in-house treated patients obtained wide margins. After first surgery, radiotherapy (protons or high-energy photons) were delivered to 3 patients. One out of the 5 patients with wide margins is still without evidence of disease at 20 months from surgery; 2 patients died without evidence of disease after 3 and 36 months from surgery. Sixteen out of 17 (94%) patients with intralesional margins underwent local progression at a median time of 18 months with a 2-year local progression-free survival of 47%. The 5-year metastasis-free survival rate was 78.3%. Seventeen patients with locally advanced and/or metastatic disease expressing platelet-derived growth factor receptor (PDGFR) beta were treated with imatinib mesylate. A RECIST stabilization of the disease was the best response observed in all treated cases. Pain relief with reduction in analgesics use was obtained in 6 out of 11 (54%) symptomatic patients. The 5- and 10-year survival rates of the entire series of patients were 76.7 and 59.7%, respectively. Despite progress of surgical techniques and the results obtained with targeted therapy, more effort is needed for better disease control. Specific experience of the multi-disciplinary therapeutic team is, however, essential to succeed in improving patients' outcome.


The Relative Contribution of Executive Functions and Aging on Attentional Control During Road Crossing.
As we age, many physical, perceptual and cognitive abilities decline, which can critically impact our day-to-day lives. However, the decline of many abilities is concurrent; thus, it is challenging to disentangle the relative contributions of different abilities in the performance deterioration in realistic tasks, such as road crossing, with age. Research into road crossing has shown that aging and a decline in executive functioning (EFs) is associated with altered information sampling and less safe crossing decisions compared to younger adults. However, in these studies declines in age and EFs were confounded. Therefore, it is impossible to disentangle whether age-related declines in EFs impact on visual sampling and road-crossing performance, or whether visual exploration, and road-crossing performance, are impacted by aging independently of a decline in EFs. In this study, we recruited older adults with maintained EFs to isolate the impacts of aging independently of a decline EFs on road crossing abilities. We recorded eye movements of younger adults and older adults while they watched videos of road traffic and were asked to decide when they could cross the road. Overall, our results show that older adults with maintained EFs sample visual information and make similar road crossing decisions to younger adults. Our findings also reveal that both environmental constraints and EF abilities interact with aging to influence how the road-crossing task is performed. Our findings suggest that older pedestrians' safety, and independence in day-to-day life, can be improved through a limitation of scene complexity and a preservation of EF abilities.


Elastomeric microposts integrated into microfluidics for flow-mediated endothelial mechanotransduction analysis.
Mechanotransduction is known as the cellular mechanism converting insoluble biophysical signals in the local cellular microenvironment (e.g. matrix rigidity, external mechanical forces, and fluid shear) into intracellular signalling to regulate cellular behaviours. While microfluidic technologies support a precise and independent control of soluble factors in the cellular microenvironment (e.g. growth factors, nutrients, and dissolved gases), the regulation of insoluble biophysical signals in microfluidics, especially matrix rigidity and adhesive pattern, has not yet been achieved. Here we reported an integrated soft lithography-compatible microfluidic methodology that could enable independent controls and modulations of fluid shear, substrate rigidity, and adhesive pattern in a microfluidic environment, by integrating micromolded elastomeric micropost arrays and microcontact printing with microfluidics. The geometry of the elastomeric micropost array could be regulated to mediate substrate rigidity and adhesive pattern, and further the elastomeric microposts could be utilized as force sensors to map live-cell subcellular contractile forces. To illustrate the general application of our methodology, we investigated the flow-mediated endothelial mechanotransduction process and examined specifically the involvement of subcellular contractile forces in the morphological realignment process of endothelial cells under a sustained directional fluid shear. Our results showed that the cytoskeletal contractile forces of endothelial cells were spatiotemporally regulated and coordinated to facilitate their morphology elongation process along the direction of flow. Together, our study provided an integrated microfluidic strategy to modulate the in vitro cellular microenvironment with both defined soluble and insoluble signals, and we demonstrated its application to investigate quantitatively the involvement of cytoskeletal contractile forces in the flow-mediated mechanotransduction process of endothelial cells.


Cognitive Dysfunction, Delirium, and Stroke in Cardiac Surgery Patients.
Neurologic injury in the form of cognitive decline, delirium, and stroke are common phenomena in patients undergoing cardiac surgery and continues to be one of the most common complication after cardiac surgery, in spite of improvements in mortality and and improved surgical and anesthetic techniques. These complications lead to a significant increase in length of stay in the intensive care unit, increased length of hospital admission, and functional impairment, resulting in not only profound negative effects on patients who experience these complications, but also to increased costs of medical care and delivery. We discuss each of these complications in regard to their risks factors, incidence, potential therapeutic modalities, and relevant intraoperative and postoperative considerations.


Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations.
Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.


Differential effects of visual feedback on subjective visual vertical accuracy and precision.
The brain constructs an internal estimate of the gravitational vertical by integrating multiple sensory signals. In darkness, systematic head-roll dependent errors in verticality estimates, as measured by the subjective visual vertical (SVV), occur. We hypothesized that visual feedback after each trial results in increased accuracy, as physiological adjustment errors (A-/E-effect) are likely based on central computational mechanisms and investigated whether such improvements were related to adaptational shifts of perceived vertical or to a higher cognitive strategy. We asked 12 healthy human subjects to adjust a luminous arrow to vertical in various head-roll positions (0 to 120deg right-ear down, 15deg steps). After each adjustment visual feedback was provided (lights on, display of previous adjustment and of an earth-vertical cross). Control trials consisted of SVV adjustments without feedback. At head-roll angles with the largest A-effect (90, 105, and 120deg), errors were reduced significantly (p<0.001) by visual feedback, i.e. roll under-compensation decreased, while precision of SVV was not significantly (p>0.05) influenced. In seven subjects an additional session with two consecutive blocks (first with, then without visual feedback) was completed at 90, 105 and 120deg head-roll. In these positions the error-reduction by the previous visual feedback block remained significant over the consecutive 18-24 min (post-feedback block), i.e., was still significantly (p<0.002) different from the control trials. Eleven out of 12 subjects reported having consciously added a bias to their perceived vertical based on visual feedback in order to minimize errors. We conclude that improvements of SVV accuracy by visual feedback, which remained effective after removal of feedback for ≥18 min, rather resulted from a cognitive strategy than by adapting the internal estimate of the gravitational vertical. The mechanisms behind the SVV therefore, remained stable, which is also supported by the fact that SVV precision - depending mostly on otolith input - was not affected by visual feedback.


Enhancing primary care support for informal carers: A scoping study with professional stakeholders.
Informal carers (i.e. people who provide unpaid care to family and/or friends) are crucial in supporting people with long-term conditions. Caring negatively impacts on carers' health and experiences of health services. Internationally and nationally, policies, legislation, professional guidance and research advocate for health and care services to do more to support carers. This study explored the views of health and social care providers, commissioners and policy makers about the role and scope for strengthening health service support for carers. Twenty-four semi-structured interviews, with 25 participants were conducted, audio-recorded, transcribed verbatim and analysed by thematic analysis. Three main themes emerged: (a) identifying carers, (b) carer support, and (c) assessing and addressing carer needs. Primary care, and other services, were seen as not doing enough for carers but having an important role in identifying and supporting carers. Two issues with carer identification were described, first people not self-identifying as carers and second most services not being proactive in identifying carers. Participants thought that carer needs should be supported by primary care in collaboration with other health services, social care and the voluntary sector. Concerns were raised about primary care, which is under enormous strain, being asked to take on yet another task. There was a clear message that it was only useful to involve primary care in identifying carers and their needs, if benefit could be achieved through direct benefits such as better provision of support to the carer or indirect benefit such as better recognition of the carer role. This study highlights that more could be done to address carers' needs through primary care in close collaboration with other health and care services. The findings indicate the need for pilots and experiments to develop the evidence base. Given the crucial importance of carers, such studies should be a high priority.


Balancing time use for children's fitness and adiposity: Evidence to inform 24-hour guidelines for sleep, sedentary time and physical activity.
Daily time spent on one activity cannot change without compensatory changes in others, which themselves may impact on health outcomes. Optimal daily activity combinations may differ across outcomes. We estimated optimal daily activity durations for the highest fitness and lowest adiposity. Cross-sectional Child Health CheckPoint data (1182 11-12-year-olds; 51% boys) from the population-based Longitudinal Study of Australian Children were used. Daily activity composition (sleep, sedentary time, light physical activity [LPA], moderate-to-vigorous physical activity [MVPA]) was from 8-day, 24-hour accelerometry. We created composite outcomes for fitness (VO2max; standing long jump) and adiposity (waist-to-height ratio; body mass index; fat-to-fat-free log-ratio). Adjusted compositional models regressed activity log-ratios against each outcome. Best activity compositions (optimal time-use zones) were plotted in quaternary tetrahedrons; the overall optimal time-use composition was the center of the overlapping area. Time-use composition was associated with fitness and adiposity (all measures p<0.001). Optimal time use differed for fitness and adiposity. While both maximized MVPA and minimized sedentary time, optimal fitness days had higher LPA (3.4 h) and shorter sleep (8.25 h), but optimal adiposity days had lower LPA (1.0 h) and longer sleep (10.9 h). Balancing both outcomes, the overall optimal time-use composition was (mean [range]): 10.2 [9.5; 10.5] h sleep, 9.9 [8.8; 11.2] h sedentary time, 2.4 [1.8; 3.2] h LPA and 1.5 [1.5; 1.5] h MVPA. Optimal time use for children's fitness and adiposity involves trade-offs. To best balance both outcomes, estimated activity durations for sleep and LPA align with, but for MVPA exceed, 24-h guidelines.


The dependence of the cardiac effects of nifedipine on the responses of the peripheral vascular system.
To elucidate the mechanisms of reduction of left ventricular end-diastolic pressure by nifedipine in certain individuals, we evaluated cardiac and peripheral hemodynamic responses in 32 patients after they were randomly assigned to nifedipine (20 mg sublingually) or to placebo treatment. Forearm plethysmography was performed during cardiac catheterization with micromanometers. No hemodynamic parameters were changed after placebo. Left ventricular end-diastolic pressure declined by 14% (p less than .02) after nifedipine in patients with impaired left ventricular function, but was unchanged in those with normal function; indexes of peripheral venous hemodynamics (forearm venous tone, forearm volume change) were not affected. In those patients with abnormal left ventricular function, forearm vascular resistance decreased 36% and forearm blood flow increased 31% (p less than .0005 for both), while neither changed in those with normal function. Cardiac output increased by 10% in patients with impaired left ventricular function but was unchanged in the remainder, while calculated total systemic resistance fell by 24% in those with abnormal left ventricular function (p less than .002 for both). Thus, reduction of left ventricular preload by nifedipine is not attributable to venous pooling, but rather this beneficial effect appears to be attributable to improved left ventricular systolic function in response to afterload reduction, particularly in patients with impaired left ventricular function.


Interaction of hemoglobin derivatives with liposomes. Membrane cholesterol protects against the changes of hemoglobin.
Hemoglobin (Hb) was incubated with small unilamellar vesicles of different lipid compositions in physiological or low pH-low ionic strength media, and the alterations in the protein and bilayer structure were analyzed by measuring (i) the sedimentation properties and elution pattern of the vesicles upon gel filtration, (ii) the quenching effect of Hb on the fluorescence of membrane-embedded probes, (iii) the intrinsic fluorescence of Hb, and (iv) the Soret spectra of Hb. The results indicate complex formation between Hb and the membrane, followed by intercalation of the protein into the bilayer. These processes can lead to secondary alterations, including aggregation, peroxidative decomposition of unsaturated fatty acids, unfolding of Hb, oxidation of the heme iron, displacement of the heme relative to globin, and oxidative or nonoxidative deconjugation of the porphyrin ring. Complex formation and intercalation of Hb into the bilayer are primarily due to hydrophobic interaction between the protein and the membrane, whereas displacement of the heme and its nonoxidative deconjugation are elicited by ionic interaction between the heme and negative membrane surface charges. These charges, on the other hand, inhibit the oxidative processes in unsaturated lipid vesicles. The rate and extent of alterations both in the protein and in the membrane show inverse correlation with the stability of the heme-globin linkage. The liquid-crystalline phase state promotes the penetration of Hb into the bilayer, whereas displacement of the heme is most expressed in the case of saturated bilayers in the gel state. Cholesterol inhibits both the hydrophobic and ionic interactions between the protein and bilayer, most remarkably the partition of the heme into negatively charged saturated bilayers. It is suggested that the effects of cholesterol are mediated through changes in membrane fluidity.


Systematic study of osteoblast response to nanotopography by means of nanoparticle-density gradients.
Features over a wide range of length scales affect the biological response to a surface. While the influence of micro-features has been extensively studied, the effect of nano-features has only rarely been systematically investigated. We have developed a simple method to produce nano-featured gradients by kinetically controlled adsorption of negatively charged silica nanoparticles onto positively charged, poly(ethylene imine) (PEI)-coated silicon wafers. Subsequent sintering of the particles allowed a tuning of the particle morphology and resulted in a firm anchoring of the particles to the surface. Particle-density gradients were characterized by atomic force microscopy (AFM). Cell experiments with rat calvarial osteoblasts (RCO) on nano-featured gradients exhibited a significant decrease in proliferation at locations with higher particle coverage. Seven days post seeding, the number of osteoblasts was eight times higher at positions without particles compared to positions with maximum particle coverage. While cells spread well and developed a well-organized actin network in the absence of particles, spreading and formation of a strong actin network was considerably hindered at locations with maximum particle density.


Symptoms are a poor indicator of reflux status after fundoplication for gastroesophageal reflux disease: role of esophageal functions tests.
If a patient develops foregut symptoms after a fundoplication, it is assumed that the operation has failed, and acid-reducing medications are often prescribed. Esophageal function tests (manometry and pH monitoring) are seldom performed early in the management of these patients. In patients who are symptomatic after fundoplication for gastroesophageal reflux disease, a symptom-based diagnosis is not accurate, and esophageal function tests should be performed routinely before starting acid-reducing medications. Prospective study. University hospital. One hundred twenty-four patients who developed foregut symptoms after laparoscopic fundoplication (average, 17 months postoperatively) underwent esophageal manometry and pH monitoring. Sixty-two patients (50%) were taking acid-reducing medications. Postoperative symptoms, use of antireflux medications, grade of esophagitis, esophageal motility, and DeMeester scores. Seventy-six (61%) of the 124 patients had normal esophageal acid exposure, while the acid exposure was abnormal in 48 patients (39%). Only 20 (32%) of the 62 patients who were taking acid-reducing medications had reflux postoperatively. Regurgitation was the only symptom that predicted abnormal reflux. These results show that (1) symptoms were due to reflux in 39% of patients only; (2) with the exception of regurgitation, symptoms were an unreliable index of the presence of reflux; and (3) 68% of patients who were taking acid-reducing medications postoperatively had a normal reflux status. Esophageal function tests should be performed early in the evaluation of patients after fundoplication to avoid improper and costly medical therapy.


The organoid-initiating cells in mouse pancreas and liver are phenotypically and functionally similar.
Pancreatic Lgr5 expression has been associated with organoid-forming epithelial progenitor populations but the identity of the organoid-initiating epithelial cell subpopulation has remained elusive. Injury causes the emergence of an Lgr5(+) organoid-forming epithelial progenitor population in the adult mouse liver and pancreas. Here, we define the origin of organoid-initiating cells from mouse pancreas and liver prior to Lgr5 activation. This clonogenic population was defined as MIC1-1C3(+)/CD133(+)/CD26(-) in both tissues and the frequency of organoid initiation within this population was approximately 5% in each case. The transcriptomes of these populations overlapped extensively and showed enrichment of epithelial progenitor-associated regulatory genes such as Sox9 and FoxJ1. Surprisingly, pancreatic organoid cells also had the capacity to generate hepatocyte-like cells upon transplantation to Fah(-/-) mice, indicating a differentiation capacity similar to hepatic organoids. Although spontaneous endocrine differentiation of pancreatic progenitors was not observed in culture, adenoviral delivery of fate-specifying factors Pdx1, Neurog3 and MafA induced insulin expression without glucagon or somatostatin. Pancreatic organoid cultures therefore preserve many key attributes of progenitor cells while allowing unlimited expansion, facilitating the study of fate determination.


Long-term outcomes in primary spinal osteochondroma: a multicenter study of 27 patients.
OBJECT Clinical outcomes in patients with primary spinal osteochondromas are limited to small series and sporadic case reports. The authors present data on the first long-term investigation of spinal osteochondroma cases. METHODS An international, multicenter ambispective study on primary spinal osteochondroma was performed. Patients were included if they were diagnosed with an osteochondroma of the spine and received surgical treatment between October 1996 and June 2012 with at least 1 follow-up. Perioperative prognostic variables, including patient age, tumor size, spinal level, and resection, were analyzed in reference to long-term local recurrence and survival. Tumor resections were compared using Enneking appropriate (EA) or Enneking inappropriate surgical margins. RESULTS Osteochondromas were diagnosed in 27 patients at an average age of 37 years. Twenty-two lesions were found in the mobile spine (cervical, thoracic, or lumbar) and 5 in the fixed spine (sacrum). Twenty-three cases (88%) were benign tumors (Enneking tumor Stages 1-3), whereas 3 (12%) exhibited malignant changes (Enneking tumor Stages IA-IIB). Sixteen patients (62%) underwent en bloc treatment-that is, wide or marginal resection-and 10 (38%) underwent intralesional resection. Twenty-four operations (92%) followed EA margins. No one received adjuvant therapy. Two patients (8%) experienced recurrences: one in the fixed spine and one in the mobile spine. Both recurrences occurred in latent Stage 1 tumors following en bloc resection. No osteochondroma-related deaths were observed. CONCLUSIONS In the present study, most patients underwent en bloc resection and were treated as EA cases. Both recurrences occurred in the Stage 1 tumor cohort. Therefore, although benign in character, osteochondromas still require careful management and thorough follow-up.


Diverse Mesorhizobium bacteria nodulate native Astragalus and Oxytropis in arctic and subarctic areas in Eurasia.
Rhizobia nodulating native Astragalus and Oxytropis spp. in Northern Europe are not well-studied. In this study, we isolated bacteria from nodules of four Astragalus spp. and two Oxytropis spp. from the arctic and subarctic regions of Sweden and Russia. The phylogenetic analyses were performed by using sequences of three housekeeping genes (16S rRNA, rpoB and recA) and two accessory genes (nodC and nifH). The results of our multilocus sequence analysis (MLSA) of the three housekeeping genes tree showed that all the 13 isolates belonged to the genus Mesorhizobium and were positioned in six clades. Our concatenated housekeeping gene tree also suggested that the isolates nodulating Astragalus inopinatus, Astragalus frigidus, Astragalus alpinus ssp. alpinus and Oxytropis revoluta might be designated as four new Mesorhizobium species. The 13 isolates were grouped in three clades in the nodC and nifH trees. 15N analysis suggested that the legumes in association with these isolates were actively fixing nitrogen.


Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele.
A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P=0.0002, summary odds ratio=2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative beta-catenin binding sites. Expression of Fat, Catnb (beta-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P=0.027), and Catnb and Enah were significantly upregulated (P=0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P=0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.


Effectiveness and cost-effectiveness of telehealthcare for chronic obstructive pulmonary disease: study protocol for a cluster randomized controlled trial.
Several feasibility studies show promising results of telehealthcare on health outcomes and health-related quality of life for patients suffering from chronic obstructive pulmonary disease, and some of these studies show that telehealthcare may even lower healthcare costs. However, the only large-scale trial we have so far - the Whole System Demonstrator Project in England - has raised doubts about these results since it conclude that telehealthcare as a supplement to usual care is not likely to be cost-effective compared with usual care alone. The present study is known as 'TeleCare North' in Denmark. It seeks to address these doubts by implementing a large-scale, pragmatic, cluster-randomized trial with nested economic evaluation. The purpose of the study is to assess the effectiveness and the cost-effectiveness of a telehealth solution for patients suffering from chronic obstructive pulmonary disease compared to usual practice. General practitioners will be responsible for recruiting eligible participants (1,200 participants are expected) for the trial in the geographical area of the North Denmark Region. Twenty-six municipality districts in the region define the randomization clusters. The primary outcomes are changes in health-related quality of life, and the incremental cost-effectiveness ratio measured from baseline to follow-up at 12 months. Secondary outcomes are changes in mortality and physiological indicators (diastolic and systolic blood pressure, pulse, oxygen saturation, and weight). There has been a call for large-scale clinical trials with rigorous cost-effectiveness assessments in telehealthcare research. This study is meant to improve the international evidence base for the effectiveness and cost-effectiveness of telehealthcare to patients suffering from chronic obstructive pulmonary disease by implementing a large-scale pragmatic cluster-randomized clinical trial. Clinicaltrials.gov, http://NCT01984840, November 14, 2013.


Current practice trends of oedema management in the hands of people with tetraplegia in Australia.
Survey research design. To describe current practice methods for oedema management in people with tetraplegia. Australia. Online survey with open and closed questions regarding clinical practice trends in the assessment and treatment of oedema in the hands in people with tetraplegia. Seventeen occupational therapists working in spinal cord injury (SCI) in Australia completed the survey. Oedema was identified by visual inspection (n = 17, 100%) and recorded using circumferential tape measurement (n = 13, 76%). Elevation was used by all participants in conjunction with compression gloves (n = 13, 76%), retrograde massage (n = 13, 76%), compression bandaging (n = 12, 71%) and the boxing glove splint (n = 9, 53%). Participants stated that oedema presented challenges to patients with difficulty exercising (n = 11, 65%), changes to body image (n = 5, 29%) and pain (n = 4, 24%). Assessment and treatment practices were not consistent. Oedema in the hands in people with tetraplegia was perceived to have various impacts on a person's rehabilitation and hand function. The findings highlight the need for research evidence to guide practice.


Cell-Free Fetal DNA, Telomeres, and the Spontaneous Onset of Parturition.
Multiple previous reports have provided compelling support for the premise that spontaneous parturition is mediated by activation of inflammation-related signaling pathways leading to increased secretion of cytokines and chemokines, the influx of neutrophils and macrophages into the pregnant uterus, increased production of uterine activation proteins (eg, connexin-43, cyclo-oxygenase-2, oxytocin receptors, etc), activation of matrix metalloproteinases, and the release of uterotonins leading to cervical ripening, membrane rupture, and myometrial contractions. The missing link has been the fetal/placental signal that triggers these proinflammatory events in the absence of microbial invasion and intrauterine infection. This article reviews the biomedical literature regarding the increase in cell-free fetal DNA (cffDNA), which is released during apoptosis in the placenta and fetal membranes at term, the ability of apoptosis modified vertebrate DNA to stimulate toll-like receptor-9 (TLR9) leading to increased release of cytokines and chemokines, and the potential "fail-safe" role for the anti-inflammatory cytokine IL-10. This article also reviews the literature supporting the key role that telomere loss plays in regard to increasing the ability of vertebrate (including placental) DNA to stimulate TLR9, and in regard to signaling the onset of apoptosis in the placenta and fetal membranes, thereby providing a biologic clock that determines the length of gestation and the timing for the onset of parturition. In summary, this literature review provides a strong rationale for future research to test the hypothesis that telomere loss and increased cffDNA levels trigger the proinflammatory events leading to the spontaneous onset of parturition in mammals: the "cffDNA/telomere hypothesis."


Geographical differences in autoantibodies and anti-infectious agents antibodies among healthy adults.
Much is known about the geoepidemiology of defined autoimmune diseases (AD); however, there is currently limited data regarding the prevalence of autoantibodies among healthy populations of different geographical areas. The aim of this study was to evaluate a large profile of autoantibodies in healthy adults from distinct global regions as well as the prevalence of anti-infectious agents antibodies in those regions. Sera samples from 557 healthy donors were obtained at six centers located in different countries (i.e., Italy, Netherlands, Israel, Mexico, Columbia, Papua New Guinea (Kitavans)). Sera were tested for the presence of antinuclear antibodies (ANA) and autoantibodies associated with thrombophilia, vasculitis, and gastrointestinal (GI) disease. Sera samples were also screened for antibodies against infectious agents (i.e., EBV, CMV, HBV, Helicobacter pylori, Treponema pallidum, and Toxoplasma gondii). Tests were performed using the BioPlex 2200 or ELISA kits (Bio-Rad Laboratories, USA). We found a significant gradient of ANA positivity among the groups: 45% of Columbians, 38% of Kitavans, 26% of Mexicans, 12% of Italians, 12% of Dutch, and 11% of Israelis were ANA positive. Geographical differences were also observed regarding the prevalence of specific autoantibodies, namely ANA: anti-dsDNA, chromatin, SmRNP, Ro/SSA, La/SSB, Scl70; GI associated: antigliadin; and thrombophilia-associated: anti-β2GP1 and prothrombin. Additionally, significant differences were observed regarding serological markers of all infectious agents screened. The observed variance between healthy ethno-geographical distinct populations in prevalence of autoantibodies may represent different genetic or environmental (e.g., prior exposure to infection) influences. Thus may illuminate possible causes of geoepidemiological differences in AD.


Raised plasma glutathione S-transferase values in hyperthyroidism and in hypothyroid patients receiving thyroxine replacement: evidence for hepatic damage.
Using plasma glutathione S-transferase measurements hepatocellular integrity was assessed in groups of hyperthyroid and hypothyroid patients before and after treatment. Ten of 14 hyperthyroid patients had clearly raised plasma glutathione S-transferase values at presentation and in each patient treatment with either iodine-131 or carbimazole resulted in a significant fall in glutathione S-transferase. The eight hypothyroid patients had normal glutathione S-transferase values at presentation and all showed a significant increase in these after thyroxine replacement therapy. In three of these patients in whom standard doses of replacement therapy were associated with a raised free thyroxine (T4) concentration but normal total and free triiodothyronine (T3) values glutathione S-transferase was increased. Similar though less consistent changes were seen in the results of standard chemical tests of liver function. It is concluded that hyperthyroidism may produce subclinical liver damage in a high proportion of patients and that this resolves with effective treatment. More important, the data suggest that hypothyroid patients receiving thyroxine replacement therapy may have similar subclinical liver damage. Patients receiving thyroxine should be monitored by the measurement of free, not total hormone concentrations, and in those in whom free T4 is raised the dose of thyroxine should be reduced. It would also be expedient to include periodic biochemical assessment of liver function in patients receiving thyroxine.


Circulating Biomarkers of Gut Barrier Function: Correlates and Nonresponse to Calcium Supplementation among Colon Adenoma Patients.
Gut barrier dysfunction contributes to several gastrointestinal disorders, including colorectal cancer, but factors associated with intestinal hyperpermeability have been minimally studied in humans. We tested the effects of two doses of calcium (1.0 or 2.0 g/d) on circulating biomarkers of gut permeability [anti-flagellin and anti-lipopolysaccharide (LPS) Ig, measured via ELISA] over a 4-month treatment period among colorectal adenoma patients in a randomized, double-blinded, placebo-controlled clinical trial (n = 193), and evaluated the factors associated with baseline levels of these biomarkers. Baseline concentrations of anti-flagellin IgA and anti-LPS IgA were, respectively, statistically significantly proportionately higher by 11.8% and 14.1% among men, 31.3% and 39.8% among those with a body mass index ≥ 35 kg/m(2), and 19.9% and 22.0% among those in the upper relative to the lowest sex-specific tertile of waist circumference. A combined permeability score (the summed optical densities of all four biomarkers) was 24.3% higher among women in the upper tertile of plasma C-reactive protein (Ptrend < 0.01). We found no appreciable effects of supplemental calcium on anti-flagellin or anti-LPS Igs. Our results suggest that (i) men and those with higher adiposity may have greater gut permeability, (ii) gut permeability and systemic inflammation may be directly associated with one another, and (iii) supplemental calcium may not modify circulating levels of gut permeability biomarkers within 4 months. Our findings may improve the understanding of the factors that influence gut permeability to inform development of treatable biomarkers of risk for colorectal cancer and other health outcomes.