Participation of underrepresented minority children in clinical trials for Fragile X syndrome and other neurodevelopmental disorders.
The purpose of this study was to identify demographic data, motivational factors and barriers for participation in clinical trials (CTs) at the University of California Davis, MIND Institute. We conducted a cross-sectional survey in 100 participants (81 females and 19 males). The participants had high education levels (only 2% had not completed high school), a mean age of 44 years (SD ± 9.899) and had at least one child with a neurodevelopmental disorder. The diagnosis of Fragile X syndrome (FXS) had a significant association with past participation in CTs (p < 0.001). A statistical significance for age of diagnosis and participation in CTs was also found (z = -2.01, p = 0.045). The motivating factors were to help find cures/treatments for neurodevelopmental disorders and to relieve symptoms related to child's diagnosis. Factors explaining lack of participation, unwillingness to participate or unsure of participation were: lack of information/knowledge about the trials, time commitment to participation (screening, appointments, assessments, laboratory tests, etc.) and low annual household income. These results show that a portion of underrepresented minorities (URM) not participating in CTs are willing to participate and suggests that reducing barriers, particularly lack of knowledge/information and time commitment to trials are needed to improve recruitment.


Rapid changes in nuclear protein tyrosine phosphorylation after growth hormone treatment in vivo. Identification of phosphorylated mitogen-activated protein kinase and STAT91.
Growth hormone (GH) plays a central role in regulating growth and intermediary metabolism in vertebrates, although the mechanisms by which GH initiates these actions are largely unknown. The GH receptor, a member of the cytokine receptor superfamily, does not demonstrate homology with any known tyrosine kinases. However, addition of GH to cells in vitro has been shown to stimulate tyrosine phosphorylation of various intracellular proteins including mitogen-activated protein kinases (MAP kinases) and the newly described Janus kinase, JAK2. Subsequent steps in GH-mediated signal transduction have not been delineated. In the present study, we have examined early events in GH action in vivo. Hypophysectomized juvenile male rats were treated with GH for 15, 30, or 60 min. Rat liver whole cell and nuclear extracts were prepared and analyzed via SDS-polyacrylamide gel electrophoresis and Western blotting techniques. GH rapidly stimulated the tyrosine phosphorylation of at least 8 nuclear proteins of 205, 91, 83, 80, 65, 53, 44, and 42 kDa, and caused the dephosphorylation of a single approximately 149-kDa protein. Using specific antibodies, we have identified three of these nuclear phosphoproteins as 42- and 44-kDa MAP kinases, and as STAT91, a 91-kDa component of the interferon-stimulated gene factor-3 protein complex. One consequence of the activation of STAT91 in the nucleus is the appearance of GH-stimulated DNA binding activity, as assessed by gel-mobility shift assay using an oligonucleotide containing a c-sis-inducible element from the c-fos promoter. These results show that nuclear protein tyrosine phosphorylation is a prominent early event in GH action in vivo and demonstrate a link between GH-stimulated signal transduction and target gene expression.


The Genetic and Environmental Factors of Primary Membranous Nephropathy: An Overview from China.
Primary membranous nephropathy (pMN) is the most common cause of nephrotic syndrome in adults. The discovery of the 2 autoantigens, M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A), has defined pMN as an autoimmune disease. A remarkable increase in the frequency of pMN in primary glomerular disease was witnessed in China. The genetic and environmental contributors to disease susceptibility have been investigated in these patients. We reviewed recent publications in genetic and environmental studies of pMN, focusing mainly on those undertaken in China. Following a genome-wide association study, the gene-gene interaction between the 2 most significant risk factors, PLA2R1 and DQA1, was validated in Chinese patients with MN. Fine mapping on human leukocyte antigen (HLA) locus found that DRB1*1501 and DRB1*0301 were risk alleles. Three amino acid residues on positions 13 and 71 of HLA-DRβ1 chain may confer the susceptibility to pMN by presenting T-cell epitopes on PLA2R. Another study found that DRB3*0202 was the most likely culprit allele for the signal at DRB1*0301. One environmental risk factor for pMN has been identified as the long-term exposure to high levels of PM2.5 in Chinese patients with MN. Each 10 μg/m3 increase in PM2.5 concentration was associated with 14% higher odds for pMN in the regions with PM2.5 above 70 μg/m3. A gene-environment interaction is suspected as an underlying mechanism for the increasing trend of pMN in China.


Clustering by plasma lipoprotein profile reveals two distinct subgroups with positive lipid response to fenofibrate therapy.
Fibrates lower triglycerides and raise HDL cholesterol in dyslipidemic patients, but show heterogeneous treatment response. We used k-means clustering to identify three representative NMR lipoprotein profiles for 775 subjects from the GOLDN population, and study the response to fenofibrate in corresponding subgroups. The subjects in each subgroup showed differences in conventional lipid characteristics and in presence/absence of cardiovascular risk factors at baseline; there were subgroups with a low, medium and high degree of dyslipidemia. Modeling analysis suggests that the difference between the subgroups with low and medium dyslipidemia is influenced mainly by hepatic uptake dysfunction, while the difference between subgroups with medium and high dyslipidemia is influenced mainly by extrahepatic lipolysis disfunction. The medium and high dyslipidemia subgroups showed a positive, yet distinct lipid response to fenofibrate treatment. When comparing our subgroups to known subgrouping methods, we identified an additional 33% of the population with favorable lipid response to fenofibrate compared to a standard baseline triglyceride cutoff method. Compared to a standard HDL cholesterol cutoff method, the addition was 18%. In conclusion, by using constructing subgroups based on representative lipoprotein profiles, we have identified two subgroups of subjects with positive lipid response to fenofibrate therapy and with different underlying disturbances in lipoprotein metabolism. The total subgroup with positive lipid response to fenofibrate is larger than subgroups identified with baseline triglyceride and HDL cholesterol cutoffs.


[Effects of metformin on the plasminogen activator system, endocrine, metabolic profiles in patients with polycystic ovary syndrome and clomiphene resistant cases].
To assess the therapeutic effects of metformin in patients with polycystic ovary syndrome (PCOS) and clomiphene (CC) resistant cases. Thirty one patients with PCOS, including 8 CC resistant cases were studied. Serum tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), menstrual and reproductive hormone patterns, lipid and glucose metabolic parameters, bilateral ovarian volume, side effects were determined before and after oral administration of metformin 375 mg three times daily for 12 - 16 weeks. Metformin and CC were co-administered in CC resistant cases who had not restored their menstrual cycle after the treatment with metformin alone for investigating ovulation rate. In the remaining non-CC resistant metformin failure cases the dosage of metformin was incrersed to 500 mg three times daily for investigating menstrual cycle. After administration of metformin for 12 - 16 weeks, serum PAI-1, luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio, androstenedione, testosterone, low density liproprotein-cholesterol, total cholesterol, fasting insulin concentration and response to oral glucose tolerant test (OGTT), diastolic blood pressure decreased significantly, while FSH and estradiol levels increased, bilateral ovarian volume shrunk significantly (P < 0.05 - 0.01). Body mass index, waist hip ratio, LH, tPA, systolic blood pressure, prolactin, fasting glucose concentration and response to OGTT, high density liproprotein-cholesterol, apoliprotein A, apoliprotein B, triglycerides levels did not change significantly (P > 0.05). Nineteen out of thirty one cases (61%) had restoration of menstrual cycle, 2 became pregnant. In 6 CC resistant cases who had not restoration of menstrual cycle after the treatment with metformin, CC induced ovulation in 12/18 cycles or 5/6 cases and 2 pregnancies achieved. In others 6 metformin failure cases the dosage of metformin was increased to 500 mg three times daily, one restored menstrual cycle and became pregnant. Metformin may ameliorate the PAI-1, endocrine, metabolic profiles and menstrual abnormalities and improve the ovarian response to CC in CC resistant cases. Metformin provides a safe and effective approach to the treatment of PCOS.


In silico assessment and structural characterization of antioxidant peptides from major yolk protein of sea urchin Strongylocentrotus nudus.
Sea urchin gonads have been demonstrated to contain major yolk protein (MYP), which can be hydrolyzed by enzymes to release biologically active peptides. The in silico analysis of the MYP sequence in the BIOPEP database showed the presence of fragments with antioxidant activity. The sequence was hydrolyzed by 21 kinds of proteases and 23 antioxidant peptides were obtained. Eight peptides, including Leu-Trp (LW), Arg-Trp (RW), Ala-Trp (AW), Thr-Trp (TW), Ala-Asp-Phe (ADF), Leu-Trp-Lys (LWK), Ser-Asp-Phe (SDF) and Leu-Tyr (LY), were screened and a score over 0.5 was obtained using PeptideRanker. The peptides LW, TW and LWK showed a stronger antioxidant capacity with IC50 values of 8.85, 9.59 and 9.62 mmol L-1, respectively, compared to that of glutathione (10.81 mmol L-1). Furthermore, AW, LW and LY showed Trolox equivalent antioxidant capacity (TEAC) values of 3.07, 1.87 and 1.52 mmol TE per mmol peptide, respectively. These results suggest that the MYP from sea urchin (S. nudus) gonads is a good source of antioxidant peptides with abundant tryptophan.


Recommendations for buprenorphine and methadone therapy in opioid use disorder: a European consensus.
Management of patients with opioid use disorder (OUD) commonly includes opioid agonist therapy (OAT) as a part of an integrated treatment plan. These interventions are associated with proven benefits to the individual and society. Areas covered: The use of methadone and buprenorphine within an integrated treatment plan in the management of patients with OUD: this work provides consensus recommendation on pharmacotherapy in OUD to assist clinicians with practical decision making in this field. Expert opinion: Pharmacotherapy is recommended as part of an integrated OUD treatment approach with psychosocial interventions, with the goal of reducing risks of illicit opioid use, overdose mortality, infection with HIV or HCV, improving health, psychological and social outcomes. Access to OAT should be prioritised in the treatment of OUD. Treatment choices in OUD pharmacotherapy should be based on the needs of the individual and characteristics of medications. Recommendations for choices of OAT are based on clinical efficacy, safety, patient preference, side effects, pharmacological interactions, quality of life, dose titration potential and outcomes (control craving, ongoing opioids consumption or other drugs, and potentially psychiatric comorbidities). Special groups, pregnant women, prisoners, patients with mental health problems have specific needs which must be addressed with expert input.


Hydrolytic Degradation and Erosion of Polyester Biomaterials.
Strategies to refine the degradation behavior of polyester biomaterials, particularly to overcome the limitations of slow hydrolytic degradation, would broaden their utility. Herein, we examine the complexities of polyester degradation behavior, its assessment and strategies for refinement. The factors governing polyester degradation are strikingly complex. In addition to the half-life of the hydrolytically-labile bond, a series of interdependent material properties must be considered. Thus, methods used to characterize such material properties, both before and during degradation, must be carefully selected. Assessment of degradation behavior is further complicated by the variability of reported test protocols and the need for accelerated rather than real-time in vitro testing conditions. Ultimately, through better control of degradation behavior and correlation of in vitro, simulated degradation to that observed in vivo, the development of superior devices prepared with polyester biomaterials may be achieved.


The Immunology of Syncytialized Trophoblast.
Multinucleate syncytialized trophoblast is found in three forms in the human placenta. In the earliest stages of pregnancy, it is seen at the invasive leading edge of the implanting embryo and has been called primitive trophoblast. In later pregnancy, it is represented by the immense, multinucleated layer covering the surface of placental villi and by the trophoblast giant cells found deep within the uterine decidua and myometrium. These syncytia interact with local and/or systemic maternal immune effector cells in a fine balance that allows for invasion and persistence of allogeneic cells in a mother who must retain immunocompetence for 40 weeks of pregnancy. Maternal immune interactions with syncytialized trophoblast require tightly regulated mechanisms that may differ depending on the location of fetal cells and their invasiveness, the nature of the surrounding immune effector cells and the gestational age of the pregnancy. Some specifically reflect the unique mechanisms involved in trophoblast cell-cell fusion (aka syncytialization). Here we will review and summarize several of the mechanisms that support healthy maternal-fetal immune interactions specifically at syncytiotrophoblast interfaces.


Rates of human-macaque interactions affect grooming behavior among urban-dwelling rhesus macaques (Macaca mulatta).
The impact of anthropogenic environmental changes may impose strong pressures on the behavioral flexibility of free-ranging animals. Here, we examine whether rates of interactions with humans had both a direct and indirect influence on the duration and distribution of social grooming in commensal rhesus macaques (Macaca mulatta). Data were collected in two locations in the city of Shimla in northern India: an urban setting and a temple area. We divided these two locations in a series of similar-sized physical blocks (N = 48) with varying rates of human-macaque interactions. We conducted focal observations on three free-ranging rhesus macaque groups, one in the urban area and two in the temple area. Our analysis shows that macaques engaged in shorter grooming bouts and were more vigilant while grooming in focal sessions during which they interacted with people more frequently, suggesting that humans directly affected grooming effort and vigilance behavior. Furthermore, we found that in blocks characterized by higher rates of human-macaque interactions grooming bouts were shorter, more frequently interrupted by vigilance behavior, and were less frequently reciprocated. Our work shows that the rates of human-macaque interaction had both a direct and indirect impact on grooming behavior and that macaques flexibly modified their grooming interactions in relation to the rates of human-macaque interaction to which they were exposed. Because grooming has important social and hygienic functions in nonhuman primates, our work suggests that human presence can have important implications for animal health, social relationships and, ultimately, fitness. Our results point to the need of areas away from people even for highly adaptable species where they can engage in social interactions without human disruption.


Immunogenicity of a synthetic peptide corresponding to a portion of the heavy chain of H3N2 influenza virus haemagglutinin.
Rabbits were immunized with a synthetic octadecapeptide corresponding to the sequence ser-91 to leu-108 of the haemagglutinin heavy chain of H3N2 influenza A viruses. They developed antibodies reactive in solid-phase radioimmunoassay (SPRIA) with the peptide and with haemagglutinins of various H3N2 viruses but not of heterotypic H1N1 and H2N2 viruses. The antibodies were also non-reactive in the haemagglutination-inhibition or neutralization test. Influenza H3N2 virus replicated in the lungs of mice immunized with the peptide to the same extent as in the control mice. Of 27 human sera possessing anti-H3N2 activity or seven sera from rabbits immunized with either virions or haemagglutinins of various influenza A viruses, none was reactive with the peptide in SPRIA.


Physiological responses to acute temperature increase in European eels Anguilla anguilla infected with Anguillicola crassus.
The swimbladder parasite, Anguillicola crassus has infected, and spread rapidly, through European eel Anguilla anguilla (L.) populations over the past 20 to 25 yr. Our aim in the present studies was to elucidate whether the presence of A. crassus in these eels alters their rapid physiological responses to an acute temperature increase, compared to the response of uninfected fish. Both infected and uninfected fish showed significant increases in plasma cortisol after 2 h at a raised environmental temperature with increased plasma glucose after 6 h. However, infected eels exhibited a slight lag in glucose mobilisation, which may be due to the metabolic cost of harbouring a sanguiverous parasite. Both infected and uninfected fish showed a significant increase in haematocrit after 6 h of temperature elevation, but only uninfected fish exhibited a significant increase in haemoglobin at this point. However, there were no significant changes in mean erythrocyte haemoglobin concentration in either group. Our results suggest that acute temperature increase alone is unlikely to cause significant mortality of A. crassus-infected European eels; however, the effects of chronic increases in temperature in combination with other factors such as toxicants and hypoxia requires examination.


Suppressor T cell circuits in contact sensitivity. III. A monoclonal T cell hybrid-derived suppressor factor specifically suppresses local DTH transfer by a DNP-specific T cell clone.
Herein we described the direct suppressive effects of a monoclonal T cell hybridoma-derived, DNP-specific suppressor T cell factor (26.10.2 TsF) on the local transfer of delayed-type hypersensitivity (DTH) by a DNP-specific BALB/c T cell clone (dD1.9). The L3T4+, Lyt-2- dD1.9 T cell clone proliferated in response to DNP-OVA and DNBS, but not TNP-OVA or TNBS, in association with I-Ed determinants present on antigen-presenting cells. Similarly, local injection of histopaque-purified dD1.9 cell blasts resulted in DNP-specific, radioresistant, I-Ed-restricted, mononuclear cell-rich ear swelling responses. Incubation in 26.10.2 TsF specifically suppressed local transfer of DNP-specific DTH by dD1.9, but not local DTH responses transferred by BALB/c T cell clones specific for TNP or GAT. The suppressive effect of 26.10.2 TsF correlated with targeting on DNP-major histocompatibility complex determinants associated with the DTH T cell (TDH) targets. 26.10.2 TsF-mediated suppression was most pronounced after exposure of dD1.9 target cells to antigen (after the stimulation phase of the T cell clone maintenance procedure), and greatly reduced when dD1.9 was cultured for long periods in the absence of DNP (after the rest phase of clone maintenance). In additional support of this hypothesis, GAT-specific TDH, normally resistant to 26.10.2 TsF-mediated suppression, were rendered susceptible to suppression after surface DNPylation. The results demonstrate a direct, antigen-specific, effector phase regulatory effect of a monoclonal TsF on a cloned, antigen-specific T cell target, and strongly suggest that suppression is mediated via targeting on DNP determinants associated with the TDH target. Simplification of complex Ts circuitry operating in suppression of the efferent limb of DTH by the use of monoclonal TsF and cloned T cell targets should provide a basis for the future study of the molecular mechanisms of immune suppression.


Health Behavior Change Interventions for Teenage and Young Adult Cancer Survivors: A Systematic Review.
It is important that teenage and young adult (TYA) cancer survivors adopt a healthy lifestyle, since health vulnerabilities associated with their diagnosis and treatment may be exacerbated by poor health behaviors. This review aims to synthesize the current literature on health behavior change interventions created specifically for TYA-aged cancer survivors. MEDLINE, EMBASE, PsycINFO, and CINAHL databases were searched for studies investigating interventions targeting one or more health behaviors, including: physical activity, diet, smoking cessation, and alcohol consumption. Studies were eligible for review if the study population were defined as TYA cancer survivors and the mean age of the sample was younger than 30 years of age. Twelve studies were identified, of which nine were randomized controlled trials. Physical activity was the most commonly targeted health behavior. Six of the 12 interventions included within this review were successful in changing health behavior. Due to the heterogeneity of intervention characteristics, the relationship between intervention efficacy or outcome and intervention content, delivery mode, or theoretical framework was not discernible. Nevertheless, trends emerged relating to the delivery and content of health behavior interventions designed specifically for TYA cancer survivors. More research is required to identify the most effective means of promoting health behavior change among the TYA cancer survivor population. Specifically, future research should focus on providing evidence of the efficiency and feasibility of interventions that use online technologies to facilitate remote intervention delivery and peer support.


Rolling up a graphene sheet.
Carbon Nanotubes, CNTs, have been described as rolled-up graphene layers. Matching this concept to experiments has been a great experimental challenge for it requires a method to exfoliate graphite, generate ordered and stable dangling carbon bonds, and roll up the layer without affecting the unpaired electrons of the dangling bonds that finally have to zip up in an orderly fashion: A tall order for any synthetic strategy. The combined use of ultrasonication of graphite in dimethylformamide and addition of ferrocene aldehyde just does it!


Formation of [4Fe-4S] clusters in the mitochondrial iron-sulfur cluster assembly machinery.
The generation of [4Fe-4S] clusters in mitochondria critically depends, in both yeast and human cells, on two A-type ISC proteins (in mammals named ISCA1 and ISCA2), which perform a nonredundant functional role forming in vivo a heterocomplex. The molecular function of ISCA1 and ISCA2 proteins, i.e., how these proteins help in generating [4Fe-4S] clusters, is still unknown. In this work we have structurally characterized the Fe/S cluster binding properties of human ISCA2 and investigated in vitro whether and how a [4Fe-4S] cluster is assembled when human ISCA1 and ISCA2 interact with the physiological [2Fe-2S](2+) cluster-donor human GRX5. We found that (i) ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state, and (ii) two molecules of [2Fe-2S](2+) GRX5 donate their cluster to a heterodimeric ISCA1/ISCA2 complex. This complex acts as an "assembler" of [4Fe-4S] clusters; i.e., the two GRX5-donated [2Fe-2S](2+) clusters generate a [4Fe-4S](2+) cluster. The formation of the same [4Fe-4S](2+) cluster-bound heterodimeric species is also observed by having first one [2Fe-2S](2+) cluster transferred from GRX5 to each individual ISCA1 and ISCA2 proteins to form [2Fe-2S](2+) ISCA2 and [2Fe-2S](2+) ISCA1, and then mixing them together. These findings imply that such heterodimeric complex is the functional unit in mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling [4Fe-4S] clusters before their transfer to the final target apo proteins.


Imaging of acute ischemic stroke.
For decades, imaging has been a critical component of the diagnostic evaluation and management of patients suspected of acute ischemic stroke (AIS). With each new advance in the treatment of AIS, the role of imaging has expanded in scope, sophistication, and importance in selecting patients who stand to benefit from potential therapies. Although the field of stroke imaging has been evolving for many years, there have been several major recent changes. Most notably, in late 2017, the window for treatment expanded to 24 h from onset of stroke symptoms in selected patients. Furthermore, for those patients in expanded time windows, guidelines issued in early 2018 now recommend the use of "advanced" imaging techniques in the acute setting, including CT perfusion and MRI, to guide therapeutic decision-making. With these and other changes, the emergency radiologist must be prepared to handle a growing volume and complexity of AIS imaging. This article reviews the various imaging modalities and techniques employed in the imaging of AIS patients, with an emphasis on recommendations from recent randomized controlled trials and national consensus guidelines.


Effect of dihydroxyanthraquinone (DHAQ) and radiation on the survival of cultured Chinese hamster ovary cells.
Dihydroxyanthraquinone (DHAQ) is currently being tested as a cancer chemotherapeutic agent because of its structural similarity to Adriamycin (ADR) and other DNA-intercalating antibiotics. The interaction of DHAQ and ionizing radiation on the induction of cell lethality was investigated in Chinese hamster ovary cells in culture. In asynchronous populations of cells, DHAQ produced a slight enhancement of radiation-induced cell lethality as evidenced by changes in both shoulder and slope of the radiation dose-survival curves. However, DHAQ had no effect on either the extent or time course of recovery from sublethal radiation damage. In synchronous populations of cells treated at various times before or after selection in mitosis, the combination of DHAQ and radiation produced greater cell killing than that predicted based on simple additivity of effect, with a decided enhancement for cells treated during S phase. These results indicate that DHAQ is similar to other DNA-intercalating antibiotics in regard to the interaction with ionizing radiation to produce cell lethality.


Night terrors in adults: phenomenology and relationship to psychopathology.
Night terrors have been classically described in children. Night terrors occurring in adults have been linked to psychopathology. Recent descriptions of sleep panic attacks have raised questions about their relationship to night terrors. Evaluations from a medically affiliated sleep disorders program were reviewed to identify adult patients presenting with events consistent with night terrors. Eleven patients were identified, 10 of whom had polysomnographic evaluation, and their records were reviewed for information relevant to night terrors and psychiatric symptoms. Six of these patients were available for further assessment which included inquiry regarding sleep events, a Structured Clinical Interview (SCID) for psychiatric disorders, and the Millon Clinical Multiaxial Inventory II (MCMI-II) for personality-related measurements. In the original sample, night terror episodes featured confused behaviors, motor activity, and absent or fragmented recall. Polysomnography documented arousals from slow wave sleep in 9 of 10 patients. All of the original patients reported psychiatric symptoms. All 6 patients who received the subsequent structured evaluation met lifetime criteria for Axis I conditions (most commonly affective and substance use disorders) and had elevated scores on the personality scales of the MCMI-II. Night terrors were not limited to psychiatric episodes. Night terrors occur in adults that are similar to episodes described in children. While distinct from sleep panic attacks, night terrors appear to occur in adults with histories of psychopathology.


Weathering the Cytokine Storm in COVID-19: Therapeutic Implications.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged in Wuhan, Hubei-China, as responsible for the coronavirus disease 2019 (COVID-19) and then spread rapidly worldwide. While most individuals remain asymptomatic or develop only mild symptoms, approximately 5% develop severe forms of COVID-19 characterized by acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF) that usually require intensive-care support and often yield a poor prognosis. The pathophysiology of COVID-19 is far from being completely understood, and the lack of effective treatments leads to a sense of urgency to develop new therapeutic strategies based on pathophysiological assumptions. The exaggerated cytokine release in response to viral infection, a condition known as cytokine release syndrome (CRS) or cytokine storm, is emerging as the mechanism leading to ARDS and MOF in COVID-19, thus endorsing the hypothesis that properly timed anti-inflammatory therapeutic strategies could improve patients' clinical outcomes and prognosis. Key Messages: The objective of this article is to explore and comment on the potential role of the promising immunomodulatory therapies using pharmacological and nonpharmacological approaches to overcome the dysregulated proinflammatory response in COVID-19.


Prospective experimental treatment of colorectal cancer patients based on organoid drug responses.
Organoid technology has recently emerged as a powerful tool to assess drug sensitivity of individual patient tumors in vitro. Organoids may therefore represent a new avenue for precision medicine, as this circumvents many of the complexities associated with DNA- or transcriptional-profiling. The SENSOR trial was a single-arm, single-center, prospective intervention trial to evaluate the feasibility of patient-derived organoids to allocate patients for treatment with off-label or investigational agents. The primary endpoint was an objective response rate of ≥20%. Patients underwent a biopsy for culture before commencing their last round standard of care. Organoids were exposed to a panel of eight drugs and patients were treated after progression on standard-of-care treatment and when a clear signal of antitumor activity was identified in vitro. Sixty-one patients were included and we generated 31 organoids of 54 eligible patients. Twenty-five cultures were subjected to drug screening and 19 organoids exhibited substantial responses to one or more drugs. Three patients underwent treatment with vistusertib and three with capivasertib. Despite drug sensitivity of organoids, patients did not demonstrate objective clinical responses to the recommended treatment. Organoid technology had limited value as a tool for precision medicine in this patient population because a large fraction of patients could not undergo treatment or because the recommended treatment did not elicit an objective response. We identified several essential parameters, such as the culture success rate, clinical deterioration of patients during standard of care, and rational design of drug panels that need to be accounted for in organoid-guided clinical studies.


Repeatability of retrobulbar blood flow velocity measured using color Doppler imaging in the Indianapolis Glaucoma Progression Study.
Determine the repeatability of color Doppler imaging (CDI) measurements in patients with open-angle glaucoma (OAG). We performed a cross-sectional, observational study of OAG patients participating in the Indianapolis Glaucoma Progression Study. Retrobulbar blood flow velocities and Pourcelot's vascular resistance index (RI) measured with CDI were examined. Two baseline measurements were obtained 1 to 2 weeks apart at the same time of day for all participants. Peak systolic and end diastolic blood flow velocities (PSV/EDV) were measured in the ophthalmic (OA), central retinal (CRA), and nasal and temporal short posterior ciliary arteries (N/TPCA) and RI was calculated. Intraclass correlation coefficient (ICC) between the 2 baselines was calculated. One hundred and sixteen patients with OAG [mean age 65.9 y (SD 10.9 y), 60% female] were examined in both baseline visits. In the OA, the intraobserver ICC for the PSV, EDV, and RI were all above 0.82. In the CRA, the intraobserver ICC for the PSV and RI were both above 0.8, whereas the EDV was 0.64. The intraobserver ICC in the N/TPCA for the PSV, EDV, and RI ranged from 0.71 to 0.88. The interobserver ICC was similar to the intraobserver ICC for the OA and the CRA but was lower than 0.7 in the EDV and RI of the T/NPCA. Blood flow velocities and calculated vascular resistance of the OA, CRA, and PCAs conducted within 2 weeks in patients with OAG are repeatable. Intraobserver CDI measurements were found more reproducible than interobserver CDI analysis.


Alternative Methods of Vaccine Delivery: An Overview of Edible and Intradermal Vaccines.
Vaccines are recognized worldwide as one of the most important tools for combating infectious diseases. Despite the tremendous value conferred by currently available vaccines toward public health, the implementation of additional vaccine platforms is also of key importance. In fact, currently available vaccines possess shortcomings, such as inefficient triggering of a cell-mediated immune response and the lack of protective mucosal immunity. In this regard, recent work has been focused on vaccine delivery systems, as an alternative to injectable vaccines, to increase antigen stability and improve overall immunogenicity. In particular, novel strategies based on edible or intradermal vaccine formulations have been demonstrated to trigger both a systemic and mucosal immune response. These novel vaccination delivery systems offer several advantages over the injectable preparations including self-administration, reduced cost, stability, and elimination of a cold chain. In this review, the latest findings and accomplishments regarding edible and intradermal vaccines are described in the context of the system used for immunogen expression, their molecular features and capacity to induce a protective systemic and mucosal response.


[Antiviral antibodies in acute laryngotracheobronchitis].
Antibodies to influenza A2, influenza B, parainfluenza 2 and 3, adenovirus and respiratory syncytial viruses were determined in thirty nine children with acute laryngotracheobronchitis; nine cases were not included in the analysis because of the presence of anticomplementary sera; 40% of cases were positive, 20% to influenza A2, 10% to influenza B (one case of double infection with influenza B and parainfluenza 2 viruses), 6.7% to respiratory syncytial virus and 3.3% to parainfluenza 2. Results are compared with previous studies done in Mexico.


Effects of glyphosate spray-drift on plant flowering.
Recent studies have shown that sub-lethal doses of herbicides may affect plant flowering, however, no study has established a direct relationship between the concentrations of deposited herbicide and plant flowering. Here the aim was to investigate the relationship between herbicide spray drift deposited on non-target plants and plant flowering in a realistic agro-ecosystem setting. The concentrations of the herbicide glyphosate deposited on plants were estimated by measuring the concentration of a dye tracer applied together with the herbicide. The estimated maximal and average deposition of glyphosate within the experimental area corresponded to 30 g glyphosate/ha (2.08% of the label rate of 1440 g a.i./ha) and 2.4 g glyphosate/ha (0.15% label rate), respectively, and the concentrations decreased rapidly with increasing distance from the spraying track. However, there were not a unique relation between distance and deposition, which indicate that heterogeneities of turbulence, wind speed and/or direction can strongly influence the deposition from 1 min to another during spraying. The effects of glyphosate on cumulative flower numbers and flowering time were modelled using Gompertz growth models on four non-target species. Glyphosate had a significantly negative effect on the cumulative number of flowers on Trifolium pratense and Lotus corniculatus, whereas there were no significant effects on Trifolium repens, and a positive, but non-significant, effect on number of flowers on Cichorium intybus. Glyphosate did not affect the flowering time of any of the four species significantly. Lack of floral resources is known to be of major importance for pollinator declines. The implications of the presented results for pesticide risk assessment are discussed.


Metabolomics of forage plants: a review.
Forage plant breeding is under increasing pressure to deliver new cultivars with improved yield, quality and persistence to the pastoral industry. New innovations in DNA sequencing technologies mean that quantitative trait loci analysis and marker-assisted selection approaches are becoming faster and cheaper, and are increasingly used in the breeding process with the aim to speed it up and improve its precision. High-throughput phenotyping is currently a major bottle neck and emerging technologies such as metabolomics are being developed to bridge the gap between genotype and phenotype; metabolomics studies on forages are reviewed in this article. Major challenges for pasture production arise from the reduced availability of resources, mainly water, nitrogen and phosphorus, and metabolomics studies on metabolic responses to these abiotic stresses in Lolium perenne and Lotus species will be discussed here. Many forage plants can be associated with symbiotic microorganisms such as legumes with nitrogen fixing rhizobia, grasses and legumes with phosphorus-solubilizing arbuscular mycorrhizal fungi, and cool temperate grasses with fungal anti-herbivorous alkaloid-producing Neotyphodium endophytes and metabolomics studies have shown that these associations can significantly affect the metabolic composition of forage plants. The combination of genetics and metabolomics, also known as genetical metabolomics can be a powerful tool to identify genetic regions related to specific metabolites or metabolic profiles, but this approach has not been widely adopted for forages yet, and we argue here that more studies are needed to improve our chances of success in forage breeding. Metabolomics combined with other '-omics' technologies and genome sequencing can be invaluable tools for large-scale geno- and phenotyping of breeding populations, although the implementation of these approaches in forage breeding programmes still lags behind. The majority of studies using metabolomics approaches have been performed with model species or cereals and findings from these studies are not easily translated to forage species. To be most effective these approaches should be accompanied by whole-plant physiology and proof of concept (modelling) studies. Wider considerations of possible consequences of novel traits on the fitness of new cultivars and symbiotic associations need also to be taken into account.


Failure to transmit diethylnitrosamine tumorigenicity from transplacentally exposed F1 generation Syrian hamsters to the respiratory tract of F2 and F3 generations.
A multigeneration study with four successive generations of Syrian hamsters was conducted to determine whether a single s.c. injection of different doses of diethylnitrosamine (DEN) (1.25, 2.5, 5, 10, and 20 mg/kg body weight) on day 15 of pregnancy induces respiratory tract tumors not only in the treated P generation mothers and their F1 progeny but also in F2 and F3 generations. In this study, the P generation mothers only were given a single injection of DEN during the period of gestation. Fifty-six % of the 36 DEN-treated mothers and 52% of their F1 generation offspring (total, 233 animals) developed neoplasms in the respiratory tract. A single respiratory tract tumor was found in one DEN-unexposed F1 generation control hamster as well as in one F2 generation animal (total, 209 animals) descended from DEN-exposed P generation. Both tumors were considered to have arisen spontaneously. No respiratory tract tumors were observed in the F3 generation (total, 160 animals) descended from a DEN-exposed P generation. Thus our results indicate that the vertical transmission of the tumorigenic effect of DEN in Syrian hamsters is limited to one generation and does not persist in the F2 and F3 generations.


A bioelectronic sensor based on canine olfactory nanovesicle-carbon nanotube hybrid structures for the fast assessment of food quality.
We developed an olfactory-nanovesicle-fused carbon-nanotube-transistor biosensor (OCB) that mimics the responses of a canine nose for the sensitive and selective detection of hexanal, an indicator of the oxidation of food. OCBs allowed us to detect hexanal down to 1 fM concentration in real-time. Significantly, we demonstrated the detection of hexanal with an excellent selectivity capable of discriminating hexanal from analogous compounds such as pentanal, heptanal, and octanal. Furthermore, we successfully detected hexanal in spoiled milk without any pretreatment processes. Considering these results, our sensor platform should offer a new method for the assessment of food quality and contribute to the development of portable sensing devices.


Systematic review of stigma reducing interventions for African/Black diasporic women.
Literature indicates that racism, sexism, homophobia and HIV-related stigma have adverse impacts on health, well-being, and quality of life among HIV-positive women of African descent (African/Black diaspora). However, limited evidence exists on the effectiveness of interventions aimed at reducing stigma tailored for these women. This study systematically reviewed randomized controlled trials (RCTs), non-randomized observational and quasi-experimental studies evaluating the effectiveness of interventions aimed at reducing stigma experienced by this population. The Cochrane methodology was used to develop a search strategy in consultation with a librarian scientist. Databases searched included the Cochrane Library, Ovid EMBASE, PsycInfo, and 10 others. Two reviewers independently assessed the studies for potential relevance and conducted the Cochrane grading of RCTs to assess risk of bias and the Newcastle-Ottawa scale to assess the quality of non-randomized studies. Eligible papers were selected if they employed an intervention design with African/Black diasporic women living with HIV as the target population and had a primary outcome of stigma reduction. Of the five studies that met all of the eligibility criteria, four demonstrated the effectiveness of interventions in reducing HIV-related stigma. Only two of the five studies were designed specifically for HIV-positive African/Black diasporic women. Limitations included the absence of interventions addressing other forms of stigma and discrimination (e.g. gender discrimination, racism, heterosexism). Our findings suggest that there are limited interventions designed to address multiple forms of stigma, including gender and racial discrimination, experienced by HIV-positive African/Black diasporic women.


Poststroke Montreal Cognitive Assessment and Recurrent Stroke in Patients With Symptomatic Intracranial Atherosclerosis.
Cognitive impairment occurs in 20%-40% of stroke patients and is a predictor of long-term morbidity and mortality. In this study, we aim to determine the association between poststroke cognitive impairment and stroke recurrence risk, in patients with anterior versus posterior circulation intracranial stenosis. This is a post-hoc analysis of the Stenting and Aggressive Medical Therapy for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial. The primary predictor was poststroke cognitive function measured by Montreal Cognitive Assessment (MOCA) at 3-6 months and the primary outcome was recurrent ischemic stroke. We used univariate and multivariable cox-regression models to determine the associations between MOCA at 3-6 months and recurrent stroke. Of the 451 patients enrolled in SAMMPRIS, 393 patients met the inclusion criteria. The mean age of the sample (in years) was 59.5 ± 11.3, 62.6% (246 of 393) were men. Fifty patients (12.7%) had recurrent ischemic stroke during a mean follow up of 2.7 years. The 3-6 month MOCA score was performed on 351 patients. In prespecified multivariable models, there was an association between 3 and 6 month MOCA and recurrent stroke (hazard ratio [HR] per point increase .93 95% confidence interval [CI] .88-.99, P = .040). This effect was present in anterior circulation stenosis (adjusted HR per point increase .92 95% CI .85-0.99, P = .022) but not in posterior circulation artery stenosis (adjusted HR per point increase 1.00 95% .86-1.16, P = .983). Overall, we found weak associations and trends between MoCA at 3-6 months and stroke recurrence but more notable and stronger associations in certain subgroups. Since our study is underpowered, larger studies are needed to validate our findings and determine the mechanism(s) behind this association.


A one-year prospective investigation of Type D personality and self-reported physical health.
Objective: Type D personality is characterised by negative affectivity (NA) and social inhibition (SI), and is often associated with poorer physical and psychological health. However, the underlying mechanisms are unclear and the literature lacks longitudinal assessment. Therefore, the aim was to prospectively examine the relationships between Type D and physical symptoms, in addition to aspects of retrospective health. Design: An online questionnaire-based study (N = 535) with a one-year follow-up (N = 160) was conducted with healthy individuals (18-65 years). Type D was assessed as both a categorical and dimensional construct. Main outcome measures: Participants completed the Type D scale-14 (DS14), Hospital Anxiety and Depression Scale (HADS), Cohen-Hoberman Inventory of Physical Symptoms (CHIPS) and Perceived Stress Scale (PSS) at both phases. Retrospective health questions and the Social Readjustment Rating Scale (SRRS) were also completed at follow-up. Results: Type D was independently related to cardiac/sympathetic, metabolic, vasovagal, muscular and headache symptoms at baseline. At follow-up stressful events and anxiety mediated the relationships between Type D and particular symptoms. Type Ds were more likely to report poorer health, increased minor illnesses, work absences, and medical information seeking. Conclusions: Type D is associated with symptoms often linked to stress. Although the relationships appear to be primarily driven by NA, these findings support the theory of a stress-related mechanism potentially underpinning the Type D-health relationship. These findings contribute to the literature continuing to highlight Type D personality as a risk factor for negative health outcomes.


Experience and Utility of Using the Participatory Research Method, Photovoice, in Individuals With Spinal Cord Injury.
Background: There is a need to engage persons with spinal cord injuries/disorders (SCI/D) in research methodologies beyond traditional approaches. This provides an opportunity for individuals to convey their perspectives in a variety of ways. Photovoice empowers people to share their perspectives through photographs and narrative; this is well-suited for individuals who are less comfortable speaking up when other methods are used, such as focus groups. Objective: To examine photovoice methodology in US Veterans with SCI/D to describe their experiences with and the utility of photovoice. We also provide a sample of content (qualitative data) to illustrate how individuals with SCI/D conceptualized function and factors important to them. Methods: Photovoice, a qualitative participatory research method, was used to collect photographs from Veterans with SCI/D, which was followed by personal narratives describing the meaning of their photos. Results: Participants (N = 9) were 64 years old, on average, and 75% had paraplegia. Participants discussed the challenges with taking photographs, but they enjoyed participating, appreciated inclusion, and hoped the information they provided would help others with disabilities. Conclusion: These findings suggest that despite challenges and ethical barriers, individuals with SCI/D are interested in, highly capable of, and should be given the opportunity to be included in studies like this that empower participants to share their views using novel ways of expression. These findings demonstrate the desirability, feasibility, and utility of using photovoice in individuals with SCI/D. This method may be used to understand factors impacting health and well-being and can be made available to individuals with SCI/D to minimize inequalities in research opportunities.


Engine Calibration With Surrogate-Assisted Bilevel Evolutionary Algorithm.
Engine calibration problems are black-box optimization problems which are evaluation costly and most of them are constrained in the objective space. In these problems, decision variables may have different impacts on objectives and constraints, which could be detected by sensitivity analysis. Most existing surrogate-assisted evolutionary algorithms do not analyze variable sensitivity, thus, useless effort may be made on some less sensitive variables. This article proposes a surrogate-assisted bilevel evolutionary algorithm to solve a real-world engine calibration problem. Principal component analysis is performed to investigate the impact of variables on constraints and to divide decision variables into lower-level and upper-level variables. The lower-level aims at optimizing lower-level variables to make candidate solutions feasible, and the upper-level focuses on adjusting upper-level variables to optimize the objective. In addition, an ordinal-regression-based surrogate is adapted to estimate the ordinal landscape of solution feasibility. Computational studies on a gasoline engine model demonstrate that our algorithm is efficient in constraint handling and also achieves a smaller fuel consumption value than other state-of-the-art calibration methods.


Molecular epidemiology of Usher syndrome in Italy.
Usher syndrome is an autosomal recessive disorder characterized by hearing and vision loss. Usher syndrome is divided into three clinical subclasses (type 1, type 2, and type 3), which differ in terms of the severity and progression of hearing loss and the presence or absence of vestibular symptoms. Usher syndrome is defined by significant genetic heterogeneity, with at least 12 distinct loci described and 9 genes identified. This study aims to provide a molecular epidemiology report of Usher syndrome in Italy. Molecular data have been obtained on 75 unrelated Italian patients using the most up-to date technology available for the screening of Usher syndrome gene mutations, i.e., the genotyping microarray developed by Asper Biotech (Tartu, Estonia), which simultaneously investigates 612 different marker positions using the well established arrayed primer extension methodology (APEX). Using this method, we found that 12% of cases (9 out of 75) harbored homozygous or compound heterozygous mutations in the gene positions analyzed, whereas 20% (15 out of 75) of the patients were characterized by the presence of only one mutated allele based on the positions analyzed. One patient was found to be compound heterozygous for mutations in two different genes and this represents an example of possible digenic inheritance in Usher syndrome. A total of 66.6% of cases (50 out of 75) were found to be completely negative for the presence of Usher syndrome gene mutations in the detected positions. Mutations detected by the array were confirmed by direct sequencing. These findings highlight the efficacy of the APEX-based genotyping approach in the molecular assessment of Usher patients, suggesting the presence of alleles not yet identified and/or the involvement of additional putative genes that may account for the pathogenesis of Usher syndrome.


Early Identification and Management of Cervical Impairments in Pediatric Patients With Concussion May Reduce Risk of Delayed Recovery.
Previous research, including high-quality systematic reviews, has found that cervical injury, which often accompanies concussive head injury, can delay recovery from concussion. One pilot randomized controlled trial found that focused cervical assessment and appropriate intervention in children and young adults with persisting postconcussive symptoms (PPCS) improved recovery outcomes. Our sports medicine clinics adopted this approach early (within 2 weeks) in children (aged 10-18 years) after concussion. This study describes our clinical management protocol and compares the recovery trajectories in children after concussion with and without a concomitant cervical injury. Prospective cohort study. Three university-affiliated outpatient sports medicine clinics from September 2016 to December 2019. One-hundred thirty-four concussed children with cervical impairment (mean age 14.9 years, 65% male, and 6.2 days since concussion) were compared with 130 concussed children without cervical impairment (mean age 14.9 years, 57% male, and 6.0 days since concussion). Examination findings related to the cervical spine (range of motion, cervical spasm, and cervical tenderness). Recovery time (measured in days), concussion symptom burden (Postconcussion Symptom Scale), and incidence of PPCS. Children with cervical impairment reported a higher initial symptom burden; however, there were no differences in recovery time (33.65 [28.20-39.09] days vs 35.98 [27.50-44.45] days, P = 0.651) or incidence of PPCS (40.0% vs 34.3%, P = 0.340). We conclude that within this pediatric population, early identification and management of cervical injuries concomitant with concussion may reduce the risk of delayed recovery.


Implementation of the WHO hand hygiene strategy in Faranah regional hospital, Guinea.
Healthcare-associated infections are the most frequent adverse events in healthcare worldwide, with limited available evidence suggesting highest burden in resource-limited settings. Recent Ebola epidemics emphasize the disastrous impact that spread of infectious agents within healthcare facilities can have, accentuating the need for improvement of infection control practices. Hand hygiene (HH) measures are considered to be the most effective tool to prevent healthcare-associated infections. However, HH knowledge and compliance are low, especially in vulnerable settings such as Guinea. The aim of PASQUALE (Partnership to Improve Patient Safety and Quality of Care) was to assess knowledge and compliance with HH and improve HH by incorporating the WHO HH Strategy within the Faranah Regional Hospital (FRH), Guinea. In a participatory approach, a team of FRH staff and leadership was invited to identify priorities of the hospital prior to the start of PASQUALE. The local hygiene committee was empowered to increase its activities and take ownership of the HH improvement strategy. A baseline assessment of knowledge, perception and compliance was performed months before the intervention. The main intervention consisted of local alcohol-based-hand-rub (ABHR) production, with final product efficacy testing, in conjunction with a training adapted to the needs identified in the baseline assessment. A follow-up assessment was conducted directly after the training. Effectiveness of the intervention was assessed via uncontrolled before-and-after comparison. Baseline knowledge score (13.0/25) showed a significant increase to 19.0/25 in follow-up. Baseline-Compliance was 23.7% and increased significantly to 71.5% in follow-up. Compliance rose significantly across all professional groups except for midwifes and in all indications for HH, with the largest in the indication "Before aseptic tasks". The increase in compliance was associated with the intervention and remained significant after adjusting for confounders. The local pharmacy successfully supplies the entire hospital. The local supply resulted in a ten-fold increase of monthly hospital disinfectant consumption. The WHO HH strategy is an adaptable and effective method to improve HH knowledge and compliance in a resource-limited setting. Local production is a feasible method for providing self-sufficient supply of ABHR to regional hospitals like the FRH. Participatory approaches like hygiene committee ownership builds confidence of sustainability.


Postcombat violent behavior in psychiatrically maladjusting soldiers.
Thirty-one psychiatrically maladjusting combat veterans, referred for psychiatric evaluation either for administrative reasons or because of specific psychiatric symptoms, were interviewed while still on active duty two months to 1 1/2 years after returning from Vietnam. Thirteen of the 31 reported at least one act of violence against another person since returning from combat. The soldiers with postcombat violence more frequently than the nonviolent had a history of fighting in childhood or adolescence, of volunteering for Vietnam, of reporting thay they had killed four or more persons, and of reenlisting for additional tours of duty in Vietnam. Maladjusting soldiers who are violent following combat may as a group be more violence-prone both before and during combat than soldiers who are not, but definitive studies are lacking.


Coating particles with carbocyanine dyes.
Imaging and reconstruction of developing neurons require cells that are labeled in a way that distinguishes them from their neighbors. This can be achieved with ballistic labeling, which refers to the delivery of a cell label by means of carrier particles (tungsten or gold) propelled from a pressurized gun. Ballistic delivery can reach many dispersed cells in one shot and can deploy a wide variety of cell markers to neurons in diverse preparations. The three most commonly used types of ballistic labels are carbocyanine dyes, dextran-conjugated fluorescent markers, and DNA plasmids. The primary advantage of ballistic labeling is that multiple dispersed cells can be labeled quickly in live or fixed tissue. This article describes a protocol for coating tungsten particles (∼1 µm in diameter) with carbocyanine dyes, which are widely used to label neurons in tissue and neural cells in suspension. These dyes are lipophilic and highly fluorescent within lipid bilayers. Because tissue damage worsens with the increasing pressure required for deeper bullet penetration, ballistic labeling of neurons is most effective when the target cells are near the surface of the preparation. This protocol was developed for labeling ganglion cells in retinal flat mounts.


The relationships between fatigue, quality of life, and family impact among children with special health care needs.
To examine the relationships among pediatric fatigue, health-related quality of life (HRQOL), and family impact among children with special health care needs (CSHCNs), specifically whether HRQOL mediates the influence of fatigue on family impact. 266 caregivers of CSHCNs were studied. The Pediatric Quality of Life Inventory Multidimensional Fatigue Scale, Pediatric Quality of Life Inventory Generic Scale, and Impact on Family Scale were used to measure fatigue, HRQOL, and family impact, respectively. Linear regressions were used to analyze the designated relationships; path analyses were performed to quantify the mediating effects of HRQOL on fatigue-family impact relationship. Although greater fatigue was associated with family impact (p < .05), the association was not significant after accounting for HRQOL. Path analyses indicated the direct effect of fatigue on family impact was not significant (p > .05), whereas physical and emotional functioning significantly mediated the fatigue-family impact relationship (p < .001). Fatigue is related to family impact among CSHCNs, acting through the impairment in HRQOL.


[Cane for the blind with a device for detecting and recognizing pedestrian obstacles].
The paper deals with the development of methods and a device for the blind to walk by orientating himself through remotely contacting study of what has happened and is happening on the road. An optoelectron method for detection of vertical obstacles and ground gaps has been proposed. The authors have drawn up the structural and functional diagrams of a device which is combined with a walking-stick and which makes it possible to detect 3 types of pedestrian obstacles with appropriate sound signalling.


Wavelet-Based Muscle Artefact Noise Reduction for Short Latency rTMS Evoked Potentials.
This paper presents a new method of reducing the noise in the EEG response signal recorded during repetitive transcranial magnetic stimulation (rTMS). This noise is principally composed of the residual stimulus artefact and millivolt amplitude compound muscle action potentials (CMAP) recorded from the scalp muscles and precludes analysis of the cortical evoked potentials, especially during the first 20-ms post stimulus. The proposed method uses the wavelet transform with a fourth-order Daubechies mother wavelet and a novel coefficient reduction algorithm based on cortical amplitude thresholds. Four other mother wavelets as well as digital filtering have been tested, and the Coiflets 2 and 3 also found to be effective with Coiflet 3 results marginally better than Daubechies 4. The approach has been tested using data recorded from 16 normal subjects during a study of cortical sensitivity to rTMS at different cortical locations using stimulation amplitudes, frequencies, and sites typically used in clinical practice to treat major depressive disorder.


Older carers in ageing societies:an evaluation of a respite care program for older carers in Western Australia.
The Australian Red Cross Older Carers Program was developed in 2003 to support the unique needs of "older carers" aged 65 and older (50 if Indigenous) who care for a person (a care recipient, usually a family member) aged 18 or older who have a permanent disability. The aim of the program was to provide intensive case planning, management, and volunteer support that would assist older carers to more readily access respite and continue their caring role in the home. To help achieve this end, ongoing individualised and holistic assistance involving older carers in decision making was an integral component of the Older Carers Program, as was the use of regular home visits by program staff. The Older Carers Program evaluation was both a process and outcome evaluation. Much of the evaluation research focused on the extent to which it had met its stated aims and objectives. However, because the program was quite new and innovative there was a significant further focus upon the processes and activities within the program. At the time the evaluation research was conducted (May 2005), the program had been in operation for 22 months. The population group was identified as those persons (older carers) who had been part of the program between July 2003 and March 2005. Of the 96 older carers who had accessed the program in the specified period, 62 agreed to participate in our research. The methodology consisted of an audit or the program database, in-depth interviews with older carers, and contextual data collection involving program staff and other stakeholders.


Learning effect of Humphrey Matrix perimetry.
Humphrey Matrix perimetry is a recent development in automated perimetry that uses frequency-doubling technology (FDT). We evaluated the learning effect of Humphrey Matrix perimetry with a full-threshold 30-2 strategy. Twenty-four patients with primary open-angle glaucoma and early visual field defects as assessed by standard automated perimetry and 24 healthy control subjects participated. All subjects had no prior experience with FDT visual field tests. Humphrey Matrix perimetry using a full-threshold 30-2 strategy was performed 3 times within 1 month. Various visual field indices were compared across multiple tests. Mean deviation (MD) showed a larger defect at the first test than at the second and third tests (p < 0.001), and the mean total improvement of the MD was 2.80 decibels (dB) in the glaucoma group and 1.71 dB in the control group. Pattern standard deviations (PSDs) were decreased as the tests were repeated, but test duration, fixation losses, and false-positive or false-negative rate were not changed significantly. Additionally, the Glaucoma Hemifield Test (GHT) showed unstable results. In patients naive to the FDT test, Humphrey Matrix perimetry showed a large learning effect on MD and PSD among the various visual field indices. The GHT results of Humphrey Matrix perimetry showed a large instability.


[Comorbidity in gout and hyperuricemia: prevalence, causes, prospects of urate lowering therapy].
Nowadays, there is increased interest in the connection of gout and asymptomatic hyperuricemia with comorbid conditions such as diabetes mellitus, cardiovascular diseases, hypertension, chronic kidney disease and other. Studies conducted over the past few decades suggest that not only gout, but also asymptomatic hyperuricemia can significantly worsen the prognosis in patients with cardiovascular diseases, as the deposition of urate crystals can be both an immediate cause and a factor in the progression of renal failure. In that way, the timely appointment of urate - lowering therapy and achieving the target serum uric acid level can not only affect joint damage, but also can significantly slow the progression of life - threatening comorbid conditions.


L stent for stomal stenosis in catheterizable channels.
Stomal stenosis in patients with catheterizable channels can be a difficult problem that is managed by surgical revision or dilation. The L stent is a short, knotted catheter that lies flush with skin. The stent is used for any stomal narrowing, typically overnight for several days. The stent bridges the area of stenosis without passing into bowel or bladder lumen. We assessed whether the L stent is effective for preventing and managing stomal stenosis. We retrospectively reviewed the records of patients with catheterizable channels. A telephone survey and chart review were done to identify patients who required an L stent and those with stomal stenosis. Patient satisfaction was evaluated with Likert scale questions. We identified 50 patients with a total of 66 catheterizable urinary and enteric channels. Eight patients with a total of 11 (17%) affected stomas had stomal stenosis. Seven of 8 patients used the L stent for management and 100% reported improvement in stenosis. Six of 7 patients used the stent or catheterization with topical betamethasone cream. Four of 7 patients used the L stent greater than 6 months postoperatively and 3 reported that stenosis occurred immediately postoperatively. All patients who used the L stent reported intermittent self-directed stent use as a prophylactic measure to prevent recurrence. Conservative management for stomal stenosis with an L stent is a simple, effective and well tolerated technique. This patient centered management significantly decreases the risk of surgical revision.


Response to pegylated interferon plus ribavirin in HIV-infected patients with chronic hepatitis C due to genotype 4.
Hepatitis C virus (HCV) genotypes 1 and 4 respond less well to pegylated interferon (pegIFN) plus ribavirin (RBV) therapy. For this reason most studies merge these two genotypes when assessing virological response. However, in most trials the HCV genotype 4 population is rather small, and conclusions are mainly derived from what occurs in HCV-1 patients. All HCV-4 patients coinfected with HIV who received pegIFN plus RBV in two different multicentre studies, PRESCO and ROMANCE, conducted respectively in Spain and Italy, were retrospectively analyzed. Baseline plasma HCV-RNA, proportion of patients with HCV-RNA <10 IU / mL at week 4 (rapid virological response), and HCV-RNA declines >2 logs at week 12 (early virological response, EVR) were all assessed as predictors of sustained virological response (SVR). Overall, 75 patients (60 men) were evaluated. Median age was 40 years and median CD4 count 598 cells / mm(3); 49% had plasma HIV-RNA <50 copies / mL; 71% had elevated liver enzymes and 31% had advanced liver fibrosis (Metavir F3-F4). Median serum HCV-RNA was 5.7 log IU / mL. Rapid virological response was attained by 10 (20%) patients and EVR by 26 (42%). Using intention-to-treat and on-treatment (OT) analyses, SVR was achieved by 21 / 75 (28%) and 21 / 62 (34%) of HCV-4 patients, respectively. In the multivariate analysis (OT), baseline HCV-RNA (OR 0.09 for every log increment; 95% CI: 0.01-0.7) and EVR (OR: 7.08; 95% CI: 1.8-27.2) were significantly and independently associated with SVR. This is the largest series of HIV-infected patients with chronic hepatitis C due to HCV-4 treated with pegIFN plus RBV examined so far and the results show that HCV-4 behaves similarly to HCV-1. Therefore, these patients should be considered as difficult to treat population. Baseline serum HCV-RNA and EVR are the best predictors of SVR in HCV-4 / HIV-coinfected patients.


Proteomic discovery of 21 proteins expressed in human plasma-derived but not platelet-derived microparticles.
Microparticles (MPs) are small membrane vesicles generated by essentially all cell types. In the plasma, most MPs are derived from platelets, but those from other sources, particularly leukocytes (macrophages, lymphocytes, and neutrophils), endothelial cells, and even smooth muscle cells can be detected and appear to play an important role in normal physiology and various diseases. In previous work we analyzed the proteome of MPs generated from isolated platelets (platelet MPs). Here, we report on a comparative analysis of microparticles isolated from plasma (plasma MPs) versus platelet MP using two complementary methods of comparative analysis. The first method, spectral count analysis, yielded 21 proteins detected in plasma MPs (with a total spectral count of 10 or greater) that were essentially absent in platelet MPs (with a total spectral count of 1 or 0). An additional two proteins (von Willebrand Factor, albumin) were present in both types of MPs but enriched in the plasma MPs. The second method, isotope-coded affinity tag (ICAT) labeling of proteins, supported the spectral count results for the more abundant proteins and provided better relative quantitation of differentially expressed proteins. Proteins present only in the plasma MPs include several associated with apoptosis (CD5-like antigen, galectin 3 binding protein, several complement components), iron transport (transferrin, transferrin receptor, haptoglobin), immune response (complement components, immunoglobulin J and kappa chains), and the coagulation process (protein S, coagulation factor VIII).


Multispectral optoacoustic tomography of matrix metalloproteinase activity in vulnerable human carotid plaques.
Elevated expression of cathepsins, integrins and matrix metalloproteinases (MMPs) is typically associated with atherosclerotic plaque instability. While fluorescent tagging of such molecules has been amply demonstrated, no imaging method was so far shown capable of resolving these inflammation-associated tags with high fidelity and resolution beyond microscopic depths. This study is aimed at demonstrating a new method with high potential for noninvasive clinical cardiovascular diagnostics of vulnerable plaques using high-resolution deep-tissue multispectral optoacoustic tomography (MSOT) technology. MMP-sensitive activatable fluorescent probe (MMPSense™ 680) was applied to human carotid plaques from symptomatic patients. Atherosclerotic activity was detected by tuning MSOT wavelengths to activation-dependent absorption changes of the molecules, structurally modified in the presence of enzymes. MSOT analysis simultaneously provided morphology along with heterogeneous MMP activity with better than 200 micron resolution throughout the intact plaque tissue. The results corresponded well with epi-fluorescence images made from thin cryosections. Elevated MMP activity was further confirmed by in situ zymography, accompanied by increased macrophage influx. We demonstrated, for the first time to our knowledge, the ability of MSOT to provide volumetric images of activatable molecular probe distribution deep within optically diffuse tissues. High-resolution mapping of MMP activity was achieved deep in the vulnerable plaque of intact human carotid specimens. This performance directly relates to pre-clinical screening applications in animal models and to clinical decision potential as it might eventually allow for highly specific visualization and staging of plaque vulnerability thus impacting therapeutic clinical decision making.


Medicaid reforms in Oregon and suboptimal utilization of dental care by women of childbearing age.
The authors conducted a study of dental services used by women of childbearing age who were enrolled in Medicaid in Oregon during the early 2000s, a period of reform during which health care coverage was expanded. They compared claims for pregnant women, women who were not pregnant and had children and women who were not pregnant and did not have children. They also compared differences in claims between those for women enrolled in managed care and those for women enrolled in fee-for-service plans. The authors computed the proportion of women for whom a dental claim was submitted in six-month spans for 2000, 2001, 2002 (before reform) and 2005 (after reform). Before and after reforms, the mean utilization rate for pregnant women, adjusted for the proportion of the period covered, decreased from 0.36 (standard deviation [SD] = 0.025) to 0.22 (SD = 0.028). Among women who were not pregnant and had children, the average adjusted rates decreased from 0.49 (SD = 0.201) to 0.21 (SD = 0.078). The pattern was similar among women who had no dependent children: rates decreased from 0.50 (SD = 0.028) to 0.19 (SD = 0.078). Most of the claims were for diagnostic services. The authors found no differences between women enrolled in managed care and those enrolled in fee-for-service plans. Contrary to their intention, health care reforms in Oregon were detrimental to the vulnerable populations that Medicaid is intended to serve. Dental care is important for maternal and child health. However, utilization is unlikely to improve without changes in Medicaid and the dental care delivery system.


Top predators in the Southern ocean: a major leak in the biological carbon pump.
Primary productivity in the Southern Ocean is approximately 3.5 gigatons of carbon per year, which accounts for nearly 15 percent of the global total. The presence of high concentrations of nitrate in Antarctic waters suggests that it might be possible to increase primary production significantly and thereby alleviate the net accumulation of atmospheric carbon dioxide. An analysis of the food web for these waters implies that the Southern Ocean may be remarkably inefficient as a carbon sink. This inefficiency is caused by the large flux of carbon respired to the atmosphere by air-breathing birds and mammals, dominant predators in the unusually simple food web of Antarctic waters. These top predators may transfer into the atmosphere as much as 20 to 25 percent of photosynthetically fixed carbon.


Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis.
The HLA-B27/β2 -microglobulin (β2 m)-transgenic (Tg) rat is a leading model of B27-associated spondyloarthritis (SpA), and the disease is dependent on the presence of intestinal bacteria. Previous studies have shown that adult HLA-B27/β2 m-Tg rats have an altered intestinal microbiota. This study sought to better define the age-dependent changes to both mucosal immune function and dysbiosis in this rat model of SpA. Intestinal contents were collected from wild-type and HLA-B27/β2 m-Tg rats postweaning (ages 3 and 6 weeks), at disease onset (age 10 weeks), and after the establishment of disease (ages ≥16 weeks). The microbial community structure was determined by 16S ribosomal RNA sequencing and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Mucosal and systemic Th1, Th17, and Treg cell responses were analyzed by flow cytometry, as was the frequency of IgA-coated intestinal bacteria. Intestinal expression of inflammatory cytokines and antimicrobial peptides (AMPs) was determined by qRT-PCR. An inflammatory cytokine signature and elevated AMP expression during the postweaning period preceded the development of clinical bowel inflammation and dysbiosis in HLA-B27/β2 m-Tg rats. An early and sustained expansion of the Th17 cell pool was specifically observed in the cecal and colonic mucosa of HLA-B27/β2 m-Tg rats. Strongly elevated intestinal colonization of Akkermansia muciniphila and an increased frequency of IgA-coated fecal bacteria were significantly associated with expression of HLA-B27 and arthritis development. HLA-B27/β2 m expression in this rat model renders the host hyperresponsive to microbial antigens from infancy. Early activation of innate immunity and expansion of a mucosal Th17 signature are soon followed by dysbiosis in HLA-B27/β2 m-Tg animals. The pathologic processes of perturbed mucosal immunity and dysbiosis strongly merit further study in both prediseased and diseased populations of patients with SpA.


Anti-CD138-targeted interferon is a potent therapeutic against multiple myeloma.
Multiple myeloma (MM), a plasma cell malignancy, is the second most prevalent hematologic malignancy in the US. Although much effort has been made trying to understand the etiology and the complexities of this disease with the hope of developing effective therapies, MM remains incurable at this time. Because of their antiproliferative and proapoptotic activities, interferons (IFNs) have been used to treat various malignancies, including MM. Although some success has been observed, the inherent toxicities of IFNs limit their efficacy. To address this problem, we produced anti-CD138 antibody fusion proteins containing either IFNα2 or a mutant IFNα2 (IFNα2(YNS)) with the goal of targeting IFN to CD138-expressing cells, thereby achieving effective IFN concentrations at the site of the tumor in the absence of toxicity. The fusion proteins inhibited the proliferation and induced apoptosis of U266, ANBL-6, NCI-H929, and MM1-144 MM cell lines. The fusion proteins decreased the expression of IFN regulatory factor 4 (IRF4) in U266. In addition, the fusion proteins were effective against primary cells from MM patients, and treatment with fusion proteins prolonged survival in the U266 murine model of MM. These studies show that IFNα antibody fusion proteins can be effective novel therapeutics for the treatment of MM.


Evaluation of the Bactericidal Activity of Galectins.
Over a century ago, Karl Landsteiner discovered that blood group antigens could predict the immunological outcome of red blood cell transfusion. While the discovery of ABO(H) blood group antigens revolutionized transfusion medicine, many questions remain regarding the development and regulation of naturally occurring anti-blood group antibody formation. Early studies suggested that blood group antibodies develop following stimulation by bacteria that express blood group antigens. While this may explain the development of anti-blood group antibodies in blood group-negative individuals, how blood group-positive individuals protect themselves against blood group-positive microbes remained unknown. Recent studies suggest that several members of the galectin family specifically target blood group-positive microbes, thereby providing innate immune protection against blood group antigen-positive microbes regardless of the blood group status of an individual. Importantly, subsequent studies suggest that this unique form of immunity may not be limited to blood group expressing microbes, but may reflect a more generalized form of innate immunity against molecular mimicry. As this form of antimicrobial activity represents a unique and unprecedented form of immunity, we will examine important considerations and methodological approaches that can be used when seeking to ascertain the potential antimicrobial activity of various members of the galectin family.


A framework for cancer surveillance in Japan.
The World Health Organization (WHO) has recommended that countries develop national cancer control programs in order to reduce the number of deaths due to preventable cancers. The national cancer control program should be comprehensive and systematic with evidence-based priority-setting and the efficient use of limited resources. In order to provide evidence-based information, cancer surveillance systems must be established with registration as a focus. Cancer registration monitors the incidence, mortality, survival, and prevalence of cancers. In Japan, however, cancer registration systems have not been either well developed or standardized until recently. In 2003, the Ministry of Health, Labour and Welfare of Japan launched the Third Term Comprehensive 10-Year Strategy Program for Cancer Control, which gave grants to several projects to enhance the dissemination and standardization of cancer registries. However, the establishment of a cancer registration system is merely the first step in the process to provide a comprehensive surveillance system that leads to a national cancer control program, as proposed by the WHO. To provide the best cancer care services equitably in Japan, cancer surveillance systems should be established without delay.


Intrapleural tissue plasminogen activator and deoxyribonuclease administered concurrently and once daily for complex parapneumonic pleural effusion and empyema.
Pleural infection is life-threatening and increasingly prevalent. In addition to usual care, twice-daily, separate administration of tissue plasminogen activator and deoxyribonuclease (tPA-DNase) reduces radiological pleural opacity with lower surgical referral rates. This retrospective cohort study examines the use of once-daily, concurrent administration of tPA-DNase for complex parapneumonic pleural effusion and empyema. Patients with pleural infection who received intrapleural tPA-DNase between October 2014 and July 2020 at Logan Hospital, where it is given concurrently and once-daily as salvage therapy, were retrospectively identified. Radiographic opacification, inflammatory markers, clinical response and complications were examined. Thirty-one patients were identified. Mean age was 48.8 years (standard deviation [SD], 17.2). Median tPA-DNase administration was 3 (interquartile range [IQR], 2-3). Chest x-ray pleural opacity decreased significantly (P = 0.047) from a median of 39.6% (IQR, 28.8-65.7%) to 9.7% (IQR, 2.5-23.2%), a median relative reduction of 75.5% (IQR, 47.7-93.9%). White cell count and C-reactive protein improved significantly (P = 0.002 and P = 0.032, respectively) from a median of 16.3 × 109 /L (IQR, 11.8-20.6 × 109 /L) to 9.9 × 109 /L (IQR, 8.0-12.3 × 109 /L) and 311.0 mg/L (IQR, 218.8-374.0 mg/L) to 69.0 mg/L (IQR, 36.0-118.0 mg/L), respectively. No patients experienced significant bleeding or died. Five patients (16.1%) were referred for surgery. This is pilot evidence that a practical regimen of concurrent, once-daily intrapleural tPA-DNase improved pleural opacification and inflammatory markers without bleeding or mortality. The surgical referral rate was higher than in studies assessing twice-daily administration, though the validity of this outcome as a measure of treatment success is limited, and further studies are needed to assess the optimal dose and frequency of intrapleural therapy and indications for surgical referral.


Neuron differentiation-related genes are up-regulated in the hypothalamus of odorant-inhaling rats subjected to acute restraint stress.
To elucidate some physiopsychological effects of a pleasant odor, we analyzed gene expression profiles in the hypothalamus of rats which, under a restraint-stressed condition, inhaled (R)-(-)-linalool. Consequently, 697 probe sets showed significant expression changes in the odorant-inhaling rats subjected to 2 h of restraint stress (false discovery rate < 0.05). We observed up-regulation of 594 among them, including genes related to neuron differentiation and transcriptional regulatory factors. Another important result was that inhalation of (R)-(-)-linalool returned the expression of 49 restraint-regulated genes to a normal condition. In contrast, the inhalation also further up-regulated the expression of 16 restraint-up-regulated genes that included those encoding heat shock proteins as factors to induce some biological responses against stresses. In the present study we thus found the substantial example that, in the hypothalamus involved in feeding behaviors, an inhaled pleasant odor acts to regulate the gene expression related to the functions of neuronal developments to cope with stresses.


The effect of cyclic nucleotides on the release of 3H-dopamine from rat striatal slices.
Slices (1.0 mm thick and 0.4 cm in diameter) obtained from rat neostriatum were preincubated with 3H-dopamine (3H-DA; 0.8 mugM) for 30 minutes and then superfused at a rate of 1.0 ml/min in glass chambers (volume, 2 ml) for varying lenghts of time prior to electrical stimulation. Superfusate effluents were continuously collected and analyzed for 3H-DA and 3H-metabolites by liquid scintillation spectrometry after separation by alumina and Dowex 50 column chromatography. 3H-DA represented only a small proportion of the spontaneous overflow of radioactivity (9.8%) but represented the largest portion recovered in the tissue (55%). After electrical stimulation of the slices (biphasic square-wave pulses, 50 pulses/sec; 1.1-msec duration; supramaximal voltage), there was a marked increase in 3H-DA and all 3H-fractions. The percent increase of 3H-DA, 3H-O-methylated + 3H-O-methylated deaminated, 3H-dihydroxyphenylacetic acid and 3H-dihydroxylphenylethanol was 549, 232, 215 AND 246%, respectively. The addition to the superfusion medium of dibutyryl adenosine 3:5-monophosphate (DBcAMP) in the presence or absence of phosphodiesterase inhibitors (3-isobutyl-1-methylxanthine, 0.5 mM, or aminophylline, 5 mM) and cyclic adenosine monophosphoric acid in the presence but not the absence of the phosphodiesterase inhibitors potentiated the electrically induced release of 3H-DA. Neither cyclic nucleotide had any effect on the spontaneous overflow of 3H-DA or metabolites, the metabolism of 3H-DA or the uptake of 3H-DA into dopaminergic neurons. Guano sine 3:5-monophosphate was without effect on the electrically induced release of 3H-DA. The ED50 for the DBcAMP potentiation of hte electrically induced release of 3H-DA was 6 mugM. These results extend to the central nervous system the possibility that adenosine 3-5-monophosphate may play a role in the regulation or modulation of monoaminergic synaptic transmission.


Growth hormone transgenic salmon pay for growth potential with increased predation mortality.
Recent advances in gene technology have been applied to create fast-growing transgenic fish, which are of great commercial interest owing to their potential to shorten production cycles and increase food production. However, there is growing concern and speculation over the impact that escaped growth hormone (GH)-transgenic fish may have on the natural environment. To predict these risks it is crucial to obtain empirical data on the relative fitness of transgenic and non-transgenic fish under nature-like conditions. Using landscaped stream aquaria with live food and predators, we show that the predation mortality of newly hatched GH-transgenic coho salmon fry (Oncorhynchus kisutch) is much higher than in non-transgenic conspecifics, and that this difference is amplified when food abundance decreases. The growth rate of transgenic and non-transgenic fish is similar at high food levels, whereas transgenic fish grow more slowly than non-transgenic fish when food abundance is reduced. Our results suggest that the fitness of young GH-transgenic coho salmon in the wild will be determined by both predation pressure and food availability.


Successful Treatment of Saksenaea sp. Osteomyelitis by Conservative Surgery and Intradiaphyseal Incorporation of Amphotericin B Cement Beads.
Osteoarticular mucormycosis cases are quite rare and challenging infections that are mostly due to direct inoculation during traumatic injury among immunocompetent patients. Classic management includes a combination of aggressive surgical debridement, which may lead to amputation, and long-term systemic liposomal amphotericin B therapy. This article describes the successful treatment of Saksenaea sp. osteomyelitis in a patient with diabetes mellitus, using a combination of systemic antifungal therapy and conservative surgery with insertion of amphotericin-impregnated cement beads.


From 'following the push of nature' to 'restoring one's proper sex'--cortisone and sex at Johns Hopkins's Pediatric Endocrinology Clinic.
In 1955, a paradigm shift in the conception of sex is said to have taken place, when psychologist John Money at Johns Hopkins's Pediatric Endocrinology Clinic argued that 'hermaphroditic' children could be assigned a sex contradictory to their biological sex. Rather than being born male or female, he claimed, these children learned to be boys or girls. Money was subsequently credited the invention of the term gender role. However, Money only confirmed a practice that was established at the clinic several years before his intervention. The clinic's director Lawson Wilkins (1894-1963) had already recommended that certain children, virilized by congenital adrenal hyperplasia, should be raised in the male sex, even though they were by all medical standards of the time female. What mattered for him was assigning the sex that seemed 'better' for these children. What constituted the 'better sex' was contingent on the child's psyche and habitus, social expectations, and on the range of medical and surgical interventions available at the time.


An edge-based approach for virtual network embedding based on the graph edit distance.
Virtualization and resource isolation techniques have enabled the efficient sharing of networked resources. How to control network resource allocation accurately and flexibly has gradually become a research hotspot due to the growth in user demands. Therefore, this paper presents a new edge-based virtual network embedding approach to studying this problem that employs a graph edit distance method to accurately control resource usage. In particular, to manage network resources efficiently, we restrict the use conditions of network resources and restrict the structure based on common substructure isomorphism and an improved spider monkey optimization algorithm is employed to prune redundant information from the substrate network. Experimental results showed that the proposed method achieves better performance than existing algorithms in terms of resource management capacity, including energy savings and the revenue-cost ratio.


In-depth global analysis of transcript abundance levels in porcine alveolar macrophages following infection with porcine reproductive and respiratory syndrome virus.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a major pathogen of swine worldwide and causes considerable economic loss. Identifying specific cell signaling or activation pathways that associate with variation in PRRSV replication and macrophage function may lead to identification of novel gene targets for the control of PRRSV infection. Serial Analysis of Gene Expression (SAGE) was used to create and survey the transcriptome of in vitro mock-infected and PRRSV strain VR-2332-infected porcine alveolar macrophages (PAM) at 0, 6, 12, 16, and 24 hours after infection. The transcriptome data indicated changes in transcript abundance occurring in PRRSV-infected PAMs over time after infection with more than 590 unique tags with significantly altered transcript abundance levels identified (P < .01). Strikingly, innate immune genes (whose transcript abundances are typically altered in response to other pathogens or insults including IL-8, CCL4, and IL-1β) showed no or very little change at any time point following infection.


Central projections of gustatory nerves in the rat.
The central distributions of gustatory and non-gustatory branches of cranial nerves V, VII, IX, and X were examined after application of horseradish peroxidase to the cut nerve. The nerves conveying gustatory information, chorda tympani (CT), greater superficial petrosal (GSP), lingual-tonsilar branch of IX (LT-IX), superior laryngeal branch of X (SL), distributed primarily to the lateral division of the nucleus of the solitary tract (NST) from its rostral pole to the obex. The CT and GSP distributions were coextensive and terminated most densely in the rostral pole of NST. The LT-IX distribution concentrated between this major CT/GSP distribution and the area postrema with a caudal extension into the interstitial nucleus of NST. This nerve also had a substantial projection, not found in other gustatory nerves, into the dorsolateral aspect of the medial NST. The SL distribution overlapped LT-IX in the caudal medulla. The lingual and inferior alveolar nerves, two oral trigeminal branches, projected to regions of NST innervated by the gustatory nerves. The cervical vagus nerve distributed primarily to the medial NST in the caudal half of the nucleus and exhibited only minimal overlap with gustatory nerve distributions. The nucleus of the solitary tract appears to have two major functional divisions--an anterior-lateral oral-gustatory half, and a posterior-medial visceral afferent half.


Hypoxia and exercise interactions on skeletal muscle insulin sensitivity in obese subjects with metabolic syndrome: results of a randomized controlled trial.
Physical activity improves insulin sensitivity in obesity. Hypoxia training is claimed to augment this effect. We tested the hypothesis that normobaric hypoxia training would improve insulin sensitivity in obese patients with metabolic syndrome. In a randomized controlled trial, 23 obese men with metabolic syndrome who were not informed of the FiO2 conditions underwent a 6-week physical exercise intervention under ambient (n = 11; FiO2 21%) conditions or hypoxia (n = 12; FiO2 15%) using a normobaric hypoxic chamber. Three 60-min sessions of interval training were performed each week at 60% of individual V̇O2max. Assessment of myocellular insulin sensitivity by euglycemic hyperinsulinemic clamp was performed in 21 of these subjects before and after 6 weeks of training. Comprehensive phenotyping also included biopsies of subcutaneous adipose tissues. The intermittent moderate physical exercise protocol did not substantially change the myocellular insulin sensitivity within 6 weeks under normoxic conditions (ISIClamp: 0.035 (IQR 0.016-0.075) vs. 0.037 (IQR 0.026-0.056) mg* kg-1 *min-1/(mU* l-1); p = 0.767). In contrast, ISIClamp improved during hypoxia training (0.028 (IQR 0.018-0.035) vs. 0.038 (IQR 0.024-0.060) mg * kg-1 *min-1/(mU *l-1); p < 0.05). Between group comparison of ISIClamp change revealed a small difference between groups (Cohen's d = 0.26). Within the hypoxic group, improvement of ISIClamp during training was associated with individual increase of circulating vascular endothelial growth factor (VEGF) levels (r = 0.678, p = 0.015), even if mean VEGF levels were not modified by any training condition. Atrial natriuretic peptide (ANP) system components were not associated with increased ISIClamp during hypoxic training. Physical training under hypoxic conditions could partially augment the favorable effects of exercise alone on myocellular insulin sensitivity in obese men with metabolic syndrome. Concomitant changes in VEGF might represent an underlying pathophysiological mechanism.


Nitric oxide production during focal cerebral ischemia in rats.
Nitric oxide has been implicated as a mediator of glutamate excitotoxicity in primary neuronal cultures. A number of indicators of brain nitric oxide production (nitric and cyclic guanosine monophosphate [cGMP] concentrations and nitric oxide synthase activity) were examined after bilateral carotid ligation and right middle cerebral artery occlusion in adult rats. Brain nitrite was significantly increased in the right versus left cortex 5, 10, and 20 minutes after middle cerebral artery occlusion (P < .05), with a return to baseline at 60 minutes. There were no significant changes in cerebellar concentrations. Cortical levels of cGMP were increased at 10, 20, and 60 minutes after occlusion, with significant right-to-left differences (P < .05). Cerebellar concentrations of cGMP were also increased but without significant side-to-side differences. Nitric oxide synthase activity increased approximately 10-fold from baseline 10 minutes after occlusion in the right cortex but decreased markedly by 60 minutes from its peak at 10 minutes. The right-to-left difference in nitric oxide synthase activity was significant at 20 minutes (P < .05). Pretreatment of rats with NG-nitro-L-arginine, a nitric oxide synthase inhibitor, abolished the rise in nitrite and cGMP. These results suggest that a sharp transient increase in the activity of nitric oxide synthase occurs during the first hour of cerebral ischemia, which leads to a burst in nitric oxide production and activation of guanylate cyclase.