Dopamine agonist-induced yawning in rats: a dopamine D3 receptor-mediated behavior.
A specific role for the dopamine D3 receptor in behavior has yet to be elucidated. We now report that dopamine D2/D3 agonists elicit dose-dependent yawning behavior in rats, resulting in an inverted U-shaped dose-response curve. A series of experiments was directed toward the hypothesis that the induction of yawning is a D3 receptor-mediated effect, whereas the inhibition of the yawning observed at higher doses is due to competing D2 receptor activity. We compared several dopaminergic agonists with a range of in vitro D3 selectivity, including PD-128,907 [(S)-(+)-(4aR, 10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol HCl], PD-128,908 [(R)-(-)-(4aS,10bS)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol HCl], quinelorane [(5aR-trans)-5,5a,6,7,8, 9,9a,10-octahydro-6-propylpyrido[2,3-g]quinazolin-2-amine dihydrochloride], pramipexole (N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine), 7-OH-DPAT [(+/-)-7-hydroxy-2-dipropylaminotetralin HBr], quinpirole [trans-(-)-(4aR)-4,4a,5,6,7,8, 8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline HCl], bromocriptine [(+)-2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl) ergotaman-3',6'-18-trione methanesulfonate], and apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol HCl] with respect to their ability to induce yawning in rats. A series of D2/D3 antagonists differing in selectivity for D3 over D2 receptors were evaluated for their ability to alter the effects of the dopamine agonists. The antagonists L-741,626 (3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole), haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone HCl), nafadotride (N-[(1-butyl-2-pyrrolidinyl)methyl]-4-cyano-1-methoxy-2-naphtha-lenecarboxamide), U99194 (2,3-dihydro-5,6-dimethoxy-N,N-dipropyl-1H-inden-2-amine maleate), SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide), and PG01037 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl) were used to determine effects on dose-response curves for D2/D3 agonist-induced yawning. In addition, the potential contribution of cholinergic and/or serotonergic mechanisms to the yawning response was investigated using a series of pharmacological tools including scopolamine [(a,S)-a-(hydroxymethyl)benzeneacetic acid (1a,2b,4b,5a,7b)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]-non7-yl ester hydrobromide], mianserin (1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine HCl), and the D3-preferring antagonists nafadotride, U99194, SB-277011A, and PG01037 to differentially modulate yawning induced by PD-128,907, physostigmine [(3aS)-cis-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol methylcarbamate hemisulfate], and N-[3-(trifluoromethyl)phenyl]piperazine HCl. The results of these experiments provide convergent evidence that dopamine D2/D3 agonist-induced yawning is a D3 agonist-mediated behavior, with subsequent inhibition of yawning being driven by competing D2 agonist activity. Thus, dopamine agonist-induced yawning may represent an in vivo method for selectively identifying D3 and D2 receptor-mediated activities.


Does hydroxychloroquine still have any role in the COVID-19 pandemic?
Introduction: The 4-aminoquinolines, chloroquine, and hydroxychloroquine have been used for over 70 years for malaria and rheumatological conditions, respectively. Their broad-spectrum antiviral activity, excellent safety profile, tolerability, low cost, and ready availability made them prime repurposing therapeutic candidates at the beginning of the COVID-19 pandemic.Areas covered: Here, the authors discuss the history of hydroxychloroquine and chloroquine, the in vitro data which led to their widespread repurposing and adoption in COVID-19 and their complex pharmacokinetics. The evidence for the use of these drugs is assessed through in vivo animal experiments and the wealth of conflicting data and interpretations published during COVID-19, including the more informative results from randomized controlled trials (RCTs). The safety aspects of these drugs, in particular cardiotoxicity, are then reviewed.Expert opinion: The evidence from clinical trials in COVID-19 supports the well-established safety record of the 4-aminoquinolines at currently recommended dosage. In hospitalized patients with severe COVID-19 RCTs show clearly that the 4-aminoquinolines are not beneficial. The only treatments with proven benefit at this stage of infection are immunomodulators (dexamethasone, IL-6 receptor antagonists). No antiviral drugs have proven life-saving in late-stage COVID-19.


Pathogenicity and drug resistance in Candida albicans and other yeast species. A review.
Pathogenic yeasts from the genus Candida can cause serious infection in humans particularly, in immunocompromised patients and are now recognized as major agents of hospital acquired (nosocomial) infections. In the recent years, there has been a marked increase in the incidence of treatment failures in candidiasis patients receiving long-term antifungal therapy, which has posed a serious problem in its successful use in chemotherapy. Candida cells acquire drug resistance (MDR) during the course of the treatment. The mechanisms of resistance to azole antifungal agents have been elucidated in Candida species and can be mainly categorized as (i) changes in the cell wall or plasma membrane, which lead to impaired drug (azole) uptake; (ii) alterations in the affinity of the drug target Erg11p (lanosterol 14alpha-demethylase) especially to azoles or in the cellular content of Erg11p due to target site mutation or overexpression of the ERG11 gene; and (iii) the efflux of drugs mediated by membrane transport proteins belonging to the ATP-binding cassette (ABC) transporters, namely CDR1 and CDR2 or to the major facilitator superfamily (MFS) transporter, CaMDR1. Many such manifestations are associated with the formation of Candida biofilms including those occurring on devices like indwelling intravascular catheters. Biofilm-associated Candida show uniform resistance to a wide spectrum of antifungal drugs. A combination of different resistance mechanisms is responsible for drug resistance in clinical isolates of Candida species.


Primary Cortisol Deficiency and Growth Hormone Deficiency in a Neonate With Hypoglycemia: Coincidence or Consequence?
Cortisol and growth hormone (GH) deficiencies are causes of neonatal hypoglycemia. When they coexist, a pituitary disorder is suspected. We present an infant with hypoglycemia in whom an ACTH receptor defect was associated with transient GH deficiency. A full-term boy with consanguineous parents presented with hypoglycemia (serum glucose 18 mg/dL) at 4 hours of life with undetectable serum cortisol (<1 μg/dL). Examination showed diffuse hyperpigmentation with normal male genitalia. Patient developed hyperbilirubinemia and elevated transaminase levels. GH levels of 6.8 ng/mL and 7.48 ng/mL during episodes of hypoglycemia, peak of 9.2 ng/mL with glucagon stimulation, and undetectable IGF-1 suggested GH deficiency. Thyroid function, prolactin, and gonadotropins were normal. Baseline ACTH was elevated at 4868 pg/mL, whereas serum cortisol remained undetectable with ACTH stimulation. Hydrocortisone replacement resulted in normalization of blood glucose and cholestasis with decline in ACTH level. GH therapy was not initiated, given improvement in cholestasis and euglycemia. An ACTH receptor defect was confirmed with molecular genetic testing that revealed homozygosity for a known mutation of the melanocortin 2 receptor (MC2R) gene. At 12 weeks, a random GH level was 10 ng/mL. IGF-1 was 75 ng/mL and 101 ng/mL at 7 and 9 months, respectively. This report describes glucocorticoid deficiency from an MC2R mutation associated with GH deficiency. With glucocorticoid replacement, GH secretion normalized. Our findings are consistent with a previously stated hypothesis that physiologic glucocorticoid levels may be required for optimal GH secretion [1].


The human Kv1.1 channel is palmitoylated, modulating voltage sensing: Identification of a palmitoylation consensus sequence.
Voltage-dependent K(+) channels rely on precise dynamic protein interactions with surrounding plasma membrane lipids to facilitate complex processes such as voltage sensing and channel gating. Many transmembrane-spanning proteins use palmitoylation to facilitate dynamic membrane interactions. Herein, we demonstrate that the human Kv1.1 ion channel is palmitoylated in the cytosolic portion of the S(2)-S(3) linker domain at residue C243. Through heterologous expression of the human Kv1.1 protein in Sf9 cells, covalent radiolabeling with [(3)H]palmitate, chemical stability studies of the [(3)H]-palmitoylated protein, and site-directed mutagenesis, C243 was identified as the predominant site of palmitoylation. The functional sequelae of palmitoylation were examined by analysis of whole cell currents from WT and mutant channels, which identified a 20-mV leftward shift in the current-voltage relationship when palmitoylation at C243 (but not with other cysteine deletions) is prevented by site-directed mutagenesis, implicating a role for palmitoylated C243 in modulating voltage sensing through protein-membrane interactions. Database searches identified an amino acid palmitoylation consensus motif (ACP/RSKT) that is present in multiple other members of the Shaker subfamily of K(+) channels and in several other unrelated regulatory proteins (e.g., CD36, nitric oxide synthase type 2, and the mannose-6 phosphate receptor) that are known to be palmitoylated by thioester linkages at the predicted consensus site cysteine residue. Collectively, these results (i) identify palmitoylation as a mechanism for K(+) channel interactions with plasma membrane lipids contributing to electric field-induced conformational alterations, and ii) define an amino acid consensus sequence for protein palmitoylation.


Palliative psychiatry for severe persistent mental illness as a new approach to psychiatry? Definition, scope, benefits, and risks.
As a significant proportion of patients receiving palliative care suffer from states of anxiety, depression, delirium, or other mental symptoms, psychiatry and palliative care already collaborate closely in the palliative care of medical conditions. Despite this well-established involvement of psychiatrists in palliative care, psychiatry does not currently explicitly provide palliative care for patients with mental illness outside the context of terminal medical illness. Based on the WHO definition of palliative care, a, a working definition of palliative psychiatry is proposed. Palliative psychiatry focuses on mental health rather than medical/physical issues. We propose that the beneficiaries of palliative psychiatry are patients with severe persistent mental illness, who are at risk of therapeutic neglect and/or overly aggressive care within current paradigms. These include long-term residential care patients with severe chronic schizophrenia and insufficient quality of life, those with therapy-refractory depressions and repeated suicide attempts, and those with severe long-standing therapy-refractory anorexia nervosa. An explicitly palliative approach within psychiatry has the potential to improve quality of care, person-centredness, outcomes, and autonomy for patients with severe persistent mental illness. The first step towards a palliative psychiatry is to acknowledge those palliative approaches that already exist implicitly in psychiatry. Basic skills for a palliative psychiatry include communication of diagnosis and prognosis, symptom assessment and management, support for advance (mental health) care planning, assessment of caregiver needs, and referral to specialized services. Some of these may already be considered core skills of psychiatrists, but for a truly palliative approach they should be exercised guided by an awareness of the limited functional prognosis and lifespan of patients with severe persistent mental illness.


Functional connectivity in the first year of life in infants at-risk for autism: a preliminary near-infrared spectroscopy study.
Autism spectrum disorder (ASD) has been called a "developmental disconnection syndrome," however the majority of the research examining connectivity in ASD has been conducted exclusively with older children and adults. Yet, prior ASD research suggests that perturbations in neurodevelopmental trajectories begin as early as the first year of life. Prospective longitudinal studies of infants at risk for ASD may provide a window into the emergence of these aberrant patterns of connectivity. The current study employed functional connectivity near-infrared spectroscopy (NIRS) in order to examine the development of intra- and inter-hemispheric functional connectivity in high- and low-risk infants across the first year of life. NIRS data were collected from 27 infants at high risk for autism (HRA) and 37 low-risk comparison (LRC) infants who contributed a total of 116 data sets at 3-, 6-, 9-, and 12-months. At each time point, HRA and LRC groups were matched on age, sex, head circumference, and Mullen Scales of Early Learning scores. Regions of interest (ROI) were selected from anterior and posterior locations of each hemisphere. The average time course for each ROI was calculated and correlations for each ROI pair were computed. Differences in functional connectivity were examined in a cross-sectional manner. At 3-months, HRA infants showed increased overall functional connectivity compared to LRC infants. This was the result of increased connectivity for intra- and inter-hemispheric ROI pairs. No significant differences were found between HRA and LRC infants at 6- and 9-months. However, by 12-months, HRA infants showed decreased connectivity relative to LRC infants. Our preliminary results suggest that atypical functional connectivity may exist within the first year of life in HRA infants, providing support to the growing body of evidence that aberrant patterns of connectivity may be a potential endophenotype for ASD.


Antibody responses to a panel of Plasmodium falciparum malaria blood-stage antigens in relation to clinical disease outcome in Sudan.
Despite many intervention programmes aimed at curtailing the scourge, malaria remains a formidable problem of human health. Immunity to asexual blood-stage of Plasmodium falciparum malaria is thought to be associated with protective antibodies of certain immunoglobulin classes and subclasses. We have analysed immunoglobulin G profiles to six leading blood-stage antigens in relation to clinical malaria outcome in a hospital-based study in Sudan. Our results revealed a linear association with anti-AMA-1-IgG1 antibodies in children <5 years and reduced risk of severe malaria, while the responses of the IgG3 antibodies against MSP-2, MSP-3, GLURP in individuals above 5 years were bi-modal. A dominance of IgG3 antibodies in >5 years was also observed. In the final combined model, the highest levels of IgG1 antibodies to AMA-1, GLURP-R0, and the highest levels of IgG3 antibodies to 3D7 MSP-2 were independently associated with protection from clinical malaria. The study provides further support for the potential importance of the studied merozoite vaccine candidate antigens as targets for parasite neutralizing antibody responses of the IgG1 and IgG3 subclasses.


Resolution of diabetes mellitus and metabolic syndrome in normal weight 24-29 BMI patients with One Anastomosis Gastric Bypass.
Diabetes mellitus type 2 (DMT2) is a major cause of death in the world. The medical therapy for this disease has had enormous progress, but it still leaves many patients exposed to the complications developed from the disease. It is well known the beneficial effects of bariatric surgery in obese diabetic patients, however it is important to investigate if the same principles of bariatric surgery that improve diabetes in obese patients, could be applied to non obese normal weight diabetics. Thirteen diabetic patients operated by One Anastomosis Gastric Bypass (BAGUA), were evaluated in the preoperative period and 1,3 and 6 months after surgery. Body weight and composition, Fasting Plasma Glucose, HbA1c levels, blood pressure and serum lipids levels were analyzed, as well as the monitoring of the immediate postoperative treatment necessities for Diabetes and other metabolic syndrome comorbidities. After the surgery the 77% of the patients resolves its T2DM, 46% from surgery, and rest noted an significant improvement of the disease in spite of having a C peptide level near to zero some of the patients. The comorbidities, mainly hypertension and lipid abnormalities experience improvement early. All patients reduce their weight and the amount of fat mass until values consistent with their age and height. The One Anastomosis Gastric Bypass leads to resolution or improvement of T2DM in non obese normal weight patients. The best results are obtained in patients with few years of diabetes, without or short term use of insulin treatment and high C-peptide levels.


Sentence Diversity in Early Language Development: Recommendations for Target Selection and Progress Monitoring.
This clinical focus article describes how to assess and when to target diverse, simple sentences as part of early language intervention. The theoretical foundations and clinical motivations for assessing sentence diversity based on unique combinations of subjects and verbs are explained, followed by a description of how to compute the measure. Sentence diversity is then related to familiar developmental measures of lexical diversity, utterance length, and grammatical complexity in a sample of 40 typically developing toddlers at 30 months of age. Descriptive and correlational analyses are used to demonstrate how sentences become more diverse as utterances also become longer and more complex. The ability to produce simple sentences with diverse subject-verb combinations is proposed as a general developmental expectation for toddlers at 30 months of age. All 40 children produced at least 10 different subject-verb combinations in 30 min of parent-toddler conversation. Sentence diversity is also associated with familiar developmental measures. Recommendations are provided for using the measure of sentence diversity to inform treatment planning and monitor progress for young children with language disorders. https://doi.org/10.23641/asha.5895976.


Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial.
Risk for future clinical outcomes is proportional to the severity of liver disease in patients with chronic hepatitis C virus (HCV). We measured disease severity by quantitative liver function tests (QLFTs) to determine cutoffs for QLFTs that identified patients who were at low and high risk for a clinical outcome. Two hundred and twenty-seven participants in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial underwent baseline QLFTs and were followed for a median of 5.5 years for clinical outcomes. QLFTs were repeated in 196 patients at month 24 and in 165 patients at month 48. Caffeine elimination rate (k(elim)), antipyrine (AP) clearance (Cl), MEGX concentration, methionine breath test (MBT), galactose elimination capacity (GEC), dual cholate (CA) clearances and shunt, perfused hepatic mass (PHM), and liver and spleen volumes (by single-photon emission computed tomography) were measured. Baseline QLFTs were significantly worse (P = 0.0017 to P < 0.0001) and spleen volumes were larger (P < 0.0001) in the 54 patients who subsequently experienced clinical outcomes. QLFT cutoffs that characterized patients as "low" and "high risk" for clinical outcome yielded hazard ratios ranging from 2.21 (95% confidence interval [CI]: 1.29-3.78) for GEC to 6.52 (95% CI: 3.63-11.71) for CA clearance after oral administration (Cl(oral)). QLFTs independently predicted outcome in models with Ishak fibrosis score, platelet count, and standard laboratory tests. In serial studies, patients with high-risk results for CA Cl(oral) or PHM had a nearly 15-fold increase in risk for clinical outcome. Less than 5% of patients with "low risk" QLFTs experienced a clinical outcome. QLFTs independently predict risk for future clinical outcomes. By improving risk assessment, QLFTs could enhance the noninvasive monitoring, counseling, and management of patients with chronic HCV.


Management of chronic lymphocytic leukemia (CLL) in the elderly: a position paper from an international Society of Geriatric Oncology (SIOG) Task Force.
Chronic lymphocytic leukemia (CLL) mainly affects older people: the median age at diagnosis is > 70 years. Elderly patients with CLL are heterogeneous with regard both to the biology of their disease and aging. Following the diagnosis of CLL in an elderly individual, careful risk assessment is essential when treatment options are evaluated. This includes not only clinical staging and evaluation of disease-specific prognostic biomarkers such as 17p deletion and TP53 mutation, but also of comorbidities, physical capacity, nutritional status, cognitive capacity, ability to perform activities of daily living and social support. Comorbidity scoring and geriatric assessment tools are helpful in achieving such multidimensional evaluation in a systematic manner. The introduction of new drugs including novel monoclonal antibodies and kinase inhibitors offers enhanced opportunities for the treatment of elderly patients with CLL. This position paper of a Task Force of the International Society of Geriatric Oncology (SIOG) reviews currently available evidence relevant to such patients. All types of elderly patient (i.e. chronological age > 65-70 years) are considered, from robust (fit) to vulnerable (unfit) to the terminally ill. Among the topics covered are the following: (i) the relationship between chronological age, prognosis and survival, (ii) assessment of biological aging, (iii) biological age as a determinant of treatment feasibility and tolerance and (iv) tailoring of both first and further-line treatment to the circumstances of the individual patient.


Effects of Protein Source on Liposome Uptake by Cells: Corona Composition and Impact of the Excess Free Proteins.
Corona formation in biological fluids strongly affects nanomedicine interactions with cells. However, relatively less is known on additional effects from the free proteins in solution. Within this context, this study aims to gain a better understanding of nanomaterial-cell interactions in different biological fluids and, more specifically, to disentangle effects due to corona composition and those from the free proteins in solution. To this aim, the uptake of liposomes in medium with bovine and human serum are compared. Uptake efficiency in the two media differs strongly, as also corona composition. However, in contrast with similar studies on other nanomaterials, despite the very different corona, when the two corona-coated liposomes are exposed to cells in serum free medium, their uptake is comparable. Thus, in this case, the observed differences in uptake depend primarily on the presence and source of the free proteins. Similar results are obtained when testing the liposomes on different human cells, as well as in murine cells and in the presence of murine serum. Overall, these results show that the protein source affects nanomedicine uptake not only due to effects on corona composition, but also due to the presence and composition of the free proteins in solution.


Why have academic medical centers survived?
Over the past decade, many observers predicted the demise of the academic medical center (AMC) due to competition from community hospitals and physicians, fragile finances, inefficiency, and organizational complexity. In 2004, we interviewed 23 AMC and community hospital administrators to determine why those predictions have proven unfounded, learn the leaders' current concerns and priorities, and to identify desirable changes. Chief concerns were reimbursement uncertainty, federal research policy, ineffective internal decision-making, and clinical quality (mentioned in more than 75% of interviews). Priorities included ensuring sufficient investment capital, revising undergraduate and graduate curricula, strengthening ties with physicians and community hospitals, attracting faculty, and meeting regulatory requirements. We advocate that the AMC: (1) modify the research model to allow greater collaboration with institutions and researchers; (2) enhance free and open export of new and proven clinical techniques and knowledge; (3) devote greater attention to meeting patients' increasing needs for counsel and guidance, not just intervention, given the plethora of complex new technologies and their promotion in the popular media; and (4) simplify their organizations. To accomplish this, it is desirable for future leaders to gain experience outside the AMC, and for faculty and institutions to be less inwardly focused and more attentive to preserving the public's trust.


Common variants in the ARC gene are not associated with cognitive abilities.
The Activity-Regulated Cytoskeleton-associated (ARC) gene encodes a protein that is critical for the consolidation of synaptic plasticity and long-term memory formation. Given ARC's key role in synaptic plasticity, we hypothesized that genetic variations in ARC may contribute to interindividual variability in human cognitive abilities or to attention-deficit hyperactivity disorder (ADHD) susceptibility, where cognitive impairment often accompanies the disorder. We tested whether ARC variants are associated with six measures of cognitive functioning in 670 healthy subjects in the Norwegian Cognitive NeuroGenetics (NCNG) by extracting data from its Genome-Wide Association Study (GWAS). In addition, the Swedish Betula sample of 1800 healthy subjects who underwent similar cognitive testing was also tested for association with 19 tag SNPs. No ARC variants show association at the study-wide level, but several markers show a trend toward association with human cognitive functions. We also tested for association between ARC SNPs and ADHD in a Norwegian sample of cases and controls, but found no significant associations. This study suggests that common genetic variants located in ARC do not account for variance in human cognitive abilities, though small effects cannot be ruled out.


Heritability of the backtest response in piglets and its genetic correlations with production traits.
The backtest response of a pig gives an indication of its coping style, that is, its preferred strategy to cope with stressful situations, which may in turn be related to production traits. The objective of this study was therefore to estimate the heritability of the backtest response and estimate genetic correlations with production traits (birth weight, growth, fat depth and loin depth). The backtest was performed by placing the piglet on its back for 60 s and the number of struggles (NrS) and vocalizations (NrV), and the latency to struggle and vocalize (LV) was recorded. In total, 992 piglets were subjected to the backtest. Heritability estimates for backtest traits were statistically moderate (although high for behavioral traits), with LV having the highest heritability estimate (0.56±0.10, P<0.001) and NrS having the lowest estimate (0.37±0.09, P<0.001). Backtest traits also had high genetic correlations with each other, with vocalization traits (NrV and LV) having the highest (-0.94±0.03, P<0.001), and NrS with NrV the lowest correlation (0.70±0.09, P<0.001). No significant correlations were found between backtest traits and production traits, but correlations between NrS and birth weight (-0.38±0.25), and NrV and loin depth (-0.28±0.19) approached significance (P=0.07). More research into genotype-by-environment interactions may be needed to assess possible connections between backtest traits and production traits, as this may depend on the circumstances (environment, experiences, etc.). In conclusion, heritability estimates of backtest traits are high and it would therefore be possible to select for them. The high genetic correlations between backtest traits indicate that it may be possible to only consider one or two traits for characterization and selection purposes. There were no significant genetic correlations found between backtest traits and production traits, although some of the correlations approached significance and hence warrant further research.


Check dam and polyacrylamide performance under simulated stormwater runoff.
High levels of turbidity and fine suspended sediments are often found in stormwater discharges from construction sites even when best management practices (BMPs) for sediment control are in place. This study evaluated turbidity reduction by three check dam types: 1) rock check dam representing a standard BMP, 2) excelsior wattle representing a fiber check dam (FCD), and 3) rock check dam wrapped with excelsior erosion control blanket (rock + excelsior ECB) representing an alternative FCD. Three check dams (all same type) were installed in a lined, 24-m ditch on a 5-7% slope and three consecutive simulated stormwater flows were run in the ditch. Additional tests were performed by adding granular polyacrylamide (PAM) on the check dams in the same manner using two sediment sources differing in clay content. Without PAM treatment, significantly higher effluent turbidity (>900 nephelometric turbidity units (NTU)) exited the ditch with rock check dams than with excelsior wattles or rock + excelsior ECBs (<440 NTU). The extent of sediment deposition between the check dam types was in the order of excelsior wattle > rock + excelsior ECB > rock check dam, indicating better water pooling behind the wattle. The PAM treatment reduced turbidity substantially (>75% relative to no PAM treatment) for all check dam types and it was very effective in excelsior wattles (<57 NTU) and rock + excelsior ECBs (<90 NTU) even during the third storm event. This study demonstrates that the passive treatment of runoff with PAM on FCDs (or rock + excelsior ECB) in construction site ditches can be very effective for sediment retention and turbidity reduction.


Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells.
The immunogenicity of long-surviving, enhanced (AS X AUG)F1 renal allografts retransplanted into secondary AS recipients was restored by the injection of small numbers of donor strain dendritic cells derived from afferent lymph. Whereas 1 X 10(4) to 5 X 10(4) dendritic cells were able to trigger an acute rejection response, neither the passenger volume of donor strain blood nor 5 X 10(6) T or B lymphocytes were able to do so, thereby demonstrating more than a 100-fold difference in immunogenic potency. It is concluded that intrarenal dendritic cells provide the major immunogenic stimulus of a kidney allograft. These results suggest that the antigenic strength of major histocompatibility complex-incompatible tissue correlates with the content of donor strain dendritic cells. They also provide further evidence that antigens of the major histocompatibility complex behave like conventional antigens unless they are on the surface of allogeneic dendritic cells.


The impact of localised general practice training on Queensland's rural and remote general practice workforce.
The diverse rural medical education initiatives that have been developed in Australia to address the medical workforce maldistribution have been less successful in many smaller and remote communities. This study explored the factors that attract and retain GP registrars and supervisors and the impact that localised training (i.e., rural and remote workplace-based training and support) has on both GP registrars and supervisors, and the GP workforce in rural and remote underserved areas. A purposive sample of 79 GP registrars, supervisors, practice managers, health services staff and community representatives living and working in areas of low GP workforce in rural and remote Australia were invited to participate in semi-structured interviews and one focus group divided over two phases. Thematic analysis was used to explore themes within the data. Attractors and barriers to rural and remote practice were identified as the main themes. Attractors include family and community lifestyle factors, individual intrinsic motivators, and remote medicine experiences. In contrast, barriers include work related, location, or family factors. Further, localised GP training was reported to specifically influence GP registrars and supervisors through education, social and financial factors. The current study has provided a contemporary overview of the issues encountered in expanding GP training capacity in rural and remote communities to improve the alignment of training opportunities with community and workforce needs. Strategies including matching scope of practice to registrar interests have been implemented to promote the attractors and lessen the barriers associated with rural and remote practice.


Family Connections: an approach for strengthening early care systems in facing depression and adversity.
Over a 4-year period, the authors worked in partnership with a large early care provider and a Head Start center to design and implement a systems-wide preventive program with the aim of increasing staff's capacity to deal with depression and related adversities in their encounters with families and children. The intervention consisted primarily of training sessions and mental health consultation. Staff interviews, focus groups, reports by consultants, observations by assessors, and documentation of staff use of sick time were used to assess program impact. Reports by staff showed that the intervention proved feasible to deliver and resulted in sustained parent, classroom, and teacher activities. Teachers were better able to deal with the challenges presented by parents and children. Results suggest that center-wide staff-focused training and consultation approaches deserve consideration.


Highlights from the 38th SABCS annual meeting, 8th - 12th December 2015, San Antonio, USA.
The 2015 San Antonio Breast Cancer Symposium (SABCS) annual meeting highlighted the latest discoveries in breast cancer research and as ever provided a unique opportunity for investigators from all over the world to meet and network. With the rapidly increasing pace of discoveries in the basic, translational, and clinical sciences, mainly because of the advent of new technologies, cancer researchers are making rapid progress that is having significant patient benefit. This year's meeting featured studies on targeted therapy plus endocrine therapy for metastatic disease with a mutation of PIK3CA, chemotherapy combinations for HER-2-positive disease, long-term outcomes of different surgeries for early-stage cancers, and the first-ever trial of a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor as an adjuvant treatment for breast cancer in postmenopausal women. In the educational session, there was significant emphasis on the role of metabolic syndrome and lifestyle on breast cancer outcome.


The possible role of the PK1 and its receptor in the etiology of the preeclampsia.
Preeclampsia (PE) is a hypertensive complication of the pregnancy. In our study we investigated the expression, localization, and signaling pathways of PK1 and PKR1 in third-trimester human placenta and myometrium and assessed the correlation between the PK1 and PKR1 expression and signaling and the incidence of the PE. We designed two study groups: pregnant PE patients and healthy, pregnant women. After collection, tissue was placed in RNAlater for RNA extraction, fixed in 4% neutral buffered formalin, and wax embedded for immunohistochemistry or placed in RPMI and transported to the laboratory for in vitro culture. We have collected and processed placental and myometrial biopsies from 40 patients - 19 were PE patients. Only the PK1 mRNA expression comparison between PE and CTRL in placenta showed statistically significant difference (p=0.004). There was statistically significant difference in cell signaling in myometrium controls in 30 minutes after ligand. The rise in pERK/tERK ratio is clearly visible in time intervals 20 and 30 minutes in controls, although with no statistical significance. There was no difference in PK1 and PKR1 localization in the placenta and myometrium in the groups. The number of PKR1 is not reduced in PE. The reduced PK1 mRNA expression is not than dependent on PKR1 mRNA expression. The data shows that ST produces much more PK1 in healthy pregnant women than those suffering from PE. We can conclude that in PE the production of PK1 is impaired and so are the endocrine functions of the ST.


The fitness cost of rifampicin resistance in Pseudomonas aeruginosa depends on demand for RNA polymerase.
Bacterial resistance to antibiotics usually incurs a fitness cost in the absence of selecting drugs, and this cost of resistance plays a key role in the spread of antibiotic resistance in pathogen populations. Costs of resistance have been shown to vary with environmental conditions, but the causes of this variability remain obscure. In this article, we show that the average cost of rifampicin resistance in the pathogenic bacterium Pseudomonas aeruginosa is reduced by the addition of ribosome inhibitors (chloramphenicol or streptomycin) that indirectly constrain transcription rate and therefore reduce demand for RNA polymerase activity. This effect is consistent with predictions from metabolic control theory. We also tested the alternative hypothesis that the observed trend was due to a general effect of environmental quality on the cost of resistance. To do this we measured the fitness of resistant mutants in the presence of other antibiotics (ciprofloxacin and carbenicillin) that have similar effects on bacterial growth rate but bind to different target enzymes (DNA gyrase and penicillin-binding proteins, respectively) and in 41 single-carbon source environments of varying quality. We find no consistent effect of environmental quality on the average cost of resistance in these treatments. These results show that the cost of rifampicin resistance varies with demand for the mutated target enzyme, rather than as a simple function of bacterial growth rate or stress.


Dynamic thermal time model of cold hardiness for dormant grapevine buds.
Grapevine (Vitis spp.) cold hardiness varies dynamically throughout the dormant season, primarily in response to changes in temperature. The development and possible uses of a discrete-dynamic model of bud cold hardiness for three Vitis genotypes are described. Iterative methods were used to optimize and evaluate model parameters by minimizing the root mean square error between observed and predicted bud hardiness, using up to 22 years of low-temperature exotherm data. Three grape cultivars were studied: Cabernet Sauvignon, Chardonnay (both V. vinifera) and Concord (V. labruscana). The model uses time steps of 1 d along with the measured daily mean air temperature to calculate the change in bud hardiness, which is then added to the hardiness from the previous day. Cultivar-dependent thermal time thresholds determine whether buds acclimate (gain hardiness) or deacclimate (lose hardiness). The parameterized model predicted bud hardiness for Cabernet Sauvignon and Chardonnay with an r(2) = 0·89 and for Concord with an r(2) = 0·82. Thermal time thresholds and (de-)acclimation rates changed between the early and late dormant season and were cultivar dependent but independent of each other. The timing of these changes was also unique for each cultivar. Concord achieved the greatest mid-winter hardiness but had the highest deacclimation rate, which resulted in rapid loss of hardiness in spring. Cabernet Sauvignon was least hardy, yet maintained its hardiness latest as a result of late transition to eco-dormancy, a high threshold temperature required to induce deacclimation and a low deacclimation rate. A robust model of grapevine bud cold hardiness was developed that will aid in the anticipation of and response to potential injury from fluctuations in winter temperature and from extreme cold events. The model parameters that produce the best fit also permit insight into dynamic differences in hardiness among genotypes.


Geographic and socio-demographic predictors of household food insecurity in Canada, 2011-12.
Household food insecurity is a potent social determinant of health and health care costs in Canada, but understanding of the social and economic conditions that underlie households' vulnerability to food insecurity is limited. Data from the 2011-12 Canadian Community Health Survey were used to determine predictors of household food insecurity among a nationally-representative sample of 120,909 households. Household food insecurity over the past 12 months was assessed using the 18-item Household Food Security Survey Module. Households were classified as food secure or marginally, moderately, or severely food insecure based on the number of affirmative responses. Multivariable binary and multinomial logistic regression analyses were used to determine geographic and socio-demographic predictors of presence and severity of household food insecurity. The prevalence of household food insecurity ranged from 11.8% in Ontario to 41.0% in Nunavut. After adjusting for socio-demographic factors, households' odds of food insecurity were lower in Quebec and higher in the Maritimes, territories, and Alberta, compared to Ontario. The adjusted odds of food insecurity were also higher among households reliant on social assistance, Employment Insurance or workers' compensation, those without a university degree, those with children under 18, unattached individuals, renters, and those with an Aboriginal respondent. Higher income, immigration, and reliance on seniors' income sources were protective against food insecurity. Living in Nunavut and relying on social assistance were the strongest predictors of severe food insecurity, but severity was also associated with income, education, household composition, Aboriginal status, immigration status, and place of residence. The relation between income and food insecurity status was graded, with every $1000 increase in income associated with 2% lower odds of marginal food insecurity, 4% lower odds of moderate food insecurity, and 5% lower odds of severe food insecurity. The probability of household food insecurity in Canada and the severity of the experience depends on a household's province or territory of residence, income, main source of income, housing tenure, education, Aboriginal status, and household structure. Our findings highlight the intersection of household food insecurity with public policy decisions in Canada and the disproportionate burden of food insecurity among Indigenous peoples.


Long-Term Efficacy of Maintenance Therapy for Multiple Myeloma: A Quantitative Synthesis of 22 Randomized Controlled Trials.
We aimed to quantitatively synthesize data from randomized controlled trials (RCTs) concerning maintenance for multiple myeloma (MM). We searched electronic literature databases and conference proceedings to identify relevant RCTs. We selected eligible RCTs using predefined selection criteria. We conducted meta-analysis comparing maintenance containing new agents and conventional maintenance, and subgroup analysis by transplantation status and mainstay agent as well. We performed trial sequential analysis (TSA) to determine adequacy of sample size for overall and subgroup meta-analyses. We performed network meta-analysis (NMA) to compare and rank included regimens. A total of 22 RCTs involving 9,968 MM patients and 15 regimens were included, the overall quality of which was adequate. Significant heterogeneity was detected for progression-free survival (PFS) but not overall survival (OS). Meta-analyses showed that maintenance containing new agents significantly improved PFS but not OS [PFS: Hazard Ratio (HR) = 0.59, 95% Confidence Interval (CI) = 0.54 to 0.64; OS: HR = 0.93, 95% CI = 0.87 to 1.00], compared with controls. Subgroup analyses revealed lenalidomide (Len)-based therapies better than thalidomide-based ones (HR = 0.50 and 0.66, respectively; P = 0.001). NMA revealed that most of the maintenance regimens containing new agents were significantly better than simple observation in terms of PFS but not OS. Len single agent was the most effective, considering PFS and OS both. We concluded that conventional maintenance has very limited effect. Maintenance containing new agents is highly effective in improving PFS, but has very limited effect on OS. Maintenance with Len may have the largest survival benefits. Emerging strategies may further change the landscape of maintenance of MM.


Anterior cruciate ligament reconstruction improves subjective ability but not neuromuscular biomechanics during dynamic tasks.
The purpose of this study was to identify high-functioning anterior cruciate ligament-deficient patients and assess the effects of reconstruction on their self-reported functionality, muscle activations and biomechanical properties. Twenty young and active patients participated pre- (11.5 ± 14.3 months post-injury) and again 10.5 ± 1.7 months post-reconstruction and were individually matched to 20 healthy controls. Participants completed hop and side cut movements while patient-related outcome measures, lower limb electromyography, kinetic, and whole body kinematic data were collected. One-dimensional statistical parametric mapping was used to test for group differences (healthy vs deficient; deficient vs reconstructed; reconstructed vs healthy). When comparing healthy to anterior cruciate ligament-deficient participants, all questionnaires indicated significant lower subjective function while the only substantial biomechanical difference between these participants was a decreased knee extensor moment in both the hop (peak difference: 0.63 Nm/kg, p < 0.001) and side cut (peak difference: 0.76 Nm/kg, p < 0.001). When comparing patients' pre- and post-reconstruction, no biomechanical differences were observed whereas only half of the questionnaires (Tegner, Lysholm, KNEES-ADL, KNEES-Slackness, KNEES-Looseness, KNEES-Sport Behaviour, IKDC, and KOOS-QoL) indicated higher function in the reconstructed state. When comparing the reconstructed patients to the healthy participants, all questionnaires were still significantly higher in the healthy controls. The reconstructed group also had a smaller flexion angle (peak difference: 14.5°, p = 0.007) and knee extensor moment (peak difference: 0.62 Nm/kg, p < 0.001) during the hop and a smaller knee extensor moment (peak difference: 0.90 Nm/kg, p < 0.001) during the side-cut task. At 10-months post-reconstruction, the current results indicate that in high-functioning anterior cruciate ligament-deficient patients, reconstruction had little impact on objective measures of functional ability during dynamic tasks although self-reported function was improved. Therapeutic prospective cohort study, Level II.


Lymphatic vessels in vascularized human corneas: immunohistochemical investigation using LYVE-1 and podoplanin.
To determine whether lymphatic vessels exist in vascularized human corneas, by using immunohistochemistry with novel markers for lymphatic endothelium. Human corneas exhibiting neovascularization secondary to keratitis, transplant rejection, trauma, and limbal insufficiency (n = 21) were assessed for lymphatic vessel content by conventional transmission electron microscopy and by immunostaining and immunoelectron microscopy with antibodies specific for the lymphatic endothelial markers, lymphatic vessel endothelial hyaluronan receptor (LYVE-1) and the 38-kDa integral membrane glycoprotein podoplanin. In addition, corneas were stained for the lymphangiogenic growth factor VEGF-C, and its receptor VEGFR3 by immunohistochemistry and in situ RNA hybridization, respectively. Thin-walled, erythrocyte-free vessels staining with lymphatic markers (LYVE-1 and podoplanin) were found to constitute 8% of all vessels, to be more common in the early course of neovascularization, to be always associated with blood vessels and stromal inflammatory cells, and to correlate significantly with the degree of corneal hemangiogenesis (r = 0.6; P = 0.005). VEGF-C, VEGFR3, podoplanin, and LYVE-1 colocalized on the endothelial lining of lymphatic vessels. With immunogold labeling, LYVE-1 and podoplanin antigen were found on endothelial cells lining vessels with ultrastructural features of lymph vessels. Immunohistochemistry with novel lymph-endothelium markers and ultrastructural analyses indicate the existence of lymphatic vessels in vascularized human corneas. Human corneal lymphangiogenesis appears to be correlated with the degree of corneal hemangiogenesis and may at least partially be mediated by VEGF-C and its receptor VEGFR3.


The Kadota Fund International Forum 2004--clinical group consensus.
The results from experimental studies indicate that hyperthermia is both an effective complementary treatment to, and a strong sensitiser of, radiotherapy and many cytotoxic drugs. Since the first international hyperthermia conference in 1975, Washington DC, techniques to increase tumour temperature have been developed and tested clinically. Hyperthermia can be applied by several methods: local hyperthermia by external or internal energy sources, perfusion hyperthermia of organs, limbs, or body cavities, and whole body hyperthermia. The clinical value of hyperthermia in combination with other treatment modalities has been shown by randomised trials. Significant improvement in clinical outcome has been demonstrated for tumours of the head and neck, breast, brain, bladder, cervix, rectum, lung, oesophagus, for melanoma and sarcoma. The addition of hyperthermia resulted in remarkably higher (complete) response rates, accompanied by improved local tumour control rates, better palliative effects, and/or better overall survival rates. Toxicity from hyperthermia cannot always be avoided, but is usually of limited clinical relevance. In spite of these good clinical results, hyperthermia has received little attention. Problems with acceptance concern the limited availability of equipment, the lack of awareness concerning clinical results, and the lack of financial resources. In this paper the most relevant literature describing the clinical effects of hyperthermia is reviewed and discussed, and means to overcome the lack of awareness and use of this modality is described.


The pathogenic basis of malaria.
Malaria is today a disease of poverty and underdeveloped countries. In Africa, mortality remains high because there is limited access to treatment in the villages. We should follow in Pasteur's footsteps by using basic research to develop better tools for the control and cure of malaria. Insight into the complexity of malaria pathogenesis is vital for understanding the disease and will provide a major step towards controlling it. Those of us who work on pathogenesis must widen our approach and think in terms of new tools such as vaccines to reduce disease. The inability of many countries to fund expensive campaigns and antimalarial treatment requires these tools to be highly effective and affordable.


Emerging Role of PACAP as a New Potential Therapeutic Target in Major Diabetes Complications.
Enduring diabetes increases the probability of developing secondary damage to numerous systems, and these complications represent a cause of morbidity and mortality. Establishing the causes of diabetes remains the key step to eradicate the disease, but prevention as well as finding therapies to ameliorate some of the major diabetic complications is an equally important step to increase life expectancy and quality for the millions of individuals already affected by the disease or who are likely to develop it before cures become routinely available. In this review, we will firstly summarize some of the major complications of diabetes, including endothelial and pancreatic islets dysfunction, retinopathy, and nephropathy, and then discuss the emerging roles exerted by the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) to counteract these ranges of pathologies that are precipitated by the prolonged hyperglycemic state. Finally, we will describe the main signalling routes activated by the peptide and propose possible future directions to focus on developing more effective peptide-based therapies to treat the major complications associated with longstanding diabetes.


Pneumococcal haemolytic uraemic syndrome in the postvaccine era.
Pneumococcal infection is a leading cause of haemolytic uraemic syndrome (HUS) and is potentially vaccine preventable. Published data suggest high mortality and poor renal outcomes. The introduction of the 7-valent pneumococcal conjugate vaccine (PCV) has seen the emergence of disease caused by non-vaccine strains, particularly 19A. We sought to describe serotype prevalence and outcomes, particularly after the introduction of the 13-valent PCV. We performed a retrospective chart review, using hospital medical records to identify cases of HUS in a tertiary paediatric hospital in Australia over a 20-year period (January 1997-December 2016). Associated pneumococcal infection was identified, and serotype data were categorised according to vaccine era: prevaccine (January 1997-December 2004), PCV7 (January 2005-June 2011) and PCV13 (July 2011-December 2016). We identified 66 cases of HUS. Pneumococcal infection was proven in 11 cases, representing 4% (1/26) of cases prior to the introduction of PCV7, 20% (3/15) in the PCV7 era and 28% (7/25) in the PCV13 era. Subtype 19A was the most prevalent pneumococcal serotype (6/11). All four patients who received PCV7 were infected with a non-vaccine serotype. Four of the five patients who received PCV13 were classed as vaccine failures. Median follow-up was 14 (range 1-108) months. Chronic kidney disease was the most common complication (4/7). We observed no mortality, neurological sequelae or progression to end-stage kidney disease. Serotype 19A is most commonly associated with pneumococcal HUS, despite the introduction of the 13-valent vaccine. Chronic kidney disease is a significant complication of pneumococcal HUS.


Understanding the transmission dynamics of Leishmania donovani to provide robust evidence for interventions to eliminate visceral leishmaniasis in Bihar, India.
Visceral Leishmaniasis (VL) is a neglected vector-borne disease. In India, it is transmitted to humans by Leishmania donovani-infected Phlebotomus argentipes sand flies. In 2005, VL was targeted for elimination by the governments of India, Nepal and Bangladesh by 2015. The elimination strategy consists of rapid case detection, treatment of VL cases and vector control using indoor residual spraying (IRS). However, to achieve sustained elimination of VL, an appropriate post elimination surveillance programme should be designed, and crucial knowledge gaps in vector bionomics, human infection and transmission need to be addressed. This review examines the outstanding knowledge gaps, specifically in the context of Bihar State, India.The knowledge gaps in vector bionomics that will be of immediate benefit to current control operations include better estimates of human biting rates and natural infection rates of P. argentipes, with L. donovani, and how these vary spatially, temporally and in response to IRS. The relative importance of indoor and outdoor transmission, and how P. argentipes disperse, are also unknown. With respect to human transmission it is important to use a range of diagnostic tools to distinguish individuals in endemic communities into those who: 1) are to going to progress to clinical VL, 2) are immune/refractory to infection and 3) have had past exposure to sand flies.It is crucial to keep in mind that close to elimination, and post-elimination, VL cases will become infrequent, so it is vital to define what the surveillance programme should target and how it should be designed to prevent resurgence. Therefore, a better understanding of the transmission dynamics of VL, in particular of how rates of infection in humans and sand flies vary as functions of each other, is required to guide VL elimination efforts and ensure sustained elimination in the Indian subcontinent. By collecting contemporary entomological and human data in the same geographical locations, more precise epidemiological models can be produced. The suite of data collected can also be used to inform the national programme if supplementary vector control tools, in addition to IRS, are required to address the issues of people sleeping outside.


Mortality Salience, System Justification, and Candidate Evaluations in the 2012 U.S. Presidential Election.
Experiments conducted during the 2004 and 2008 U.S. presidential elections suggested that mortality salience primes increased support for President George W. Bush and Senator John McCain, respectively. Some interpreted these results as reflecting "conservative shift" following exposure to threat, whereas others emphasized preferences for "charismatic" leadership following exposure to death primes. To assess both hypotheses in the context of a new election cycle featuring a liberal incumbent who was considered to be charismatic, we conducted four experiments shortly before the 2012 election involving President Barack Obama and Governor Mitt Romney. Contrary to earlier studies, there was little evidence that mortality salience, either by itself or in interaction with political orientation, affected overall candidate ratings or voting intentions. However, a significant interaction between mortality salience and system justification in some studies indicated a more circumscribed effect. The failure to "replicate" previous results in the context of this election may be attributable to disagreement among participants as to which of the candidates better represented the societal status quo.


Protective humoral response against pneumococcal infection in mice elicited by recombinant bacille Calmette-Guérin vaccines expressing pneumococcal surface protein A.
Pneumococcal surface protein A (PspA), a cell-surface protein present on all strains of pneumococci, has been shown to elicit protective antibody responses in mice in the absence of capsular polysaccharide. Whereas PspA is polymorphic, considerable cross-reactivity and cross-protection have been demonstrated among PspA proteins of pneumococci exhibiting different capsular and PspA serotypes. A gene segment encoding the nonrepetitive variable NH2-terminal portion of PspA has been cloned into three distinct recombinant Bacille Calmette-Guérin (rBCG) vectors, allowing for expression of PspA as a cytoplasmic or secreted protein, or a chimeric exported membrane-associated lipoprotein. All rBCG-PspA strains elicited comparable anti-PspA ELISA titers, ranging from 10(4) to 10(5) (reciprocal titers) in both BALB/c and C3H/HeJ mice. However, protective responses were observed only in animals immunized with the rBCG-PspA vaccines expressing PspA as a secreted protein or chimeric exported lipoprotein. In addition, anti-PspA immune sera elicited by the rBCG vaccines passively protected X-linked immunodeficient mice from lethal challenge with the highly virulent, encapsulated WU2 strain of Streptococcus pneumoniae and two additional virulent strains exhibiting heterologous PspA and capsular serotypes. These studies confirm previous PspA immunization studies showing cross-protection against heterologous serotypes of S. pneumoniae and demonstrate a potential for rBCG-based PspA vaccines to elicit protective humoral responses against pneumococcal disease in humans.


Metabolic syndrome and risk factors for non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD), hepatic manifestation of metabolic syndrome, has been considered the most common liver disease nowadays, which is also the most frequent cause of elevated transaminases and cryptogenic cirrhosis. The greatest input of fatty acids into the liver and consequent increased beta-oxidation contribute to the formation of free radicals, release of inflammatory cytokines and varying degrees of hepatocytic aggression, whose histological expression may vary from steatosis (HS) to non-alcoholic steatohepatitis (NASH). The differentiation of these forms is required by the potential risk of progression to cirrhosis and development of hepatocellular carcinoma. To review the literature about the major risk factors for NAFLD in the context of metabolic syndrome, focusing on underlying mechanisms and prevention. PubMed, MEDLINE and SciELO data basis analysis was performed to identify studies describing the link between risk factors for metabolic syndrome and NAFLD. A combination of descriptors was used, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, metabolic syndrome and risk factors. At the end, 96 clinical and experimental studies, cohorts, meta-analysis and systematic reviews of great impact and scientific relevance to the topic, were selected. The final analysis of all these data, pointed out the central obesity, type 2 diabetes, dyslipidemia and hypertension as the best risk factors related to NAFLD. However, other factors were highlighted, such as gender differences, ethnicity, genetic factors and the role of innate immunity system. How these additional factors may be involved in the installation, progression and disease prognosis is discussed. Risk factors for NAFLD in the context of metabolic syndrome expands the prospects to 1) recognize patients with metabolic syndrome at high risk for NAFLD, 2) elucidate pathways common to other co-morbidities, 3) determine risk factors associated with a worse prognosis, 4) develop therapeutic strategies with goal of reducing risk factors, 5) apply acquired knowledge in public health policies focusing on preventive strategies.


Cannabis for cancer - illusion or the tip of an iceberg: a review of the evidence for the use of Cannabis and synthetic cannabinoids in oncology.
A flowering plant of variegated ingredients and psychoactive qualities, Cannabis has long been used for medicinal and recreational purposes. Regulatory approvals have been gained across a broad range of palliative and therapeutic indications, and in some cases, included in standard treatment guidelines. The use of Cannabis and cannabinoid-based-medicines in oncology is summarized in this article. Cannabinoids are classified according to natural and synthetic subtypes and their mechanisms of action expounded. The variability of available products is discussed in the clinical context and data regarding chemotherapy-induced nausea and vomiting, cancer-related pain, anorexia, insomnia, and anxiety are presented. Moreover, immunological and antineoplastic effects in preclinical and clinical trials are addressed. Concepts such as synergism or opposition with conventional treatment modalities, the sequence of administration and dosage, molecular cross-talk and malignancy-cannabinoid congruence, are explored. Finally, side-effects, limitations in trial design and legislation barriers are related. Sufficient evidence supports the use of Cannabis for palliative indications in oncology; however, patients should be carefully selected, guided and followed. Promising research suggests the potent antineoplastic activity, but more data must be accrued before conclusions can be drawn.


Serum gamma-glutamyltransferase is inversely associated with dietary total and coffee-derived polyphenol intakes in apparently healthy Japanese men.
Serum γ-glutamyltransferase (GGT) has been proposed as a marker of oxidative stress. Here, we examined the association between serum GGT and the dietary intake of polyphenols, which have antioxidant properties. A cross-sectional survey including 7960 apparently healthy Japanese men (aged 22-86 years) who participated in health checkups was conducted in Shizuoka, Japan. We analyzed these subjects' clinical serum parameters and lifestyle factors, including dietary polyphenol intake, which was evaluated by a self-administered questionnaire and by matching the subjects' food consumption data with our original polyphenol content database. The average intake of polyphenols was 1157 ± 471 mg/day, and green tea was the largest source of polyphenols at 40%, followed by coffee at 36%. Dividing the population according to quintiles of total polyphenol intake, the difference in polyphenol intake from coffee between the groups was much greater than the difference in polyphenol intake from green tea. The analysis of the association between polyphenol intake and biological parameters showed a significant negative association between polyphenol intake and the levels of systolic and diastolic blood pressure (SBP and DBP), GGT, and alanine aminotransferase (ALT) after adjusting for age, smoking habit, energy intake and alcohol intake. The GGT levels were inversely associated with the polyphenol intake from coffee, but not with that from green tea. Multivariable linear regression analyses demonstrated that the subjects' GGT levels were negatively and independently associated with their polyphenol intake. The intake of total polyphenol including coffee as a major contributor is inversely associated with the serum GGT concentration in Japanese males.


Blockchain-Enabled iWellChain Framework Integration With the National Medical Referral System: Development and Usability Study.
Medical referral is the transfer of a patient's care from one physician to another upon request. This process involves multiple steps that require provider-to-provider and provider-to-patient communication. In Taiwan, the National Health Insurance Administration (NHIA) has implemented a national medical referral (NMR) system, which encourages physicians to refer their patients to different health care facilities to reduce unnecessary hospital visits and the financial stress on the national health insurance. However, the NHIA's NMR system is a government-based electronic medical referral service, and its referral data access and exchange are limited to authorized clinical professionals using their national health smart cards over the NHIA virtual private network. Therefore, this system lacks scalability and flexibility and cannot establish trusting relationships among patients, family doctors, and specialists. To eliminate the existing restrictions of the NHIA's NMR system, this study developed a scalable, flexible, and blockchain-enabled framework that leverages the NHIA's NMR referral data to build an alliance-based medical referral service connecting health care facilities. We developed a blockchain-enabled framework that can integrate patient referral data from the NHIA's NMR system with electronic medical record (EMR) and electronic health record (EHR) data of hospitals and community-based clinics to establish an alliance-based medical referral service serving patients, clinics, and hospitals and improve the trust in relationships and transaction security. We also developed a blockchain-enabled personal health record decentralized app (DApp) based on our blockchain-enabled framework for patients to acquire their EMR and EHR data; DApp access logs were collected to assess patients' behavior and investigate the acceptance of our personal authorization-controlled framework. The constructed iWellChain Framework was installed in an affiliated teaching hospital and four collaborative clinics. The framework renders all medical referral processes automatic and paperless and facilitates efficient NHIA reimbursements. In addition, the blockchain-enabled iWellChain DApp was distributed for patients to access and control their EMR and EHR data. Analysis of 3 months (September to December 2018) of access logs revealed that patients were highly interested in acquiring health data, especially those of laboratory test reports. This study is a pioneer of blockchain applications for medical referral services, and the constructed framework and DApp have been applied practically in clinical settings. The iWellChain Framework has the scalability to deploy a blockchain environment effectively for health care facilities; the iWellChain DApp has potential for use with more patient-centered applications to collaborate with the industry and facilitate its adoption.


Influences of reference plane and direction of measurement on eye aberration measurement.
We explored effects of measurement conditions on wave aberration estimates for uncorrected, axially myopic model eyes. Wave aberrations were initially referenced to either the anterior corneal pole or the natural entrance pupil of symmetrical eye models, with rays traced into the eye from infinity (into the eye) to simulate normal vision, into the eye from infinity and then back out of the eye from the retinal intercepts (into/out of the eye), or out of the eye from the retinal fovea (out of the eye). The into-the-eye and out-of-the-eye ray traces gave increases in spherical aberration as myopia increased, but the into/out-of-the-eye ray trace showed little variation in spherical aberration. Reference plane choice also affected spherical aberration. Corresponding residual aberrations were calculated after the models had been optically corrected, either by placing the object or image plane at the paraxial far point or by modifying corneas to simulate laser ablation corrections. Correcting aberrations by ablation was more complete if the original aberrations were referenced to the cornea rather than to the entrance pupil. For eyes corrected by spectacle lenses, failure to allow for effects of pupil magnification on apparent entrance pupil diameter produced larger changes in measured aberrations. The general findings regarding choice of reference plane and direction of measurement were found to be equally applicable to eyes that lacked rotational symmetry.


Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine.
The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge. Clozapine, an atypical antipsychotic drug, has long been of scientific interest, but its clinical development has been delayed because of an associated risk of agranulocytosis. This report describes a multicenter clinical trial to assess clozapine's efficacy in the treatment of patients who are refractory to neuroleptics. DSM-III schizophrenics who had failed to respond to at least three different neuroleptics underwent a prospective, single-blind trial of haloperidol (mean dosage, 61 +/- 14 mg/d) for six weeks. Patients whose condition remained unimproved were then randomly assigned, in a double-blind manner, to clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Two hundred sixty-eight patients were entered in the double-blind comparison. When a priori criteria were used, 30% of the clozapine-treated patients were categorized as responders compared with 4% of chlorpromazine-treated patients. Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Although no cases of agranulocytosis occurred during this relatively brief study, in our view, the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients.


Multimodality imaging of β-cells in mouse models of type 1 and 2 diabetes.
β-Cells that express an imaging reporter have provided powerful tools for studying β-cell development, islet transplantation, and β-cell autoimmunity. To further expedite diabetes research, we generated transgenic C57BL/6 "MIP-TF" mice that have a mouse insulin promoter (MIP) driving the expression of a trifusion (TF) protein of three imaging reporters (luciferase/enhanced green fluorescent protein/HSV1-sr39 thymidine kinase) in their β-cells. This should enable the noninvasive imaging of β-cells by charge-coupled device (CCD) and micro-positron emission tomography (PET), as well as the identification of β-cells at the cellular level by fluorescent microscopy. MIP-TF mouse β-cells were multimodality imaged in models of type 1 and type 2 diabetes. MIP-TF mouse β-cells were readily identified in pancreatic tissue sections using fluorescent microscopy. We show that MIP-TF β-cells can be noninvasively imaged using microPET. There was a correlation between CCD and microPET signals from the pancreas region of individual mice. After low-dose streptozotocin administration to induce type 1 diabetes, we observed a progressive reduction in bioluminescence from the pancreas region before the appearance of hyperglycemia. Although there have been reports of hyperglycemia inducing proinsulin expression in extrapancreatic tissues, we did not observe bioluminescent signals from extrapancreatic tissues of diabetic MIP-TF mice. Because MIP-TF mouse β-cells express a viral thymidine kinase, ganciclovir treatment induced hyperglycemia, providing a new experimental model of type 1 diabetes. Mice fed a high-fat diet to model early type 2 diabetes displayed a progressive increase in their pancreatic bioluminescent signals, which were positively correlated with area under the curve-intraperitoneal glucose tolerance test (AUC-IPGTT). MIP-TF mice provide a new tool for monitoring β-cells from the single cell level to noninvasive assessments of β-cells in models of type 1 diabetes and type 2 diabetes.


Telehealth interventions for schizophrenia-spectrum disorders and clinical high-risk for psychosis individuals: A scoping review.
Despite its increased use in mental health, both health care provision by telehealth and research are in the early stages. Videoconferencing, a telehealth subfield, has been mainly used for the medication management and delivery of psychological treatments for mood, adjustment and anxiety disorders, and to a lesser extent for psychotic disorders. The focus of this scoping review is on studies using videoconferencing for intervention for individuals with a diagnosis of schizophrenia-spectrum disorder and those who may be considered to be in the very early stages of psychosis (clinical high risk). The aim of this review is to assess the feasibility, acceptability and clinical benefits of videoconferencing interventions and compare them with face-to-face interventions for this population. A scoping review of peer-reviewed original research on the use of videoconferencing for intervention purposes in individuals with a schizophrenia-spectrum disorder or at clinical high risk. Out of 13,750 citations, 60 articles were retrieved for detailed evaluation, resulting in 14 eligible studies (N = 439 individuals). There was no study reporting on videoconferencing interventions for individuals at clinical high risk. All the studies reported that videoconferencing implementation was feasible, and most of them described high acceptance by individuals with a schizophrenia-spectrum disorder. However, selection bias of studies was high, and overall methodological quality was poor. Videoconferencing interventions seem feasible for participants with schizophrenia-spectrum disorder who showed high acceptance of this intervention modality.


The hitchhiking effect on linkage disequilibrium between linked neutral loci.
We analyzed a three-locus model of genetic hitchhiking with one locus experiencing positive directional selection and two partially linked neutral loci. Following the original hitchhiking approach by Maynard Smith and Haigh, our analysis is purely deterministic. In the first half of the selected phase after a favored mutation has entered the population, hitchhiking may lead to a strong increase of linkage disequilibrium (LD) between the two neutral sites if both are <0.1 s away from the selected site (where s is the selection coefficient). In the second half of the selected phase, the main effect of hitchhiking is to destroy LD. This occurs very quickly (before the end of the selected phase) when the selected site is between both neutral loci. This pattern cannot be attributed to the well-known variation-reducing effect of hitchhiking but is a consequence of secondary hitchhiking effects on the recombinants created in the selected phase. When the selected site is outside the neutral loci (which are, say, <0.1s apart), however, a fast decay of LD is observed only if the selected site is in the immediate neighborhood of one of the neutral sites (i.e., if the recombination rate r between the selected site and one of the neutral sites satisfies r<<0.1 s). If the selected site is far away from the neutral sites (say, r > 0.3 s), the decay rate of LD approaches that of neutrality. Averaging over a uniform distribution of initial gamete frequencies shows that the expected LD at the end of the hitchhiking phase is driven toward zero, while the variance is increased when the selected site is well outside the two neutral sites. When the direction of LD is polarized with respect to the more common allele at each neutral site, hitchhiking creates more positive than negative linkage disequilibrium. Thus, hitchhiking may have a distinctively patterned LD-reducing effect, in particular near the target of selection.


An Open Data Format for Visualization and Analysis of Cross-Linked Mass Spectrometry Results.
Protein-protein interactions are an important element in the understanding of protein function, and chemical cross-linking shotgun mass spectrometry is rapidly becoming a routine approach to identify these specific interfaces and topographical interactions. Protein cross-link data analysis is aided by dozens of algorithm choices, but hindered by a lack of a common format for representing results. Consequently, interoperability between algorithms and pipelines utilizing chemical cross-linking remains a challenge. pepXML is an open, widely-used format for representing spectral search algorithm results that has facilitated information exchange and pipeline development for typical shotgun mass spectrometry analyses. We describe an extension of this format to incorporate cross-linking spectral search results. We demonstrate application of the extension by representing results of multiple cross-linking search algorithms. In addition, we demonstrate adapting existing pepXML-supporting software pipelines to analyze protein cross-linking results formatted in pepXML. Graphical Abstract .


Effect of a robotic rehabilitation device on upper limb function in a sub-acute cervical spinal cord injury population.
Robotic rehabilitation devices have been suggested as a tool to increase the amount of rehabilitation delivered after a neurological injury. Clinical robotic rehabilitation studies of the upper extremity have generally focused on stroke survivors. We present the results of a multi-center pilot study where an upper-limb robotic rehabilitation device (Armeo Spring®, Hocoma AG) was incorporated into the rehabilitation program of 12 subjects with sub-acute cervical spinal cord injury (motor level C4-C6, AIS A-D). Outcomes were measured using two tests of upper extremity function: ARAT and GRASSP. The change in scores for the arm receiving the Armeo training were not statistically significant when compared to the arm not receiving the Armeo training at discharge from therapy and over follow up assessments (8.7 +/- 2.9 compared to 7.4 +/- 2.5 for ARAT at discharge, p = 0.98, and 13.0 +/- 3.2 compared to 13.3 +/- 3.3 for GRASSP at discharge, p = 0.69). Nevertheless, subjects with some minimal (partial) hand function at baseline had a significantly larger increase in GRASSP scores than subjects with no minimal hand function preserved at baseline (19.3 +/- 2.4 compared to 6.6 +/- 4.7, p = 0.02). This suggests that the initial functional capabilities of patients can influence the benefits measured after robotic rehabilitation training and heterogeneous subject populations should be avoided in early phase studies.


Dental therapy before and after radiotherapy--an evaluation on patients with head and neck malignancies.
The present investigation evaluates the dental care situation of patients with head and neck cancer before and after radiotherapy. The situations of these patients in 1993 and 2005 were compared to detect similarities, differences and developments. In the years 1993 and 2005, 37 and 36 patients, respectively, with head and neck cancer treated by the local departments of otorhinolaryngology and of radiotherapy were examined consecutively according to their aftercare appointments. Time points of radiotherapy treatment of the patients evaluated in 1993 varied from 1984 to 1993. The patients evaluated in 2005 had received radiotherapy between 1998 and 2005. Therefore the applied radiotherapeutic regimen differed not only between the two groups of patients, but also within each group. The information for these investigations was provided anonymously. It was evaluated with descriptive statistics. The evaluation of the data shows distinct differences with respect to preventive and therapeutic dental care measures. In 2005, 35 out of 36 patients (97.2%) had a dental consultation before radiotherapy (1993, 65%). All 27 dentate patients (100%) obtained a splint for fluoride application (1993, none). 29% fewer edentulous patients were seen than in 1993. The number of teeth destroyed decreased from 19.2% (1993) to 7.8% in 2005. Mycoses due to Candida spp. and chronic failures in wound healing were rare (5.5%). In the course of the 12 years, prophylactic measures, such as the application of splints for fluoride treatment, were intensified. However, concepts for the dental care of patients undergoing radiotherapy, especially following the radiation, should be widened to avoid ruined teeth and long delayed wound healings.


Repeatedly high polycyclic aromatic hydrocarbon exposure and cockroach sensitization among inner-city children.
Exposures to traffic-related air pollutants including polycyclic aromatic hydrocarbons (PAH) have been associated with the development and exacerbation of asthma. However, there is limited evidence on whether these pollutants are associated with the development of cockroach sensitization, a strong risk factor for urban asthma. We hypothesized that repeatedly high PAH exposure during childhood would be associated with increased risk of new cockroach sensitization. As part of the research being conducted by the Columbia Center for Children's Environmental Health (CCCEH) birth cohort study in New York, a spot urine sample was collected from children at age 5 years (2003-2008) and again at age 9-10 years (2008-2012; n=248) and analyzed for 10 PAH metabolites. Repeatedly high PAH (High-High) exposure was defined as measures above median for age 5 PAH metabolites at both time points. Child blood samples at age 5 and 9 years were analyzed for total, anti-cockroach, mouse, dust mite, cat and dog IgE. Relative risks (RR) were estimated with multivariable modified Poisson regression. Individual PAH metabolite levels, except for 1-naphthol (1-OH-NAP), increased by 10-60% from age 5 to age 9-10. The prevalence of cockroach sensitization increased from 17.6% (33/188) at age 5 to 33.0% (62/188) at 9 years (p=0.001). After controlling for potential covariates including cockroach sensitization at age 5 in regression analyses, positive associations were found between repeatedly high exposure (High-High) to 1-OH-NAP, 3-hydroxyphenanthrene (3-OH-PHEN), or 1-hydroxypyrene (1-OH-PYR) and cockroach sensitization at age 9 (p-values<0.05). Compared to Low-Low exposure, the relative risk (RR) [95% CI] with repeatedly high exposure was 1.83 [1.06-3.17] for 1-OH-NAP, 1.54 [1.06-2.23] for 3-OH-PHEN, and 1.59 [1.04-2.43] for 1-OH-PYR. Repeatedly high levels of urinary PAH metabolites during childhood may increase likelihood of sensitization to cockroach allergen in urban inner-city children at age 9 years.


Behavioural pharmacology of octopamine, tyramine and dopamine in honey bees.
In the honey bee, responsiveness to sucrose correlates with many behavioural parameters such as age of first foraging, foraging role and learning. Sucrose responsiveness can be measured using the proboscis extension response (PER) by applying sucrose solutions of increasing concentrations to the antenna of a bee. We tested whether the biogenic amines octopamine, tyramine and dopamine, and the dopamine receptor agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN) can modulate sucrose responsiveness. The compounds were either injected into the thorax or fed in sucrose solution to compare different methods of application. Injection and feeding of tyramine or octopamine significantly increased sucrose responsiveness. Dopamine decreased sucrose responsiveness when injected into the thorax. Feeding of dopamine had no effect. Injection of 6,7-ADTN into the thorax and feeding of 6,7-ADTN reduced sucrose responsiveness significantly. These data demonstrate that sucrose responsiveness in honey bees can be modulated by biogenic amines, which has far reaching consequences for other types of behaviour in this insect.


The PKC, HOG and Ca2+ signalling pathways co-ordinately regulate chitin synthesis in Candida albicans.
Chitin is an essential component of the fungal cell wall and its synthesis is under tight spatial and temporal regulation. The fungal human pathogen Candida albicans has a four member chitin synthase gene family comprising of CHS1 (class II), CHS2 (class I), CHS3 (class IV) and CHS8 (class I). LacZ reporters were fused to each CHS promoter to examine the transcriptional regulation of chitin synthesis. Each CHS promoter had a unique regulatory profile and responded to the addition of cell wall damaging agents, to mutations in specific CHS genes and exogenous Ca2+. The regulation of both CHS gene expression and chitin synthesis was co-ordinated by the PKC, HOG MAP kinase and Ca2+/calcineurin signalling pathways. Activation of these pathways also resulted in increased chitin synthase activity in vitro and elevated cell wall chitin content. Combinations of treatments that activated multiple pathways resulted in synergistic increases in CHS expression and in cell wall chitin content. Therefore, at least three pathways co-ordinately regulate chitin synthesis and activation of chitin synthesis operates at both transcriptional and post-transcriptional levels.


Biological Markers in DCIS and Risk of Breast Recurrence: A Systematic Review.
Understanding of the biology and clinical behavior of ductal carcinoma in situ (DCIS) is currently inadequate. The aim of this comprehensive review was to identify important molecular biological markers associated with DCIS and candidate markers associated with increased risk of ipsilateral recurrence after diagnosis of DCIS. A comprehensive systematic review was performed to identify studies published in the past 10 years that investigated biological markers in DCIS. To be included in this review, studies that investigated the rate of biological expression of markers had to report on at least 30 patients; studies that analyzed the recurrence risk associated with biomarker expression had to report on at least 50 patients. There were 6,252 patients altogether in our review. Biological markers evaluated included steroid receptors, proliferation markers, cell cycle regulation and apoptotic markers, angiogenesis-related proteins, epidermal growth factor receptor family receptors, extracellular matrix-related proteins, and COX-2. Although the studies in this review provide valuable preliminary information regarding the expression and prognostic significance of biomarkers in DCIS, common limitations of published studies (case-series, cohort, and case-control studies) were that they were limited to small patient cohorts in which the extent of surgery and use of radiotherapy or endocrine therapy varied from patient to patient, and variable methods of determining biomarker expression. These constraints made it difficult to interpret the absolute effect of expression of various biomarkers on risk of local recurrence. No prospective validation studies were identified. As the study of biomarkers are in their relative infancy in DCIS compared with invasive breast cancer, key significant prognostic and predictive markers associated with invasive breast cancer have not been adequately studied in DCIS. There is a critical need for prospective analyses of novel and other known breast cancer molecular markers in large cohorts of patient with DCIS to differentiate indolent from aggressive DCIS and better tailor the need and extent of current therapies.


Mif deficiency promotes adiposity in fructose-fed mice.
The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in inflammation, regulation of energy metabolism and glucocorticoid action. Chronic low-grade inflammation may be caused by fructose intake, contributing to visceral adipose tissue (VAT) dysfunction. Since MIF is a known antagonist of glucocorticoid signaling, and deregulated glucocorticoid signaling can contribute to lipid metabolism disturbances, we hypothesized that altered MIF signaling might underlie fructose-induced adiposity through glucocorticoid action. We analyzed physiological and biochemical parameters, adipose tissue histology, insulin sensitivity and lipid metabolism in WT and MIF-/- C57Bl/6J mice consuming 20% fructose solution for 9 weeks. Glucocorticoid prereceptor metabolism and glucocorticoid receptor (GR) protein level were examined in VAT, together with the expression of glucocorticoid-target genes involved in lipid metabolism. The expression of adipogenic and lipogenic transcriptional regulators peroxisome proliferator-activated receptor gamma (PPARG) and sterol regulatory element-binding protein 1c (SREBP1c) was also assessed. Results showed disturbed insulin sensitivity in all MIF-/- mice, regardless of the diet. Mice on fructose diet had increased energy intake, but increased visceral adiposity and enlarged adipocytes were observed only in fructose-fed MIF-/- mice. Increased VAT corticosterone level and 11 beta-hydroxysteroid dehydrogenase type 1, hexose-6-phosphate dehydrogenase and GR protein levels were observed in the same animals, together with induced expression of examined lipogenic genes and accumulation of PPARG and SREBP1c. In conclusion, the results showed that dietary fructose was associated with increased visceral adiposity through activation of GR-regulated lipogenic genes, but only in the absence of MIF, which set the state of hyperinsulinemia and insulin resistance.


Recellularization of a novel off-the-shelf valve following xenogenic implantation into the right ventricular outflow tract.
Current research on valvular heart repair has focused on tissue-engineered heart valves (TEHV) because of its potential to grow similarly to native heart valves. Decellularized xenografts are a promising solution; however, host recellularization remains challenging. In this study, decellularized porcine aortic valves were implanted into the right ventricular outflow tract (RVOT) of sheep to investigate recellularization potential. Porcine aortic valves, decellularized with sodium dodecyl sulfate (SDS), were sterilized by supercritical carbon dioxide (scCO2) and implanted into the RVOT of five juvenile polypay sheep for 5 months (n = 5). During implantation, functionality of the valves was assessed by serial echocardiography, blood tests, and right heart pulmonary artery catheterization measurements. The explanted valves were characterized through gross examination, mechanical characterization, and immunohistochemical analysis including cell viability, phenotype, proliferation, and extracellular matrix generation. Gross examination of the valve cusps demonstrated the absence of thrombosis. Bacterial and fungal stains were negative for pathogenic microbes. Immunohistochemical analysis showed the presence of myofibroblast-like cell infiltration with formation of new collagen fibrils and the existence of an endothelial layer at the surface of the explant. Analysis of cell phenotype and morphology showed no lymphoplasmacytic infiltration. Tensile mechanical testing of valve cusps revealed an increase in stiffness while strength was maintained during implantation. The increased tensile stiffness confirms the recellularization of the cusps by collagen synthesizing cells. The current study demonstrated the feasibility of the trans-species implantation of a non-fixed decellularized porcine aortic valve into the RVOT of sheep. The implantation resulted in recellularization of the valve with sufficient hemodynamic function for the 5-month study. Thus, the study supports a potential role for use of a TEHV for the treatment of valve disease in humans.


Adult paravertebral pleomorphic rhabdomyosarcoma infiltrating diffusely the whole spinal axis. Case report.
The authors report a unique case of diffuse spinal metastatic disease due to a pleomorphic rhabdomyosarcoma (RMS) in an adult. In addition to its overall rarity, peculiar characteristics of the particular tumor included its site of origin, demonstrated radiologically as the lumbar paravertebral musculature (psoas muscle) and the transcanalicular spread into the vertebral canal, resulting in thecal compression at multiple levels. The salient clinicopathological characteristics of RMS, as they related particularly to the spine, are subsequently discussed and a short review of the major therapeutic modalities for these tumors is offered.


Management of people with venous leg ulcers by Australian general practitioners: An analysis of the national patient-encounter data.
Venous Leg Ulcers cost Australia's healthcare system millions yearly, as they are underdiagnosed, and possibly undertreated. Most Venous Leg Ulcers are seen in general practice. However, it is currently unknown as to what treatment actions are most common in these contexts. Understanding how they are managed in these settings can improve healthcare delivery and patient outcomes. Using cross-sectional general practitioner patient encounter data collected April 2006 to March 2016 from the Bettering the Evaluation and Care of Health program, a continuous national study of general practice clinical activity in Australia, we aimed to describe the characteristics of venous leg ulcer management by general practitioners in Australia. Among the 972 100 general practitioner-patient encounters recorded, 3604 (0.34%) involved management of VLU. Male general practitioners managed Venous Leg Ulcers significantly more often than female general practitioners. Most Venous Leg Ulcers were treated via dressings (76%) and/or pharmacological treatments (25.7%), with few patients receiving the best practice treatment of medical compression (2.1%) or referral (4.9%). Patients with new (first visit) Venous Leg Ulcers were more likely to receive pharmacological treatments and to be referred elsewhere, and less likely to receive dressings than patients receiving follow-up care. There appears to be a large gap between best practice guidelines and actual Venous Leg Ulcers treatments, as referrals and appropriate treatment was low. Further longitudinal studies are needed to determine the effectiveness of care for people with Venous Leg Ulcers who are managed by general practitioners.


Social constructions of gender roles, gender-based violence and HIV/AIDS in two communities of the Western Cape, South Africa.
The links between gender roles, gender-based violence and HIV/AIDS risk are complex and culturally specific. In this qualitative study we investigated how women and men in two black communities in the Western Cape, South Africa, constructed their gender identities and roles, how they understood gender-based violence, and what they believed about the links between gender relations and HIV risk. First we conducted 16 key informant interviews with members of relevant stakeholder organisations. Then we held eight focus group discussions with community members in single-sex groups. Key findings included the perception that although traditional gender roles were still very much in evidence, shifts in power between men and women were occurring. Also, gender-based violence was regarded as a major problem throughout communities, and was seen to be fuelled by unemployment, poverty and alcohol abuse. HIV/AIDS was regarded as particularly a problem of African communities, with strong themes of stigma, discrimination, and especially 'othering' evident. Developing effective HIV/AIDS interventions in these communities will require tackling the overlapping as well as divergent constructions of gender, gender violence and HIV which emerged in the study.


SARS-CoV-2 outbreak on the Caribbean islands of the Dutch Kingdom: a unique challenge.
As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic progresses, countries are depending on one another to acquire knowledge regarding effective measures to contain the virus. Public health measures to suppress transmissions have proven successful in Singapore, Hong Kong and Taiwan. Implementing and adhering to these interventions is challenging, with governments struggling to find a balance between necessary mitigation and suppression strategies, and interruptions of social-economic activities. While large high-income countries are struggling to keep their health systems and economies moving forward, small island developing states are facing even more significant challenges. Many Caribbean islands, including the six islands within the Dutch Kingdom, have been quick to implement stringent public health measures, yet they are facing unique challenges.