In vitro holding security of four friction knots of monofilament or multifilament suture used as a first throw for vascular ligation.
To evaluate holding security of 4 friction knots created with various monofilament and multifilament sutures in a vascular ligation model. 280 friction knot constructs. 10 friction knots of 4 types (surgeon's throw, Miller knot, Ashley modification of the Miller knot, and strangle knot) created with 2-0 monofilament (polyglyconate, polydioxanone, poliglecaprone-25, and glycomer-631) and braided multifilament (silk, lactomer, and polyglactin-910) sutures were separately tied on a mock pedicle and pressure tested to the point of leakage. Linear regression analysis was performed to compare leakage pressures among suture materials (within friction knot type) and among knot types (within suture material). Mean leakage pressure of surgeon's throws was significantly lower than that of all other knots tested, regardless of the suture material used. All the other knots had mean leakage pressures considered supraphysiological. Significant differences in mean leakage pressure were detected between various friction knots tied with the same type of suture and various suture types used to create a given knot. Variability in leakage pressure among knots other than the surgeon's throw was greatest for poliglecaprone-25 and lowest for polydioxanone. Most differences in knot security, although statistically significant, may not have been clinically relevant. However, results of these in vitro tests suggested the surgeon's throw should be avoided as a first throw for pedicle ligation and that poliglecaprone-25 may be more prone to friction knot slippage than the other suture materials evaluated.


Hypovolemia and hypovolemic shock in children with nephrotic syndrome.
Hypovolemic shock is not an uncommon presentation in nephrotic syndrome, yet it is seldom mentioned in the literature. This study was performed to investigate the prevalence of hypovolemia and hypovolemic shock in the acute nephrotic stage, and the association of hemoconcentration and abdominal pain with hypovolemic status. Two hundred and twenty-five patients with a total of 328 admissions to the pediatric ward of our hospital during 1983 to 1996 were retrospectively reviewed for hypovolemic episodes. Clinical presentation and laboratory data including hemoglobin, serum sodium, albumin, cholesterol, and triglyceride levels were investigated. Thirteen patients with 19 episodes (5.8%) of hypovolemic shock were found, and had more severe hemoconcentration (hemoglobin 19.6 +/- 2.2 g/dL) and hyponatremia (127.3 +/- 7.2 mEq/L). Another 33 patients with 41 symptomatic hypovolemic episodes without hypotension (12.5%) were found, and their hemoglobin levels were higher compared to patients without hypovolemic symptoms. Among 61 episodes of abdominal pain and hemoconcentration, 58 were responsive to albumin infusion. This suggested the presence of hypovolemia. Twenty patients had abdominal pain without hemoconcentration, and 18 of them had primary peritonitis. Hypovolemia was found in patients at the acute nephrotic stage, and was usually associated with hemoconcentration and abdominal pain. A combined examination of hemoglobin and serum sodium is the best indicator of hypovolemic status. Both primary peritonitis and hypovolemic episodes should be taken into consideration when managing abdominal pain in children with nephrotic syndrome.


Molecular regulation of bone marrow metastasis in prostate and breast cancer.
Metastasis is a multistep process, which refers to the ability to leave a primary tumor through circulation toward the distant tissue and form a secondary tumor. Bone is a common site of metastasis, in which osteolytic and osteoblastic metastasis are observed. Signaling pathways, chemokines, growth factors, adhesion molecules, and cellular interactions as well as miRNAs have been known to play an important role in the development of bone metastasis. These factors provide an appropriate environment (soil) for growth and survival of metastatic tumor cells (seed) in bone marrow microenvironment. Recognition of these factors and determination of their individual roles in the development of metastasis and disruption of cellular interactions can provide important therapeutic targets for treatment of these patients, which can also be used as prognostic and diagnostic biomarkers. Thus, in this paper, we have attempted to highlight the molecular regulation of bone marrow metastasis in prostate and breast cancers.


Plasma and urine nitric oxide levels in healthy Turkish children.
Nitric oxide (NO) is an important messenger molecule with a wide range of actions in virtually all cell systems and organs. In kidneys it participates in glomerular and medullary hemodynamics, tubuloglomerular feed-back, renin secretion, and extracellular fluid balance. Although the role of NO in regulating renal function in adults is well-established, it has recently been suggested that NO has a more critical role in maintaining basal renal blood flow and glomerular filtration rate (GFR) in the developing kidney. NO is rapidly metabolized to the stable end products nitrite and nitrate, which are more slowly excreted into the urine. Thus these metabolites can be recommended as useful markers of endogenous NO synthase activity, despite limited data about age-related changes in in-vivo NO production. The aims of this study were to determine age-related normal reference values of serum and urinary NO metabolites and to assess the probable relationship between these metabolites and the GFR. Normal levels of NO end products in blood and urine of 296 healthy children (117 female, 179 male) between the ages of 0 and 16 were investigated, as was whether these values change with age. Serum and urinary nitrate levels did not differ according to sex. Serum nitrate levels are higher in younger children, especially in the newborn period, and decrease with age. Nitrate levels in urine are higher in younger children with a peak in infancy (1 month to 1 year) and decrease with age. It was demonstrated that this decrease in serum and urinary nitrate levels with age parallels the increase in GFR. In conclusion, urinary NO products may be an indirect marker of serum NO levels and NO might have an important regulatory function both in the maintenance of renal function and in the maturation of the developing kidneys.


Nitrogen fixation and transcriptome of a new diazotrophic Geomonas from paddy soils.
Nitrogen gas (N2) fixation driven by diazotrophs is a crucial process for supplying nitrogen to paddy soil ecosystems. The genus Geomonas has been considered to be an important potential diazotroph in paddy soils, but direct experimental evidence of the nitrogen-fixing ability of Geomonas in pure culture is still lacking. Hence, we aimed to demonstrate this nitrogen-fixing capability and shed light on how this process was regulated in response to ammonium (NH4 +) in Geomonas. In this study, we determined that a key nitrogenase gene (nifH) was present in 50 isolates from paddy soils. Members of Geomonas contained the minimum nitrogen fixation gene cluster (nifBHDKEN) based on genomic analysis, implying Geomonas species had the potential to fix nitrogen. Acetylene reduction assay (ARA), 15N2 isotope labeling, and total nitrogen accumulation assays validated that Geomonas was, indeed, able to fix nitrogen in pure culture. Under nitrogen-fixing conditions, the cell morphology of Geomonas changed from short rod-shaped (with NH4 +) to long rod-shaped and flagella became longer and thicker. The expression of genes correlated to nitrogen fixation in the Geomonas transcriptome was quantified in response to NH4 +. Expression of genes associated with nitrogenase, flavin-based electron bifurcation complexes (such as the FixAB system), NH4 + uptake, and transformation (e.g., glutamine and glutamate synthetases) were significantly upregulated under nitrogen-fixing conditions, suggesting these mechanisms might be involved in N2 fixation in Geomonas. These results were verified by RT-qPCR. Taken together, our results demonstrate that Geomonas species possess the ability to fix N2 and expand our understanding on the ecological significance and potential applications of Geomonas in paddy soil ecosystems. IMPORTANCE The ability of Geomonas species to fix nitrogen gas (N2) is an important metabolic feature for its application as a plant growth-promoting rhizobacterium. This research is of great importance as it provides the first comprehensive direct experimental evidence of nitrogen fixation by the genus Geomonas in pure culture. We isolated a number of Geomonas strains from paddy soils and determined that nifH was present in these strains. This study demonstrated that these Geomonas species harbored genes encoding nitrogenase, as do Geobacter and Anaeromyxobacter in the same class of Deltaproteobacteria. We demonstrated N2-dependent growth of Geomonas and determined regulation of gene expression associated with nitrogen fixation. The research establishes and advances our understanding of nitrogen fixation in Geomonas.


Fibrillarin promotes homologous recombination repair by facilitating the recruitment of recombinase RAD51 to DNA damage sites.
Eukaryotic organisms constantly face a wide range of internal and external factors that cause damage to their DNA. Failure to accurately and efficiently repair these DNA lesions can result in genomic instability and the development of tumors (Canela et al., 2017). Among the various forms of DNA damage, DNA double-strand breaks (DSBs) are particularly harmful. Two major pathways, non-homologous end joining (NHEJ) and homologous recombination (HR), are primarily responsible for repairing DSBs (Katsuki et al., 2020; Li and Yuan, 2021; Zhang and Gong, 2021; Xiang et al., 2023). NHEJ is an error-prone repair mechanism that simply joins the broken ends together (Blunt et al., 1995; Hartley et al., 1995). In contrast, HR is a precise repair process. It involves multiple proteins in eukaryotic cells, with the RAD51 recombinase being the key player, which is analogous to bacterial recombinase A (RecA) (Shinohara et al., 1992). The central event in HR is the formation of RAD51-single-stranded DNA (ssDNA) nucleoprotein filaments that facilitate homology search and DNA strand invasion, ultimately leading to the initiation of repair synthesis (Miné et al., 2007; Hilario et al., 2009; Ma et al., 2017).


Pharmacokinetic modelling and Bayesian estimation-assisted decision tools to optimize vancomycin dosage in neonates: only one piece of the puzzle.
Introduction: Vancomycin is commonly administered to neonates, while observational data on therapeutic drug monitoring (TDM, trough levels) suggest that vancomycin exposure and dosage remain substandard. Area covered: Data on vancomycin pharmacokinetics (PK) and its covariates are abundant. Consequently, modeling is an obvious tool to improve targeted exposure, with a shift from TDM trough levels to area under the curve (AUC24h) targets, as in adults. Continuous administration appeared as a practice to facilitate AUC24h target attainment, while Bayesian model-supported targeting emerged as a novel tool. However, the AUC24h/MIC (minimal inhibitory concentration) target itself should consider neonate-specific aspects (bloodstream infections, coagulase-negative staphylococci, protein binding, underexplored causes of variability, like assays, preparation and administration inaccuracies, or missing covariates). Expert opinion: To improve targeted exposure in neonates, initial vancomycin prescription should be based on 'a priori model-based individual dosing' using validated dosing regimens, followed by further tailoring by dosing optimization applying Bayesian estimation-assisted TDM. Future research should focus on the feasibility to integrate these tools (individualized dosing, Bayesian models) in clinical practice, and to perform PK/PD studies in the relevant animal models and human neonatal setting (coagulase-negative staphylococci, bloodstream infections).


Computational study and molecular orbital analysis of NMR shielding, spin-spin coupling, and electric field gradients of azido platinum complexes.
(195)Pt, (14)N, and (15)N NMR data for five azido (N(3)(-)) complexes are studied using relativistic density functional theory (DFT). Good agreement with experiment is obtained for Pt and N chemical shifts as well as Pt-N J-coupling constants. Calculated (14)N electric field gradients (EFGs) reflect experimentally observed trends for the line broadening of azido (14)N NMR signals. A localized molecular orbital analysis of the nitrogen EFGs and chemical shifts is performed to explain some interesting trends seen experimentally and in the first-principles calculations: (i) (14)N NMR signals for the Pt-coordinating (N(α)) nuclei in the azido ligands are much broader than for the central (N(β)) or terminal (N(γ)) atoms. The N(β) signals are particularly narrow; (ii) compared to N(γ), the N(α) nuclei are particularly strongly shielded; (iii) N(β) nuclei have much larger chemical shifts than N(α) and N(γ) ; and (iv) The Pt-N(α) J-coupling constants are small in magnitude when considering the formal sp hybridization of N(α). It is found that for N(α) a significant shielding reduction due to formation of the dative N(α)-Pt bond is counterbalanced by an increased shielding from spin-orbit (SO) coupling originating at Pt. Upon coordination, the strongly delocalized π system of free azide localizes somewhat on N(β) and N(γ). This effect, along with rehybridization at N(α) upon bond formation with Pt, is shown to cause a deshielding of N(γ) relative to N(α) and a strong increase of the EFG at N(α). The large 2p character of the azide σ bonds is responsible for the particularly high N(β) chemical shifts. The nitrogen s-character of the Pt-N(α) bond is low, which is the reason for the small J-coupling. Similar bonding situations are likely to be found in azide complexes with other transition metals.


Altered expression of growth-regulated protooncogenes in human malignant plasma cells.
The expression of three growth-regulated protooncogenes, c-myc, c-myb, and p53, and the S-phase-specific histone H3 gene, was compared in bone marrow cells from multiple myeloma patients and normal controls by measuring the amount of specific RNA by Northern blot analysis. Four samples contained at least 72% of myeloma cells, one sample 43%, and one 11%. Expression of the protooncogenes was similar in normal and myeloma bone marrow cells, whereas that of histone H3 gene was significantly reduced (between 10 and 15 times) in samples containing at least 43% of malignant plasma cells and not detectable in those containing more than 72% of neoplastic cells. Protooncogene levels of expression were compared to those of the H3 gene to distinguish the increased expression of a growth-regulated gene due to a true deregulation from overexpression reflecting solely an increase in the fraction of cycling cells. The ratios of expression of protooncogenes to histone H3 were markedly increased in multiple myeloma cells; the highest ratios were found in the patients with the highest number of malignant plasma cells. These results suggest that the expression of three growth-regulated oncogenes (c-myc, c-myb, p53) is altered in myelomatous plasma cells.


Who's Got the Booze? The Role of Access to Alcohol in the Relations Between Social Status and Individual Use.
The findings of previous research that examined relationships between popularity and alcohol use in adolescents have been mixed, and few hypotheses have proposed mechanisms for this relationship. The current study expands on previous literature (a) by examining a possible mechanism that can explain the relation between popularity and alcohol use (home access to alcohol) and (b) by using another sociometric measure ("betweenness"), beyond popularity, that may relate more to home alcohol access. Using network-level data from adolescents in 9th-11th grades in eight schools within two in-home waves of the National Longitudinal Study of Adolescent to Adult Health (Add Health), we examined two sociometric measures of social status: popularity (number of schoolmates who nominated participants as a friend) and betweenness (level of ties participants have to multiple social subgroups within a network). Betweenness, but not popularity, related to later alcohol use. Having home access to alcohol positively related to later alcohol use, and having friends with home access to alcohol negatively related to later alcohol use. Alcohol access was also related to later sociometric status. Friends' alcohol access negatively related to later betweenness, and personal alcohol access moderated other pathways predicting betweenness. Betweenness appears to play a unique role in the association between social status and alcohol use in adolescent social networks. This is potentially tied to specific ways in which adolescents may be able to access alcohol (through home or through friends with access at home). More research is necessary to examine the ways in which multiple sociometric statuses relate to the contexts in which adolescents access and use alcohol.


Physical and Pharmacologic Restraint in Hospitalized Children With Autism Spectrum Disorder.
Children with autism spectrum disorder (ASD) have high rates of cooccurring conditions and are hospitalized longer and more frequently than children without ASD. Little is known about use of involuntary physical or pharmacologic restraint in hospitalized children with ASD. This study compares use of restraint because of violent or self-injurious behavior during inpatient pediatric hospitalization in children with ASD compared with typical peers. This retrospective cohort study examines electronic health records of all children aged 5 to 21 years admitted to a pediatric medical unit at a large urban hospital between October 2016 and October 2021. Billing diagnoses from inpatient encounters identified ASD and cooccurring diagnoses. Clinical orders identified physical and pharmacologic restraint. Propensity score matching ensured equivalency between ASD and matched non-ASD groups on demographic factors. Logistic regression determined the odds of restraint in children with ASD compared with children without ASD, controlling for hospitalization factors and cooccurring diagnoses. Of 21 275 hospitalized children, 367 (1.7%) experienced restraint and 1187 (5.6%) had ASD. After adjusting for reason for admission, length of stay, and cooccurring mental health, developmental, and behavioral disorders, children with ASD were significantly more likely to be restrained than children without ASD (odds ratio 2.3, 95% confidence interval 1.6-3.4; P < .001). Hospitalized children with ASD have significantly higher odds of restraint for violent or self-injurious behavior compared with children without ASD after accounting for reason for admission, length of hospitalization and cooccurring diagnoses. Work is needed to modify the hospital environment for children with ASD to reduce behavioral dysregulation and restraint.


Effect of prostaglandins on pancreatic circulation in anesthetized dogs.
To assess the contribution of prostaglandins (PGs) to the maintenance of vascular tone and exocrine secretion in the pancreas, the effects of several products of arachidonic acid metabolism on the blood flow and flow rate of exocrine secretion were examined in the isolated blood perfused pancreas of the pentobarbital-anesthetized dog with and without pretreatment with the cyclooxygenase inhibitors, indomethacin (2 mg/kg i.v.) or sodium meclofenamate (10 mg/kg i.v.). Intra-arterial administration of PGE2, PGI2 and thromboxane B2 at doses of 30 to 300 ng/kg produced vasodilation and increased flow of blood to the pancreas. Injections of either PGF2 alpha, 30 to 300 ng/kg, or PGD2, 10 to 100 ng/kg, produced a biphasic effect, viz., transient vasoconstriction followed by a prolonged vasodilation. Administration of either indomethacin or sodium meclofenamate significantly reduced pancreatic blood flow (P less than .01). In animals pretreated with either of the cyclooxygenase inhibitors, the effect of PGE2, PGI2 or PGD2 to increase blood flow to the pancreas was prolonged in duration. Administration of either PGs, thromboxane B2 or cyclooxygenase inhibitors did not markedly alter the flow rate of exocrine pancreatic secretion. These data indicate that one or more products of arachidonic acid formed through the cyclooxygenase pathway contribute to the maintenance of pancreatic vascular bed in a dilated state.


Cerebellum and psychiatric disorders.
The objective of this update article is to report structural and functional neuroimaging studies exploring the potential role of cerebellum in the pathophysiology of psychiatric disorders. A non-systematic literature review was conducted by means of Medline using the following terms as a parameter: "cerebellum", "cerebellar vermis", "schizophrenia", "bipolar disorder", "depression", "anxiety disorders", "dementia" and "attention deficit hyperactivity disorder". The electronic search was done up to April 2008. Structural and functional cerebellar abnormalities have been reported in many psychiatric disorders, namely schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, dementia and attention deficit hyperactivity disorder. Structural magnetic resonance imaging studies have reported smaller total cerebellar and vermal volumes in schizophrenia, mood disorders and attention deficit hyperactivity disorder. Functional magnetic resonance imaging studies using cognitive paradigms have shown alterations in cerebellar activity in schizophrenia, anxiety disorders and attention deficit hyperactivity disorder. In dementia, the cerebellum is affected in later stages of the disease. Contrasting with early theories, cerebellum appears to play a major role in different brain functions other than balance and motor control, including emotional regulation and cognition. Future studies are clearly needed to further elucidate the role of cerebellum in both normal and pathological behavior, mood regulation, and cognitive functioning.


Design, synthesis and application of spiro[4.5]cyclohexadienones via one-pot sequential p-hydroxybenzylation/oxidative dearomatization.
One-pot sequential p-hydroxybenzylation/oxidative dearomatization/spiroannulation has been designed for the efficient construction of tetrahydrofuran containing spiro-cyclohexadienones. This reaction proceeds through the p-hydroxybenzylation of 1,3-diketones with p-hydroxybenzyl alcohol via quinone methide formation followed by oxidative dearomatization/spiroannulation with suitable alcohols. The Friedel-Crafts alkylation of spiro[4.5]cyclohexadienones with indoles provided a broad array of highly diastereoselective C-3 alkylated spirocycles and cyclohepta[b]indoles depending upon the ring size of the fused cyclic ketones.


Optical coherence tomography (OCT) to image active and inactive retinoblastomas as well as retinomas.
To illustrate Optical Coherence Tomography (OCT) images of active and inactive retinoblastoma (Rb) tumours. Current observational study included patients diagnosed with retinoblastoma and retinoma who were presented at Amsterdam UMC and Jules-Gonin Eye Hospital, between November 2010 and October 2017. Patients aged between 0 and 4 years were imaged under general anaesthesia with handheld OCT in supine position. Patients older than 4 years were imaged with the conventional OCT (Heidelberg Engineering, Heidelberg Spectralis, Germany). All patients included were divided into two groups: active and inactive tumours (retinoma and regression patterns). Patients' medical records and OCT images were analysed during meetings via discussions by ophthalmologists and physicists. Twelve Dutch and 8 Swiss patients were divided into two groups: 2 patients with active tumour versus 18 patients with inactive tumour. Subsequently, inactive group could be divided in two groups, which consisted of 10 patients with retinoma and 8 patients with different regression pattern types. Of all included patients, 15 were male (75%). Median age at diagnosis was 18.0 months (range 0.19-715.2 months). A total of 12 retinoblastoma (active and inactive) and 8 retinoma foci were investigated by OCT. No distinction could be made between active and inactive tumours using only OCT. Optical coherence tomography alone cannot distinguish between active and inactive Rbs. However, handheld OCT adds useful information to the established imaging techniques in the monitoring and follow-up of retinoblastoma patients. With this study, we provide an overview of OCT images of active and inactive Rbs.


Measurements of the wavelength dependence and other properties of stellar scintillation at Mauna Kea, Hawaii.
The variance of intensity of stellar scintillation has been measured as a function of wavelength using photon counting and on-line digital analysis techniques. The experimental data are consistent with that predicted by the theory of Tatarski. Measurements of the temporal correlation function of intensity and the higher moments of the probability density function of scintillation are also described. Time scales in the 1.7-10-msec range were observed, and the observed higher moments were consistently lower than those predicted by a log normal distribution. All the measurements were made at Mauna Kea Observatory, Hawaii.


Screening for prostate cancer (PC)--an update on recent findings of the European Randomized Study of Screening for Prostate Cancer (ERSPC).
Introduction for screening for prostate cancer as a healthcare policy is desirable provided its effectiveness can be shown in terms of decreasing prostate cancer mortality at an acceptable price in terms of quality of life and costs. The European Randomized Study of Screening for Prostate Cancer (ERSPC) was initiated in 1993 and should in 2008 have the power to produce the required information. The structure and status of ERSPC. ERSPC is a randomized controlled trial running in eight European countries (Belgium, Finland, France, Italy, The Netherlands, Spain, Sweden, and Switzerland). A total of 267,994 have been randomized to screening vs. control. An interim look at the data has taken place in 2006; the advice of the Data Monitoring Committee was to continue the study. This was based on a total of 23,794 deaths in both study groups, 6,033 cases of prostate cancer detected in both groups of which about 1, 200 had died. Contributions to a better understanding of the screening methodology. ERSPC has contributed with a large number of publications, either coming from individual centers or combining data of several centers. A complete listing can be found at www.erspc.org. Lead-time and overdiagnosis with the screening regimen utilized in ERSPC Rotterdam were established to amount to 10.3 years and 54%. This information is of great importance for the development of further screening strategies. During the process of ERSPC, digital rectal examination was omitted and replaced by the inclusion of PSA 3-4 as a biopsy indication. The data on which this decision has been based were published and validated. Overdiagnosis and overtreatment have an adverse influence on quality of life, as it will be included in the evaluation of ERSPC. The recent development of a nomogram for the identification of indolent disease is a major step to improve on this outcome parameter. The application of this nomogram to screen detected cases allows the the advice "active observation" to about 30% of such patients. ERSPC is set to show or exclude at least a 25% reduction in prostate cancer mortality through screening. Many pending problems still have to be resolved prior to the introduction of populations based screening as a worldwide healthcare policy.


A multidisciplinary program to educate and advocate for living donors.
Education is critical in decision making and the informed consent process in prospective living donors. Little has been written about how and what living donors should be taught. This article describes a multidisciplinary program for living donor education at the University of Virginia. The goals of the program are to impart information needed for prospective donors to make an informed decision and to independently evaluate donors' medical and psychosocial suitability. A partnership between the transplant department and an independent donor advocacy team establishes an environment conducive to education. By embracing independence, transparency, partnership, and advocacy, our program permits bidirectional education. This partnership facilitates unbiased understanding and appreciation of this education and considers each individual's unique circumstances when making informed decisions. Likewise, prospective donors educate the team about their circumstances, which helps the team safeguard the prospective donor and may enhance the safety of prospective donors and the perceived integrity of living organ donation.


Assisted Reproductive Technology and Newborn Size in Singletons Resulting from Fresh and Cryopreserved Embryos Transfer.
The aim of this study was two-fold: to investigate the association of Assisted Reproductive Technology (ART) and small newborn size, using standardized measures; and to examine within strata of fresh and cryopreserved embryos transfer, whether this association is influenced by parental infertility diagnoses. We used a population-based retrospective cohort from Michigan (2000-2009), Florida and Massachusetts (2000-2010). Our sample included 28,946 ART singletons conceived with non-donor oocytes and 4,263,846 non-ART singletons. Regression models were used to examine the association of ART and newborn size, measured as small for gestational age (SGA) and birth-weight-z-score, among four mutually exclusive infertility groups: female infertility only, male infertility only, combined female and male infertility, and unexplained infertility, stratified by fresh and cryopreserved embryos transfer. We found increased SGA odds among ART singletons from fresh embryos transfer compared with non-ART singletons, with little difference by infertility source [adjusted odds-ratio for SGA among female infertility only: 1.18 (95% CI 1.10, 1.26), male infertility only: 1.20 (95% CI 1.10, 1.32), male and female infertility: 1.18 (95% CI 1.06, 1.31) and unexplained infertility: 1.24 (95% CI 1.10, 1.38)]. Conversely, ART singletons, born following cryopreserved embryos transfer, had lower SGA odds compared with non-ART singletons, with mild variation by infertility source [adjusted odds-ratio for SGA among female infertility only: 0.56 (95% CI 0.45, 0.71), male infertility only: 0.64 (95% CI 0.47, 0.86), male and female infertility: 0.52 (95% CI 0.36, 0.77) and unexplained infertility: 0.71 (95% CI 0.47, 1.06)]. Birth-weight-z-score was significantly lower for ART singletons born following fresh embryos transfer than non-ART singletons, regardless of infertility diagnoses.


[The prevalence of refractive, anisometropic amblyopia in adults without strabismus and with contact lens correction].
The paper presents results after examination of 1260 adults (2547 eyes), aged from 18 to 55 years, for the period from 1982 to 1988. The examination was carried out in order to reveal the incidence of refractive, anisometropic amblyopia without strabismus in persons using glasses (a control group) and contact lenses as well as to determine a degree of spheric, astigmatic refraction in development of amblyopia on the background of contact lenses. It was found that amblyopia on the background of contact correction, as compared with glass correction, develops rarer making up 22.03% of them low degree of amblyopia is recorded in 51,16%, moderate--in 35,65% high--in 13,19% to the total number of amblyopic eyes examined. Direct relationship between the number of amblyopic eyes and degree of astigmatism and anisometropia is revealed. Detection of amblyopia in adults without strabismus with subsequent contact correction and treatment is considered to be necessary for medical and labour rehabilitation of such patients.


Appropriateness of Outpatient Antibiotic Use in Seniors across Two Canadian Provinces.
Antimicrobials are among the most prescribed medications in Canada, with over 90% of antibiotics prescribed in outpatient settings. Seniors prescribed antimicrobials are particularly vulnerable to adverse drug events and antimicrobial resistance. The extent of inappropriate antibiotic prescribing in outpatient Canadian medical practice, and the potential long-term trends in this practice, are unknown. This study is the first in Canada to examine prescribing quality across two large-scale provincial healthcare systems to compare both quantity and quality of outpatient antibiotic use in seniors. Population-based analyses using administrative health databases were conducted in British Columbia (BC) and Ontario (ON), and all outpatient, oral antimicrobials dispensed to seniors (≥65 years) from 1 January 2000 to 31 December 2018 were identified. Antimicrobials were linked to an indication using a 3-tiered hierarchy. Tier 1 indications, which always require antibiotics, were given priority, followed by Tier 2 indications that sometimes require antibiotics, then Tier 3, which never require antibiotics. Prescription rates were calculated per 1000 population, and trends were examined overall, by drug class, and by patient demographics. Prescribing remained steady in both provinces, with 11,166,401 prescriptions dispensed overall in BC, and 27,656,014 overall in ON. BC prescribed at slightly elevated rates (range: 790 to 930 per 1000 residents), in comparison to ON (range: 745 to 785 per 1000 residents), throughout the study period. For both provinces, a Tier 3 diagnosis was the most common reason for antibiotic use, accounting for 50% of all indication-associated antibiotic prescribing. Although Tier 3 indications remained the most prescribed-for diagnoses throughout the study period, a declining trend over time is encouraging, with much room for improvement remaining. Elevated prescribing to seniors continues across Canadian outpatient settings, and prescribing quality is of high concern, with 50% of all antimicrobials prescribed inappropriately for common infections that do not require antimicrobials.


Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk.
Epidermal infiltration of neutrophils is a hallmark of psoriasis, where their activation leads to release of neutrophil extracellular traps (NETs). The contribution of NETs to psoriasis pathogenesis has been unclear, but here we demonstrate that NETs drive inflammatory responses in skin through activation of epidermal TLR4/IL-36R crosstalk. This activation is dependent upon NETs formation and integrity, as targeting NETs with DNase I or CI-amidine in vivo improves disease in the imiquimod (IMQ)-induced psoriasis-like mouse model, decreasing IL-17A, lipocalin2 (LCN2), and IL-36G expression. Proinflammatory activity of NETs, and LCN2 induction, is dependent upon activation of TLR4/IL-36R crosstalk and MyD88/nuclear factor-kappa B (NF-κB) down-stream signaling, but independent of TLR7 or TLR9. Notably, both TLR4 inhibition and LCN2 neutralization alleviate psoriasis-like inflammation and NETs formation in both the IMQ model and K14-VEGF transgenic mice. In summary, these results outline the mechanisms for the proinflammatory activity of NETs in skin and identify NETs/TLR4 as novel therapeutic targets in psoriasis.


The cultural and biochemical characters of Streptococcus milleri strains isolated from human sources.
A collection of 346 strains of Streptococcus milleri from a variety of human sources was examined culturally and biochemically, and for the presence of Lancefield group antigens. Most of the strains were non-haemolytic and ungroupable, but 25% were beta haemolytic and 19% were alpha haemolytic; 28% possessed a group antigen (A, 5%; C, 6%, F, 14%, G, 3%). These antigens were present in 69% of beta-haemolytic but in only 13% of alpha-haemolytic or non-haemolytic strains; beta haemolysis occurred in 82% of group-F strains, 43% of other groupable strains and 11% of ungroupable strains.The following reactions were given by > 80% of S. milleri strains: hydrolysis of arginine and aesculin, a positive Voges-Proskauer reaction, and acidification of trehalose, lactose, salicin and sucrose. A minority of strains showed enhancement of growth by CO(2), bile tolerance, NaCl tolerance, and ability to acidify other sugars, notably mannitol, raffinose and melibiose. Departures from the modal pattern of biochemical reactions showed a weak correlation with the type of haemolysis and the presence or absence of a group antigen but were not sufficiently systematic for clear-cut subdivisions to be recognized within the species.S. milleri therefore appeared to comprise a ;central' group of non-haemolytic strains that rarely formed a Lancefield-group antigen, in which the aesculin reaction was nearly always positive, lactose was usually acidified, and a considerable minority showed enhancement of growth by CO(2) and bile tolerance. Deviations from this pattern were of two main types. (1) ;Loss' of one or more of these reactions, which tended to be associated with beta-haemolysis and presence of a group antigen. In these respects, alpha-haemolytic strains tended to occupy an intermediate position. (2) ;Gain' of the ability to acidify additional sugars, notably raffinose and melibiose or mannitol; this occurred mainly among otherwise typical non-haemolytic strains that were rarely groupable.Only 12% of isolations from the bloodstream of patients suffering from systemic infections were beta haemolytic and only 18% possessed a group antigen, but a considerably greater proportion of those from visceral abscesses were beta haemolytic (28%). Among isolations from superficial lesions in some body sites there were considerably greater proportions of beta-haemolytic and groupable strains; thus, nearly one-half of those isolated from the abdomen other than the female genital tract were beta-haemolytic and over one-half were groupable. On the other hand, strains from the teeth and gums were nearly always non-haemolytic and ungroupable, and most vaginal isolations were of non-haemolytic strains with a wide sugar-fermentation pattern.


In silico Analyses of Immune System Protein Interactome Network, Single-Cell RNA Sequencing of Human Tissues, and Artificial Neural Networks Reveal Potential Therapeutic Targets for Drug Repurposing Against COVID-19.
Background: There is pressing urgency to identify therapeutic targets and drugs that allow treating COVID-19 patients effectively. Methods: We performed in silico analyses of immune system protein interactome network, single-cell RNA sequencing of human tissues, and artificial neural networks to reveal potential therapeutic targets for drug repurposing against COVID-19. Results: We screened 1,584 high-confidence immune system proteins in ACE2 and TMPRSS2 co-expressing cells, finding 25 potential therapeutic targets significantly overexpressed in nasal goblet secretory cells, lung type II pneumocytes, and ileal absorptive enterocytes of patients with several immunopathologies. Then, we performed fully connected deep neural networks to find the best multitask classification model to predict the activity of 10,672 drugs, obtaining several approved drugs, compounds under investigation, and experimental compounds with the highest area under the receiver operating characteristics. Conclusion: After being effectively analyzed in clinical trials, these drugs can be considered for treatment of severe COVID-19 patients. Scripts can be downloaded at https://github.com/muntisa/immuno-drug-repurposing-COVID-19.


Cucumber mosaic virus D satellite RNA-induced programmed cell death in tomato.
D satellite RNA (satRNA) with its helper virus, namely, cucumber mosaic virus, causes systemic necrosis in tomato. The infected plant exhibits a distinct spatial and temporal cell death pattern. The distinct features of chromatin condensation and nuclear DNA fragmentation indicate that programmed cell death is involved. In addition, satRNA localization and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling show that cell death is initiated from the infected phloem or cambium cells and spreads to other nearby infected cells. Timing of the onset of necrosis after inoculation implicates the involvement of cell developmental processes in initiating tomato cell death. Analysis of the accumulation of minus- and plus-strand satRNAs in the infected plants indicates a correlation between high amounts of minus-strand satRNA and tomato cell death.


Silver accumulation in Daphnia magna in the presence of reactive sulfide.
Previously, we demonstrated a higher silver body burden when Daphnia magna were exposed to silver in the presence of environmentally relevant concentrations (25 nM) of reactive sulfide, but the explanation was unclear. In the present study, D. magna were exposed to AgNO3 (0.93 microg Ag/L=8.6 nM as a mixture of cold Ag and (110m)Ag) in synthetic water in either the presence or absence of 25 nM sulfide as zinc sulfide clusters. After 1-h exposure, daphnids were transferred to clean water for up to 5-h depuration. At different times of Ag exposure and depuration, daphnids were randomly sampled for whole body silver burden. Also, after 1 h, daphnids were sampled for silver accumulation in "gills" (small organs on the thoracic appendages), digestive tract, and carcass. Other groups were exposed to the same silver and sulfide concentrations for 1 h and then sampled for whole-body autoradiography. Silver body burden was about two-fold higher in the presence of sulfide. A two-fold increase in silver burden in "gills" and digestive tract, but not in carcass, was also observed in the presence of sulfide. Absolute differences due to sulfide were greatest in digestive tract and explained most of the difference in whole body burden. Transfer to clean water caused a significant drop in silver concentration in whole body and all compartments to similar levels in the two groups after 5-h depuration. These results indicate that the higher silver body burden observed in the presence of sulfide is mainly due to sulfide-bound silver in the digestive tract of the daphnids. This conclusion is supported by autoradiography, which showed a high concentration of silver in the digestive tract of daphnids exposed to Ag/sulfide.


Intermittent Fasting on Neurologic Diseases: Potential Role of Gut Microbiota.
As the global population ages, the prevalence of neurodegenerative diseases is surging. These disorders have a multifaceted pathogenesis, entwined with genetic and environmental factors. Emerging research underscores the profound influence of diet on the development and progression of health conditions. Intermittent fasting (IF), a dietary pattern that is increasingly embraced and recommended, has demonstrated potential in improving neurophysiological functions and mitigating pathological injuries with few adverse effects. Although the precise mechanisms of IF's beneficial impact are not yet completely understood, gut microbiota and their metabolites are believed to be pivotal in mediating these effects. This review endeavors to thoroughly examine current studies on the shifts in gut microbiota and metabolite profiles prompted by IF, and their possible consequences for neural health. It also highlights the significance of dietary strategies as a clinical consideration for those with neurological conditions.


Spaceflight-related suboptimal conditions can accentuate the altered gravity response of Drosophila transcriptome.
Genome-wide transcriptional profiling shows that reducing gravity levels during Drosophila metamorphosis in the International Space Station (ISS) causes important alterations in gene expression: a large set of differentially expressed genes (DEGs) are observed compared to 1g controls. However, the preparation procedures for spaceflight and the nonideal environmental conditions on board the ISS subject the organisms to additional environmental stresses that demonstrably affect gene expression. Simulated microgravity experiments performed on the ground, under ideal conditions for the flies, using the random position machine (RPM), show much more subtle effects on gene expression. However, when the ground experiments are repeated under conditions designed to reproduce the additional environmental stresses imposed by spaceflight procedures, 79% of the DEGs detected in the ISS are reproduced by the RPM experiment. Gene ontology analysis of them shows they are genes that affect respiratory activity, developmental processes and stress-related changes. Here, we analyse the effects of microgravity on gene expression in relation to the environmental stresses imposed by spaceflight. Analysis using 'gene expression dynamics inspector' (GEDI) self-organizing maps reveals a subtle response of the transcriptome to microgravity. Remarkably, hypergravity simulation induces similar response of the transcriptome, but in the opposite direction, i.e. the genes promoted under microgravity are usually suppressed under hypergravity. These results suggest that the transcriptome is finely tuned to normal gravity and that microgravity, together with environmental constraints associated with space experiments, can have profound effects on gene expression.


The role of telomerase protein TERT in Alzheimer's disease and in tau-related pathology in vitro.
The telomerase reverse transcriptase protein TERT has recently been demonstrated to have a variety of functions both in vitro and in vivo, which are distinct from its canonical role in telomere extension. In different cellular systems, TERT protein has been shown to be protective through its interaction with mitochondria. TERT has previously been found in rodent neurons, and we hypothesize that it might have a protective function in adult human brain. Here, we investigated the expression of TERT at different stages of Alzheimer's disease pathology (Braak Stages I-VI) in situ and the ability of TERT to protect against oxidative damage in an in vitro model of tau pathology. Our data reveal that TERT is expressed in vitro in mouse neurons and microglia, and in vivo in the cytoplasm of mature human hippocampal neurons and activated microglia, but is absent from astrocytes. Intriguingly, hippocampal neurons expressing TERT did not contain hyperphosphorylated tau. Vice versa, neurons that expressed high levels of pathological tau did not appear to express TERT protein. TERT protein colocalized with mitochondria in the hippocampus of Alzheimer's disease brains (Braak Stage VI), as well as in cultured neurons under conditions of oxidative stress. Our in vitro data suggest that the absence of TERT increases ROS generation and oxidative damage in neurons induced by pathological tau. Together, our findings suggest that TERT protein persists in neurons of the adult human brain, where it may have a protective role against tau pathology.


Analysis of isoaccepting transfer ribonucleic acid species of Bacillus subtilis: changes in chromatography of transfer ribonucleic acids associated with stage of development.
Changes in chromatographic profiles of tyrosyl-, leucyl-, tryptophanyl-, and lysyl-transfer ribonucleic acids (tRNAs) are presented as a function of the growth stage in Bacillus subtilis. All of the tRNA groups investigated expressed different temporal patterns of change in isoaccepting species. Tyrosyl-tRNAs were the earliest to change and were followed by changes in leucyl- and then tryptophanyl-tRNAs. Lysyl-tRNAs were unique in having two times of change: one early and one very late. As an aid in understanding the temporal aspect of tRNA alterations during sporulation, the chromatographic profiles of aminoacyl tRNAs from an early blocked asporogenous mutant were studied. The asporogenous mutant used was blocked at the axial filament stage, stage 0 of sporulation. Nevertheless, those tRNAs which showed differences between the spore and cells in exponential growth exhibited similar changes in the asporogenous mutant after 24 h of growth. The data suggest that several tRNA changes occur during development in B. subtilis but that the events leading to these changes are either independent of, or occur before, stage 0 of sporulation, except in the case of lysyl-tRNA.


Agroecology research in Europe funded by European and transnational programmes: current status and perspectives.
Background: Redesigning the agri-food system through agroecology represents a common ambition among practitioners, activists and scholars to achieve environmental and socio-economic sustainability. Research can have a main role to support this path. Although it seems that there is a gradual increasing body of agroecology research, it clearly lacks good knowledge about this. The main objective of this study was therefore to map research projects related to agroecology in Europe with the aim to characterize European research in terms of implementation of agroecology elements, identify needs for future cross collaboration between countries and networks, and support the setting up of appropriate research agendas fostering agroecology research in Europe. Methods: A desktop research with different databases related to European and transnational funding programmes was carried out to identify funded research projects involved in agroecology. The obtained projects were used to perform a social network analysis. Furthermore, two surveys were conducted, one with coordinators of identified projects and a second one for researchers engaged in agroecology. Results: Our study highlighted a predominant trajectory of agroecology research prone to the transformation of the agri-food system. France, Germany, Italy, Netherlands, Portugal, Spain, and United Kingdom were the most active countries engaged in agroecology research. In all surveys, issues related to efficiency improvement, synergies strengthening, local economy development, and co-creation and sharing of knowledge were the most implemented to support agri-food transformation. Transdisciplinary approaches were mainly addressed by European projects. Surveys reported a limited participation of value chain actors, while researchers, farmers, and their associations were the most involved. Survey respondents suggested to increase project duration and introduce flexibility methods to modulate research actions according to dynamic of the contexts. Conclusion: On the basis of the results, some policy recommendations were provided to fostering agroecology research in Europe and its contribution for transformation of agri-foods systems.


Pancreatic transdifferentiation in porcine liver following lentiviral delivery of human furin-cleavable insulin.
Type I diabetes mellitus (TID) results from the autoimmune destruction of the insulin-producing pancreatic β-cells. Gene therapy is one strategy being actively explored to cure TID by affording non-β-cells the ability to secrete insulin in response to physiologic stimuli. In previous studies, we used a novel surgical technique to express furin-cleavable human insulin (INS-FUR) in the livers of streptozotocin (STZ)-diabetic Wistar rats and nonobese diabetic (NOD) mice with the use of the HMD lentiviral vector. Normoglycemia was observed for 500 and 150 days, respectively (experimental end points). Additionally, some endocrine transdifferentiation of the liver, with storage of insulin in granules, and expression of some β-cell transcription factors (eg, Pdx1, Neurod1, Neurog3, Nkx2-2, Pax4) and pancreatic hormones in both studies. The aim of this study was to determine if this novel approach could induce liver to pancreatic transdifferentiation to reverse diabetes in pancreatectomized Westran pigs. Nine pigs were used in the study, however only one pig maintained normal fasting blood glucose levels for the period from 10 to 44 days (experimental end point). This animal was given 2.8 × 10(9) transducing units/kg of the lentiviral vector expressing INS-FUR. A normal intravenous glucose tolerance test was achieved at 30 days. Reverse-transcription polymerase chain reaction analysis of the liver tissue revealed expression of several β-cell transcription factors, including the key factors, Pdx-1 and Neurod1, pancreatic hormones, glucagon, and somatostatin; however, endogenous pig insulin was not expressed. Triple immunofluorescence showed extensive insulin expression, as was previously observed in our studies with rodents. Additionally, a small amount of glucagon and somatostatin protein expression was seen. Collectively, these data indicate that pancreatic transdifferentiation of the liver tissue had occurred. Our data suggest that this regimen may ultimately be used clinically to cure TID, however more work is required to replicate the successful reversal of diabetes in increased numbers of pigs.


Association of Advanced Glycation End Products with coronary Artery Calcification in Japanese Subjects with Type 2 Diabetes as Assessed by Skin Autofluorescence.
Advanced glycation end products (AGE) are considered to be among the critical pathogenic factors involved in the progression of diabetic complications. Skin autofluorescence (AF), a noninvasive measurement of AGE accumulation, has been recognized as a useful and convenient marker for diabetic vascular diseases in Caucasians. This study aimed to evaluate the association of tissue AGE, assessed using skin AF, with coronary artery calcification in Japanese subjects with type 2 diabetes. In total, 122 Japanese subjects with type 2 diabetes enrolled in this cross-sectional study underwent multi-slice computed tomography for total coronary artery calcium scores (CACS) estimation and examination with a skin AF reader. Skin AF positively correlated with age, sex, diabetes duration, pulse wave velocity, systolic blood pressure, serum creatinine, and CACS. In addition, skin AF results negatively correlated with BMI, eGFR, and serum C-peptide concentration. According to multivariate analysis, age and systolic blood pressure showed strong positive correlation and eGFR showed negative correlation with skin AF values. Multiple linear regression analyses revealed a significant positive correlation between skin AF values and logCACS, independent of age, sex, diabetes duration, HbA1c, BMI, IMT, and blood pressure. However, skin AF showed no association with serum levels of AGE, such as Nε-(carboxymethyl) lysine and 3-deoxyglucosone. Skin AF results positively correlated with CACS in Japanese subjects with type 2 diabetes. This result indicates that AGE plays a role in the pathogenesis of diabetic macrovascular disease. Measurement of skin AF values may be useful for assessing the severity of diabetic complications in Japanese subjects.


Direct evidence for fluid membranes.
We describe a new kind of cell motility that provides direct, visual evidence for the fluid nature of cell membranes. The movement involves continual, unidirectional rotation of one part of a devescovinid flagellate in relation to a neighboring part, at speeds up to one rotation/1.5 sec (room temperature). Rotation includes the plasma membrane, using the flagellar bases and ectosymbiotic bacteria embedded in pockets of the membrane as visible markers. The plasma membrane between the rotating and stationary surfaces is continuous, without fusions with other membranes, and has the typical trilaminar structure of other cell membranes. The nucleus, helical Golgi complex, and stiff central axostyle also rotate. The head of the flagellate always rotates clockwise (as viewed from the anterior end) in relation to the body, but when the head becomes stuck to debris, the body rotates counterclockwise. Evidence suggests that the microtubular axostyle generates the motive force for rotation.


Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.
Selective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers. Patients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity. Fifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002). Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.


Microvascular decompression or neuromodulation in patients with SUNCT and trigeminal neurovascular conflict?
Objectives To assess the effectiveness of neuromodulation and trigeminal microvascular decompression (MVD) in patients with medically-intractable short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). Methods Two patients with medically refractory SUNCT underwent MVD following beneficial but incomplete response to neuromodulation (occipital nerve stimulation and deep brain stimulation). MRI confirmed neurovascular conflict with the ipsilateral trigeminal nerve in both patients. Results Although neuromodulation provided significant benefit, it did not deliver complete relief from pain and management required numerous postoperative visits with adjustment of medication and stimulation parameters. Conversely, MVD was successful in eliminating symptoms of SUNCT in both patients with no need for further medical treatment or neuromodulation. Conclusion Neuromodulation requires expensive hardware and lifelong follow-up and maintenance. These case reports highlight that microvascular decompression may be preferable to neuromodulation in the subset of SUNCT patients with ipsilateral neurovascular conflict.


Mexican Trypanosoma cruzi T. cruzi I strains with different degrees of virulence induce diverse humoral and cellular immune responses in a murine experimental infection model.
It is has been shown that the majority of T. cruzi strains isolated from Mexico belong to the T. cruzi I (TCI). The immune response produced in response to Mexican T. cruzi I strains has not been well characterized. In this study, two Mexican T. cruzi I strains were used to infect Balb/c mice. The Queretaro (TBAR/MX/0000/Queretaro)(Qro) strain resulted in 100% mortality. In contrast, no mortality was observed in mice infected with the Ninoa (MHOM/MX/1994/Ninoa) strain. Both strains produced extended lymphocyte infiltrates in cardiac tissue. Ninoa infection induced a diverse humoral response with a higher variety of immunoglobulin isotypes than were found in Qro-infected mice. Also, a stronger inflammatory TH1 response, represented by IL-12p40, IFNgamma, RANTES, MIG, MIP-1beta, and MCP-1 production was observed in Qro-infected mice when compared with Ninoa-infected mice. We propose that an exacerbated TH1 immune response is a likely cause of pathological damage observed in cardiac tissue and the primary cause of death in Qro-infected mice.


Redox reactions of [FeFe]-hydrogenase models containing an internal amine and a pendant phosphine.
A diiron dithiolate complex with a pendant phosphine coordinated to one of the iron centers, [(μ-SCH2)2N(CH2C6H4-o-PPh2){Fe2(CO)5}] (1), was prepared and structurally characterized. The pendant phosphine is dissociated together with a CO ligand in the presence of excess PMe3, to afford [(μ-SCH2)2N(CH2C6H4-o-PPh2){Fe(CO)2(PMe3)}2] (2). Redox reactions of 2 and related complexes were studied in detail by in situ IR spectroscopy. A series of new Fe(II)Fe(I) ([3](+) and [6](+)), Fe(II)Fe(II) ([4](2+)), and Fe(I)Fe(I) (5) complexes relevant to Hox, Hox(CO), and Hred states of the [FeFe]-hydrogenase active site were detected. Among these complexes, the molecular structures of the diferrous complex [4](2+) with the internal amine and the pendant phosphine co-coordinated to the same iron center and the triphosphine diiron complex 5 were determined by X-ray crystallography. To make a comparison, the redox reactions of an analogous complex, [(μ-SCH2)2N(CH2C6H5){Fe(CO)2(PMe3)}2] (7), were also investigated by in situ IR spectroscopy in the absence or presence of extrinsic PPh3, which has no influence on the oxidation reaction of 7. The pendant phosphine in the second coordination sphere makes the redox reaction of 2 different from that of its analogue 7.


Estimation in a Cox proportional hazards cure model.
Some failure time data come from a population that consists of some subjects who are susceptible to and others who are nonsusceptible to the event of interest. The data typically have heavy censoring at the end of the follow-up period, and a standard survival analysis would not always be appropriate. In such situations where there is good scientific or empirical evidence of a nonsusceptible population, the mixture or cure model can be used (Farewell, 1982, Biometrics 38, 1041-1046). It assumes a binary distribution to model the incidence probability and a parametric failure time distribution to model the latency. Kuk and Chen (1992, Biometrika 79, 531-541) extended the model by using Cox's proportional hazards regression for the latency. We develop maximum likelihood techniques for the joint estimation of the incidence and latency regression parameters in this model using the nonparametric form of the likelihood and an EM algorithm. A zero-tail constraint is used to reduce the near nonidentifiability of the problem. The inverse of the observed information matrix is used to compute the standard errors. A simulation study shows that the methods are competitive to the parametric methods under ideal conditions and are generally better when censoring from loss to follow-up is heavy. The methods are applied to a data set of tonsil cancer patients treated with radiation therapy.


[Prevalence of musculoskeletal disorders in nursing professionals].
A cross-sectional study estimated the prevalence of work-related musculoskeletal disorders among nursing assistants in Salvador, Bahia. Three hundred and eight workers, randomly selected, answered a questionnaire applied by trained interviewers during working hours. The majority of respondents worked the day shift and did not usually work overtime. About 34% reported having another regular job. Average time in the formal or informal labor market was 19 years. There was high occupational exposure to repetitive hand movements, standing posture, walking, inadequate postures of the trunk and manual handling of loads. The prevalence of work-related musculoskeletal disorders in at least one body segment was 83.4%.The most affected body segments were: low back (53.9%), legs (51.9%), neck (36.4%), upper back (35.7%) and shoulders (33.8%). There was high prevalence of work-related musculoskeletal disorders in the studied population, which points out to the need for improvements in the working conditions of those professionals.


Variation in survival of children with central nervous system (CNS) malignancies diagnosed in Europe between 1978 and 1992: the EUROCARE study.
EUROCARE is a population-based survival study including data from European Cancer Registries. The present paper analyses survival after a malignant neoplasm of the central nervous system (CNS) in childhood (aged 0--14 years at diagnosis). The database includes 6130 cases from 34 population-based registries in 17 countries: 1558 were primitive neuroectodermal tumours (PNET) and 4087 astrocytoma, ependymoma or other gliomas: these morphologies were grouped in the analyses in order to reduce the diagnostic variability among the registries. 87% of cases were microscopically diagnosed (range among registries 71--100%) and losses to follow-up were limited to 2% (range 0--14%). Actuarial analyses indicate that the European (weighted) average of 5 years cumulative survival for cases diagnosed in 1978--1989 was 53% (95% confidence interval (CI) 49--57) for CNS neoplasms, 44% (95% CI 37--50) for PNET and 60% (95% CI 55--65) for the glioma-related types. Analysis of the sub-set of cases diagnosed in 1985--1989 revealed better results: cumulative survival at 5 years was 61% (95% CI: 55--65) for all CNS neoplasms; 48% (95% CI 41--56) for PNET and 68% (95% CI 62--73) for glioma-related types. Compared with older children, infants showed poorer prognosis: in 1978--1989 the 5-year survival rate was 33% (95% CI 23--45) and in 1985--1989 it was 46% (95% CI 34--59). Variability among countries was very large, with 5-year survival for CNS tumours diagnosed in 1985--1989 ranging from 28% in Estonia (95% CI 17--43) to 73% Sweden (95% CI 59--83) and 75% in Iceland (95% CI 35--95) and 73% in Finland (95% CI 66--79). Time trends were studied in a multivariate analysis observing a reduction in the risk of death in periods of diagnosis 1982--1985 (hazard ratio (HR)=0.85; 95% CI 0.78--0.93) and 1986--1989 (HR=0.70; 95% CI 0.64--0.77) compared with 1978--1981. The analysis were extended to 1990--1992 for the countries whose registries provided data for that period did not indicate any further progress. Results of this study confirm the large variability in European countries and indicate a positive trend in the survival probability for cases diagnosed in the 1980s.


Integrated Knowledge Translation: illustrated with outcome research in mental health.
Through this article the authors present a case summary of the early phases of research conducted with an Integrated Knowledge Translation (iKT) approach utilizing four factors: research question, research approach, feasibility, and outcome. iKT refers to an approach for conducting research in which community partners, referred to as knowledge users, are engaged in the entire research process. In this collaborative approach, knowledge users and researchers jointly devise the entire research agenda beginning with the development of the research question(s), determination of a feasible research design and feasible methods, interpretation of the results, dissemination of the findings, and the translation of knowledge into practice or policy decisions. Engaging clinical or community partners in the research enterprise can enhance the utility of the research results and facilitate its uptake. This collaboration can be a complex arrangement and flexibility may be required to accommodate the various configurations that the collaboration can take. For example, the research question can be jointly determined and refined; however, one person must take the responsibility for orchestrating the project, including preparing the proposal and application to the Research Ethics Board. This collaborative effort also requires the simultaneous navigation of barriers and facilitators to the research enterprise. Navigating these elements becomes part of the conduct of research with the potential for rewarding results, including an enriched work experience for clinical partners and investigators. One practice implication is that iKT may be considered of great utility to service providers due to its field friendly nature.


Transesophageal echocardiography measurements of aortic annulus diameter using biplane mode in patients undergoing transcatheter aortic valve implantation.
Aortic stenosis (AS) is a relevant common valve disorder. Severe AS and symptoms and/or left ventricular dysfunction (EF <50%) have the indication for aortic valve replacement (AVR). Majority of the patients with AS are elderly often with co-morbidities and generally have high preoperative risk. Transcatheter aortic valve implantation (TAVI) is offered in this group. Four different sizes of Corevalve prosthesis are available. Correct measurement of aortic size prior to TAVI is of great important to choose the right prosthesis size to avoid among others paravalvular leak or prosthesis patient mismatch.Aim of the study is to assess the aortic annulus diameter in patients undergoing TAVI by biplane (BP) mode using transesophageal echocardiography (TEE) and compare it to two-dimensional (2D) transthoracic echocardiography (TTE) and 2DTEE using three-dimensional (3D) TEE as reference method. The study population consisted of 50 patients retrospectively (24 men and 26 women, mean age 85±8 years of age) who all had undergone echocardiography examination prior to TAVI. The mean aortic annulus diameter was 20.4±2.2 mm with TTE, 22.3±2.5 mm with 2DTEE, 22.9±1.9 mm with BP-mode and 23.1±1.9 mm with 3DTEE. TTE underestimated the mean aortic annulus diameter in comparison to transesophageal imaging modalities (p<0.001). Using 3DTEE, 2% of patients were unsuitable for TAVI due to a too-small AoA (n=1). This figure was similar with BP (4%, n=2; p=1.00) but considerably larger with 2DTTE (36%, n=18; p < 0.001) and 2DTEE (12%, n=6; p=0.06). There was a strong correlation between BP-mode and 3DTEE for assessment of aortic annulus diameter (r-value 0.88) with small mean difference (-0.2±0.9 mm) whereas the other modalities showed larger 95% confidence interval and modest correlation (2DTTE vs. 3DTEE, -6.3 to 0.9 mm, r=0.64 and 2DTEE vs. 3DTEE, -4.8 to 3.2 mm, r=0.61). A multi-dimensional method is preferred to assess aortic annulus diameter in TAVI patients since there is risk of underestimation using single plane. Biplane mode is the method of choice in view of speedy post-processing with no need for expensive dedicated software. Lastly, single plane methods lead to misclassification of patients as unsuitable for TAVI. This may be of major clinical importance.


Evaluating four mathematical models for nitrous oxide production by autotrophic ammonia-oxidizing bacteria.
There is increasing evidence showing that ammonia-oxidizing bacteria (AOB) are major contributors to N(2)O emissions from wastewater treatment plants (WWTPs). Although the fundamental metabolic pathways for N(2)O production by AOB are now coming to light, the mechanisms responsible for N(2)O production by AOB in WWTP are not fully understood. Mathematical modeling provides a means for testing hypotheses related to mechanisms and triggers for N(2)O emissions in WWTP, and can then also become a tool to support the development of mitigation strategies. This study examined the ability of four mathematical model structures to describe two distinct mechanisms of N(2)O production by AOB. The production mechanisms evaluated are (1) N(2)O as the final product of nitrifier denitrification with NO(2)- as the terminal electron acceptor and (2) N(2)O as a byproduct of incomplete oxidation of hydroxylamine (NH(2)OH) to NO(2)-. The four models were compared based on their ability to predict N(2)O dynamics observed in three mixed culture studies. Short-term batch experimental data were employed to examine model assumptions related to the effects of (1) NH4+ concentration variations, (2) dissolved oxygen (DO) variations, (3) NO(2)- accumulations and (4) NH(2OH as an externally provided substrate. The modeling results demonstrate that all these models can generally describe the NH4+, NO(2)-, and NO(3)- data. However, none of these models were able to reproduce all measured N(2)O data. The results suggest that both the denitrification and NH(2)OH pathways may be involved in N(2)O production and could be kinetically linked by a competition for intracellular reducing equivalents. A unified model capturing both mechanisms and their potential interactions needs to be developed with consideration of physiological complexity.


Treatment decision-making in breast cancer: the patient-doctor relationship.
A diagnosis of breast cancer, whether the disease is early or advanced, can be devastating. With this in mind, constructive patient-physician relationships are essential to minimizing disease-related stress and anxiety, as patients undergo treatment and learn to cope with their diagnosis. Good communication skills are vital, and achieve measurable benefits, yet doctors receive very little training in communication. Patients may find it difficult to process large amounts of information, may not understand medical terminology, and can become confused or scared during discussions. They may need time to absorb information, and discuss it with friends and family, before treatment decisions are made. Patient awareness of treatment options is greater than ever, largely because of media exposure and the internet. Consequently, patients' expectations and desire to be involved in treatment choice are increasing, although some patients still prefer to leave decision-making to their doctor. Information about potential side-effects and other treatment burdens is vital, if patients are to make truly informed choices. Knowing in advance what side effects may be encountered, and how to manage them, can also help to improve adherence to treatment, which is necessary for patients to gain the maximum benefit. Side effects that patients find most problematic often differ from those that most concern doctors. Individual patients have different needs and expectations that must be respected, but ensuring that they understand their diagnosis, and the expected benefits and potential risks of treatment, is the key to establishing a good therapeutic relationship and providing the best possible care.


Slow kinetics of inositol 1,4,5-trisphosphate-induced Ca2+ release: is the release 'quantal' or 'non-quantal'?
Inositol 1,4,5-trisphosphate (InsP3)-induced Ca2+ release from intracellular stores is generally assumed to be a 'quantal' process because low InsP3 concentrations mobilize less Ca2+ than high concentrations and a submaximal concentration does not release all the InsP3-mobilizable Ca2+. However, some recent reports questioned the generally accepted view that a low dose of InsP3 is unable to empty the whole store. We have now challenged the stores of permeabilized A7r5 cells in InsP3 for much longer periods than previously reported, to assess directly whether the slow phase of the release would empty the whole store (a non-quantal response) or only a fraction of it (a quantal response). Addition of a maximal [InsP3] at the end of a prolonged (92 min) stimulation with a submaximal [InsP3] resulted in additional Ca2+ release. Experiments in which the stores were challenged with different submaximal InsP3 concentrations for long time periods revealed that a lower [InsP3] never released the same amount of Ca2+ as a higher [InsP3]. This quantal pattern of Ca2+ release occurred both at 25 degrees C and at 4 degrees C. There was a time-dependent increase in the fraction of Ca2+ recruited by the lower compared with the higher [InsP3]. This recruitment of Ca2+ persisted if the [InsP3] was decreased, but was largely prevented by palmitoyl-CoA, a potent blocker of the luminal Ca2+ translocation between individual store units. ATP, in the presence of InsP3, released Ca2+ under conditions permitting the recruitment of no additional InsP3 receptors, indicating that an all-or-none emptying of a fraction of the stores cannot be the only mechanism responsible for quantal Ca2+ release in A7r5 cells. We conclude that some of the previously published evidence for a non-quantal Ca2+ release pattern should be reinterpreted.


All-phosphorus flexible devices with non-collinear electrodes: a first principles study.
With the continuous expansion of the family of two-dimensional (2D) materials, flexible electronics based on 2D materials have quickly emerged. Theoretically, predicting the transport properties of the flexible devices made up of 2D materials using first principles is of great importance. Using density functional theory combined with the non-equilibrium Green's function formalism, we calculated the transport properties of all-phosphorus flexible devices with non-collinear electrodes, and the results predicted that the device with compressed metallic phosphorene electrodes sandwiching a P-type semiconducting phosphorene shows a better and robust conducting behavior against the bending of the semiconducting region when the angle between the two electrodes is less than 45°, which indicates that this system is very promising for flexible electronics. The calculation of a quantum transport system with non-collinear electrodes demonstrated in this work will provide more interesting information on mesoscopic material systems and related devices.


Neonates need tailored drug formulations.
Drugs are very strong tools used to improve outcome in neonates. Despite this fact and in contrast to tailored perfusion equipment, incubators or ventilators for neonates, we still commonly use drug formulations initially developed for adults. We would like to make the point that drug formulations given to neonates need to be tailored for this age group. Besides the obvious need to search for active compounds that take the pathophysiology of the newborn into account, this includes the dosage and formulation. The dosage or concentration should facilitate the administration of low amounts and be flexible since clearance is lower in neonates with additional extensive between-individual variability. Formulations need to be tailored for dosage variability in the low ranges and also to the clinical characteristics of neonates. A specific focus of interest during neonatal drug development therefore is a need to quantify and limit excipient exposure based on the available knowledge of their safety or toxicity. Until such tailored vials and formulations become available, compounding practices for drug formulations in neonates should be evaluated to guarantee the correct dosing, product stability and safety.


Early Noninvasive Detection of Response to Targeted Therapy in Non-Small Cell Lung Cancer.
With the advent of precision oncology, there is an urgent need to develop improved methods for rapidly detecting responses to targeted therapies. Here, we have developed an ultrasensitive measure of cell-free tumor load using targeted and whole-genome sequencing approaches to assess responses to tyrosine kinase inhibitors in patients with advanced lung cancer. Analyses of 28 patients treated with anti-EGFR or HER2 therapies revealed a bimodal distribution of cell-free circulating tumor DNA (ctDNA) after therapy initiation, with molecular responders having nearly complete elimination of ctDNA (>98%). Molecular nonresponders displayed limited changes in ctDNA levels posttreatment and experienced significantly shorter progression-free survival (median 1.6 vs. 13.7 months, P < 0.0001; HR = 66.6; 95% confidence interval, 13.0-341.7), which was detected on average 4 weeks earlier than CT imaging. ctDNA analyses of patients with radiographic stable or nonmeasurable disease improved prediction of clinical outcome compared with CT imaging. These analyses provide a rapid approach for evaluating therapeutic response to targeted therapies and have important implications for the management of patients with cancer and the development of new therapeutics.Significance: Cell-free tumor load provides a novel approach for evaluating longitudinal changes in ctDNA during systemic treatment with tyrosine kinase inhibitors and serves an unmet clinical need for real-time, noninvasive detection of tumor response to targeted therapies before radiographic assessment.See related commentary by Zou and Meyerson, p. 1038.


Infection with multiple strains of Borrelia burgdorferi sensu stricto in patients with Lyme disease.
To assess human skin biopsy specimens from erythema migrans lesions for the presence of infection with multiple strains of the Lyme disease spirochete, Borrelia burgdorferi. Skin biopsy specimens were obtained prospectively from patients with erythema migrans. To determine allelic differences and strain identification of B burgdorferi, the biopsy specimens were analyzed by cold single-strand conformation polymorphism of an amplified fragment of the outer surface protein C (ospC) gene. Further single-strand conformation polymorphism patterns of amplified ospC genes from culture isolates were compared with polymerase chain reaction products obtained directly from erythema migrans biopsy specimens. A private dermatology office and a university medical center outpatient department. Sixteen patients presenting with erythema migrans. Two of the 16 patients in this cohort were infected with 2 B burgdorferi sensu stricto strains, as evidenced by 2 ospC alleles in their skin biopsy results. This is the first documented description of the existence of more than a single strain of B burgdorferi sensu stricto in a human specimen.


Hard to Swallow: A Phenomenological Exploration of the Experience of Caring for Individuals With Myotonic Dystrophy and Dysphagia.
Myotonic dystrophy (DM1), a genetic, multisystemic disorder, is the most prevalent adult form of muscular dystrophy. Dysphagia is a common symptom that may be difficult to diagnose and treat and can be associated with increased morbidity and mortality. Preexisting cognitive impairment or apathy, both well described in the DM1 literature, may contribute to management challenges. Caregivers may become important for managing a family member's swallowing dysfunction. Although clinicians place great importance on swallowing difficulties, it is unknown how dysphagia impacts patients and their caregivers. Therefore, the purpose of this study was to explore the experiences of caregivers living with those with DM1and dysphagia. An interpretive phenomenological approach was used to study the lived experience of six caregivers for individuals with DM1 and dysphagia. Audio-taped semistructured interviews were used for data collection, and data were analyzed using van Manen's steps for phenomenological analysis. Despite the potential for dysphagia to cause morbidity and mortality in individuals with DM1, caregivers did not describe this as a problematic symptom. Instead, they highlighted more debilitating symptoms like fatigue or weakness and discussed the caregiving experience. Themes pertaining to participants' lived body, lived relationality, lived time, and lived space were identified. Healthcare providers need to balance issues of clinical concern with those that are important for individuals and their family members. Assessments of caregiver knowledge and burden at each clinic visit may be warranted.


A retrospective analysis of blood culture-negative endocarditis at a tertiary care centre in Switzerland.
Numerous studies from different countries have contributed to an improved understanding of blood culture-negative infective endocarditis. However, little is known about its epidemiology and microbiology in Switzerland. We aimed to assess the epidemiology and microbiology of blood culture-negative endocarditis at the University Hospital Zurich, Switzerland. We screened all patients hospitalised between 1997 and 2020 with possible or definite endocarditis at our institution. Thereof, we identified all cases with blood culture-negative endocarditis and retrospectively retrieved patient characteristics, microbiological, histopathological, radiographic and surgical data from medical records. Among 861 patients screened, 66 (7.7%) cases of blood culture-negative endocarditis were identified. Thereof, 31 cases could be microbiologically documented or not documented (n = 30), and in five cases a non-infectious aetiology was confirmed. Endocarditis predominantly affected men (77%) and the left heart (79%); predisposing factors were prosthetic valves (42%), congenital heart disease (35%) and prior endocarditis (14%). The most common reasons for negative blood cultures were antibiotic treatment prior to blood culture sampling (35%), fastidious and slow growing microorganisms (30%) and definite non-infective endocarditis (8%). Coxiella burnetii and Bartonella spp. were the most common fastidious bacteria identified. In addition to serology, identification of causative microorganisms was possible by microbiological and/or histopathological analysis of tissue samples, of which polymerase chain reaction testing (PCR) of the 16S ribosomal RNA proved to be most successful. The present study provides a detailed analysis of blood culture-negative endocarditis over a time span of more than 20 years in Zurich, Switzerland. Antibiotic treatment prior to blood collection, and fastidious and slow growing organisms were identified as main reasons for sterile blood cultures. Typical culture-negative bacteria were mainly found by PCR and/or culture of tissue samples.


Bone ageing: genetics versus environment.
Bone ageing results from a complex interaction between genetic and environmental factors (such as diet, climate and physical exercise) throughout human life. According to current literature, the most popular measures of bone ageing are osseometric measurements (OSM), bone mineral density (BMD) and osseographic scores (OSS), based on descriptive criteria of bone age. Plain roentgenography allows simultaneous assessment of all three measures. Ethnic differences with regard to these bone ageing characteristics have prompted us to study to the process anew, with the aim of elucidation the nature of the genetic and environmental components involved, and the possible interaction(s) between them. Despite abundant data on ethnic differences regarding these measures, modern knowledge on the genetics of these processes has derived primarily from the family studies of BMD, which pointed to strong involvement of the familial factors on bone mass. Segregation analysis performed by us in two ethnically different samples of pedigrees revealed a significant effect of the putative major gene on BMD of both compact and cancellous bone. The major finding of our bivariate segregation analysis was that it lead to the acceptance of the hypothesis predicating a single major locus with pleiotropy to both cancellous and compact BMD, but clearly rejecting the polygenic hypotheses. Our study of cortical index (CI) provided evidence that a single potential major gene controls not only the baseline trait level, but also the age at onset of the involutive bone changes, and the rate of the CI change with age. When we examined the environmental vs genetic influences on OSS variation in 32 human populations, we found very little environmental effect on the rate of bone change (r2 = 0.107), but a substantial effect on this rate of the genetic differences between populations (r = 0.480). Clarification of the genetic basis of bone ageing could have wide-ranging applications in the prevention and treatment of bone degenerative diseases such as osteoporosis and osteoarthritis, before irreversible damage takes place. There is thus a need to target the genetic analysis of BMD and the biochemical regulating factors of bone turnover through the use of molecular genetic techniques.


A detailed analysis of menstrual blood loss in women using Norplant and Nestorone progestogen-only contraceptive implants or vaginal rings.
Changes to the pattern of menstrual bleeding are almost universal in women using progestogen-only methods of contraception, and are an important cause of discontinuation of these methods. The present study was designed to explore the changes in menstrual bleeding patterns and objectively measure menstrual blood loss (MBL) in 110 women before and during one year of use of 4 different progestogen-only contraceptives: Norplant subdermal levonorgestrel implants; Nestorone progestogen 4-cm or 6-cm implants nominally delivering 100 microg or 150 microg daily; or a vaginal ring (CVR) delivering 100 microg of Nestorone (NES) daily (CVR users were limited to only 6 months of use). Groups could not be directly compared because of the differences in numbers of subjects and durations of treatment. The total MBL during each of the three 8-week collection periods during treatment decreased significantly in each group compared to the total blood loss in the two control cycles (greater than 50% decrease in all groups during the first 6 months), although the differences between individual women at the extremes remained considerable. The highest blood loss measured on any single day during the treatment collection periods was significantly reduced (p <0.001) in users of all four devices in all three collection periods compared to the control period (CVR users did not have a 3rd collection period). The Nestorone-releasing CVR was associated with an 88% reduction in mean MBL and a high incidence of amenorrhea at 6 months. There was considerable variation in percentage reduction in total blood loss at 6 and 12 months between individual women ranging from 100% (women with amenorrhea) to a small minority experiencing an increase compared with control cycles. The increases in measured blood loss during treatment were almost entirely in women with light bleeding in the control period and were related to prolonged episodes of light bleeding rather than heavy bleeding. Women contemplating use of a progestogen-only contraceptive method need to be counseled about alterations to the menstrual cycle but can be reassured that total blood loss will usually be much less than with normal cycles.


Autonomic microganglion cells: a source of acetylcholine in the rat carotid body.
Hypoxic chemosensitivity of peripheral arterial chemoreceptors and the ventilatory response to O2 deprivation increases with postnatal development. Multiple putative neurotransmitters, which are synthesized in the carotid body (CB), are thought to mediate signals generated by hypoxia. Acetylcholine (ACh) is believed to be a major excitatory neurotransmitter participating in hypoxic chemosensitivity. However, it is not known whether ACh originates from type I cells in the CB. In these studies, we tested the hypothesis that choline acetyltransferase (ChAT) and vesicular ACh transporter (VAChT) mRNAs are expressed in the CB and that mRNA levels would increase with postnatal maturation or exposure to hypoxia. Semiquantitative in situ hybridization histochemistry and immunohistochemistry were used to localize cholinergic markers within neurons and cells of the rat CB, the nodose-petrosal-jugular ganglion complex, and the superior cervical ganglion up to postnatal day 28. We show that the pattern of distribution, in tissue sections, is similar for both ACh markers; however, the level of VAChT mRNA is uniformly greater than that of ChAT. VAChT mRNA and immunoreactivity are detected abundantly in the nodose-petrosal-jugular ganglion complex in a number of microganglion cells embedded in nerve fibers innervating the CB for all postnatal groups, whereas ChAT mRNA is detected in only a few of these cells. Contrary to our hypothesis, postnatal maturation caused a reduction in ACh trait expression, whereas hypoxic exposure did not induce the upregulation of VAChT and ChAT mRNA levels in the CB, microganglion, or within the ganglion complex. The present findings indicate that the source of ACh in the CB is likely within autonomic microganglion cells and cholinergic nerve terminals.


Victims' Retrospective Explanations of Sibling Sexual Violence.
While sibling sexual abuse may be the most common form of sexual violence within the family, relatively few studies have been conducted on this topic. The current study addresses this gap in the literature through analyses of thematic categories in narratives gathered from an online survey of sibling sexual violence. Survivors were asked to report why they believed their siblings had become sexually abusive toward them. Participants believed that their abusers had learned to be abusive due to their own victimization or exposure to pornography, were abusive to establish dominance over them, or had some undisclosed mental illness. While the study does not claim to test these explanations or include abusers' own narratives, it offers insight as to how sibling sexual violence survivors make sense of their experiences and assign blame to abusers and their families. It also offers insights into future inquiries about sibling sexual abuse.


Maternal socialization of positive affect: the impact of invalidation on adolescent emotion regulation and depressive symptomatology.
This study examined the relations among maternal socialization of positive affect (PA), adolescent emotion regulation (ER), and adolescent depressive symptoms. Two hundred early adolescents, 11-13 years old, provided self-reports of ER strategies and depressive symptomatology; their mothers provided self-reports of socialization responses to adolescent PA. One hundred and sixty-three mother-adolescent dyads participated in 2 interaction tasks. Adolescents whose mothers responded in an invalidating or "dampening" manner toward their PA displayed more emotionally dysregulated behaviors and reported using maladaptive ER strategies more frequently. Adolescents whose mothers dampened their PA more frequently during mother-adolescent interactions, and girls whose mothers reported invalidating their PA, reported more depressive symptoms. Adolescent use of maladaptive ER strategies mediated the association between maternal invalidation of PA and early adolescents' concurrent depressive symptoms.


From enzyme maturation to synthetic chemistry: the case of hydrogenases.
Water splitting into oxygen and hydrogen is one of the most attractive strategies for storing solar energy and electricity. Because the processes at work are multielectronic, there is a crucial need for efficient and stable catalysts, which in addition have to be cheap for future industrial developments (electrolyzers, photoelectrochemicals, and fuel cells). Specifically for the water/hydrogen interconversion, Nature is an exquisite source of inspiration since this chemistry contributes to the bioenergetic metabolism of a number of living organisms via the activity of fascinating metalloenzymes, the hydrogenases. In this Account, we first briefly describe the structure of the unique dinuclear organometallic active sites of the two classes of hydrogenases as well as the complex protein machineries involved in their biosynthesis, their so-called maturation processes. This knowledge allows for the development of a fruitful bioinspired chemistry approach, which has already led to a number of interesting and original catalysts mimicking the natural active sites. More specifically, we describe our own attempts to prepare artificial hydrogenases. This can be achieved via the standard bioinspired approach using the combination of a synthetic bioinspired catalyst and a polypeptide scaffold. Such hybrid complexes provide the opportunity to optimize the system by manipulating both the catalyst through chemical synthesis and the protein component through mutagenesis. We also raise the possibility to reach such artificial systems via an original strategy based on mimicking the enzyme maturation pathways. This is illustrated in this Account by two examples developed in our laboratory. First, we show how the preparation of a lysozyme-{Mn(I)(CO)3} hybrid and its clean reaction with a nickel complex led us to generate a new class of binuclear Ni-Mn H2-evolving catalysts mimicking the active site of [NiFe]-hydrogenases. Then we describe how we were able to rationally design and prepare a hybrid system, displaying remarkable structural similarities to an [FeFe]-hydrogenase, and we show here for the first time that it is catalytically active for proton reduction. This system is based on the combination of HydF, a protein involved in the maturation of [FeFe]-hydrogenase (HydA), and a close mimic of the active site of this class of enzymes. Moreover, the synthetic [Fe2(adt)(CO)4(CN)2](2-) (adt(2-)= aza-propanedithiol) mimic, alone or within a HydF hybrid system, was shown to be able to maturate and activate a form of HydA itself lacking its diiron active site. We discuss the exciting perspectives this "synthetic maturation" opens regarding the "invention" of novel hydrogenases by the chemists.


miRNA signature of unfolded protein response in H9c2 rat cardiomyoblasts.
Glucose and oxygen deprivation during ischemia is known to affect the homeostasis of the endoplasmic reticulum (ER) in ways predicted to activate the unfolded protein response (UPR). Activation of UPR signalling due to ER stress is associated with the development of myocardial infarction (MI). MicroRNAs (miRNAs) are key regulators of cardiovascular development and deregulation of miRNA expression is involved in the onset of many cardiovascular diseases. However, little is known about the mechanisms regulating the miRNA expression in the cardiovascular system during disease development and progression. Here we performed genome-wide miRNA expression profiling in rat cardiomyoblasts to identify the miRNAs deregulated during UPR, a crucial component of ischemia. We found that expression of 86 microRNAs changed significantly during conditions of UPR in H9c2 cardiomyoblasts. We found that miRNAs with known function in cardiomyoblasts biology (miR-206, miR-24, miR-125b, miR-133b) were significantly deregulated during the conditions of UPR in H9c2 cells. The expression of miR-7a was upregulated by UPR and simulated in vitro ischemia in cardiomyoblasts. Further, ectopic expression of miR-7a provides resistance against UPR-mediated apoptosis in cardiomyoblasts. The ample overlap of miRNA expression signature between our analysis and different models of cardiac dysfunction further confirms the role of UPR in cardiovascular diseases. This study demonstrates the role of UPR in deregulating the expression of miRNAs in MI. Our results provide novel insights about the molecular mechanisms of deregulated miRNA expression during the heart disease pathogenesis.