Subcellular localization and tissue distribution of sialic acid precursor-forming enzymes.
The enzymes UDP-N-acetylglucosamine pyrophosphorylase, UDP-N-acetylglucosamine 2-epimerase, N-acetylmannosamine kinase, N-acetylglucosamine kinase and N-acetylglucosamine 2-epimerase, which are involved in the metabolism of N-acetylneuraminic acid, were studied in rat with regard to their subcellular localization and tissue distribution. The subcellular distribution studies in liver indicated that the enzymes are localized in the soluble cell fraction. In other tissues the comparison of enzyme activities in homogenates with that in high-speed supernatants led to a similar conclusion. UDP-N-acetylglucosamine pyrophosphorylase, N-acetylglucosamine kinase and N-acetylglucosamine 2-epimerase were detected in almost all tissues studied. UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase, two enzymes considered to be key enzymes in the N-acetylneuraminic acid biosynthesis, were detected only in sialoglycoprotein-secreting tissues, i.e. liver, salivary gland and intestinal mucosa. The low activity of the key enzymes in other tissues suggests that the biosynthetic pathway of N-acetylneuraminic acid is not the same in various tissues.


Incidence of post-transfusion hepatitis in Taiwan before and after introduction of anti-HCV testing.
The effectiveness of second-generation anti-hepatitis C virus antibody (anti-HCV) screening of blood donations for the prevention of non-A, non-B post-transfusion hepatitis (NANB PTH) was assessed. A prospective study of 192 transfusion recipients was performed to compare the incidence of NANB PTH after the introduction of the second-generation anti-HCV test with the incidence before its introduction. We used a polymerase chain reaction to detect HCV-RNA and HBV-DNA in the sera of patients with NANB PTH. The incidence of acute post-transfusion hepatitis C was 11% (8 of 71) before the screening for anti-HCV as compared with 2.5% (3 of 121) after the screening (p < 0.05). Viremia was detected within the first five weeks of infection in 10 patients with acute post-transfusion hepatitis C. However, there was no significant difference in the incidence of non-A, non-B, non-C (NANBNC) PTH before screening (3 of 71, 4.2%) compared with after screening (3 of 121, 2.5%). Usually, NANBNC PTH was not clinically important. Anti-HCV screening of blood donors significantly reduces the incidence of post-transfusion hepatitis C, but not the incidence of NANBNC PTH.


Telehealth Opportunities in the COVID-19 Pandemic Early Days: What Happened, Did Not Happen, Should Have Happened, and Must Happen in the Near Future?
The objective of this communication is to offer a better understanding of the value of telemedicine in health care, particularly its role in creating opportunities for continuity of care to patients in a complex and novel setting as were the circumstances of the early COVID-19 pandemic times. Crisis time is also a time for opportunities. With regard to telehealth, all players (providers, staff, and patients) should be informed about its benefits and should also become familiar with the use of the various telehealth options and this will only be achieved through large information campaigns necessary enriched by local teaching and training programs in both public and private institutions. The final aim is to launch the debate and foster ideas useful throughout the pandemic. This article covers the experiences of physicians as well as health professionals in the Iberian Peninsula (Spain and Portugal), to provide a clearer idea of what has happened and how we can improve it with the possibilities provided by telemedicine, while at the same time to put in evidence that public health systems need to be rethought to provide solutions to situations such as that we are experiencing.


[Hydrogen sulfide water balneum effect on erythrocyte superoxide dismutase activity in patients with rheumatoid arthritis--in vitro study].
The aim of the study was to investigate, in vitro, hydrogen sulphide water balneum effect on erythrocyte superoxide dismutase activity in patients with rheumatoid arthritis. Erythrocytes from 29 consecutive patients with rheumatoid arthritis (11 men, 18 women) aged 54 years were obtained. The control group comprised of 30 healthy subjects with a mean age of about 40 years. Patients with rheumatoid arthritis were subdivided into two groups: with active disease (18 patients) and in remission (11 patients), and secondly into patients receiving (21 subjects) and not receiving (8 subjects) non-steroidal anti-inflammatory drugs. For erythrocyte superoxide dismutase activity evaluation, with method of Misra i Fridovich was used. Superoxide dismutase activity was assessed after 5, 10, 15, and 20 minutes erythrocytes incubation with hydrogen sulphide water. The mean baseline erythrocyte superoxide dismutase activity (T0) was in rheumatoid arthritis patients 1589.95+/-208.41 U/gHb and was 1622.12+/-321+/-321.58 U/gHb in the control group (ns). After 5 and 10 minutes of incubation with hydrogen sulphide water T0-T5 i T5-T10 erythrocyte superoxide dismutase activity increased significantly (p<0.05) in rheumatoid arthritis patients. In rheumatoid arthritis patients erythrocyte superoxide dismutase activity was higher and increased significantly when compared with control group. It seems that hydrogen sulphide water balneum produces an antioxidant effect on erythrocyte status in patients with rheumatoid arthritis.


Comparison of glucosamine sulfate and a polyherbal supplement for the relief of osteoarthritis of the knee: a randomized controlled trial [ISRCTN25438351].
The efficacy and safety of a dietary supplement derived from South American botanicals was compared to glucosamine sulfate in osteoarthritis subjects in a Mumbai-based multi-center, randomized, double-blind study. Subjects (n = 95) were screened and randomized to receive glucosamine sulfate (n = 47, 1500 mg/day) or reparagen (n = 48, 1800 mg/day), a polyherbal consisting of 300 mg of vincaria (Uncaria guianensis) and 1500 mg of RNI 249 (Lepidium meyenii) administered orally, twice daily. Primary efficacy variable was response rate based on a 20% improvement in WOMAC pain scores. Additional outcomes were WOMAC scores for pain, stiffness and function, visual analog score (VAS) for pain, with assessments at 1, 2, 4, 6 and 8 weeks. Tolerability, investigator and subject global assessments and rescue medication consumption (paracetamol) were measured together with safety assessments including vital signs and laboratory based assays. Subject randomization was effective: age, gender and disease status distribution was similar in both groups. The response rates (20% reduction in WOMAC pain) were substantial for both glucosamine (89%) and reparagen (94%) and supported by investigator and subject assessments. Using related criteria response rates to reparagen were favorable when compared to glucosamine. Compared to baseline both treatments showed significant benefits in WOMAC and VAS outcomes within one week (P < 0.05), with a similar, progressive improvement over the course of the 8 week treatment protocol (45-62% reduction in WOMAC or VAS scores). Tolerability was excellent, no serious adverse events were noted and safety parameters were unchanged. Rescue medication use was significantly lower in the reparagen group (p < 0.01) at each assessment period. Serum IGF-1 levels were unaltered by treatments. Both reparagen and glucosamine sulfate produced substantial improvements in pain, stiffness and function in subjects with osteoarthritis. Response rates were high and the safety profile was excellent, with significantly less rescue medication use with reparagen. Reparagen represents a new natural productive alternative in the management of joint health. Current Controlled Trials ISRCTN25438351.


Electronic structural critique of interesting thermal and optical properties of C17Ge germagraphene.
In this communication, we report a theoretical attempt to understand the involvement of the electronic structure in determining the optical and thermal properties of C17Ge germagraphene, a buckled two-dimensional material. The structure is found to be a direct bandgap semiconductor with low carrier effective mass. Our study has revealed the effect of spin-orbit coupling on the band structure, and the appearance of spin Hall current on the material. The selectively high blue to ultraviolet light absorption, and a refractive index comparable to flint glass, open up the possible applicability of this material for optical devices. From an electronic structural point of view, we investigate the reason behind its moderately high Seebeck coefficient and power factor which are comparable to traditional thermoelectric materials. Besides its narrow bandgap and relatively smaller work function of 4.361 eV, compared to graphene (4.390 eV) and germanene (4.682 eV), ensures easier removal of electrons from the surface. This material turns out to be an excellent alternative for future semiconductor applications, from optical to thermal devices.


Role of ATF4 in skeletal muscle atrophy.
Here, we discuss recent work focused on the role of activating transcription factor 4 (ATF4) in skeletal muscle atrophy. Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression; however, the transcriptional regulatory proteins responsible for those changes are not yet well defined. Recent work indicates that some forms of muscle atrophy require ATF4, a stress-inducible bZIP transcription factor subunit that helps to mediate a broad range of stress responses in mammalian cells. ATF4 expression in skeletal muscle fibers is sufficient to induce muscle fiber atrophy and required for muscle atrophy during several stress conditions, including aging, fasting, and limb immobilization. By helping to activate specific genes in muscle fibers, ATF4 contributes to the expression of numerous mRNAs, including at least two mRNAs (Gadd45a and p21) that encode mediators of muscle fiber atrophy. Gadd45a promotes muscle fiber atrophy by activating the protein kinase MEKK4. p21 promotes atrophy by reducing expression of spermine oxidase, a metabolic enzyme that helps to maintain muscle fiber size under nonstressed conditions. In skeletal muscle fibers, ATF4 is critical component of a complex and incompletely understood molecular signaling network that causes muscle atrophy during aging, fasting, and immobilization.


p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response.
Autophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress.


PLIS: A metabolomic response monitor to a lifestyle intervention study in older adults.
The response to lifestyle intervention studies is often heterogeneous, especially in older adults. Subtle responses that may represent a health gain for individuals are not always detected by classical health variables, stressing the need for novel biomarkers that detect intermediate changes in metabolic, inflammatory, and immunity-related health. Here, our aim was to develop and validate a molecular multivariate biomarker maximally sensitive to the individual effect of a lifestyle intervention; the Personalized Lifestyle Intervention Status (PLIS). We used 1 H-NMR fasting blood metabolite measurements from before and after the 13-week combined physical and nutritional Growing Old TOgether (GOTO) lifestyle intervention study in combination with a fivefold cross-validation and a bootstrapping method to train a separate PLIS score for men and women. The PLIS scores consisted of 14 and four metabolites for females and males, respectively. Performance of the PLIS score in tracking health gain was illustrated by association of the sex-specific PLIS scores with several classical metabolic health markers, such as BMI, trunk fat%, fasting HDL cholesterol, and fasting insulin, the primary outcome of the GOTO study. We also showed that the baseline PLIS score indicated which participants respond positively to the intervention. Finally, we explored PLIS in an independent physical activity lifestyle intervention study, showing similar, albeit remarkably weaker, associations of PLIS with classical metabolic health markers. To conclude, we found that the sex-specific PLIS score was able to track the individual short-term metabolic health gain of the GOTO lifestyle intervention study. The methodology used to train the PLIS score potentially provides a useful instrument to track personal responses and predict the participant's health benefit in lifestyle interventions similar to the GOTO study.


Changes occurring in chloroplasts of Phaseolus following infection by Sclerotinia: a cytochemical study.
Dramatic changes occur in the ultrastructure of chloroplasts within host tissues during the infection of Phaseolus by the plant pathogenic fungus Sclerotinia. Electron-opaque deposits develop initially in the peripheral region of the chloroplast stroma, in cells in advance of the hyphal front. As infection continues, the amount and intensity of deposition increases and spreads throughout the chloroplast. The deposits possess a high degree of structural integrity in the form of a crystalline square lattice with 10 nm periodicity. Enzyme digestion studies have been used to show that the deposits are proteinaceous. Similar deposits are also induced by treatment with oxalic and citric acids, but not by the potassium salts of these acids buffered at pH 7.2. It is suggested that a pH change within the chloroplasts, resulting from oxalic acid secretion by the fungus, is responsible for induction of protein deposition. The likelihood that the deposits are ribulose, 1,5-bisphosphate carboxylase-oxygenase is discussed.


No evidence of inbreeding depression in fast declining herds of migratory caribou.
Identifying inbreeding depression early in small and declining populations is essential for management and conservation decisions. Correlations between heterozygosity and fitness (HFCs) provide a way to identify inbreeding depression without prior knowledge of kinship among individuals. In Northern Quebec and Labrador, the size of two herds of migratory caribou (Rivière-George, RG and Rivière-aux-Feuilles, RAF) has declined by one to two orders of magnitude in the last three decades. This raises the question of a possible increase in inbreeding depression originating from, and possibly contributing to, the demographic decline in those populations. Here, we tested for the association of genomic inbreeding indices (estimated with 22,073 SNPs) with body mass and survival in 400 caribou sampled in RG and RAF herds between 1996 and 2016. We found no association of individual heterozygosity or inbreeding coefficient with body mass or annual survival. Furthermore, those genomic inbreeding indices remained stable over the period monitored. These results suggest that the rapid and intense demographic decline of the herds did not cause inbreeding depression in those populations. Although we found no evidence for HFCs, if demographic decline continues, it is possible that such inbreeding depression would be triggered.


Point Prevalence Survey of Antimicrobial Use and Resistance during the COVID-19 Era among Hospitals in Saudi Arabia and the Implications.
The inappropriate prescribing of antimicrobials increases antimicrobial resistance (AMR), which poses an appreciable threat to public health, increasing morbidity and mortality. Inappropriate antimicrobial prescribing includes their prescribing in patients hospitalized with COVID-19, despite limited evidence of bacterial infections or coinfections. Knowledge of current antimicrobial utilization in Saudi Arabia is currently limited. Consequently, the objective of this study was to document current antimicrobial prescribing patterns among Saudi hospitals during the COVID-19 pandemic. This study included patients with or without COVID-19 who were admitted to five hospitals in Makkah, Saudi Arabia. Data were gathered using the Global PPS methodology and analyzed using descriptive statistics. Out of 897 hospitalized patients, 518 were treated with antibiotics (57.7%), with an average of 1.9 antibiotics per patient. There were 174 culture reports collected, representing 36.5% of all cases. The most common indication for antibiotics use was community-acquired infections, accounting for 61.4% of all cases. 'Watch' antibiotics were the most commonly prescribed antibiotics, with the cephalosporins and carbapenems representing 38.7% of all antibiotics prescribed, followed by the penicillins (23.2%). Notably, Piperacillin/Tazobactam and Azithromycin were prescribed at relatively higher rates for COVID-19 patients. These findings highlight the need for continuous efforts to optimize the rational use of antibiotics through instigating appropriate antimicrobial stewardship programs in hospitals and, as a result, reduce AMR in the country.


Implications for Ezetimibe Therapy Use Based on IMPROVE-IT Criteria.
In the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), simvastatin/ezetimibe combination was associated with a 6% relative risk reduction in the combined cardiovascular outcome compared with simvastatin alone in patients with acute coronary syndrome. Given strict inclusion criteria (low-density lipoprotein cholesterol 50-125 mg/dL and no use of statins more potent than simvastatin 40 mg), the implications of this important trial in routine acute coronary syndrome care are unknown. We identified patients with acute coronary syndrome from the Veterans Affairs health care system over a 5-year period and determined what proportion would be candidates for ezetimibe on the basis of IMPROVE-IT criteria. We then evaluated what proportion could potentially see an increase in ezetimibe use if IMPROVE-IT criteria are not strictly followed. Of 219,625 patients with acute coronary syndrome, 69,508 (31.6%) would qualify for ezetimibe on the basis of strict criteria. Among those who did not meet IMPROVE-IT criteria (n = 150,117), ezetimibe could potentially be prescribed by clinicians in a further 28% of patients (n = 61,635) using statins more potent than simvastatin 40 mg, 7.1% of patients (15,527) with a documented statin intolerance, and 10.4% of patients (22,758) with low-density lipoprotein cholesterol >125 mg/dL. Our results provide a first look at the implications of this trial in a large health care system. Although 31.6% of patients would qualify for ezetimibe, there is a large potential for an increase in ezetimibe use in acute coronary syndrome outside of the strict trial inclusions. These findings call for a discussion on ezetimibe's role in patients with acute coronary syndrome already taking high-intensity statins or those with statin intolerance.


Electroencephalographic assessment in patients with Rett syndrome during cognitive stimulation by means of eye tracking technology and alternative and augmentative communication systems.
Rett syndrome (RTT) is considered a rare disease despite being the leading genetic disorder to cause severe intellectual disability in women. There is no cure for RTT, so the treatment is symptomatic and supporting, requiring a multidisciplinary approach. Occupational therapy can help girls and their families to improve communication, being one of the main concerns when verbal language and intentional hand movement are impaired or lost. This paper presents a pilot study of cognitive training through the combined use of eye-tracking technology (ETT) and augmentative and alternative communication (AAC) using the Peabody Picture Vocabulary Test (PPVT-IV). The objective was to evaluate brain activation by means of electroencephalography (EEG) during the stimulation of non-verbal communication. EEG data were recorded during an eyes-open resting state (EO-RS) period and during cognitive stimulation via AAC activity. To assess their effect, both signals were compared at the spectral level, focusing on frequency, brain symmetry and connectivity. During the task, a redistribution of power towards fast frequency bands was observed, as well as an improvement in the brain symmetry index (BSI) and functional synchronicity through increased coherence. Therefore, the results of the spectral analysis showed a possible deviation from the pathological pattern, manifesting a positive effect in the use of non-verbal cognitive stimulation activities. In conclusion, it was observed that it is possible to establish a cognitive training system that produces brain activation and favors communication and learning despite intentional language loss.Clinical Relevance- This manifests a method of cognitive training that would induce brain activation in RTT patients with absence of intentional communication. The evaluation system through spectral analysis could complement the standardized protocols to asses communication that are based on verbal and motor production.


A translation frameshift mutation induced by a cytosine insertion in the polycystic kidney disease 2 gene (PDK2).
Mutations in the PKD2 gene on the long arm of chromosome 4 are responsible for approximately 15% of cases of polycystic kidney disease. Perhaps the only difference from the more common ADPKD1 cases is the rate of progression of cystic changes, and the age of onset, which is 10-15 years later for the ADPKD2 form. In Cyprus there are at least three large families, documented by molecular linkage analysis, that map to the PKD2 locus. For two of them the defects were recently shown to be nonsense mutations at positions arginine 742 and glutamine 405. In this report, we describe the mutation in the third family, CY1602. For this, the entire coding sequence was systematically screened by single strand conformation analysis and heteroduplex formation. A novel mutation was identified in exon 2 where a new cytosine residue was inserted immediately after codon 231 (231insC). It causes a translation frameshift and is expected to lead to the introduction of 37 novel amino acids before the translation reaches a new STOP codon. It is the most amino terminal mutation reported to date, and based on the protein's modeled structure, is predicted to be within the first transmembrane domain. It is the fourth PKD2 mutation reported thus far, and the first which is not a nonsense mutation.


Is calcium oxalate nucleation in postprandial urine of males with idiopathic recurrent calcium urolithiasis related to calcium phosphate nucleation and the intensity of stone formation? Studies allowing insight into a possible role of urinary free citrate and protein.
In idiopathic recurrent urolithiasis (IRCU) calcium oxalate and calcium phosphate are components of stones. It is not sufficiently known whether in urine the nucleation (liquid-solid transition) of each salt requires a different environment, if so which environment, and whether there is an impact on stone formation. Nucleation was induced by in vitro addition of oxalate or calcium to post-test meal load whole urine of male stone patients (n=48), showing normal daily and baseline fasting oxaluria. The maximally tolerated (until visible precipitates occur) concentration of oxalate (T-Ox) or calcium (T-Ca) was determined; additionally evaluated were other variables in urine, including total, complexed and free citrate (F-Cit), protein (albumin, non-albumin protein) and the clinical intensity (synonymous metabolic activity; MA) of IRCU. In the first of three trials the accumulation of substances in stone-forming urine was verified (trial-V); in the second (clinical trial 1) two strata of T-Ox (Low, High) were compared; in the third (clinical trial 2) IRCU patients (n=27) and a control group (n=13) were included to clarify whether in stone-forming urine the first crystal formed was calcium oxalate or calcium phosphate, and to identify the state of F-Cit. T-Ox was studied at the original pH (average < 6.0), T-Ca at prefixed pH 6.0; the precipitates were subjected to electron microscopy and element analysis. Trial-V: Among the urinary substances accumulating at the indicated pHs were calcium, oxalate and phosphate, and the crystal-urine ratios were compatible with the nucleation of calcium oxalate, calcium-poor and calcium-rich calcium phosphate; citrate, protein and potassium also accumulated. Clinical trial 1: the two strata exhibited an inverse change of T-Ox and T-Ca, the ratio T-Ox/T-Ca and MA. The initial (before induction of Ox or Ca excess) supersaturation of calcium oxalate and brushite were unchanged, with the difference of proteinuria being borderline. Several correlations were significant (p < or = 0.05): urine pH with citrate and volume, protein with volume and MA, T-Ox with T-Ca and MA. Clinical trial 2: in patients with reduced urine volume and moderate urine calcium excess, the first precipitate appeared to be calcium oxalate, followed by amorphous calcium phosphate. Conversely, when the calcium excess was extreme, calcium-rich hydroxyapatite developed, followed by calcium oxalate; F-Cit, not total and complexed citrate, was decreased in IRCU vs. male controls; F-Cit rose pH-dependently, and the ratio F-Cit at original pH vs. F-Cit at pH 6.0 correlated inversely with the nucleation index T-Ox/T-Ca; MA correlated inversely with the ratio F-Cit at pH 6.0, respectively, original pH, but directly with the urinary albumin/non-albumin protein ratio. In summary 1) to study calcium oxalate and calcium phosphate nucleation in whole urine of IRCU patients is feasible; 2) at this crystallization stage the two substances, dominant in calcium stones, appear intimately linked, 3) in stone-forming urine, calcium phosphate may be ubiquitously present, likely as particles < 0.22 microm; 4) together with co-precipitation of calcium oxalate and calcium phosphate, low F-Cit and alteration of proteinuria may act in concert and accelerate stones.


[Models of bone defects in rabbits used to evaluate the bone graft materials efficacy].
The review deals with the main types of experimental models of bone defects of the skull in rabbits. The information about the types of critical defects, methods of their modeling and the possibilities of application of the described models in the studies of bone graft materials in dentistry and maxillofacial surgery is systematized.


Tertiary lymphoid organs are associated with the progression of kidney damage and regulated by interleukin-17A.
Background: Tertiary lymphoid organs (TLOs) occur after multiple chronic kidney injuries. interleukin-17A (IL-17A) has been reported to associate with the development of TLOs in inflammatory diseases. However, regulation of the renal TLOs and its clinical significance to the pathogenesis of chronic kidney injury are unknown. Methods: To evaluate the clinical significance and regulation of renal TLOs, we analyzed the progression of patients with kidney damage based on the existence and absence of TLOs in a larger multicenter cohort. We also blocked the recruitment of lymphocyte cells into the kidney by FTY720 (fingolimod) in vivo. Besides, we used aged IL-17A genetic knocked out mice and IL-17A-neutralizing antibody to explore the role of IL-17A in renal TLOs formation. Results: We demonstrated that renal TLOs of IgA nephropathy patients were associated with disease severity and were independent risk factors for renal progression after adjustment for age, sex, mean arterial pressure, proteinuria and, baseline eGFR and MEST-C score, especially in the early stage. Plasma levels of TLO-related chemokines CXCL13, CCL19, and CCL21 were higher in patients with renal TLOs. Inhibiting the formation of renal TLOs by FTY720 could reduce the intrarenal inflammation and fibrosis, and early intervention was found to be more effective. IL-17A was increased in renal TLOs models, and genetic depletion of IL-17A or treatment with anti-IL-17A antibody resulted in a marked reduction of the TLOs formation as well as alleviation of renal inflammation and fibrosis. Conclusion: These results indicate that TLOs are associated with the progression of kidney damage and regulated by IL-17A and may be effective targets for the treatment of kidney damage.


[The 1978 TNM system for cancer of the breast: proposal for a modification].
The authors study the 5 and 10 years survival of 1.058 cases of breast carcinoma treated between 1963 and 1981, classified according to the pTNM system. They suggest the convenience of eliminating some of the combinations in order to obtain a good correlation with prognostic criteria. The authors propose a modification of the TNM system with closer clinical significance.


Population health in Europe: how much is attributable to health care?
Does health care save lives? Commentators such as McKeown and Illich, writing in the 1960s, argued that it contributed very little to population health, and might even be harmful. However, they were writing about a period when health care had relatively little to offer compared to today. More recent reviews of the contribution of health care to health have led to a consensus that McKeown was correct to the extent that 'curative medical measures played little role in mortality decline prior to mid-20th century'. But the rapidly changing scope and nature of health care means it cannot be assumed that this is still the case. Thus, several writers have described often quite substantial improvements in death rates from conditions for which effective interventions have been introduced. Yet the debate continues, with some arguing that health care is making an increasingly important impact on overall levels of health while others contend that it is in the realm of broader policies, such as education, transport and housing that we should look to for future advances in health. Inevitably, this is to a considerable extent a false dichotomy. Both are important. But how much does health care contribute to population health?


Coincidence detection and changes of synaptic efficacy in spiny stellate neurons in rat barrel cortex.
Paired whole-cell voltage recordings were made from synaptically connected spiny stellate neurons in layer 4 of the barrel field in young (P14) rat somatosensory cortex. When postsynaptic action potentials (APs) followed each of 5 presynaptic APs in a 10- or 20-Hz train by less than 25 ms, subsequent unitary EPSP amplitudes were persistently reduced. Induction of long-term depression (LTD) depended on activation of group II metabotropic glutamate receptors, but not on NMDA or AMPA receptors. Reducing postsynaptic increases in intracellular calcium ([Ca2+]i) by intracellular loading with a fast- (BAPTA) or a slow- (EGTA) acting Ca2+ buffer blocked synaptic depression. Analysis of EPSP failures suggested mediation of LTD by a reduction in release probability. We propose a mechanism by which coincident activity results in long-lasting reduction of synaptic efficacy between synaptically connected neurons.


Epidemiology of age-dependent prevalence of Bovine Herpes Virus Type 1 (BoHV-1) in dairy herds with and without vaccination.
Many studies report age as a risk factor for BoHV-1 infection or seropositivity. However, it is unclear whether this pattern reflects true epidemiological causation or is a consequence of study design and other issues. Here, we seek to understand the age-related dynamics of BoHV-1 seroprevalence in seasonal calving Irish dairy herds and provide decision support for the design and implementation of effective BoHV-1 testing strategies. We analysed seroprevalence data from dairy herds taken during two Irish seroprevalence surveys conducted between 2010 and 2017. Age-dependent seroprevalence profiles were constructed for herds that were seropositive and unvaccinated. Some of these profiles revealed a sudden increase in seroprevalence between adjacent age-cohorts, from absent or low to close to 100% of seropositive animals. By coupling the outcome of our data analysis with simulation output of an individual-based model at the herd scale, we have shown that these sudden increases are related to extensive virus circulation within a herd for a limited time, which may then subsequently remain latent over the following years. BoHV-1 outbreaks in dairy cattle herds affect animals independent of age and lead to almost 100% seroconversion in all age groups, or at least in all animals within a single epidemiological unit. In the absence of circulating infection, there is a year-on-year increase in the age-cohort at which seroprevalence changes from low to high. The findings of this study inform recommendations regarding testing regimes in the context of contingency planning or an eradication programme in seasonal calving dairy herds.


Associations between neighborhood violence during pregnancy and birth outcomes: evidence from São Paulo's Western Region Birth Cohort.
Low birth weight and prematurity remain leading causes of infant mortality and morbidity globally. Although extensive literature has highlighted the importance of socioenvironmental characteristics for birth outcomes, the role of indirect violence on health remains fairly understudied. Using geocoded birth records from the ongoing Western Region Birth Cohort (Região Oeste Coorte - ROC-Cohort) of infants born between 2012 and 2014 and geocoded crime reports, we assessed the associations between exposure to violent crimes during pregnancy within a 1-km radius of the mother's residence and low birth weight, preterm delivery, and being born small-for-gestational-age. Violent crime exposure was categorized into quintiles. Multivariate logistic regressions were used to examine the associations between violence exposure and birth outcomes. Models were adjusted for sex, maternal age and education, socioeconomic status, and risk factors such as hypertension, diabetes, smoking, and drinking during pregnancy. Among the 5268 children included, the average crime exposure during the first two trimesters of pregnancy ranged from 0.44 violent crimes in the least exposed quintile to 12.74 crimes in the most exposed. Compared to children with the lowest violence exposure, children in the highest exposure quintile had higher odds of being born small-for-gestational-age (1.41[1.06-1.89]), preterm (1.35[1.01-1.80]), and low birth weight (1.42[1.03-1.98]). While socioeconomic status and maternal education were positively associated with lower violence exposure, no associations were found between these characteristics and birth outcomes. Higher exposure to violent crimes in the close vicinity of pregnant women's residence is associated with substantial increases in the odds of adverse birth outcomes. Policies to improve neighborhood safety can potentially contribute not only to the short-term wellbeing of populations but may also have large social, economic, and health benefits in the long term.


Nerve growth factor modulates TRPV1 expression and function and mediates pain in chronic pancreatitis.
The pathogenesis of pain in chronic pancreatitis (CP) is poorly understood and treatment remains difficult. We hypothesized that nerve growth factor (NGF) plays a key role in this process via its effects on the transient receptor potential vanilloid 1, TRPV1. CP was induced by intraductal injection of trinitrobenzene sulfonic acid in rats. After 3 weeks, anti-NGF antibody or control serum was administered daily for 1 week. Pancreatic hyperalgesia was assessed by nocifensive behavioral response to electrical stimulation of the pancreas as well as by referred somatic pain assessed by von Frey filament testing. TRPV1 currents in pancreatic sensory neurons were examined by patch-clamp. The expression and function of TRPV1 in pancreas-specific nociceptors was examined by immunostaining and quantification of messenger RNA levels. Blockade of NGF significantly attenuated pancreatic hyperalgesia and referred somatic pain compared with controls. It also decreased TRPV1 current density and open probability and reduced the proportion of pancreatic sensory neurons that expressed TRPV1 as well as levels of TRPV1 in these neurons. These findings emphasize a key role for NGF in pancreatic pain and highlight the role it plays in the modulation of TRPV1 expression and activity in CP.


Positive association in the absence of linkage suggests a minor role for the glucokinase gene in the pathogenesis of type 2 (non-insulin-dependent) diabetes mellitus amongst south Indians.
Mutations of the glucokinase gene have been implicated in the development of glucose intolerance in pedigrees with maturity-onset diabetes of the young. However, the contribution of the glucokinase gene to the aetiology of common Type 2 (non-insulin-dependent) diabetes mellitus is uncertain. We have studied the role of the glucokinase gene in the pathogenesis of Type 2 diabetes in South Indians, using both population-association and linkage methodology. A pair of CA-repeat sequences (GCK(3') and GCK(5')) straddling the glucokinase gene were employed as markers, each subject being typed using the polymerase chain reaction and polyacrylamide gel electrophoresis. Comparisons of allele frequencies at these markers were made between 168 Type 2 diabetic subjects and 70 racially-matched control subjects. No differences in allele frequencies were apparent at the GCK(5') marker; however, there were significant differences in allele frequencies at the GCK(3') marker between the Type 2 diabetic subjects and control subjects (chi 2 = 11.6, df = 3, p = 0.009) with an increase of the z allele (78.0% vs 66.4%) and a decrease of the z + 2 allele (13.7% vs 25.0%) amongst the diabetic subjects. Linkage between glucose intolerance and the glucokinase gene was studied in 53 nuclear pedigrees under a variety of genetic models. Linkage was excluded (lod score < -2) at a recombination fraction of zero under five of the ten models used and highly unlikely (-2 < lod score < -1) under the others. The combination of positive association and negative linkage suggests that glucokinase acts as a minor gene influencing the development of Type 2 diabetes within this population.


Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions.
We have examined the expression of chemokines and their receptors in the atopic dermatitis-like (AD-like) lesions of NC/Nga mice. Such lesions develop when the mice are kept in conventional conditions, but not when they are kept isolated from specific pathogens. The thymus- and activation-regulated chemokine TARC is unexpectedly highly expressed in the basal epidermis of 14-week-old mice with lesions, whereas it is not expressed in the skin without lesions. Production of TARC by keratinocytes was confirmed by culturing murine keratinocytic cell line cells (PAM212) with TNF-alpha, IFN-gamma, or IL-1beta. Expression of another Th2 chemokine, macrophage-derived chemokine (MDC), was observed in the skin from mice kept in both conventional and pathogen-free conditions, but expression of MDC was increased severalfold in the skin with lesions. The cellular origin of MDC was identified to be dermal dendritic cells. Infiltration of the skin by IL-4-producing T cells and mast cells, and the increase of CCR4 mRNA in the skin, coincided with the development of AD lesions. These observations indicate that TARC and MDC actively participate in the pathogenesis of AD-like lesions in NC/Nga mice and that these Th2 chemokines could be novel targets for intervention therapy of AD in humans.


Cholesterol-lowering activity of sesamin is associated with down-regulation on genes of sterol transporters involved in cholesterol absorption.
Sesame seed is rich in sesamin. The present study was to (i) investigate the plasma cholesterol-lowering activity of dietary sesamin and (ii) examine the interaction of dietary sesamin with the gene expression of sterol transporters, enzymes, receptors, and proteins involved in cholesterol metabolism. Thirty hamsters were divided into three groups fed the control diet (CON) or one of two experimental diets containing 0.2% (SL) and 0.5% (SH) sesamin, respectively, for 6 weeks. Plasma total cholesterol (TC) levels in hamsters given the CON, SL, and SH diets were 6.62 ± 0.40, 5.32 ± 0.40, and 5.00 ± 0.44 mmol/L, respectively, indicating dietary sesamin could reduce plasma TC in a dose-dependent manner. Similarly, the excretion of total fecal neutral sterols was dose-dependently increased with the amounts of sesamin in diets (CON, 2.65 ± 0.57; SL, 4.30 ± 0.65; and SH, 5.84 ± 1.27 μmol/day). Addition of sesamin into diets was associated with down-regulation of mRNA of intestinal Niemann-Pick C1 like 1 protein (NPC1L1), acyl-CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP-binding cassette transporters subfamily G members 5 and 8 (ABCG5 and ABCG8). Results also showed that dietary sesamin could up-regulate hepatic cholesterol-7α-hydroxylase (CYP7A1), whereas it down-regulated hepatic 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase and liver X receptor alpha (LXRα). It was concluded that the cholesterol-lowering activity of sesamin was mediated by promoting the fecal excretion of sterols and modulating the genes involved in cholesterol absorption and metabolism.


The effect of platelet rich plasma on angiogenesis in ischemic flaps in VEGFR2-luc mice.
To improve skin flap healing, one promising strategy in reconstructive surgery might be to optimize platelet rich plasma (PRP) bioactivity and the ischemia-altered expression of genes. We studied both the effect of PRP on ischemic flaps, and whether in vivo bioluminescence imaging (BLI) is a suitable method for the longitudinal monitoring of angiogenesis in surgical wounds. Axial murine skin flaps were created in four experimental groups. In vivo measurements of VEGFR2 expression levels were made every other day until the 14th day. The local VEGF level and microvessel density were quantified on the 14th day via ELISA and immunohistochemistry, and flap survival rates were measured. We demonstrated that PRP and induced ischemia have a beneficial influence on angiogenesis and flap healing. Combining the two resulted in a significantly robust increase in angiogenesis and flap survival rate that was corroborated by bioluminescence imaging of VEGFR2 activity. This study shows that angiogenic effects of PRP may be potentialized by the stimulus of induced ischemia during free flap harvesting, and thus the two procedures appear to have a synergistic effect on flap healing. This study further demonstrates that BLI of modulated genes in reconstructive surgery is a valuable model for longitudinal in vivo evaluation of angiogenesis.


Objectively determined habitual physical activity in South African adolescents: the PAHL study.
There is limited data on objectively determined habitual physical activity (PA) in 16-year old South African adolescents. The purpose of this study was to objectively determine the habitual PA of adolescents from the North West Province of South Africa by race and gender. Adolescents (137 girls, 89 boys) from the ongoing Physical Activity and Health Longitudinal Study (PAHL study), participated in the present study. Habitual PA was objectively recorded by means of the Actiheart® over a period of 7 days. Time spent in moderate-to-vigorous intensity physical activity (MVPA) was assessed. Average MVPA for the study sample was 50.9 ± 40.3 minutes/day. Girls were significantly more active than boys expending more time in MVPA (61.13 ± 52.2 minutes/day; p < 0.05) than boys (35.0 ± 32.9 minutes/day). Although white adolescents spent more time in MVPA than black adolescents, there was no significant difference in MVPA between black (47.87 ± 39.6 minutes/day; p = 0.58) and white adolescents (59.5 ± 41.8 minutes/day). Physical activity varies by both gender and race in adolescents from the North West Province of South Africa. Objectively determined data from our study indicates that girls habitually spend more time in MVPA per day than boys, and that white adolescents habitually engage in more MVPA than black adolescents. Seeing as the average MVPA per day for the entire study sample falls below the recommended daily average of 60 minutes/day, adolescents should be the foremost targets of interventions aimed at enhancing habitual PA.


Affinity capture of uropathogenic Escherichia coli using pigeon ovalbumin-bound Fe3O4@Al2O3 magnetic nanoparticles.
Escherichia coli and Staphylococcus saprophyticus are the most common causes of urinary tract infections, with 80% of these infections caused by uropathogenic E. coli. Because the P fimbriae of E. coli have specificity toward Gal(alpha1-4)Gal beta units, pigeon ovalbumin (POA), whose structure contains terminal Gal(alpha1-4)Gal beta moieties, was used as a probe for interaction with P fimbriated E. coli. The functional affinity probes for these bacteria by immobilizing POA--a phosphoprotein--onto the surface of magnetic iron oxide nanoparticles (NPs) coated with alumina (Fe3O4@Al2O3), using the phosphate units of POA as linking groups for the formation of phosphate-alumina complexes. The immobilization process occurred within 30 s when performing the reaction under microwave heating. The magnetic POA-Fe3O4@Al2O3 NPs generated using this facile approach exhibited specificity toward P fimbriated E. coli. The bacteria targeted by the affinity probes were characterized by matrix-assisted laser desorption/ionization mass spectrometry. The detection limit toward uropathogenic bacteria when using this approach was approximately 9.60 x 10(4) cfu/mL (0.5 mL).


The role of GABAA receptors in mediating the effects of alcohol in the central nervous system.
Ethanol is a chemically simple compound that produces many well-known effects in humans. The prevailing idea for many years was that ethanol and other alcohols exerted their effects on the central nervous system (CNS) by non-selectively disrupting the lipid bilayers of neurons. However, in recent years, there has been an accumulation of evidence pointing to the importance of ligand-gated ion channels (LGICs) in mediating the effects of ethanol. Of these LGICs, gamma-aminobutyric acid type A (GABAA) receptors appear to occupy a central role in mediating the effects of ethanol in the CNS. GABA is the primary inhibitory neurotransmitter in the mammalian CNS, and activation of GABAA receptors by GABA tends to decrease neuronal excitability. This article reviews several aspects of GABAA receptor and ethanol interactions, including the evidence for short- and long-term modulation of GABAA receptors by ethanol and evidence for a GABAA receptor-related genetic component of alcoholism.


New high performance SAW convolvers used in high bit rate and wideband spread spectrum CDMA communications system.
New surface acoustic wave (SAW) convolver structures with high conversion efficiency and self-temperature compensation characteristics have been developed. Strong piezoelectric substrates, regardless of temperature coefficients of delay (TCD), can be used in these convolvers. New demodulation techniques using the developed SAW convolver for high bit rate and wideband spread spectrum code division multiple access (CDMA) communications have also been developed. I- and Q-channel demodulation data can be derived directly from binary phase shift keying (BPSK) or quadri-phase shift keying (QPSK) CDMA signals. In an experiment using a 128 degrees YX-LiNbO(3) substrate, CDMA signals of 9 Mbps (megabits per second) with 60 Mcps (megachips per second) spread by 13-chip Barker code and 11 Mbps with 140 Mcps spread by 25-chip Shiba's code were clearly demodulated, demonstrating the effectiveness of these techniques for use in future CDMA communications.


Broad-spectrum health improvements with one year of soccer training in inactive mildly hypertensive middle-aged women.
The study tested the hypothesis that long-term soccer training has positive impact on cardiovascular profile, body composition, bone health, and physical capacity in inactive, pre-menopausal women with mild hypertension. The study applied a randomized controlled design in which physically inactive middle-aged women were separated into a soccer training group (n=19; SOC) and a control group (n=12; CON). SOC performed 128±29 (±SD) one-h small-sided soccer training sessions over one year. Blood pressure, body composition, blood lipid profile, and fitness level were determined pre- and post-intervention. Over one year, mean arterial pressure decreased more in SOC than in CON (-5±7 vs +4±5 mmHg; P<.05). Total-body fat mass decreased more (P<.05) in SOC than in CON (-2.5±2.5 vs +0.6±3.2 kg; P<.05), while the change scores for lean body mass were not significantly different in SOC (2.6±2.7 kg) compared to CON (1.1±1.9 kg, P=.09). Over one year, change scores in whole-body bone mineral density (0.004±0.032 vs -0.019±0.026 g·cm2 ) as well as bone mineral content (30±70 vs -39±113 g) were positive in SOC compared to CON (P<.05). Post-intervention plasma triglycerides decreased more (-0.1±0.7 vs +0.2±0.2 mmol·L-1 ) and HDL cholesterol increased more (0.2±0.7 vs -0.2±0.2 mmol·L-1 ) in SOC than in CON (P<.05). Yo-Yo intermittent endurance level 1 (122±105 vs 2±21%) and 20-m sprint performance (6±6 vs -1±2%) increased more (P<.05) in SOC than in CON. In conclusion, long-term soccer training resulted in broad-spectrum improvements in the health profile of untrained, pre-menopausal women with mild hypertension, including cardiovascular, metabolic, and musculo-skeletal benefits.


Amiloride-insensitive Na+-H+ exchange: a candidate mediator of erythrocyte Na+-Li+ countertransport.
Erythrocyte Na+-Li+ countertransport shows an increased activity in essential hypertension and diabetic nephropathy, but its nature remains unknown. This amiloride-insensitive membrane transport may not be a mode of operation of the amiloride-sensitive NHE1, the only Na+-H+ exchange isoform found in human erythrocytes. Whether an independent, although unknown, amiloride-insensitive isoform mediates Na+-Li+ countertransport is unclear. Na+-H+ exchange activity was measured in acid-loaded erythrocytes. Dimethylamiloride, a specific inhibitor of Na+-H+ exchange and phloretin, a known inhibitor of Na+-Li+ countertransport, gave a reduction in H+-driven Na+ influx (by 31 and 37%, respectively). This effect was additive, and a 66% reduction in H+-driven Na+ influx was found in the presence of both inhibitors. Internal acidification, a stimulus for Na+-H+ exchange, enhanced Na+-Li+ countertransport activity (from 287 +/- 55 to 1213 +/- 165 micromol x Lcell(-1) h(-1), mean +/- SEM, P = 0.003). This transport remained sensitive to phloretin under both conditions. Conversely, external acidification decreased Na+-Li+ countertransport activity (as expected for a Na+-H+ exchanger). Competition between internal H+ and Li+ or Na+ for a common binding site was present. Finally, similar kinetic parameters for external Na+ characterized Na+-Li+ countertransport and the phloretin-sensitive component of H+-driven Na+ influx. These findings suggest that both Na+-Li+ countertransport and the amiloride-insensitive, phloretin-sensitive component of H+-driven Na+ influx can be mediated by a previously unrecognized novel amiloride-insensitive Na+-H+ exchange isoform in human erythrocytes.


Nonligamentous Soft Tissue Pathology About the Knee: A Review.
Knee pain is one of the most frequent complaints evaluated by orthopedic surgeons. It encompasses a broad range of pathology and can present in a variety of ways. Most of this pain can be attributed to essential structures of the knee, including the menisci, cruciate or collateral ligaments, and articular cartilage. However, there are underrecognized structures in and around the knee that can frequently be a cause of knee pathology and pain. Knee pain stemming from these structures may be missed or incorrectly diagnosed, and these patients often present for second and third opinions because of failure to diagnose and treat the underlying pathology. The synovial plica, suprapatellar pouch, lateral retinaculum, infrapatellar fat pad, and infrapatellar branch of the saphenous nerve are less common but still significant causes of knee pain. Although initial treatment involves various nonoperative modalities, operative treatment is often warranted. Operative and nonoperative management of these soft tissue structures may occur in isolation or with concomitant procedures, including knee ligament reconstruction, total knee arthroplasty, tibial tuberosity osteotomy, or lysis of adhesions. With proper recognition of the role of these structures in knee pain, the orthopedic surgeon can offer a valuable primary or adjunctive treatment option for patients with knee pain, especially those without localizing signs of meniscal, ligamentous, or cartilage damage.


Novice riders and the predictors of riding without motorcycle protective clothing.
While helmet usage is often mandated, few motorcycle and scooter riders make full use of protection for the rest of the body. Little is known about the factors associated with riders' usage or non-usage of protective clothing. Novice riders were surveyed prior to their provisional licence test in NSW, Australia. Questions related to usage and beliefs about protective clothing, riding experience and exposure, risk taking and demographic details. Multivariable Poisson regression models were used to identify factors associated with two measures of usage, comparing those who sometimes vs rarely/never rode unprotected and who usually wore non-motorcycle pants vs motorcycle pants. Ninety-four percent of eligible riders participated and usable data was obtained from 66% (n=776). Factors significantly associated with riding unprotected were: youth (17-25 years) (RR = 2.00, 95% CI: 1.50-2.65), not seeking protective clothing information (RR = 1.29, 95% CI = 1.07-1.56), non-usage in hot weather (RR = 3.01, 95% CI: 2.38-3.82), awareness of social pressure to wear more protection (RR = 1.48, 95% CI: 1.12-1.95), scepticism about protective benefits (RR = 2.00, 95% CI: 1.22-3.28) and riding a scooter vs any type of motorcycle. A similar cluster of factors including youth (RR = 1.17, 95% CI: 1.04-1.32), social pressure (RR = 1.32, 95% CI: 1.16-1.50), hot weather (RR = 1.30, 95% CI: 1.19-1.41) and scooter vs motorcycles were also associated with wearing non-motorcycle pants. There was no evidence of an association between use of protective clothing and other indicators of risk taking behaviour. Factors strongly associated with non-use of protective clothing include not having sought information about protective clothing and not believing in its injury reduction value. Interventions to increase use may therefore need to focus on development of credible information sources about crash risk and the benefits of protective clothing. Further work is required to develop motorcycle protective clothing suitable for hot climates.


Evaluation of vibrated fluidized bed techniques in coating hemosorbents.
A coating technique employing a vibrated fluidized bed was used to apply an ultrathin (2 microns) cellulose nitrate coating to synthetic bead activated charcoal. In vitro characteristics of the resulting coated sorbent, including permeability to model small and middle molecules, and mechanical integrity, were evaluated to determine the suitability of the process in coating granular sorbents used in hemoperfusion. Initial tests suggest the VFB-applied CN coating is both highly uniform and tightly adherent and warrants further investigation as a hemosorbent coating.


An Overlooked Paleotetraploidization in Cucurbitaceae.
Cucurbitaceae plants are of considerable biological and economic importance, and genomes of cucumber, watermelon, and melon have been sequenced. However, a comparative genomics exploration of their genome structures and evolution has not been available. Here, we aimed at performing a hierarchical inference of genomic homology resulted from recursive paleopolyploidizations. Unexpectedly, we found that, shortly after a core-eudicot-common hexaploidy, a cucurbit-common tetraploidization (CCT) occurred, overlooked by previous reports. Moreover, we characterized gene loss (and retention) after these respective events, which were significantly unbalanced between inferred subgenomes, and between plants after their split. The inference of a dominant subgenome and a sensitive one suggested an allotetraploid nature of the CCT. Besides, we found divergent evolutionary rates among cucurbits, and after doing rate correction, we dated the CCT to be 90-102 Ma, likely common to all Cucurbitaceae plants, showing its important role in the establishment of the plant family.


Auditory recognition memory in 2-month-old infants as assessed by event-related potentials.
Previous studies of auditory recognition memory in sleeping newborns reported 2 event-related potential (ERP) components, P2 and negative slow wave (NSW), reflecting voice discrimination and detection of novelty, respectively. In the present study, using high-density recording arrays, ERPs were acquired from 26 2-month-old awake infants as they were presented with a familiar and unfamiliar voice (i.e., mother and stranger) with equal probability. In addition to P2 and NSW, we observed a positive slow wave (PSW) over the right temporo-parietal scalp, indicating memory updating. Our study suggests that infants appear to have the capacity to encode novel stimuli as early as 2 months of age.


[Ultrastructural characteristics of Proteus vulgaris and Proteus mirabilis cells differing in the capacity for swarming].
Specific differences in the structure of colonies and the location of microbial cells in colonies, characteristic for aggregating and nonaggregating genetically related pairs of P. vulgaris and P. mirabilis strains, have been demonstrated by means of transmission and scanning electron microscopy. In calculating the number of flagellae per 100 outlines of microbial bodies revealed in negatively stained preparations, the fact that both aggregating and nonaggregating bacteria possess practically the same number of flagellae, on the average 4-8 flagellae per microbial cell outline, has been established. This fact indicates that the presence of flagellae in microbial cells is unrelated to their capacity for swarming.


Requirement for down-regulation of the CCAAT-binding activity of the NF-Y transcription factor during skeletal muscle differentiation.
NF-Y is composed of three subunits, NF-YA, NF-YB, and NF-YC, all required for DNA binding. All subunits are expressed in proliferating skeletal muscle cells, whereas NF-YA alone is undetectable in terminally differentiated cells in vitro. By immunohistochemistry, we show that the NF-YA protein is not expressed in the nuclei of skeletal and cardiac muscle cells in vivo. By chromatin immunoprecipitation experiments, we demonstrate herein that NF-Y does not bind to the CCAAT boxes of target promoters in differentiated muscle cells. Consistent with this, the activity of these promoters is down-regulated in differentiated muscle cells. Finally, forced expression of the NF-YA protein in cells committed to differentiate leads to an impairment in the down-regulation of cyclin A, cyclin B1, and cdk1 expression and is accompanied by a delay in myogenin expression. Thus, our results indicate that the suppression of NF-Y function is of crucial importance for the inhibition of several cell cycle genes and the induction of the early muscle-specific program in postmitotic muscle cells.


Innovate 4 Change: An interdisciplinary nursing student-led hackathon.
Health care challenges are increasingly complex. Nursing student involvement in hackathons can help create a sustainable culture of innovation and leadership within nursing. To host and evaluate the inaugural Innovate 4 Change Hackathon. Nursing student-led interdisciplinary teams worked together for 5 weeks to solve pressing health care problems, ultimately pitching ideas for prizes. Seven teams with 33 students represented multiple disciplines. For nearly 70% of participants, hackathons were a new experience. Nursing students were on every team, representing 50% of the participants. Nurse-led hackathons help students gain experience in innovative problem-solving and elevate confidence. They provide a structured format to learn about nursing innovation, design thinking, and business models while also challenging students to address problems related to health equity, clinical care, health care delivery, and policy.


[Chronic cholecystitis simulating gallbladder tumor with liver abscess. Case report].
We report on a 58 year-old male who presented with nausea, a painful tumor palpable in the upper right epigastrium, moderate fever without leukocytosis. Both ultrasonic scan and subsequent computerized tomography lead to the primary diagnosis of a malignant tumor of the gall bladder infiltrating the liver and inducing an intrahepatic abscess formation in segments 4b and 3. The patient was scheduled for emergency operation, i.e. abscess drainage, cholezystectomy, and hemihepatectomy. However, at operation a purulent chronic cholezystitis was found without involvement of the liver itself. Consequently, a cholezystectomy was necessary and performed. Histological examination of the gall bladder revealed no signs of malignancy. The patient had an uneventful recovery and was discharged on post-operative day seven. This case report shows the difficulties in the differential diagnosis of inflammable processes and malignancies, which affect the gall bladder and adhering structures. A chronic inflammable process can mimic solid tumors. Despite cost-effective diagnostic tools the correct diagnosis was finally found by surgery.


Application of AN69 hydrogel to islet encapsulation. Evaluation in streptozotocin-induced diabetic rat model.
The polymer AN69 (polyacrylonitrile-sodium methallylsulfonate) is a reference in biocompatibility in the field of hemodialysis. Its use for the encapsulation of living cells has been already described, but this study is the first description of AN69 hydrogel-encapsulated islet isograft in streptozotocin (STZ) diabetic rats. The aim of this work is to evaluate the biocompatibility of the AN69 hydrogel by comparison of the efficacy of free versus encapsulated islets transplanted to balance diabetes. Pancreatic islets are isolated from adult male Lewis rats by a standard collagenase digestion and purified on Ficoll density gradients. The AN69 hollow fiber is obtained by coextrusion of an 8% AN69 collodion. The hollow fiber is filled with islets suspended in agarose at the final concentration of 10,000 islets/ml, closed with surgical clips and implanted. The recipients are rendered diabetic by intravenous injection of STZ. The experimental design includes 4 groups of 8 rats: group 1: control, group 2: diabetic rats intraperitoneally implanted with 6000 free islets, group 3: diabetic rats intraperitoneally implanted with 9000 encapsulated islets, group 4: diabetic control. Weight and fasting glycemia are evaluated twice a week, diuresis once a week. After free islet implantation, rat survival is improved with glycemia below 250 mg/dl during 22 days. Compared to group 2, the status of group 3 is better, with a glycemia below 250 mg/dl during at least 70 days. This tends to demonstrate the biocompatibility of AN69 and is the first step of the validation of the use of AN69 for living cell encapsulation.


Glucocorticoid Nanoparticles Show Full Therapeutic Efficacy in a Mouse Model of Acute Lung Injury and Concomitantly Reduce Adverse Effects.
Glucocorticoids (GCs) are widely used to treat inflammatory disorders such as acute lung injury (ALI). Here, we explored inorganic-organic hybrid nanoparticles (IOH-NPs) as a new delivery vehicle for GCs in a mouse model of ALI. Betamethasone (BMZ) encapsulated into IOH-NPs (BNPs) ameliorated the massive infiltration of neutrophils into the airways with a similar efficacy as the free drug. This was accompanied by a potent inhibition of pulmonary gene expression and secretion of pro-inflammatory mediators, whereas the alveolar-capillary barrier integrity was only restored by BMZ in its traditional form. Experiments with genetically engineered mice identified myeloid cells and alveolar type II (AT II) cells as essential targets of BNPs in ALI therapy, confirming their high cell-type specificity. Consequently, adverse effects were reduced when using IOH-NPs for GC delivery. BNPs did not alter T and B cell numbers in the blood and also prevented the induction of muscle atrophy after three days of treatment. Collectively, our data suggest that IOH-NPs target GCs to myeloid and AT II cells, resulting in full therapeutic efficacy in the treatment of ALI while being associated with reduced adverse effects.


Tonic cuff pressure pain sensitivity in chronic pain patients and its relation to self-reported physical activity.
Physical inactivity is a global health concern and a significant problem among chronic pain patients. They often experience pain flare-ups when they try to increase their physical activity level. Most research on the relationship between pain sensitivity and physical activity has been on healthy participants. Data on chronic pain patients are lacking. Using cuff pressure algometry, this study investigated tonic cuff pressure pain sensitivity and its associations to self-reported physical activity and other patient-reported outcomes in chronic pain patients. Chronic pain patients (n=78) were compared to healthy controls (n=98). Multivariate data analysis was used to investigate the associations between tonic cuff pressure pain sensitivity, physical activity, and other patient-reported outcome measures. The three most important variables for group discrimination were perceived health status (EQVAS: p(corr)=-0.85, i.e., lower in patients), depression (HADS-D: p(corr)=0.81, i.e., higher in patients), and the tonic cuff pressure pain sensitivity variable maximum pain intensity (VAS-peak-arm: p(corr)=0.75, i.e., higher in patients). In patients, the most important predictors for high VAS-peak-arm were female sex (p(corr)=-0.75), higher number of painful regions (p(corr)=0.72), higher pain intensity (p(corr)=0.55), followed by lower level of self-reported physical activity (p(corr)=-0.39). VAS-peak-arm in patients correlated negatively with self-reported physical activity (rho=-0.28, p=0.018). Physical activity may be the most important patient-changeable variable correlating to pain sensitivity. This study highlights the importance of more research to further understand how increased physical activity may decrease pain sensitivity in chronic pain patients.


Probing the mRNA processing body using protein macroarrays and "autoantigenomics".
Messenger RNA processing bodies (P-bodies) are cellular structures that have a direct role in mRNA degradation. P-bodies have also been implicated in RNAi-mediated post-transcriptional gene silencing. Despite the important roles of P-bodies in cellular biology, the constituents of P-bodies and their organization have been only partially defined. Approximately 5% of patients with the autoimmune disease primary biliary cirrhosis have antibodies directed against these structures. Recent advances in protein macroarray technology permit the simultaneous screening of thousands of proteins for reactivity with autoantibodies. We used serum from patients with anti-P-body autoantibodies to screen a protein macroarray and identified 67 potential autoantigens. Immunoreactive proteins included four known P-body components and three additional primary biliary cirrhosis autoantigens. Y-box protein 1 (YB-1), a 50-kDa RNA-binding protein that was not previously known to be a P-body component, was recognized by serum from four of seven patients. YB-1 colocalized with P-body components DCP1a and Ge-1. In cells subjected to arsenite-induced oxidative stress, YB-1 localized to TIA-containing stress granules. Both YB-1 and the previously identified P-body component RAP55 translocated from P-bodies to stress granules during oxidative stress. During recovery, however, the reappearance of YB-1 in P-bodies was delayed compared with that of RAP55, suggesting that YB-1 and RAP55 may have different functions. This study demonstrates that the combination of human autoantibodies and protein macroarray technology provides a novel method for identifying and characterizing components of mRNA P-bodies.


Ferroptosis: regulated cell death.
Ferroptosis is a recently identified form of regulated cell death that differs from other known forms of cell death morphologically, biochemically, and genetically. The main properties of ferroptosis are free redox-active iron and consequent iron-dependent peroxidation of polyunsaturated fatty acids in cell membrane phospholipids, which results in the accumulation of lipid-based reactive oxygen species due to loss of glutathione peroxidase 4 activity. Ferroptosis has increasingly been associated with neurodegenerative diseases, carcinogenesis, stroke, intracerebral haemorrhage, traumatic brain injury, and ischemia-reperfusion injury. It has also shown a significant therapeutic potential in the treatment of cancer and other diseases. This review summarises current knowledge about and the mechanisms that regulate ferroptosis.


Single-Center Evaluation of the Pharmacokinetics and Safety of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Mild to Moderate Hepatic Impairment.
Azilsartan medoxomil (AZL-M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose-dependent manner. It is a prodrug that is not detected in blood after its oral administration because of its rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite, M-II, and minor metabolites. The objective of this study was to determine the effect of mild to moderate hepatic impairment on the pharmacokinetics of AZL and its major metabolite. This was a single-center, open-label, phase 1 parallel-group study that examined the single-dose (day 1) and multiple-dose (days 4-8) - 40 mg - pharmacokinetics of AZL and M-II in 16 subjects with mild and moderate hepatic impairment by Child-Pugh classification (n = 8 per group) and subjects (n = 16) matched based on age, sex, race, weight, and smoking status. Mild or moderate hepatic impairment did not cause clinically meaningful increases in exposure to AZL and M-II. Mild or moderate hepatic impairment had no clinically meaningful effect on the plasma protein binding of AZL and M-II. Single and multiple doses of AZL-M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL-M is required for subjects with mild and moderate hepatic impairment.


History of standard scoring, notation, and summation of neuromuscular signs. A current survey and recommendation.
In this article, we trace the history of scoring, notation, and summation of the neuromuscular signs of muscle weakness and decrease of tendon reflexes and sensation. We recommend a standard system to promote consistency in the effort introduced by Mitchell and Lewis to "represent systems and force by their signs." The scoring of neuromuscular signs began with Mitchell and Lewis in the 19th century who used pluses, minuses, and N (for normal) to express the activity of muscle stretch reflexes. Henry Plummer introduced an ordinal scoring approach for muscle weakness, reflex decrease and increase, and sensation loss. In 1919, he and Walter Sheldon and Henry Woltman introduced standard pre-printed examination forms with written instructions for notation and scoring. Robert Lovett, a Boston orthopedist, scored weak muscles of poliomyelitis patients from 2 (mild weakness) to 6 (paralyzed), 1 being normal. Lovett's approach was used, after reversing the order of the grades and decreasing each grade by 1, by a Committee of the Medical Research Council for evaluating return of muscle weakness after nerve injury. Despite dissimilarity to existing reflex and sensation scores and uneven width of grades, this approach was widely adopted for use in neurologic practice. We introduced the Neuropathy Impairment Score using a combination of the Mitchell, Plummer, and Lovett approaches, summing all individual scores of a standard set of neuromuscular examinations. In a non-representative survey of 19 neuromuscular physicians from different countries, we find that there is a considerable variability in the approaches used for grading. Assuming that scoring is useful, we herein suggest (a) impairments should be scored separately from hyperfunction and (b) for the scoring of impairments (muscle weakness, reflex decrease, and sensation loss), the same ordinal scoring approach should be used with 0 as normal and 1, 2, ... representing increasing impairment based on the judgment of percentage abnormality with corrections made for age, sex, physical fitness, and physical characteristics.


A Community-Based Early Childhood Development Center Platform Promoting Diversified Diets and Food Production Increases the Mean Probability of Adequacy of Intake of Preschoolers in Malawi: A Cluster Randomized Trial.
Young children in Malawi consume low-quality diets lacking micronutrients critical for their development. To evaluate the impact of an agriculture and nutrition behavior change communication (BCC) intervention implemented through community-based childcare centers on the nutrient adequacy of diets of children living in food-insecure settings in Malawi. A cluster randomized trial was undertaken in 60 community-based childcare centers, including 1248 children aged 3-6 y. Nutrient intakes were estimated using interactive, multipass 24-h recall. Dietary adequacy was estimated through the probability of adequacy (PA) and mean probability of adequacy (MPA) of 11 micronutrients. Impacts were assessed by difference-in-difference (DID) estimates, adjusted for geographic clustering and child age and sex. Intervention groups were similar for most baseline characteristics. Loss to follow-up was low (7% over a 12-mo period) and participation in the intervention was high (>90% enrollment and 80% attendance during the 5 d before the survey). Positive impacts were found for the PA of several individual micronutrient intakes: vitamin A [DID: 9 percentage points (pp), SE 3 pp], vitamin C (14 pp, SE 3 pp), riboflavin (11 pp, SE 3 pp), zinc (8 pp, SE 3 pp), and for the MPA for the 11 nutrients considered (5 pp, SE 1 pp). These impacts were driven by effects on younger children (aged 3-4 y). Using a preschool platform to implement a nutrition-sensitive BCC intervention is an effective strategy to improve the adequacy of micronutrient intake of preschool children in food-insecure settings. The trial was registered at ISCRCTN as ISCRCTN96497560.


Twelve-year mortality in HIV-infected patients receiving antiretroviral therapy: the role of social vulnerability. The ANRS CO8 APROCO-COPILOTE cohort.
Although the role of clinical/biological factors associated with mortality has already been explored in HIV-infected patients on antiretroviral therapy (ART), to date little attention has been given to the potential role of social vulnerability. This study aimed to construct an appropriate measure of social vulnerability and to evaluate whether this measure is predictive of increased mortality risk in ART-treated patients followed up in the ANRS CO8 APROCO-COPILOTE cohort. The cohort enrolled 1,281 patients initiating a protease inhibitor-based regimen in 1997-1999. Clinical/laboratory data were collected every 4 months. Self-administered questionnaires collected psycho-social/behavioural characteristics at enrolment (month [M] 0), M4 and every 8-12 months thereafter. A multiple correspondence analysis using education, employment and housing indicators helped construct a composite indicator measuring social vulnerability. The outcome studied was all-cause deaths occurring after M4. The relationship between social vulnerability and mortality, after adjustment for other predictors, was studied using a shared-frailty Cox model, taking into account informative study dropout. Over a median (IQR) follow-up of 7.9 (3.0-11.2) years, 121 deaths occurred among 1,057 eligible patients, corresponding to a mortality rate (95% CI) of 1.64 (1.37, 1.96)/100 person-years. Leading causes of death were non-AIDS defining cancers (n=26), AIDS (n=23) and cardiovascular diseases (n=12). Social vulnerability (HR [95% CI] =1.2 [1.0, 1.5]) was associated with increased mortality risk, after adjustment for other known behavioural and bio-medical predictors. Social vulnerability remains a major mortality predictor in ART-treated patients. A real need exists for innovative interventions targeting individuals cumulating several sources of social vulnerability, to ensure that social inequalities do not continue to lead to higher mortality.


Anticoagulation for Stroke Prevention in Older Adults with Atrial Fibrillation and Comorbidity: Current Evidence and Treatment Challenges.
The burden of atrial fibrillation (AF) is projected to increase substantially over the next decade in parallel with the aging of the population. The increasing age, level of comorbidity, and polypharmacy will complicate the treatment of older adults with AF. For instance, advanced age and chronic kidney disease have been shown to increase the risk of both thromboembolism and bleeding in patients with AF. Frailty, recurrent falls and polypharmacy, while very common among elderly patients with AF, are often overlooked in the clinical decision making despite their significant interaction with oral anticoagulant (OAC) and profound impact on the patient's clinical outcomes. Such factors should be recognized, evaluated and considered in a comprehensive decision-making process. The introduction of non-vitamin K oral anticoagulants has radically changed the management of AF allowing for a more individualized selection of OAC. An understanding of the available data regarding the performance of each of the available OAC in a variety of at risk patient populations is paramount for the safe and effective management of this patient population. The aim of this review is to appraise the current evidence, point out the gaps in knowledge, and provide recommendations regarding stroke prevention in older adults with AF and comorbid conditions.


The Sensory Ecology of Speciation.
In this work, we explore the potential influence of sensory ecology on speciation, including but not limited to the concept of sensory drive, which concerns the coevolution of signals and sensory systems with the local environment. The sensory environment can influence individual fitness in a variety of ways, thereby affecting the evolution of both pre- and postmating reproductive isolation. Previous work focused on sensory drive has undoubtedly advanced the field, but we argue that it may have also narrowed our understanding of the broader influence of the sensory ecology on speciation. Moreover, the clearest examples of sensory drive are largely limited to aquatic organisms, which may skew the influence of contributing factors. We review the evidence for sensory drive across environmental conditions, and in this context discuss the importance of more generalized effects of sensory ecology on adaptive behavioral divergence. Finally, we consider the potential of rapid environmental change to influence reproductive barriers related to sensory ecologies. Our synthesis shows the importance of sensory conditions for local adaptation and divergence in a range of behavioral contexts and extends our understanding of the interplay between sensory ecology and speciation.


Induction of micronuclei in maize root-tip cells and a correlation with forward mutation at the yg2 locus.
A standard protocol for a micronucleus assay in root tips of Zea mays was developed and calibrated using 137Cs gamma radiation, ethylmethanesulfonate (EMS), and N-ethyl-N-nitrosourea (ENU). The root tips were sampled 1, 3, and 5 days after the treatment period. Primary root tips (sampled 1 day after treatment) were the most responsive with the highest frequencies of micronuclei. The frequencies then decreased to control values after 3 days. By treating the same kernels for this assay and the yellow-green-2 (yg2) forward mutation assay, it was possible to analyze and compare the induction kinetics of micronuclei formation in root-tip cells and forward mutation at the yg2 locus in leaf primordial cells. Forward mutation at the yg2 locus by gamma rays, EMS, or ENU exhibited one hit kinetics. The induction of micronuclei demonstrated nonlinear kinetics with a significant increase over controls above 200 rads gamma rays, 10 mM EMS, or 250 microM ENU. ENU induced a higher frequency of micronuclei at all treatment concentrations than did gamma radiation or EMS. The data suggest that a higher relative proportion of yg2 mutant sectors induced by ENU may be due to chromosome aberrations than those induced by gamma radiation or EMS.


Reducing radiation dose without compromising image quality in preoperative perforator flap imaging with CTA using ASIR technology.
Computed tomographic angiography (CTA) has become a mainstay in preoperative perforator flap planning in the modern era of reconstructive surgery. However, the increased use of CTA does raise the concern of radiation exposure to patients. Several techniques have been developed to decrease radiation dosage without compromising image quality, with varying results. The most recent advance is in the improvement of image reconstruction using an adaptive statistical iterative reconstruction (ASIR) algorithm. We sought to evaluate the image quality of ASIR in preoperative deep inferior epigastric perforator (DIEP) flap surgery, through a direct comparison with conventional filtered back projection (FBP) images. A prospective review of 60 consecutive ASIR and 60 consecutive FBP CTA images using similar protocol (except for radiation dosage) was undertaken, analyzed by 2 independent reviewers. In both groups, we were able to accurately identify axial arteries and their perforators. Subjective analysis of image quality demonstrated no statistically significant difference between techniques. ASIR can thus be used for preoperative imaging with similar image quality to FBP, but with a 60% reduction in radiation delivery to patients.


The atherosclerotic risk profile is affected differently by fish flesh with a similar EPA and DHA content but different n-6/n-3 ratio.
The aim of this study was to evaluate the effect of consuming gilthead sea bream fillets, with different n-6/ n-3 ratios, on atherosclerotic biomarkers. Twenty healthy subjects were included in a randomised single-blinded cross-over trial. Participants were randomized into 2 groups, both of which received approximately 630 g per week of gilthead sea bream fed with either 100% fishmeal (FM) or partial replacement with plant proteins (PP) over two consecutive 10 week periods, respectively. Group A consumed firstly the FM fillets followed by the PP fillets, whereas the reverse order was adopted for group B. Group A reported a significant decrease of 29.3% (Δ = -26 mg/dL) in total cholesterol after the first phase of the intervention, before returning to baseline levels after the dietary intervention with fish fed with PP. Similarly, in group A, both LDL-cholesterol and triglycerides decreased significantly by 21.6% (Δ = -19 mg/dL) and 11.7% (Δ = -10.7 mg/dL), respectively, before increasing again after the intervention. Improvements in the inflammatory cytokines, interleukin-6 and -8 were also noted. Moreover, whole blood viscosity appeared significantly improved in group A, as seen by a significant increase of 7.59% (Δ = +4.59 mPA) for erythrocyte filtration rate. In conclusion, similar EPA+DHA content with different n- 6/n-3 ratio fish flesh intake was shown to have varied affects on lipid, inflammatory and haemorheological parameters in a group of healthy subjects.


Diversity and Structure of Diazotrophic Communities in Mangrove Rhizosphere, Revealed by High-Throughput Sequencing.
Diazotrophic communities make an essential contribution to the productivity through providing new nitrogen. However, knowledge of the roles that both mangrove tree species and geochemical parameters play in shaping mangove rhizosphere diazotrophic communities is still elusive. Here, a comprehensive examination of the diversity and structure of microbial communities in the rhizospheres of three mangrove species, Rhizophora apiculata, Avicennia marina, and Ceriops tagal, was undertaken using high-throughput sequencing of the 16S rRNA and nifH genes. Our results revealed a great diversity of both the total microbial composition and the diazotrophic composition specifically in the mangrove rhizosphere. Deltaproteobacteria and Gammaproteobacteria were both ubiquitous and dominant, comprising an average of 45.87 and 86.66% of total microbial and diazotrophic communities, respectively. Sulfate-reducing bacteria belonging to the Desulfobacteraceae and Desulfovibrionaceae were the dominant diazotrophs. Community statistical analyses suggested that both mangrove tree species and additional environmental variables played important roles in shaping total microbial and potential diazotroph communities in mangrove rhizospheres. In contrast to the total microbial community investigated by analysis of 16S rRNA gene sequences, most of the dominant diazotrophic groups identified by nifH gene sequences were significantly different among mangrove species. The dominant diazotrophs of the family Desulfobacteraceae were positively correlated with total phosphorus, but negatively correlated with the nitrogen to phosphorus ratio. The Pseudomonadaceae were positively correlated with the concentration of available potassium, suggesting that diazotrophs potentially play an important role in biogeochemical cycles, such as those of nitrogen, phosphorus, sulfur, and potassium, in the mangrove ecosystem.


PPARalpha deficiency in inflammatory cells suppresses tumor growth.
Inflammation in the tumor bed can either promote or inhibit tumor growth. Peroxisome proliferator-activated receptor (PPAR)alpha is a central transcriptional suppressor of inflammation, and may therefore modulate tumor growth. Here we show that PPARalpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of the endogenous angiogenesis inhibitor thrombospondin-1 and prevents tumor growth. Bone marrow transplantation and granulocyte depletion show that PPARalpha expressing granulocytes are necessary for tumor growth. Neutralization of thrombospondin-1 restores tumor growth in PPARalpha-deficient mice. These findings suggest that the absence of PPARalpha activity renders inflammatory infiltrates tumor suppressive and, thus, may provide a target for inhibiting tumor growth by modulating stromal processes, such as angiogenesis.


[Pain treatment in patients with hemophilia].
Pain in patients with hemophilia is an urgent problem. The possibilities of using analgesic drugs are interesting by virtue of the specific features of pain syndrome and the problems of treatment in these patients. Foreign and Russian trials using current analgesics are analyzed; difficulties in choosing analgesic therapy and in performing anesthesia mode in patients with congenital hypocoagulation and hyperalgesia are discussed.


Impact of Red Blood Cell Antigen Matching on Alloimmunization and Transfusion Complications in Patients with Sickle Cell Disease: A Systematic Review.
Red blood cells (RBC) transfusion is critical in managing acute and chronic complications in sickle cell disease (SCD); however, it is complicated by RBC alloimmunization, iron overload, transfusion reactions and infection. Several reports documented an increased incidence of alloantibodies in transfused individuals with SCD, especially for Rh and Kell antigens. As a result, the National Institutes of Health Expert Panel and British Society for Haematology guidelines recommend primary matching for C/c, E/e and K antigens in addition to ABO/RhD for RBC transfusions. However, the evidence supporting these recommendations was cited as limited and understanding of alloimmunization in SCD is evolving. To examine the limitations of the evidence, we undertook a systematic review of evidence behind recommendations for limited and extended serologic and genotypic RBC antigen matching to reduce alloimmunization, autoimmunization and transfusion reactions. Searches of PubMed, Embase, Cochrane, and Web of Science databases using MeSH index and free text terms between 1976 through October 2015 and papers and captured through July 2016 through review references in papers, word of mouth, and ongoing Google Scholar and Medline Alerts identified 303 unique articles. Nineteen articles met inclusion criteria and were classified by the Oxford Centre Evidence Based levels of evidence. Strengthening the Reporting of Observational Studies in Epidemiology checklists were completed for 18 of the 19 studies. There were no prospective randomized controlled trials. Sixteen of the articles were cohort studies, two were cross-sectional studies, and one decision tree model examining costs. Low-quality evidence from observational cohort studies supports that alloimmunization prevalence can be decreased by extending serological RBC antigen matching. Transfusion reactions are generally poorly and inconsistently reported. There was no evidence reporting the effect prophylactic genotypic matching has on alloimmunization, autoimmunization or transfusion reactions. There were no studies comparing prophylactic genotypic matching to serologic matching. High-quality evidence was lacking to support clinical decision making regarding best transfusion practices. Multicenter prospective randomized clinical trials are needed to determine best strategies for reducing the rate of alloimmunization using serologic and genotypic matching.


The epidemiology of HIV among men who have sex with men in countries with generalized HIV epidemics.
Key populations at high risk for HIV acquisition and transmission, such as MSM, have long been identified as essential subpopulations for epidemiological surveillance of the HIV epidemic. However, surveillance systems in the context of generalized and widespread HIV epidemics have traditionally excluded these men. Emerging and consistent data highlight the disproportionate burden of HIV among MSM that exists when compared with other men of reproductive age across countries with generalized epidemics. Correlates of prevalent HIV infection include individual-level determinants of HIV acquisition and transmission similar to that found in concentrated HIV epidemics and community-level structural factors, such as stigma, being blackmailed, and history of homophobic abuse. HIV incidence was only available from two countries (Kenya, Thailand) with generalized HIV epidemics, but in both settings was an order of magnitude higher than that of other populations. The data presented here suggest that the dynamics of HIV infection among men are more similar across the world than they are different. Many HIV epidemics among average-risk reproductive age adults are slowing across both generalized and concentrated settings. It is in this context that high HIV incidence is observed among MSM, especially young MSM. This trend suggests a change in the trajectory of these HIV epidemics, a change that we may miss if we continue to understudy these populations based on unproved and dated assumptions.


Low levels of interferon-gamma in nasal fluid accompany raised levels of T-helper 2 cytokines in children with ongoing allergic rhinitis.
The T-helper 2 (Th2) cytokines interleukin-(IL-) 4, IL-5, IL-6, IL-10 and the Th1 cytokine IFN-gamma and their associations with eosinophil, eosinophil cationic protein (ECP) and immunoglobulin (Ig) E were studied in nasal lavage fluid from 60 school children with allergic seasonal rhinitis and 36 nonatopic healthy controls, before and during the pollen season. Eosinophil differential counts and IgE increased significantly in the patients during the pollen season. The eosinophil differential counts, ECP and IgE were all significantly higher during the season than in specimens simultaneously obtained from the nonatopic controls. Before season, the levels of ECP and IgE, but not eosinophils, were significantly higher in the patients than in the controls. During the season the nasal lavage fluid levels of IFN-gamma were significantly lower and the IL-4/IFN-gamma quotients significantly higher in the allergic than in the control children. In the allergic children, but not in the controls, the nasal fluid levels of the Th2 cytokines IL-4, IL-5 and IL-10 increased during the season, and together with IL-6, were correlated with the differential counts of eosinophils, and with the levels of ECP and IgE. These findings are compatible with the hypothesis that a deficient release of the Th1 cytokine IFN-gamma plays an important role in the pathogenesis of allergic inflammation. Regardless of whether the defective IFN-gamma secretion is primary or a consequence of suppression by other cytokines, it will in the atopic subjects enhance the release of Th2 cytokines, which in turn will facilitate the development of allergic inflammation.


Adolescent multiple risk behaviours cluster by number of risks rather than distinct risk profiles in the ALSPAC cohort.
Experimentation with new behaviours during adolescence is normal. However, engagement in two or more risk behaviours, termed multiple risk behaviours is associated with socioeconomic disadvantage and poor health and social outcomes. Evidence of how adolescents cluster based on their risk behaviours is mixed. Latent Class Analysis was used to study patterns of engagement in 10 self-reported risk behaviours (including substance use, self-harm and sexual health) from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort at ages 15-16 years. Data was available for 6556 adolescents. Associations between risk profile and sex were explored. A 3-class model for both females and males was deemed to have acceptable fit. Whilst we found evidence of a sex difference in the risk behaviours reported within each class, the sex-specific results were very similar in many respects. For instance, the prevalence of membership of the high-risk class was 8.5% for males and 8.7% for females and both groups had an average of 5.9 behaviours. However, the classes were both statistically dubious, with class separation (entropy) being poor as well as conceptually problematic, because the resulting classes did not provide distinct profiles and varied only by quantity of risk-behaviours. Clusters of adolescents were not characterised by distinct risk behaviour profiles, and provide no additional insight for intervention strategies. Given this is a more complicated, software-specific method, we conclude that an equally effective, but more readily replicable approach is to use a count of the number of risk behaviours.


Basolateral amygdala corticotropin releasing factor receptor 2 interacts with nonmuscle myosin II to destabilize memory in males.
Preclinical studies show that inhibiting the actin motor ATPase nonmuscle myosin II (NMII) with blebbistatin (Blebb) in the basolateral amgydala (BLA) depolymerizes actin, resulting in an immediate, retrieval-independent disruption of methamphetamine (METH)-associated memory in male and female adult and adolescent rodents. The effect is highly selective, as NMII inhibition has no effect in other relevant brain regions (e.g., dorsal hippocampus [dPHC], nucleus accumbens [NAc]), nor does it interfere with associations for other aversive or appetitive stimuli, including cocaine (COC). To understand the mechanisms responsible for drug specific selectivity we began by investigating, in male mice, the pharmacokinetic differences in METH and COC brain exposure . Replicating METH's longer half-life with COC did not render the COC association susceptible to disruption by NMII inhibition. Therefore, we next assessed transcriptional differences. Comparative RNA-seq profiling in the BLA, dHPC and NAc following METH or COC conditioning identified crhr2, which encodes the corticotropin releasing factor receptor 2 (CRF2), as uniquely upregulated by METH in the BLA. CRF2 antagonism with Astressin-2B (AS2B) had no effect on METH-associated memory after consolidation, allowing for determination of CRF2 influences on NMII-based susceptibility. Pretreatment with AS2B prevented the ability of Blebb to disrupt an established METH-associated memory. Alternatively, combining CRF2 overexpression and agonist treatment, urocortin 3 (UCN3), in the BLA during conditioning rendered COC-associated memory susceptible to disruption by NMII inhibition, mimicking the Blebb-induced, retrieval-independent memory disruption seen with METH. These results suggest that BLA CRF2 receptor activation during memory formation in male mice can prevent stabilization of the actin-myosin cytoskeleton supporting the memory, rendering it vulnerable to disruption by NMII inhibition. CRF2 represents an interesting target for BLA-dependent memory destabilization via downstream effects on NMII.