Best Practices for Conducting Clinical Trials With Indigenous Children in the United States.
We provide guidance for conducting clinical trials with Indigenous children in the United States. We drew on extant literature and our experience to describe 3 best practices for the ethical and effective conduct of clinical trials with Indigenous children. Case examples of pediatric research conducted with American Indian, Alaska Native, and Native Hawaiian communities are provided to illustrate these practices. Ethical and effective clinical trials with Indigenous children require early and sustained community engagement, building capacity for Indigenous research, and supporting community oversight and ownership of research. Effective engagement requires equity, trust, shared interests, and mutual benefit among partners over time. Capacity building should prioritize developing Indigenous researchers. Supporting community oversight and ownership of research means that investigators should plan for data-sharing agreements, return or destruction of data, and multiple regulatory approvals. Indigenous children must be included in clinical trials to reduce health disparities and improve health outcomes in these pediatric populations. Establishment of the Environmental Influences on Child Health Outcomes Institutional Development Award States Pediatric Clinical Trials Network (ECHO ISPCTN) in 2016 creates a unique and timely opportunity to increase Indigenous children's participation in state-of-the-art clinical trials.


Coiled-coil domain containing protein 124 is a novel centrosome and midbody protein that interacts with the Ras-guanine nucleotide exchange factor 1B and is involved in cytokinesis.
Cytokinetic abscission is the cellular process leading to physical separation of two postmitotic sister cells by severing the intercellular bridge. The most noticeable structural component of the intercellular bridge is a transient organelle termed as midbody, localized at a central region marking the site of abscission. Despite its major role in completion of cytokinesis, our understanding of spatiotemporal regulation of midbody assembly is limited. Here, we report the first characterization of coiled-coil domain-containing protein-124 (Ccdc124), a eukaryotic protein conserved from fungi-to-man, which we identified as a novel centrosomal and midbody protein. Knockdown of Ccdc124 in human HeLa cells leads to accumulation of enlarged and multinucleated cells; however, centrosome maturation was not affected. We found that Ccdc124 interacts with the Ras-guanine nucleotide exchange factor 1B (RasGEF1B), establishing a functional link between cytokinesis and activation of localized Rap2 signaling at the midbody. Our data indicate that Ccdc124 is a novel factor operating both for proper progression of late cytokinetic stages in eukaryotes, and for establishment of Rap2 signaling dependent cellular functions proximal to the abscission site.


Regulation of coronary venular barrier function by blood borne inflammatory mediators and pharmacological tools: insights from novel microvascular wall models.
We hypothesized that postcapillary venules play a central role in the control of the tightness of the coronary system as a whole, particularly under inflammatory conditions. Sandwich cultures of endothelial cells and pericytes of precapillary arteriolar or postcapillary venular origin from human myocardium as models of the respective vascular walls (sandwich cultures of precapillary arteriolar or postcapillary venular origin) were exposed to thrombin and components of the acutely activatable inflammatory system, and their hydraulic conductivity (L(P)) was registered. L(P) of SC-PAO remained low under all conditions (3.24 ± 0.52·10(-8)cm·s(-1)·cmH(2)O(-1)). In contrast, in the venular wall model, PGE(2), platelet-activating factor (PAF), leukotriene B(4) (LTB(4)), IL-6, and IL-8 induced a prompt, concentration-dependent, up to 10-fold increase in L(P) with synergistic support when combined. PAF and LTB(4) released by metabolically cooperating platelets, and polymorphonuclear leucocytes (PMNs) caused selectively venular endothelial cells to contract and to open their clefts widely. This breakdown of the barrier function was preventable and even reversible within 6-8 h by the presence of 50 μM quercetin glucuronide (QG). LTB(4) synthesis was facilitated by biochemical involvement of erythrocytes. Platelets segregated in the arterioles and PMNs in the venules of blood-perfused human myocardium (histological studies on donor hearts refused for heart transplantation). Extrapolating these findings to the coronary microcirculation in vivo would imply that the latter's complex functionality after accumulation of blood borne inflammatory mediators can change rapidly due to selective breakdown of the postcapillary venular barrier. The resulting inflammatory edema and venulo-thrombosis will severely impair myocardial performance. The protection afforded by QG could be of particular relevance in the context of cardiosurgical intervention.


Genome-wide analysis of gene regulation mechanisms during Drosophila spermatogenesis.
During Drosophila spermatogenesis, testis-specific meiotic arrest complex (tMAC) and testis-specific TBP-associated factors (tTAF) contribute to activation of hundreds of genes required for meiosis and spermiogenesis. Intriguingly, tMAC is paralogous to the broadly expressed complex Myb-MuvB (MMB)/dREAM and Mip40 protein is shared by both complexes. tMAC acts as a gene activator in spermatocytes, while MMB/dREAM was shown to repress gene activity in many cell types. Our study addresses the intricate interplay between tMAC, tTAF, and MMB/dREAM during spermatogenesis. We used cell type-specific DamID to build the DNA-binding profiles of Cookie monster (tMAC), Cannonball (tTAF), and Mip40 (MMB/dREAM and tMAC) proteins in male germline cells. Incorporating the whole transcriptome analysis, we characterized the regulatory effects of these proteins and identified their gene targets. This analysis revealed that tTAFs complex is involved in activation of achi, vis, and topi meiosis arrest genes, implying that tTAFs may indirectly contribute to the regulation of Achi, Vis, and Topi targets. To understand the relationship between tMAC and MMB/dREAM, we performed Mip40 DamID in tTAF- and tMAC-deficient mutants demonstrating meiosis arrest phenotype. DamID profiles of Mip40 were highly dynamic across the stages of spermatogenesis and demonstrated a strong dependence on tMAC in spermatocytes. Integrative analysis of our data indicated that MMB/dREAM represses genes that are not expressed in spermatogenesis, whereas tMAC recruits Mip40 for subsequent gene activation in spermatocytes. Discovered interdependencies allow to formulate a renewed model for tMAC and tTAFs action in Drosophila spermatogenesis demonstrating how tissue-specific genes are regulated.


A novel and low-cost CuPc@C catalyst derived from the compounds of sunflower straw and copper phthalocyanine pigment for oxygen reduction reaction.
A series of carbon and phthalocyanine catalysts were prepared with uniform and stretchable sunflower straw biological materials as the carbon source and inexpensive copper phthalocyanine (CuPc) pigment as a nitrogen doping source by a facile high-temperature carbonization method. This kind of biomass carbon material sunflower straw with abundant pore structure and sponge-like expansion and contraction functions can not only be used as a source of porous carbon in biomass carbon materials, but also as a carbon carrier with high specific surface area to provide nanoparticle adhesion sites. When it was immersed in the copper phthalocyanine pigment solution, more active sites could be exposed, so that CuPc particles could be uniformly doped and distributed on the porous carbon material. As a result, thanks to the doping of nitrogen atoms and the improvement of graphitization degree, the composite catalyst treated at 800 °C (CuPc@C-800) exhibits a porous structure with a 38 mV lower on-set potential and a high stability of 87.4% compared to commercial Pt/C (20%) catalyst. These results demonstrate that CuPc@C series composite catalysts have a splendid electrochemical performance in oxygen reduction reaction catalysts, which can start a new direction for later workers to study combining the properties of biomass carbon material and the phthalocyanine series of catalysts.


'She met her (boy)friend online': Negotiating gender identity and sexuality among young Thai women in online space.
This paper focuses on the experiences of women 15-24 years old living in one suburban district in Bangkok. Its objectives are to analyse processes of building and negotiating social identity and femininity in online spaces by young women; the ways in which young women express their sexuality using online technologies; connections between the 'online' and 'offline' worlds in terms of emotions as well as social and sexual networks; and traditional values regarding female sexuality reproduced through online media and how young women negotiate and resist these. Content and narrative analyses were conducted using qualitative data from 9 focus-group discussions and 14 narrative interviews. Findings indicated that the online media serve as tools that help young women develop and express their gender identities. Mobile phones and the Internet facilitate communication in order to express love, responsibility, intimacy and sexual desires. Discourse on women's chastity, which puts pressure on women to maintain their virginity, still influences online and mobile contents, messages and images among young women. However, women also exerted agency in negotiating and expressing their sexuality, both online and offline.


Optimizing Surgical Procedures of Auricular Keloids According to Their Anatomic Morphological Features.
Aesthetic surgical reconstruction of auricular keloids is still a conundrum. This study introduces our experiences in analyzing the anatomic morphological features of auricular keloids, and devising optimized surgical procedures accordingly. A total of 129 ears with auricular keloids were classified and operated. All patients were followed up for at least 12 months. According to their anatomic positions, auricular keloids were divided into 3 Groups (A, B, and C). The morphological features of keloids were further interpreted according to Chang-Park classification of earlobe keloids. The authors optimized surgical procedures according to the anatomic morphological features from a range of surgical techniques. The recurrence rate of Group C was statistically higher than Group A and B. There was no significant difference in recurrence rate between keloids treated with "primary suture" and "filleted flaps." According to the anatomic positions and morphological features of auricular keloids, we could conveniently devise optimized surgical strategies to obtain aesthetic reconstruction of auricular keloids.


Comparison of the oral bioavailability and tissue disposition of monensin and salinomycin in chickens and turkeys.
The current study describes the pharmacokinetic parameters of two carboxylic polyether ionophores: monensin in turkeys and salinomycin in chickens. These data can be used to understand and predict the occurrence of undesirable residues of coccidiostats in edible tissues of these animal species. Special attention is paid to the distribution of residues between the different edible tissues during and at the end of the treatment period. For the bioavailability studies, monensin was administered to turkeys intravenously, in the left wing vein, at a dose of 0.4 mg /kg and orally at a dose of 20 mg /kg. Salinomycin was administered to chickens intravenously, in the left wing vein, at a dose of 0.25 mg /kg and orally at a dose of 2.5 mg /kg. Residue studies were carried out with supplemented feed at the rate of 100 mg /kg of feed for monensin in turkeys and 70 mg /kg for salinomycin in chickens, respectively. Coccidiostats had a low bioavailability in poultry (around 30% for monensin in chickens, around 1% for monensin in turkeys and around 15% for salinomycin in chickens). Monensin in chickens had a longer terminal half-life (between 3.07 and 5.55 h) than both monensin in turkeys (between 1.36 and 1.55 h) and salinomycin in chickens (between 1.33 and 1.79 h). The tissue /plasma partition coefficients showed a higher affinity of both monensin and salinomycin for fat, followed by liver and muscle tissue. The depletion data showed a fairly rapid elimination of coccidiostats in all the tissues after cessation of treatment. According to the results of depletion studies, a withdrawal period of 1 day seems sufficient to avoid undesirable exposure of consumers.


T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism.
We investigated the mechanisms by which T-cell cytokines are able to influence the Toll-like receptor (TLR)-induced, vitamin D-dependent antimicrobial pathway in human monocytes. T-cell cytokines differentially influenced TLR2/1-induced expression of the antimicrobial peptides cathelicidin and DEFB4, being up-regulated by IFN-γ, down-regulated by IL-4, and unaffected by IL-17. The Th1 cytokine IFN-γ up-regulated TLR2/1 induction of 25-hydroxyvitamin D-1α-hydroxylase (i.e., CYP27B1), leading to enhanced bioconversion of 25-hydroxyvitamin D(3) (25D(3)) to its active metabolite 1,25D(3). In contrast, the Th2 cytokine IL-4, by itself and in combination with the TLR2/1 ligand, induced catabolism of 25D(3) to the inactive metabolite 24,25D(3), and was dependent on expression of vitamin D-24-hydroxylase (i.e., CYP24A1). Therefore, the ability of T-cell cytokines to differentially control monocyte vitamin D metabolism represents a mechanism by which cell-mediated immune responses can regulate innate immune mechanisms to defend against microbial pathogens.


L-type voltage-dependent calcium channels as therapeutic targets for neurodegenerative diseases.
Ca(2+) is a highly versatile intracellular second messenger in the central nervous system, and regulates many complicated cellular processes, including excitation, plasticity and apoptosis. Influx of Ca(2+) from the extracellular fluid is required for sustained elevation of the cytosolic Ca(2+) concentration and full activation of Ca(2+)-dependent processes. Voltage-dependent Ca(2+) channels (VDCCs) serve as the principal routes of Ca(2+) entry into electrically excitable cells such as neurons. The nervous system expresses VDCCs with unique cellular and subcellular distribution and specific functions. L-type voltage-dependent Ca(2+) channels (L-VDCCs) are distributed at neuronal cell bodies, dendrites and spines, and the postsynaptic L-VDCCs regulate neuronal excitability and gene expression. Presynaptic P/Qand N-type VDCCs trigger neurotransmitter release, and T-type channels support neuronal rhythmic burst firing. Evidence from natural mutants, knockout mice, and human genetic disorders indicates a fundamental role of some VDCCs in a wide variety of neurological disorders, including vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD) and Prion disease. Amyloid β peptides, causative factors for AD, potentiate the influx of Ca(2+) into neurons via L-VDCCs. L-VDCCs blockers prevent neurons from undergoing amyloid β-induced apoptosis. The present review highlights some recent findings on biochemical characterizations, physiological functions, pathological roles and pharmacological applications of the L-VDCCs and their implication in neurologic diseases.


Epstein-Barr virus lacking latent membrane protein 2 immortalizes B cells with efficiency indistinguishable from that of wild-type virus.
Epstein-Barr virus (EBV) is a human herpesvirus that efficiently transforms and immortalizes human primary B lymphocytes. In this study, the role of latent membrane protein 2 (LMP2) in EBV growth transformation was investigated. LMP2 is a virally encoded membrane protein expressed in EBV-immortalized B cells previously shown to be nonessential for EBV transformation. However, a recent study reported that LMP2 may be an important determinant for efficient B cell transformation (Brielmeier et al., Journal of General Virology 77, 2807-2818, 1996). In this study a deletion mutation was introduced into the LMP2 gene using an E. coli mini-EBV construct containing sufficient EBV DNA to result in growth transformation of primary B cells. In an alternative approach, the introduction of the gene encoding the enhanced green fluorescent protein (EGFP) by homologous recombination into the LMP2 gene of EBV strain B95-8, generating the same LMP2 deletion mutation is reported. Careful quantification of B cell transformation using the EGFP+ LMP2- recombinant virus determined that in liquid culture medium or in culture medium containing soft agarose there was no difference in the ability of LMP2- virus to immortalize primary human B cells when compared to that of wild-type virus.


[Case of systemic sclerosis sine scleroderma showing pulmonary venula lesion that suggests pulmonary veno-occlusive disease].
A 77-year-old woman was admitted to our hospital because of an abnormal chest shadow. She complained of shortness of breath on effort. Chest CT showed patchy areas of ground-glass opacity in right S2 and S6. A high titer of antinuclear antibody with a discrete speckled pattern on immunofluorescent staining was disclosed, and she was positive for anticentromere antibodies. Pulmonary arterial hypertension was found by right heart catheterization. Biopsy by video-assisted thoracoscopic surgery was performed. About one month after surgery, she started to need to inhale oxygen due to gradually progressing dyspnea. Continuous PGI2 administration was not very effective, but administration of methylprednisolone and prednisolone induced improvement of her symptoms. Histopathologic examination of biopsy revealed extensive and diffuse occlusion of pulmonary veins. The pathological diagnosis suggested a pulmonary veno-occlusive disease. Clinical data suggested the association between systemic sclerosis sine scleroderma and probable pulmonary veno-occclusive disease.


Molecular resolution friction microscopy of Cu phthalocyanine thin films on dolomite (104) in water.
The reliability of ultrathin organic layers as active components for molecular electronic devices depends ultimately on an accurate characterization of the layer morphology and ability to withstand mechanical stresses on the nanoscale. To this end, since the molecular layers need to be electrically decoupled using thick insulating substrates, the use of AFM becomes mandatory. Here, we show how friction force microscopy (FFM) in water allows us to identify the orientation of copper(ii)phthalocyanine (CuPc) molecules previously self-assembled on a dolomite (104) mineral surface in ultra-high vacuum. The molecular features observed in the friction images show that the CuPc molecules are stacked in parallel rows with no preferential orientation with respect to the dolomite lattice, while the stacking features resemble well the single CuPc crystal structure. This proves that the substrate induction is low and makes friction force microscopy in water a suitable alternative to more demanding dynamic AFM techniques in ultra-high vacuum.


Pancreatic pseudocyst of gastrohepatic ligament: a case report and review of management.
Pancreatic pseudocyst of gastrohepatic or hepatoduodenal ligament and of liver is rare entity. Probably, pancreatic pseudocyst ascends via these ligaments to liver due to complex attachment of peritoneum. Very few cases have been reported in literature. Hereby, we report a case of pancreatic pseudocyst of hepatoduodenal ligament in patient who presented with pain and lump in epigastric region. This is an extrapancreatic extension of pancreatic pseudocyst and a high suspicion of this cyst (gastrohepatic ligament cyst) should be kept in mind as differential diagnosis of epigastric mass.


[Unhealthy behaviors and their reasons in the thinking of employees].
This paper outlines the beliefs of Polish employees about adverse effects of their own behavior on the health state along with underlying reasons for its health-damaging forms. The research was carried out in 2002 as a questionnaire-based interview. It covered a random sample of 1134 employees working in 250 enterprises that hire over 100 people. More than a half of respondents positively evaluated the influence of their behavior on health, but only 12% of them did avoid any type of health-damaging behavior. The respondents believed that in their conduct the following factors were most detrimental to their health: shortage of rest (50%), neglect of physical fitness (38%), smoking (34%), unhealthy nutrition (33%) and disregard to morbid symptoms (28%). Among the reasons for unhealthy behavior they emphasized various habitual aspects, the wish to derive pleasure, relaxation, and sense of freedom, and also avoidance of thinking about adverse effects of such a behavior. Health education should to a much greater degree take into account individual motives for health-damaging behavior instead of focusing on dissemination of general knowledge.


A new radiopaque surgical suture.
We have developed a new X-ray visible suture. It is a polyester suture containing platinum wires. The radiopaque suture was used clinically in 43 cases, and was useful in the following situations: (1) as a marker for post-operative angiography (post-operative graft angiography of aorto-coronary bypass or Brockenbrough's method), (2) as a marker for evaluation of valve reconstructive surgery or surgery of intracardiac anomalies, and (3) as a guideline for second radical repair after primary operation.


Risk of solid subsequent malignant neoplasms after childhood Hodgkin lymphoma-Identification of high-risk populations to guide surveillance: A report from the Late Effects Study Group.
Survivors of Hodgkin lymphoma (HL) in childhood have an increased risk of subsequent malignant neoplasms (SMNs). Herein, the authors extended the follow-up of a previously reported Late Effects Study Group cohort and identified patients at highest risk for SMNs to create evidence for risk-based screening recommendations. The standardized incidence ratio was calculated using rates from the Surveillance, Epidemiology, and End Results program as a reference. The risk of SMN was estimated using proportional subdistribution hazards regression. The cohort included 1136 patients who were diagnosed with HL before age 17 years between 1955 and 1986. The median length of follow-up was 26.6 years. In 162 patients, a total of 196 solid SMNs (sSMNs) were identified. Compared with the general population, the cohort was found to be at a 14-fold increased risk of developing an sSMN (95% confidence interval, 12.0-fold to 16.3-fold). The cumulative incidence of any sSMN was 26.4% at 40 years after a diagnosis of HL. Risk factors for breast cancer among females were an HL diagnosis between ages 10 years and 16 years and receipt of chest radiotherapy. Males treated with chest radiotherapy at age <10 years were found to be at highest risk of developing lung cancer. Survivors of HL who were treated with abdominal/pelvic radiotherapy and high-dose alkylating agents were found to be at highest risk of developing colorectal cancer and females exposed to neck radiotherapy at age <10 years were at highest risk of thyroid cancer. By age 50 years, the cumulative incidence of breast, lung, colorectal, and thyroid cancer was 45.3%, 4.2%, 9.5%, and 17.3%, respectively, among those at highest risk. Survivors of childhood HL remain at an increased risk of developing sSMNs. In the current study, subgroups of survivors of HL at highest risk of specific sSMNs were identified, and evidence for screening provided.


Immunological profiling in long COVID: overall low grade inflammation and T-lymphocyte senescence and increased monocyte activation correlating with increasing fatigue severity.
Many patients with SARS-CoV-2 infection develop long COVID with fatigue as one of the most disabling symptoms. We performed clinical and immune profiling of fatigued and non-fatigued long COVID patients and age- and sex-matched healthy controls (HCs). Long COVID symptoms were assessed using patient-reported outcome measures, including the fatigue assessment scale (FAS, scores ≥22 denote fatigue), and followed up to one year after hospital discharge. We assessed inflammation-related genes in circulating monocytes, serum levels of inflammation-regulating cytokines, and leukocyte and lymphocyte subsets, including major monocyte subsets and senescent T-lymphocytes, at 3-6 months post-discharge. We included 37 fatigued and 36 non-fatigued long COVID patients and 42 HCs. Fatigued long COVID patients represented a more severe clinical profile than non-fatigued patients, with many concurrent symptoms (median 9 [IQR 5.0-10.0] vs 3 [1.0-5.0] symptoms, p<0.001), and signs of cognitive failure (41%) and depression (>24%). Immune abnormalities that were found in the entire group of long COVID patients were low grade inflammation (increased inflammatory gene expression in monocytes, increased serum pro-inflammatory cytokines) and signs of T-lymphocyte senescence (increased exhausted CD8+ TEMRA-lymphocytes). Immune profiles did not significantly differ between fatigued and non-fatigued long COVID groups. However, the severity of fatigue (total FAS score) significantly correlated with increases of intermediate and non-classical monocytes, upregulated gene levels of CCL2, CCL7, and SERPINB2 in monocytes, increases in serum Galectin-9, and higher CD8+ T-lymphocyte counts. Long COVID with fatigue is associated with many concurrent and persistent symptoms lasting up to one year after hospitalization. Increased fatigue severity associated with stronger signs of monocyte activation in long COVID patients and potentially point in the direction of monocyte-endothelial interaction. These abnormalities were present against a background of immune abnormalities common to the entire group of long COVID patients.


Postinduction transcriptional repression of E-selectin and vascular cell adhesion molecule-1.
TNF-alpha induction of the E-selectin and vascular cell adhesion molecule-1 (VCAM-1) genes leads to transient accumulation of high levels of mRNA in endothelial cells. The increase in these mRNAs after induction is due to an increase in the rate of gene transcription, which is maintained for several hours in the continuous presence of cytokine. Cytokine-induced transcriptional activation of these genes requires the transcription factor, nuclear factor-kappaB. Following removal of TNF-alpha, there is rapid postinduction transcriptional repression common to both of these genes. The repression is protein synthesis dependent and correlates with protein synthesis-dependent loss of both the p50 and p65 subunits of nuclear factor-kappaB from the nucleus. IkappaBalpha is capable of specifically displacing endothelial-derived heterodimeric p50/p65 from the E-selectin and VCAM-1 kappaB elements, while having no effect on binding of p50 homodimer. In the presence of agents that block proteasomal degradation of IkappaBalpha, endogenous IkappaBalpha can be visualized in the nucleus of both resting and TNF-alpha-activated endothelial cells. Endogenous IkappaBalpha is readily detected in the nucleus of HeLa cells, and its nuclear localization is increased following removal of TNF-alpha. Repression of E-selectin and VCAM-1 transcription following cytokine removal requires the loss of nuclear p50 and p65, and involves IkappaBalpha. This postinduction transcription repression mechanism may be one component of a program that prevents inappropriate and prolonged expression of adhesion molecules.


Distributions, associations, and partial aggregate exposure of pesticides and polynuclear aromatic hydrocarbons in the Minnesota Children's Pesticide Exposure Study (MNCPES).
The Minnesota Children's Pesticide Exposure Study (MNCPES) provides exposure, environmental, and biologic data relating to multipathway exposures of children for four primary pesticides (chlorpyrifos, malathion, diazinon, and atrazine), 14 secondary pesticides, and 13 polynuclear aromatic hydrocarbons (PAHs). Monitoring was performed on a probability-based sample of 102 children aged 3-12 in Minneapolis/St. Paul and in a nearby rural area (Goodhue and Rice counties). This paper provides estimated distributions of this population's exposures and exposure-related measurements and examines associations among the various measures via rank (Spearman) correlations. In addition, it provides some aggregate and cumulative exposure estimates for pesticides, and compares the relative intakes from inhalation and dietary ingestion. Intakes for the four primary pesticides appeared to come principally from the ingestion rather than the inhalation route; this was clearly true for chlorpyrifos but was less certain for the other three primary pesticides because of their higher degree of nondetects. Solid food rather than beverages was clearly the main contributor to the ingestion intake. Despite the dominance of the ingestion route, the urinary metabolite of chlorpyrifos exhibited a stronger association with the air measurements than with the dietary measures. Personal-air samples exhibited strong rank correlations with indoor air samples for chlorpyrifos, malathion, and diazinon (0.81, 0.51, and 0.62, respectively), while personal-air atrazine levels correlated well with outdoor levels (0.69); personal-air diazinon levels also correlated well with outdoor levels (0.67). For the PAHs, many significant associations were evident among the various air samples and for the air samples with the dust samples, especially for those compounds with consistently high percent measurable values (particularly fluoranthene, phenanthrene, and pyrene).


Phytochemical profile and antimicrobial activity of essential oils from two Syzygium species against selected oral pathogens.
The genus Syzygium (Myrtaceae) comprises several essential oil-rich species that are utilized traditionally for treating tooth infections and toothache. The current study aimed to extract essential oils (EOs) from the leaves of Syzygium samarangense and Syzygium malaccense cultivated in Egypt for the first time and screen their antimicrobial potential against oral-related pathogens. The intended EOs were extracted using hydrodistillation (HD) by boiling fresh leaves with distilled water; supercritical fluid (SF) by extracting the dried leaves using supercritical CO2 at 40 °C and 150 bar; and the headspace (HS) in which the fresh leaves were heated in a glass vial and the vaporized aroma were analyzed. The volatile constituents were analyzed using GC/MS and identified by comparing the experimental Kovats' retention indices with the literature. The antimicrobial activity was assessed against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Candida albicans using agar diffusion, microwell dilution, and biofilm formation assays. Statistical significance (p < 0.05) was determined by applying one-way ANOVA and Duncan's post hoc test. The yield of the extracted EOs differs between the applied methods, and the SF approach harvested the maximum (0.52-0.46%). The GC-MS analysis of SF EOs revealed a discrepancy between the two species. Since S. malaccense showed an abundance of hydrocarbons represented mainly by squalene (60.60%), S. samarangense was deemed to have oxygenated sesquiterpenes exemplified in globulol (52.09%). On the other side, the HD and HS EOs were sequentially comparable, while differed in the percentage of their majors. γ-terpinene (33.06%) pioneered the HS-derived aroma of S. malaccense, while S. samarangense was abundant with α-pinene (30.18%). Concurrently, the HD EOs of S. malaccense and S. samarangense were commonly denoted by caryophyllene oxide (8.19%-18.48%), p-cymene (16.02%- 19.50%), and γ-terpinene (12.20%-17.84). Ultimately, both species EOs exhibited broad-spectrum antimicrobial potential, although the HD EO was more potent than the SF EO. The HD EOs of both species potently inhibited the growth of E. coli (MIC 3.75 µL/mL) and suppressed C. albicans biofilm formation by 83.43 and 87.27%, respectively. The SF-EOs efficiently suppressed the biofilm formation of Gram-positive bacteria by 76.45%-82.95%. EOs extracted from both species by different methods possessed a unique blend of volatile components with broad-spectrum antimicrobial activity. They were promoted as bioactive hits for controlling oral infections, however further investigations concerning their safety in clinical settings are needed.


Investigation of crashes at pedestrian hybrid beacons: Results of a large-scale study in Arizona.
The pedestrian hybrid beacon (PHB) is a traffic control device used at pedestrian crossings. A recent Arizona Department of Transportation research effort investigated changes in crashes for different severity levels and crash types (e.g., rear-end crashes) due to the PHB presence, as well as for crashes involving pedestrians and bicycles. Two types of methodologies were used to evaluate the safety of PHBs: (a) an Empirical Bayes (EB) before-after study, and (b) a long-term cross-sectional observational study. For the EB before-after evaluation, the research team considered three reference groups: unsignalized intersections, signalized intersections, and both unsignalized and signalized intersections combined. For the signalized and combined unsignalized and signalized intersection groups, all crash types considered showed statistically significant reductions in crashes (e.g., total crashes, fatal and injury crashes, rear-end crashes, fatal and injury rear-end crashes, angle crashes, fatal and injury angle crashes, pedestrian-related crashes, and fatal and injury pedestrian-related crashes). A cross-sectional study was conducted with a larger number of PHBs (186) to identify relationships between roadway characteristics and crashes at PHBs, especially with respect to the distance to an adjacent traffic control signal. The distance to an adjacent traffic signal was found to be significant only at the α = 0.1 level, and only for rear-end and fatal and injury rear-end crashes. This analysis represents the largest known study to date on the safety impacts of PHBs, along with a focus on how crossing and geometric characteristics affect crash patterns. The study showed the safety benefits of PHBs for both pedestrians and vehicles. Practical Applications: The findings from this study clearly support the installation of PHBs at midblock or intersection crossings, as well as at crossings on higher-speed roads.


IL-5 is required for eosinophil recruitment, crystal deposition, and mononuclear cell recruitment during a pulmonary Cryptococcus neoformans infection in genetically susceptible mice (C57BL/6).
CBA/J (highly resistant), BALB/c (moderately resistant), and C57BL/6 (susceptible) mice displayed three resistance patterns following intratracheal inoculation of Cryptococcus neoformans 52. The inability to clear the infection correlated with the duration of the eosinophil infiltrate in the lungs. The role of IL-5 in promoting the pulmonary eosinophilia and subsequent inflammatory damage in susceptible C57BL/6 mice was investigated. C57BL/6 mice developed a chronic alveolar, peribronchiolar, and perivascular eosinophilia following C. neoformans infection. This resulted in the accumulation of intracellular Charcot-Leyden-like crystals in alveolar macrophages by wk 4 and the extracellular deposition of these crystals in the bronchioles with associated destruction of airway epithelium by wk 6. IL-5 mRNA was expressed in the lungs, and injections of anti-IL-5 mAb prevented eosinophil recruitment and crystal deposition but did not alter cryptococcal clearance. Depletion of CD4+ T cells (but not CD8+) ablated IL-5 production by lung leukocytes in vitro and eosinophil recruitment in vivo. Neutralization of IL-5 also inhibited the recruitment of macrophages, CD8+ T lymphocytes, and B lymphocytes by 47 to 57%. Anti-IL-5 mAb inhibited CD4+ T lymphocyte recruitment by 30% but did not affect neutrophil recruitment. Thus, the development of a chronic eosinophil infiltrate in the lungs of C. neoformans-infected C57BL/6 mice is a nonprotective immune response that causes significant lung pathology. Furthermore, IL-5 promotes the recruitment and activation of eosinophils, resulting in the recruitment of additional macrophages and lymphocytes into the lungs.


Identification of key residues in virulent canine distemper virus hemagglutinin that control CD150/SLAM-binding activity.
Morbillivirus cell entry is controlled by hemagglutinin (H), an envelope-anchored viral glycoprotein determining interaction with multiple host cell surface receptors. Subsequent to virus-receptor attachment, H is thought to transduce a signal triggering the viral fusion glycoprotein, which in turn drives virus-cell fusion activity. Cell entry through the universal morbillivirus receptor CD150/SLAM was reported to depend on two nearby microdomains located within the hemagglutinin. Here, we provide evidence that three key residues in the virulent canine distemper virus A75/17 H protein (Y525, D526, and R529), clustering at the rim of a large recessed groove created by beta-propeller blades 4 and 5, control SLAM-binding activity without drastically modulating protein surface expression or SLAM-independent F triggering.


Biosynthesis and secretion of functional protein S by a human megakaryoblastic cell line (MEG-01).
A human megakaryoblastic cell line (MEG-01) was investigated for the presence of protein S in culture medium and cell lysates using a specific enzyme-linked immunoassay (ELISA) and a functional assay. When 5 X 10(5) MEG-01 cells/mL was subcultured in RPMI 1640 medium with 10% fetal calf serum (FCS), the concentration of protein S antigen in the culture medium increased progressively with time from less than 8 ng/mL on day 0 to 105.6 +/- 6.0 ng/mL on day 13. Vitamin K2(1 microgram/mL) increased the production of functional protein S, whereas warfarin (1 microgram/mL) profoundly decreased the quantity and the specific activity of secreted protein S. By an indirect immunofluorescent technique, protein S antigen was detected in both MEG-01 cells and human bone marrow megakaryocytes. Immunoblot analysis of culture medium revealed two distinct bands (mol wt 84,000 and 78,000) that are identical to the doublets of purified plasma protein S. De novo synthesis of protein S was demonstrated by the presence of specific immunoprecipitable radioactivity in the medium after 5 hours of labeling of the cells with [35S]-methionine as a 84,000 mol wt protein. Plasma protein S levels of nine patients with severe aplastic anemia were not significantly different from those of normal controls. These results suggest that megakaryocytes produce functional protein S and contain the enzymes required for the carboxylation of selected glutamic acid residues, and that protein S synthesized by megakaryocytes does not represent a main source of plasma protein S.


Suicide attempts and completions in the emergency department in Veterans Affairs Hospitals.
This is the first study of suicide attempts and completions in the emergency department (ED) in a large national medical system. All root cause analysis (RCA) reports completed of suicides and suicide attempts that occurred in ED in the Veterans Health Administration between 1 December 1999 and 31 December 2009 were reviewed. The method, location, anchor point for hanging and implement for cutting as well as the root causes were categorised. Ten per cent of all RCA reports of suicides and suicide attempts that occur within the hospital occur in the ED. Hanging, cutting and strangulation were the most common methods. The most common anchor point for hanging was doors, and the most common implement for cutting was a razor blade. In eight of the 10 cases of cutting, the implement was brought into the ED. The most common root causes were problems communicating risk and being short-staffed. Based on these results the following recommendations are made for helping to reduce suicide attempts in the ED: (1) use a systematic protocol and checklist to review mental health holding areas periodically in the ED for suicidal hazards; (2) develop and implement specialised protocols for suicidal patients that include continuous observation when possible; (3) conduct thorough contraband searches with suicidal patients; (4) designate specialised holding areas, when practically possible, for suicidal patients that are free of anchor points for hanging, sharps and medications, and medical equipment; and are isolated from exits to reduce the risk of elopement.


Breathlessness in amyotrophic lateral sclerosis: A case report on the role of osteoporosis in the worsening of respiratory failure.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative multisystem disorder, presenting with limb or bulbar onset. To date, there is no cure for ALS. At some stage of the disease, patients may complain of breathlessness due to respiratory failure, thus needing a noninvasive mechanical ventilation (NIMV) support. However, breathlessness is a symptom that may be induced by different causes that must be taken into consideration in ALS management. We report the case of an 81-year-old man, with a spinal onset ALS, who was admitted to our clinic to start NIMV because of respiratory involvement. After 3 weeks from NIMV performed at night time, with beneficial effects, he suddenly complained of breathlessness even at rest and in standing position. Respiratory and cardiac assessments did not show new clinical events, indicating the worsening respiratory function. Due to a history of osteoporosis which was treated with biphosphonates and even though no previous bone trauma or falls were reported, we performed a spine computed tomography scan. The findings indicated multiple dorsal vertebral fractures which was a probable cause for breathlessness. Considering the neurodegenerative disease associated to respiratory failure, the cardiovascular risk factors and the age, the patient refused to undergo a surgery with kyphoplasty. A spine support was then prescribed, together with analgesic medications, with significant alleviation of pain and breathlessness. The occurrence of breathlessness in a patient with ALS cannot always be related to the bulbar involvement. Other causes should be taken into account, especially when there is sudden worsening of symptoms in spite of good clinical response and compliance to NIMV treatment.


Role of GATA factor Nil2p in nitrogen regulation of gene expression in Saccharomyces cerevisiae.
We have identified the product of the NIL2 gene of Saccharomyces cerevisiae which contains a zinc finger region highly homologous to those of the GATA factors Gln3p and Nil1p as an antagonist of Nil1p and to a lesser extent of Gln3p. The expression of many nitrogen-regulated genes of Saccharomyces cerevisiae requires activation by GATA factor Gln3p or Nil1p and is prevented by the presence of glutamine in the growth medium. Disruption of NIL2 results in a great increase in the expression of NIL1 and of GAP1, the structural gene for the general amino acid permease, in glutamine-grown cells in response to activation by Nil1p. The primary effect of the elimination of Nil2p appears to be an increase in the intracellular level of Nil1p, which in turn is responsible for increased expression of GAP1. Experiments using an artificial UAS (upstream activating site) consisting of three GATAAGATAAG sites revealed that Nil2p exerts its effect by competing primarily with Nil1p and less effectively with Gln3p for these sites. Apparently, the principal role of Nil2p is to prevent activation of transcription by Nil1p unless Nil1p has been converted to a more active state by the absence of glutamine and glutamate.


Peripheral Veno-Arterial-Extracorporeal Membrane Oxygenation for Refractory Septic Shock in Children: A Multicenter Review.
Extracorporeal membrane oxygenation (ECMO) is utilized as a rescue therapy in the management of pediatric patients with refractory septic shock. Multiple studies support the use of a central cannulation strategy in these patients. This study aimed to assess the survival of and identify mortality risk factors in pediatric patients supported with peripheral veno-arterial (VA) ECMO in the setting of septic shock. We retrospectively reviewed and compared clinical characteristics of 40 pediatric patients supported with peripheral VA ECMO for refractory septic shock, at two tertiary care children's hospitals from 2006 to 2020. Our hypothesis was that peripheral VA ECMO is effective in supporting cardiac function and improving tissue oxygenation in most pediatric patients with refractory septic shock. The overall rate of survival to discharge was 52.5%, comparable to previously reported survival for pediatric sepsis on ECMO. With the exclusion of patients with an oncologic process, the survival rate rose to 62.5%. There was a statistically significant difference in mean pump flow rates within 2 hours of initiation of ECMO between survivors and non-survivors (98 mL/kg/min vs 76 mL/kg/min, P = .050). There was no significant difference between pre-ECMO vasoactive inotropic score (VIS) in survivors and non-survivors. A faster decrease in VIS in the first 24 hours was associated with lower mortality. From this large case series, we conclude that peripheral VA ECMO is a safe and effective modality to support pediatric patients with refractory septic shock, provided there is establishment of high ECMO pump flows in the first few hours after cannulation and improvement in the VIS.


Public health impacts of foodborne mycotoxins.
Mycotoxins are toxic and carcinogenic metabolites produced by fungi that colonize food crops. The most agriculturally important mycotoxins known today are aflatoxins, which cause liver cancer and have also been implicated in child growth impairment and acute toxicoses; fumonisins, which have been associated with esophageal cancer (EC) and neural tube defects (NTDs); deoxynivalenol (DON) and other trichothecenes, which are immunotoxic and cause gastroenteritis; and ochratoxin A (OTA), which has been associated with renal diseases. This review describes the adverse human health impacts associated with these major groups of mycotoxins. First, we provide background on the fungi that produce these different mycotoxins and on the food crops commonly infected. Then, we describe each group of mycotoxins in greater detail, as well as the adverse effects associated with each mycotoxin and the populations worldwide at risk. We conclude with a brief discussion on estimations of global burden of disease caused by dietary mycotoxin exposure.


The Chinese community smoking cessation project: a community sensitive intervention trial.
This paper describes (1) the design, methods and baseline data of the first smoking cessation clinical trial for Chinese Americans with medical conditions - Chinese Community Smoking Cessation Project (CCSCP); (2) the collaborative process between researchers and the Chinese community; and (3) the barriers and facilitators of implementing the study. CCSCP was a culturally tailored, randomized, smoking cessation trial testing the efficacy of an intensive (physician advice, in-person counseling with nicotine replacement therapy, 5 telephone calls) compared to a minimal (physician advice and self-help manual) intervention. The study applied a community-sensitive research method involving community members in all phases of the research process in San Francisco Bay Area during 2001-2007. CCSCP recruited 464 smokers from health care facilities (79%) located in Chinese neighborhoods and through Chinese language media (21%). Baseline assessments and interventions were conducted in-person using translated and tested questionnaire and intervention materials. The majority of the participants were men (91%) with a mean age of 58.3 years, foreign born (98%), with less than high school education (58%), spoke no English (42%) and in non-skilled or semi-skilled occupations (60%) with <$20,000 household income (51%). Participants smoked regularly on an average 38.6 +/- 17 years, smoked 9.1 +/- 8 cigarettes per day and 85% smoked daily. Cultural tailoring of recruitment methods and intervention design led to successful enrollment and retention of participants, overcoming barriers faced by the participants. Community sensitive collaborative process facilitated implementation of study protocol in community health care settings.


Molecularly Imprinted Nanoparticles (NanoMIPs) Selective for Proteins: Optimization of a Protocol for Solid-Phase Synthesis Using Automatic Chemical Reactor.
Molecularly imprinted polymer nanoparticles (nanoMIPs) are receiving broad interest as robust and highly selective synthetic receptors for a variety of molecules. Due to their stability, inexpensive synthesis and easy implementation, they are considered a promising alternative to antibodies in sensors, diagnostics and separation applications. The most challenging targets for the production of synthetic receptors are proteins due to their fragile nature and the multitude of possible binding sites in their structure. Herein, we describe the modification and optimization of the protocol for synthesis of nanoMIPs with specificity for proteins using the prototype of an automated solid-phase synthesizer. Using an automated system gives an advantage for the simple, fast and fully controlled, reproducible production of nanoMIPs. The molecular imprinting in the reactor is performed using a template covalently immobilized on a solid support, in mild conditions suitable for preserving protein native structure. The validation of the protocol was made by assessing the ability to regenerate a solid-phase, and by measuring affinity and specificity of nanoparticles. As a model protein, we have chosen trypsin since its enzymatic activity can be easily monitored by using a commercial colorimetric assay. Different protocols were tested for their ability to improve the yield of high affinity nanoparticles in the final elution.


Perceptual learning as improved probabilistic inference in early sensory areas.
Extensive training on simple tasks such as fine orientation discrimination results in large improvements in performance, a form of learning known as perceptual learning. Previous models have argued that perceptual learning is due to either sharpening and amplification of tuning curves in early visual areas or to improved probabilistic inference in later visual areas (at the decision stage). However, early theories are inconsistent with the conclusions of psychophysical experiments manipulating external noise, whereas late theories cannot explain the changes in neural responses that have been reported in cortical areas V1 and V4. Here we show that we can capture both the neurophysiological and behavioral aspects of perceptual learning by altering only the feedforward connectivity in a recurrent network of spiking neurons so as to improve probabilistic inference in early visual areas. The resulting network shows modest changes in tuning curves, in line with neurophysiological reports, along with a marked reduction in the amplitude of pairwise noise correlations.


Molecular characterization of methicillin-resistant Staphylococcus aureus isolated over a 2-year period in a Qatari hospital from multinational patients.
Global spread of epidemic methicillin-resistant Staphylococcus aureus (MRSA) is an issue of increasing clinical concern especially problematic community-associated (CA) -MRSA. However, data regarding MRSA epidemiology in regions of the Middle East, including Qatar, are still insufficient. A representative subset of 61 MRSA isolates from multinational patients from hospital in Qatar during a 2-year period (2009/2010) was examined. Molecular characterization for MRSA isolates was performed by pulsed-field gel electrophoresis (PFGE), SCCmec, spa and dru typing, and PCR for the presence of the arginine catabolic mobile element and genes for the Panton-Valentine leukocidin (PVL). Prevalence of MRSA among S. aureus isolated was 176/840 (21%). Of the 61 MRSA isolates examined, three (5%) represented hospital-acquired infection. By PFGE, 32 isolates (52%) were CA-MRSA USA300 (n = 4), USA400 (n = 3), USA1100/Southwest (SW) Pacific (n = 17) and ST80-MRSA-IV (n = 8) strains. The remaining isolates were well-known healthcare-associated EMRSA-15 (n = 8) and USA800 (n = 13). Three isolates were USA900, one was USA1200 and four were unrelated to any known strains in the international database. Unexpectedly, the USA900 isolates were all positive for PVL and USA400 isolates were PVL negative. Five of the eight EMRSA-15 isolates were PVL positive. ST80-MRSA-IV and USA300 strains exhibited typical dru types (dt10a and dt9g, respectively). Eleven different spa types were observed in this study. All USA300 isolates were arginine catabolic mobile element positive. The high prevalence of CA-MRSA, especially including USA300, in this setting underscores the importance of global epidemiological monitoring to better understand and hopefully help prevent the emergence and spread of these problem pathogens in patient populations.


Kinetochore assembly and heterochromatin formation occur autonomously in Schizosaccharomyces pombe.
Kinetochores in multicellular eukaryotes are usually associated with heterochromatin. Whether this heterochromatin simply promotes the cohesion necessary for accurate chromosome segregation at cell division or whether it also has a role in kinetochore assembly is unclear. Schizosaccharomyces pombe is an important experimental system for investigating centromere function, but all of the previous work with this species has exploited a single strain or its derivatives. The laboratory strain and most other S. pombe strains contain three chromosomes, but one recently discovered strain, CBS 2777, contains four. We show that the genome of CBS 2777 is related to that of the laboratory strain by a complex chromosome rearrangement. As a result, two of the kinetochores in CBS 2777 contain the central core sequences present in the laboratory strain centromeres, but lack adjacent heterochromatin. The closest block of heterochromatin to these rearranged kinetochores is ∼100 kb away at new telomeres. Despite lacking large amounts of adjacent heterochromatin, the rearranged kinetochores bind CENP-A(Cnp1) and CENP-C(Cnp3) in similar quantities and with similar specificities as those of the laboratory strain. The simplest interpretation of this result is that constitutive kinetochore assembly and heterochromatin formation occur autonomously.


Angiotensin II blockade [corrected] enhances baroreflex control of sympathetic outflow in heart failure.
Enhanced sympathetic outflow is seen in both patients with congestive heart failure and animals with experimental heart failure. In a previous study, we demonstrated that the baroreflex control of heart rate was impaired in conscious rabbits with pacing-induced heart failure and that this impairment was partially restored by blockade of angiotensin II type 1 (AT1) receptors. In the present study, we determined the interaction between the renin-angiotensin system and baroreflex control of renal sympathetic nerve activity in normal conscious rabbits and conscious rabbits with pacing-induced heart failure before and after AT1 receptor blockade. Heart failure was induced by rapid ventricular pacing at a rate of 360 to 380 beats per minute for an average of 16.7 +/- 0.6 days. To generate baroreflex curves, we altered arterial pressure by administering phenylephrine and sodium nitroprusside. A sigmoidal logistic function was fit to renal sympathetic nerve activity-mean arterial pressure relationships for analysis of several components of baroreflex function. AT1 receptors were blocked by intravenous administration of the specific antagonist L-158,809. In normal rabbits, there was no significant difference in any parameter of baroreflex function before and after blockade of AT1 receptors. In contrast, blockade of AT1 receptors enhanced baroreflex sensitivity in heart failure rabbits. The maximal gain increased to 5.0 +/- 0.7% renal sympathetic nerve activity/mm Hg from 2.6 +/- 0.3 (P < .05). Although L-158,809 had no effect on baseline renal sympathetic nerve activity in normal rabbits, analysis of the data in the heart failure rabbits indicated that baseline renal sympathetic nerve activity was reduced from 33 +/- 5% to 17 +/- 4% after L-158,809 administration after adjustment for changes in arterial pressure. These data suggest that angiotensin II plays a role in baroreflex impairment in this model of heart failure and may be in part responsible for the depressed baroreflex sensitivity observed in heart failure.


Reproductive development and parental investment during pregnancy: moderating influence of mother's early environment.
The association between a woman's age at menarche and the birth weight of her children is highly variable across human populations. Life history theory proposes that a woman's early environment may moderate this association and thus account for some of the variation between populations. According to one life history theory model, for individuals who develop in a childhood environment of high local mortality rates (experienced subjectively as psychosocial stress), it can be adaptive to mature earlier, have more offspring during their reproductive lifetime, and reduce investment in each offspring. In an environment of low psychosocial stress, however, it may be adaptive to mature later, have fewer offspring, and invest more in each. In this study, birth weight and proportionate birth weight (neonate's birth weight as a percentage of its mother's prepregnancy weight) were used as measures of parental investment during pregnancy. In a sample of 580 first-time mothers, we tested the hypothesis that the psychosocial stress experienced as a child would moderate the association between age at menarche and investment during pregnancy. We found that earlier menarche in those women who experienced stressful life events before 15 years of age was associated with a lower birth weight and proportionate birth weight. Conversely, in those who reported no childhood stressors, earlier menarche was associated with increased birth weight and proportionate birth weight. Our data suggest that the moderating influence of the childhood psychosocial environment on the association between age at menarche and parental investment throughout gestation operates in a dose-dependent manner.


COVID-19 and risk of subsequent life-threatening secondary infections: a matched cohort study in UK Biobank.
With the increasing number of people infected with and recovered from coronavirus disease 2019 (COVID-19), the extent of major health consequences of COVID-19 is unclear, including risks of severe secondary infections. Based on 445,845 UK Biobank participants registered in England, we conducted a matched cohort study where 5151 individuals with a positive test result or hospitalized with a diagnosis of COVID-19 were included in the exposed group. We then randomly selected up to 10 matched individuals without COVID-19 diagnosis for each exposed individual (n = 51,402). The life-threatening secondary infections were defined as diagnoses of severe secondary infections with high mortality rates (i.e., sepsis, endocarditis, and central nervous system infections) from the UK Biobank inpatient hospital data, or deaths from these infections from mortality data. The follow-up period was limited to 3 months after the initial COVID-19 diagnosis. Using a similar study design, we additionally constructed a matched cohort where exposed individuals were diagnosed with seasonal influenza from either inpatient hospital or primary care data between 2010 and 2019 (6169 exposed and 61,555 unexposed individuals). After controlling for multiple confounders, Cox models were used to estimate hazard ratios (HRs) of life-threatening secondary infections after COVID-19 or seasonal influenza. In the matched cohort for COVID-19, 50.22% of participants were male, and the median age at the index date was 66 years. During a median follow-up of 12.71 weeks, the incidence rate of life-threatening secondary infections was 2.23 (123/55.15) and 0.25 (151/600.55) per 1000 person-weeks for all patients with COVID-19 and their matched individuals, respectively, which corresponded to a fully adjusted HR of 8.19 (95% confidence interval [CI] 6.33-10.59). The corresponding HR of life-threatening secondary infections among all patients with seasonal influenza diagnosis was 4.50, 95% CI 3.34-6.08 (p for difference < 0.01). Also, elevated HRs were observed among hospitalized individuals for life-threatening secondary infections following hospital discharge, both in the COVID-19 (HR = 6.28 [95% CI 4.05-9.75]) and seasonal influenza (6.01 [95% CI 3.53-10.26], p for difference = 0.902) cohorts. COVID-19 patients have increased subsequent risks of life-threatening secondary infections, to an equal extent or beyond risk elevations observed for patients with seasonal influenza.


Two purified factors bind to the same sequence in the enhancer of mouse MHC class I genes: one of them is a positive regulator induced upon differentiation of teratocarcinoma cells.
The MHC class I murine and beta-2-microglobulin genes are silent in embryonal carcinoma (EC) cells but are induced upon differentiation of these cells. We have previously shown that enhancer-like sequences located in the promoter of the H-2Kb gene are non-functional in F9 and PCC3 cells. We have previously purified a 48 kd protein (KBF1) from a mouse T cell line which binds to a palindromic sequence located in this enhancer and to a similar sequence in the promoter of the beta-2-microglobulin gene. We describe here the purification of a second protein (KBF2, 58 kd) which also binds to this sequence. While both activities are present in differentiated cells, KBF1 binding activity is absent in undifferentiated EC cells, where the palindromic sequence shows no enhancer activity. Upon differentiation, KBF1 binding activity is induced and the palindromic sequence becomes active as an enhancer. Thus, the absence of KBF1 activity in undifferentiated EC cells is at least in part responsible for the lack of expression of H-2 class I and beta-2-microglobulin genes in these cells and suggests that KBF1 activity is regulated during differentiation.


High fidelity sorting of remarkably similar components via metal-mediated assembly.
Subtle differences in ligand coordination angle and rigidity lead to high fidelity sorting between individual components displaying identical coordination motifs upon metal-mediated self-assembly. Narcissistic self-sorting can be achieved between highly similar ligands that vary minimally in rigidity and internal coordination angle upon combination with Fe(ii) ions and 2-formylpyridine. Selective, sequential cage formation can be precisely controlled in a single flask from a mix of three different core ligands (and 33 total components) differing only in the hybridization of one group that is uninvolved in the metal coordination process.


Identification of Hypotensive Emergency Department Patients with Cardiogenic Etiologies.
Identify predictors of cardiogenic etiology among emergency department (ED) patients with hypotension, and use these predictors to create a clinical tool to discern cardiogenic etiology of hypotension. This secondary analysis evaluated a prospective cohort of consecutive patients with hypotension in an urban, academic, tertiary care ED from November 2012 to September 2013. We included adults with hypotension, defined as a new vasopressor requirement, systolic blood pressure (SBP) < 90 mm Hg after at least 1 L of crystalloid or 2 units packed red blood cells, or SBP < 90 mm Hg and fluids withheld due to concern for fluid overload. The primary outcome was cardiogenic etiology, adjudicated by two physician chart review, with 25% paired chart review (kappa = 0.92). We used multivariable logistic regression to predict cardiogenic etiology, utilizing clinical data abstracted from the electronic medical record. We created a prediction score from significant covariates and calculated its test characteristics for cardiogenic hypotension. Of 700 patients with hypotension, 107 (15.3%, 95% CI: 12.6%-18.0%) had cardiogenic etiology. Independent predictors of cardiogenic etiology were shortness of breath (OR 4.1, 95% CI: 2.5-6.7), troponin > 0.1 ng/mL (37.5, 7.1-198.2), electrocardiographic ischemia (8.9, 4.0-19.8), history of heart failure (2.0, 1.1-3.3), and absence of fever (4.5, 2.3-8.7) (area under the curve [AUC] = 0.83). The prediction score created from these predictors yielded 78% sensitivity and 77% specificity for cardiogenic etiology (AUC = 0.827). Clinical predictors offer reasonable ED screening sensitivity for cardiogenic hypotension, while demonstrating sufficient specificity to facilitate early cardiac interventions.


Probing the mid-gorge of cholinesterases with spacer-modified bivalent quinazolinimines leads to highly potent and selective butyrylcholinesterase inhibitors.
The spacer structure of homobivalent quinazolinimes acting as potent acetyl-(AChE)- and butyrylcholinesterase (BChE) inhibitors was chemically modified introducing tertiary amine and acyl-amide moieties, and the activities at both ChEs were evaluated. Molecular docking was applied to explain the data and probe the capacity of the mid-gorge site of both ChEs. The novel spacer structures considerably alter the biological profile of bivalent quinazolinimines with regard to both inhibitory activity and selectivity. Mutual interaction of binding to the various sites of the enzymes was further investigated by applying also different spacer lengths and ring sizes of the alicycle of the tricyclic quinazolinimines. In order to achieve selectivity toward BChE and to improve inhibitory activities, the spacer structure was optimized and identified a highly potent and selective BChE inhibitor.


Unusual membrane bound intranuclear inclusions in human fibroblasts infected with herpes simplex.
Examination of brain tissue taken at autopsy from a 55-year old male showed the presence of herpes simplex viral antigen by immunofluorescence techniques. A suspension of this tissue was inoculated into cultures of human diploid fibroblasts. After 72 h, viral particles at different stages of development were seen inside the nuclei. Envelopment of the viral particles seemed to occur in association with the nuclear membranes, endoplasmic reticulum, cytoplasmic vacuoles and plasma membranes. Severely altered nuclear membranes, with as many as 4 to 8 layers of nuclear envelope, emphasized the common occurrence of membrane reduplication associated with herpes simplex infection. Unusual membrane-bound, dense, rounded inclusions, 100 to 500 nm in diameter, were present in the nucleus. These inclusions apparently were formed between the inner and outer lamellae of the nuclear membrane.


Anthropometric and Physical Profiles of English Academy Rugby Union Players.
The purpose of this study was to evaluate the anthropometric and physical characteristics of English regional academy rugby union players by age category (under 16s, under 18s and under 21s). Data were collected on 67 academy players at the beginning of the preseason period and comprised anthropometric (height, body mass, and sum of 8 skinfolds) and physical (5-, 10-, 20-, and 40-m sprint, acceleration, velocity, and momentum; agility 505; vertical jump; Yo-Yo intermittent recovery test level 1; 30-15 intermittent fitness test; absolute and relative 3 repetition maximum front squat, split squat, bench press, prone row, and chin; and isometric mid-thigh pull). One-way analysis of variance demonstrated significant increases across the 3 age categories (p ≤ 0.05) for height (e.g., 16s = 178.8 ± 7.1; 18s = 183.5 ± 7.2; 21s = 186.7 ± 6.61 cm), body mass (e.g., 16s = 79.4 ± 12.8; 18s = 88.3 ± 11.9; 21s = 98.3 ± 10.4 kg), countermovement jump height and peak power, sprint momentum, velocity, and acceleration; absolute, relative, and isometric (e.g., 16s = 2,157.9 ± 309.9; 18s = 2,561.3 ± 339.4; 21s = 3,104.5 ± 354.0 N) strength. Momentum, maximal speed, and the ability to maintain acceleration were all discriminating factors between age categories, suggesting that these variables may be more important to monitor rather than sprint times. These findings highlight that anthropometric and physical characteristics develop across age categories and provide comparative data for English Academy Rugby Union players.


Adherence to health care regimens among elderly women.
This study examined selected components of nurse practitioners' care to determine which contributed most to the intent to adhere to the care plan. High and low levels of components of care (technical quality, psychosocial, and patient participation) were depicted by videotapes of a patient visit to a nurse practitioner. The videotapes were randomly selected and shown in 26 senior citizen nutrition centers in a metropolitan area. Elderly women indicated how likely they would be to adhere if they had been the patient in the tape. High psychosocial care was the only component significantly related to intent to adhere; however, the significance did not hold in an analysis of covariance when individual characteristics were controlled. Individual characteristics related to high intent to adhere were widowed marital status, religion, perceived importance of the examination, social network, and preexisting satisfaction with health care.


Effect of backward walking on attention: possible application on ADHD.
The human requires attentive effort as assessed in dual-task experiments. Consistently, an attentive task can modify the walking pattern and a attention deficit and hyperactivity disorder (ADHD) is accompanied by gait modifications. Here we investigated the relationships between backward walking and attentive performances in ADHD children (n=13) and healthy age-, height and weight matched controls (n=17). We evaluated the attentive/impulsive profile by means of a Go/No-Go task and the backward and forward gait parameters by step length, cadence and Froude number. Moreover, to test the causal relationship between attention and gait parameters, we trained children to walk backward. The training program consisted of 10 min backward walking session, thrice a week for two months. Results showed a significant negative correlation between Froude number during backward walking and reaction time in the Go/No-Go test. Besides, after training with backward walking control children increased their cadence by 9.3% and their Froude number by 17% during backward walking. Conversely, ADHD children did not modify their walking parameters after training, and showed a significant reduction in their number of errors in the Go/No-Go task (-49%) compared to the score before the training. These data suggest that specific physical training with attention-demanding tasks may improve attentive performance.


A comparison of the in vitro activity of two antibiotics against bovine ureaplasmas.
A comparison of the in vitro activity of rosaramicin and minocin against 52 bovine Ureaplasma sp. strains, 20 of which were isolated from semen, 23 from vaginal swabs, and nine from preputial washings, has shown that both antibiotics have good inhibitory action against the strains tested. Rosaramicin was ureaplasmacidal in most instances at, or close to the inhibitory level while for most strains studied a ureaplasmacidal level of minocin was not found.


Effects of human calcitonin on pain in the treatment of Tietze's syndrome.
Tietze's syndrome consists of pain, tenderness, and swelling of the costosternal or sternoclavicular joints. The etiology is unknown, although microtrauma or rare infections have been though to be responsible for the lesion. Conventional therapy consists of anti-inflammatory drugs, sometimes combined with chemotherapeutic agents and antibiotics. Surgery is usually deemed necessary for cases that do not respond to conventional therapy. Experience with the use of human calcitonin in five patients suffering from severe Tietze's syndrome who did not respond to conventional therapy is reported. Symptoms improved within seven days, and all symptoms and signs had disappeared after one month of treatment. The beneficial effects of calcitonin are believed to result from the hormone's well-known analgesic and immunomodulating effects.


Plate prebending using a three-dimensional-printed model affords effective anatomical reduction in clavicular shaft fractures.
A precontoured plate rarely fits properly within the patient's clavicle and must be bent intraoperatively. This study aimed to determine whether anatomical reduction could be achieved using a plate bent before surgery. This study included 87 consecutive patients with displaced mid-shaft clavicle fractures who underwent plate fixation and were followed-up for a minimum of 1 year. After exclusions, 39 consecutive patients underwent fixation with a precontoured plate bent intraoperatively (intraoperative bending group), and 28 underwent fixation with the plate bent preoperatively (preoperative bending group). Using free software and a three-dimensional (3D) printer, ipsilateral clavicle 3D-printed models were constructed. Using plain radiographs, the distance between the edge of the lateral inferior cortex and the medial inferior cortex was measured. The angle between the line connecting the inferior cortex edge and the line passing through the flat portion of the superior cortex of the distal clavicle was measured. Mean length differences between the ipsilateral and contralateral clavicle were smaller on both anteroposterior (AP; P=0.032) and axial images (P=0.029) in the preoperative bending group. The mean angular differences on both AP (P=0.045) and axial images (P=0.008) were smaller in the preoperative bending group. No significant differences were observed between the two groups in functional scores at the last follow-up. Smaller differences in length and angle between the ipsilateral and contralateral clavicle, indicative of reduction, were observed in the preoperative bending group. Using the precontoured technique with low expense, the operation was performed more effectively as reflected by a shorter operation time. Level of evidence: III.


Gunshot and explosion injuries: characteristics, outcomes, and implications for care of terror-related injuries in Israel.
An increase of terror-related activities may necessitate treatment of mass casualty incidents, requiring a broadening of existing skills and knowledge of various injury mechanisms. To characterize and compare injuries from gunshot and explosion caused by terrorist acts. A retrospective cohort study of patients recorded in the Israeli National Trauma Registry (ITR), all due to terror-related injuries, between October 1, 2000, to June 30, 2002. The ITR records all casualty admissions to hospitals, in-hospital deaths, and transfers at 9 of the 23 trauma centers in Israel. All 6 level I trauma centers and 3 of the largest regional trauma centers in the country are included. The registry includes the majority of severe terror-related injuries. Injury diagnoses, severity scores, hospital resource utilization parameters, length of stay (LOS), survival, and disposition. A total of 1155 terror-related injuries: 54% by explosion, 36% gunshot wounds (GSW), and 10% by other means. This paper focused on the 2 larger patient subsets: 1033 patients injured by terror-related explosion or GSW. Seventy-one percent of the patients were male, 84% in the GSW group and 63% in the explosion group. More than half (53%) of the patients were 15 to 29 years old, 59% in the GSW group and 48% in the explosion group. GSW patients suffered higher proportions of open wounds (63% versus 53%) and fractures (42% versus 31%). Multiple body-regions injured in a single patient occurred in 62% of explosion victims versus 47% in GSW patients. GSW patients had double the proportion of moderate injuries than explosion victims. Explosion victims have a larger proportion of minor injuries on one hand and critical to fatal injuries on the other. LOS was longer than 2 weeks for 20% (22% in explosion, 18% in GSW). Fifty-one percent of the patients underwent a surgical procedure, 58% in the GSW group and 46% in explosion group. Inpatient death rate was 6.3% (65 patients), 7.8% in the GSW group compared with 5.3% in the explosion group. A larger proportion of gunshot victims died during the first day (97% versus 58%). GSW and injuries from explosions differ in the body region of injury, distribution of severity, LOS, intensive care unit (ICU) stay, and time of inpatient death. These findings have implications for treatment and for preparedness of hospital resources to treat patients after a terrorist attack in any region of the world. Tailored protocol for patient evaluation and initial treatment should differ between GSW and explosion victims. Hospital organization toward treating and admitting these patients should take into account the different arrival and injury patterns.


Defensive function of herbivore-induced plant volatile emissions in nature.
Herbivore attack is known to increase the emission of volatiles, which attract predators to herbivore-damaged plants in the laboratory and agricultural systems. We quantified volatile emissions from Nicotiana attenuata plants growing in natural populations during attack by three species of leaf-feeding herbivores and mimicked the release of five commonly emitted volatiles individually. Three compounds (cis-3-hexen-1-ol, linalool, and cis-alpha-bergamotene) increased egg predation rates by a generalist predator; linalool and the complete blend decreased lepidopteran oviposition rates. As a consequence, a plant could reduce the number of herbivores by more than 90% by releasing volatiles. These results confirm that indirect defenses can operate in nature.


Erythrocyte membrane: chemical modification.
Erythrocytes treated with 1-fluoro-2,4-dinitrobenzene become permeable to Na(+) and K(+), but not to small water-soluble nonelectrolytes hemoglobin, and eventually lyse inisotonic buffer. Erythrocytes treated with 1,5-difluoro-2,4-dinitrobenzene become permeable to Na(+) and K(+) but do not lyse in buffer or in water, even after extraction with lipid solvents. The difluoro compound crosslinks the membrane and increases its strength. Both reagents appear to remove the positive fixed charge responsible for the cation impermeability of the normal cell.


Reproductive isolation in hybrid mice due to spermatogenesis defects at three meiotic stages.
Early in the process of speciation, reproductive failures occur in hybrid animals between genetically diverged populations. The sterile hybrid animals are often males in mammals and they exhibit spermatogenic disruptions, resulting in decreased number and/or malformation of mature sperms. Despite the generality of this phenomenon, comparative study of phenotypes in hybrid males from various crosses has not been done, and therefore the comprehensive genetic basis of the disruption is still elusive. In this study, we characterized the spermatogenic phenotype especially during meiosis in four different cases of reproductive isolation: B6-ChrX(MSM), PGN-ChrX(MSM), (B6 × Mus musculus musculus-NJL/Ms) F(1), and (B6 × Mus spretus) F(1). The first two are consomic strains, both bearing the X chromosome of M. m. molossinus; in B6-ChrX(MSM), the genetic background is the laboratory strain C57BL/6J (predominantly M. m. domesticus), while in PGN-ChrX(MSM) the background is the PGN2/Ms strain purely derived from wild M. m. domesticus. The last two cases are F(1) hybrids between mouse subspecies or species. Each of the hybrid males exhibited cell-cycle arrest and/or apoptosis at either one or two of three distinct meiotic stages: premeiotic stage, zygotene-to-pachytene stage of prophase I, and metaphase I. This study shows that the sterility in hybrid males is caused by spermatogenic disruptions at multiple stages, suggesting that the responsible genes function in different cellular processes. Furthermore, the stages with disruptions are not correlated with the genetic distance between the respective parental strains.


2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene.
2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency is a novel inborn error of isoleucine degradation. In this article, we report the elucidation of the molecular basis of MHBD deficiency. To this end, we purified the enzyme from bovine liver. MALDI-TOF mass spectrometry analysis revealed that the purified protein was identical to bovine 3-hydroxyacyl-CoA dehydrogenase type II. The human homolog of this bovine enzyme is a short-chain 3-hydroxyacyl-CoA dehydrogenase, also known as the "endoplasmic reticulum-associated amyloid-beta binding protein" (ERAB). This led to the identification of the X-chromosomal gene involved, which previously had been denoted "HADH2." Sequence analysis of the HADH2 gene from patients with MHBD deficiency revealed the presence of two missense mutations (R130C and L122V). Heterologous expression of the mutant cDNAs in Escherichia coli showed that both mutations almost completely abolish enzyme activity. This confirms that MHBD deficiency is caused by mutations in the HADH2 gene.


Anaerobic Degradation of the Plant Sugar Sulfoquinovose Concomitant With H2S Production: Escherichia coli K-12 and Desulfovibrio sp. Strain DF1 as Co-culture Model.
Sulfoquinovose (SQ, 6-deoxy-6-sulfoglucose) is produced by plants and other phototrophs and its biodegradation is a relevant component of the biogeochemical carbon and sulfur cycles. SQ is known to be degraded by aerobic bacterial consortia in two tiers via C3-organosulfonates as transient intermediates to CO2, water and sulfate. In this study, we present a first laboratory model for anaerobic degradation of SQ by bacterial consortia in two tiers to acetate and hydrogen sulfide (H2S). For the first tier, SQ-degrading Escherichia coli K-12 was used. It catalyzes the fermentation of SQ to 2,3-dihydroxypropane-1-sulfonate (DHPS), succinate, acetate and formate, thus, a novel type of mixed-acid fermentation. It employs the characterized SQ Embden-Meyerhof-Parnas pathway, as confirmed by mutational and proteomic analyses. For the second tier, a DHPS-degrading Desulfovibrio sp. isolate from anaerobic sewage sludge was used, strain DF1. It catalyzes another novel fermentation, of the DHPS to acetate and H2S. Its DHPS desulfonation pathway was identified by differential proteomics and demonstrated by heterologously produced enzymes: DHPS is oxidized via 3-sulfolactaldehyde to 3-sulfolactate (SL) by two NAD+-dependent dehydrogenases (DhpA, SlaB); the SL is cleaved by an SL sulfite-lyase known from aerobic bacteria (SuyAB) to pyruvate and sulfite. The pyruvate is oxidized to acetate, while the sulfite is used as electron acceptor in respiration and reduced to H2S. In conclusion, anaerobic sulfidogenic SQ degradation was demonstrated as a novel link in the biogeochemical sulfur cycle. SQ is also a constituent of the green-vegetable diet of herbivores and omnivores and H2S production in the intestinal microbiome has many recognized and potential contributions to human health and disease. Hence, it is important to examine bacterial SQ degradation also in the human intestinal microbiome, in relation to H2S production, dietary conditions and human health.


Sacrococcygeal teratoma in infants and children.
The purpose of this study is to share our experience with extensive sacrococcygeal teratoma, paying particular attention to neurological function, intraoperative hemorrhage, rate of tumor recurrence, and the surgical procedure. Infants and children with sacrococcygeal teratoma were selected and generally examined in order to detect other associated anomalies. Patients with giant sacrococcygeal tumor and high output heart failure were managed by the abdominosacral route while patients with small sacrococcygeal tumor and normal cardiac function were managed by the sacral approach. All operated patients were observed and followed-up regularly for a period of 1-3 years after tumor excision. This study presents 22 patients with sacrococcygeal teratoma managed over a period of 40 months; 18 patients presented in the first 2 months of life and four children aged 2-4 years. Fifteen patients were treated by sacral excision and seven patients were corrected by abdomenosacral excision and temporary colostomy. Benign teratoma presented in 17 patients, one of whom died (6%), and five patients had malignant tumor, one of whom died (20%). The fecal and urinary state was good in all patients treated by the sacral route. Patients corrected by abdominosacral excision showed varied degrees of urinary incontinence and constipation. Survival in excised malignant tumor was good following chemotherapy; three patients received chemotherapy with a 70% survival rate. Benign sacrococcygeal teratoma has an excellent outcome after early surgery, but the incidences of malignancy increase if resection is delayed.


Leveraging Artificial Intelligence and Digital Health to Address Health-Related Social Needs and Optimize Risk-Based Value in Orthopaedic Surgery.
As the health care landscape evolves toward value-based care and emphasizes health-related social needs, the importance of developing health policies and digital health solutions that foster health equity and risk-based reimbursement strategies has grown. Orthopaedic surgery, catering to a diverse patient population but challenged by a lack of workforce diversity, encounters distinct opportunities and obstacles in adopting digital health technologies for delivering equitable, high-value care. The integration of health-related social needs into the emerging value-based care model and risk-based reimbursement policies is important. Furthermore, the potential of incorporating robust artificial intelligence governance and big data analytics to enhance patient outcomes and support orthopaedic surgeons in treating their patient populations should be studied. There are crucial considerations for creating comprehensive digital health platforms tailored for orthopaedic surgery, and the significance of specialty-specific advocacy and collaboration among clinicians, policymakers, and MedTech companies cannot be understated.


A new indole-3-carbinol tetrameric derivative inhibits cyclin-dependent kinase 6 expression, and induces G1 cell cycle arrest in both estrogen-dependent and estrogen-independent breast cancer cell lines.
Indole-3-carbinol (I3C), autolysis product of glucosinolates present in cruciferous vegetables, has been indicated as a promising agent in preventing the development and progression of breast cancer. I3C has been shown to inhibit the growth of human cancer cells in vitro and possesses anticarcinogenic activity in vivo. Because I3C is unstable and may be converted into many polymeric products in the digestive tract, it is not yet clear whether the biological activity observed can be attributed to I3C or some of its polymeric products. In this study we synthesized a stable I3C cyclic tetrameric derivative and investigated its effects on a panel of human breast cancer cell lines. The I3C tetramer suppressed the growth of both estrogen receptor (ER) -positive (MCF-7, 734B, and BT474) and ER-negative (BT20, MDA-MB-231, and BT539) human breast cancer cell lines, and it was found to induce G(1) cell cycle arrest in a dose-dependent manner without evidence of apoptosis, suggesting a growth arrest via a cytostatic mechanism. At the molecular level, the tetramer inhibited cyclin-dependent kinase (CDK) 6 expression and activity, induced an increase in the level of p27(kip1), and reduced the level of retinoblastoma protein expression. Contrarily to CDK6, the level of CDK4, the other kinase involved in the G(1) phase of the cell cycle, remains unchanged. Interestingly, the tetramer resulted about five times more active than I3C in suppressing the growth of human breast cancer cells. On the whole, our data suggest that the I3C tetrameric derivative is a novel lead inhibitor of breast cancer cell growth that may be a considered a new, promising therapeutic agent for both ER+ and ER- breast cancer.


Response of SI cortex to ipsilateral, contralateral and bilateral flutter stimulation in the cat.
While SII cortex is considered to be the first cortical stage of the pathway that integrates tactile information arising from both sides of the body, SI cortex is generally not considered as a region in which neuronal response is modulated by simultaneous stimulation of bilateral (and mirror-image) skin sites. Optical intrinsic signal imaging was used to evaluate the response of SI and SII in the same hemisphere to 25 Hz sinusoidal vertical skin displacement stimulation ("skin flutter") applied contralaterally, ipsilaterally, and bilaterally (simultaneously) to the central pads of the forepaws. A localized increase in absorbance in both SI and SII occurred in response to both contralateral and bilateral flutter stimulation. Ipsilateral flutter stimulation evoked a localized increase in absorbance in SII, but little or no change in SI absorbance. In the forepaw representational region of SI, however, bilateral stimulation of the central pads evoked a response substantially smaller (approximately 30-35% smaller) than the response to flutter stimulation of the contralateral central pad. The finding that the response of SI cortex to bilateral central pad flutter stimulation is substantially smaller than the response evoked by a contralateral flutter stimulus, together with the recently published observation that a region located posteriorly in SII responds with a substantially larger response to a bilateral flutter stimulus than the response evoked from the contralateral central pad, lead us to propose that the SI activity evoked by contralateral skin stimulation is suppressed/inhibited (via corticocortical connections between SII and SI in the same hemisphere) by the activity a simultaneous ipsilateral skin stimulus evokes in posterior SII.


Long-term analysis of the use of transanal rectal advancement flaps for complicated anorectal/vaginal fistulas.
Transanal rectal advancement flap (TRAF) is a surgical option in the management of rectovaginal and other complicated fistulas involving the anorectum. Most reported series have a short follow-up. This study was undertaken to determine the long-term success, safety, applicability, and factors affecting recurrence in patients managed with TRAF, including patients with Crohn's disease. Retrospective analysis of all patients undergoing endorectal advancement flaps at a single institution between 1988 and 1993 was performed. One hundred one patients were identified (70 percent female; 30 percent male). Included were 52 patients with rectovaginal, 46 with anal perineal, and 3 with rectourethral fistulas. Causes were obstetric injury in 13 patients, Crohn's disease in 47, cryptoglandular in 19, mucosal ulcerative colitis in 7, and surgical trauma or undefined causes in 15 patients. No mortality occurred. Median follow-up was 31 (range, 1-79 months). Immediate failure (within one week of the repair) was seen in 6 percent of patients. Statistically (P<0.001) higher recurrence rates were observed in patients who had undergone previous repairs. Mean hospital stay was four days. Overall recurrence was seen in 29 patients (29 percent). Seventy-five percent of all recurrences occurred within the first 15 months; however, recurrence was noted for up to 55 months after repair. Etiology of fistula, use of constipating medications, antibiotic use, and most importantly associated Crohn's disease did not statistically affect recurrence rates. Failure rate was only influenced by previous number of repairs. TRAF is a safe technique for managing complicated anorectal and rectovaginal fistulas, including patients with Crohn's disease. Long-term follow-up is essential to accurately report recurrence rates.


Cord blood 8-isoprostane in the preterm infant.
Cord blood 8-isoprostane (8-IP) is a marker of lipid peroxidation in the peripartum period. The independent association with degree of prematurity is not well-described. To identify patterns of lipid peroxidation among early, moderate and late preterm infants, and to understand how cord blood 8-IP varies with gestational age (GA) and related covariates. Mother-infant pairs from 237 preterm births were studied as part of a longitudinal birth cohort study. GA subgroups were defined as extremely (≤28w), moderately (29-33w), and late (34-36w) preterm. Cord blood 8-IP was measured using EIA. Elevated 8-IP (4th quartile) was the primary outcome for multivariate logistic regression models, which were adjusted for maternal age/race, multiple gestation and infant gender, as well as other relevant covariates. Elevated 8-IP was associated with extremely preterm birth (OR=4.31; 95% CI=1.90, 9.76), and was inversely associated with increasing GA (OR=0.88; 95% CI=0.80, 0.97). Elevated 8-IP was also associated with decreasing birth weight (BW), clinical chorioamnionitis, fetal inflammatory response of the placenta (FIR), and signs of perinatal depression. The GA on 8-IP association appeared to be modified by several maternal disease and fetal-infant factors. Lastly, the indirect associations between log-transformed 8-IP, GA and BW appeared to be most prominent for GA<30w and for BW<2000g. Lipid peroxidation in preterm birth, and the relative influence of accompanying peripartum factors, varies according to degree of prematurity. These findings have important implications for the developmental regulation of antioxidant defense and its impact on neonatal outcomes.


In situ surface-enhanced Raman scattering spectroelectrochemistry of oxygen species.
In situ surface-enhanced Raman scattering (SERS) combined with electrochemical analysis is applied to the determination of oxygen species on silver electrodes in alkaline hydroxide aqueous solution at room temperature and gold electrodes in carbonate melts at high temperature. This technique, referred to as SERS spectroelectrochemistry, reveals Raman spectral lines in the 500-1100 cm(-1) range under electrode potential scanning, assignable to superoxide ions (O2-) and peroxide ions (O2(2-)) on the electrode surface. These lines for oxygen molecule species have potential dependence with changing potential. In the alkaline hydroxide aqueous solution, the Raman peaks due to oxygen molecules are observed at potentials between 0.2 V and -0.8 V (vs. Ag/AgCl) only in the cathodic scan. This irreversible behavior in cyclic voltammograms indicates the existence of an intermediate stage in the oxygen reduction process, in which oxygen is released from the AgO films on the electrode at potentials corresponding to the onset of the last current peak in the voltammogram. This liberated oxygen molecule remains in solution at the interface until hydroxyls or water molecules are formed when the potential reaches the potential zero charge (PZC). In the high-temperature carbonate melts, Raman lines at 1047, 1080, and 800 cm(-1) are apparent for the eutectic (62 + 38) mol% (Li + K)CO3 melt at 923 K, and at 735 cm(-1) for the Li2CO3 melt at 1123 K. These results suggest that oxygen reduction in the Li2CO3 melt involves only peroxide ions, while that in (62 + 38) mol% (Li + K)CO3 involves both peroxide and superoxide ions at the three-phase boundary interface.


Evaluation of impairment of the upper extremity.
Evaluation of impairment of the upper extremity is the product of a team effort by the physician, occupational therapist, physical therapist, and rehabilitation counselor. A careful recording of the anatomic impairment should be made because this is critical in determining the subsequent functional activities of the extremity. The measurement criteria for clinical and functional evaluation includes condition assessment instruments. Some assess the neurovascular system, others assess movements including the monitoring of articular motion and musculotendinous function. Sensibility assessment instruments measure sympathetic response and detect single joint stimulus, discrimination, quantification, and recognition abilities. A detailed description of each assessment is recorded and physical capacity evaluation is only one component of the entire vocational evaluation. This evaluation answers questions regarding the injured worker's ability to return to his previous job. The work simulator is a useful instrument that allows rehabilitation and testing of the injured upper extremity. Job site evaluation includes assessment criteria for work performance, work behavior, and work environment.


The Cuban Propolis Component Nemorosone Inhibits Proliferation and Metastatic Properties of Human Colorectal Cancer Cells.
The majority of deaths related to colorectal cancer (CRC) are associated with the metastatic process. Alternative therapeutic strategies, such as traditional folk remedies, deserve attention for their potential ability to attenuate the invasiveness of CRC cells. The aim of this study is to investigate the biological activity of brown Cuban propolis (CP) and its main component nemorosone (NEM) and to describe the molecular mechanism(s) by which they inhibit proliferation and metastatic potential of 2 CRC cell lines, i.e., HT-29 and LoVo. Our results show that CP and NEM significantly decreased cell viability and inhibited clonogenic capacity of CRC cells in a dose and time-dependent manner, by arresting the cell cycle in the G0/G1 phase and inducing apoptosis. Furthermore, CP and NEM downregulated BCL2 gene expression and upregulated the expression of the proapoptotic genes TP53 and BAX, with a consequent activation of caspase 3/7. They also attenuated cell migration and invasion by inhibiting MMP9 activity, increasing E-cadherin and decreasing β-catenin and vimentin expression, proteins involved in the epithelial-mesenchymal transition (EMT). In conclusion NEM, besides displaying antiproliferative activity on CRC cells, is able to decrease their metastatic potential by modulating EMT-related molecules. These finding provide new insight about the mechanism(s) of the antitumoral properties of CP, due to NEM content.