Impairment of the endothelial glycocalyx in cardiogenic shock and its prognostic relevance.
In cardiogenic shock (CS), pathophysiological changes include microcirculatory dysfunction, vascular leakage, and an increase in platelet and leukocyte adhesion to the endothelium, as well as endothelial activation and dysfunction. The endothelial glycocalyx has been recognized as a central modulator of these processes. Glycosaminoglycan heparan sulfate is a major component of the glycocalyx of endothelial cells, and syndecan-1 (S1) represents the most prevalent proteoglycan. The aim of the current study was to investigate circulating levels of the glycocalyx components in patients with infarct-related CS. In 184 patients with CS complicating acute myocardial infarction, blood samples were collected at admission and after one day. Intra-aortic balloon pumping was used in 94 patients (51%). Glycosaminoglycan heparan sulfate and S1 were measured using standard enzyme-linked immunosorbent assay kits. All-cause mortality at 30 days was used for outcome assessment. Levels of S1 decreased between days 1 and 2 (339 [interquartile range [QR], 109-852] vs. 220 [IQR, 57-606] ng/mL; P = 0.01). In contrast, glycosaminoglycan heparan sulfate increased over time (1.9 [IQR, 0.3-6.4] vs. 7.1 [IQR, 3.7-11.7] mg/mL; P < 0.001). Survivors at 30 days had lower admission S1 levels (P < 0.001). In multivariable analysis, S1 remained an independent predictor of 30-day mortality (odds ratio per μg/mL, 2.2 [95% confidence interval, 1.30-3.58]; P = 0.003) together with serum lactate, age, and ejection fraction. Increased levels of S1 are an independent predictor of short-term mortality in patients with acute myocardial infarction and CS.ClinicalTrials.gov Identifier: NCT00491036.


Inhibitory effects of flavonoids on molybdenum hydroxylases activity.
Molybdenum hydroxylases, aldehyde oxidase and xanthine oxidase, are metalloflavoproteins that catalyze both oxidation and reduction of a broad range of drugs and other xenobiotics indicating the importance of these enzymes in drug oxidation, detoxification and activation. Both enzymes are also involved in some physiological processes and also the metabolism of some endogenous compounds which may indicate their important roles in in vivo conditions. Superoxide radical and hydrogen peroxide produced during molybdenum hydroxylases-catalyzed reactions may be relevant in various disease conditions. Therefore, the interference with the function of molybdenum hydroxylases could be of great importance. Flavonoids are a large group of polyphenolic compounds that are able to interfere with xanthine oxidase and aldehyde oxidase function. As flavonoids are consumed in high content in our daily life, their potential to interfere with molybdenum hydroxylases could be a serious concern for consumer safety. However, the subject has not received enough attention and has usually been overshadowed by that of cytochrome P450 as the most important drug metabolizing enzyme system. The present review focuses on the different aspects of flavonoids interaction with molybdenum hydroxylases considering literature published mainly in the last 2 decades. The review also provides insight into some research areas that may offer a great potential for future studies.


[Immediate results of conservative treatment of patients with unreconstructable critical limb ischaemia and trophic changes].
The purpose of the study was to comparatively assess efficacy of using agents belonging to the group of prostaglandin E1 in comprehensive conservative treatment of patients with unreconstructable critical limb ischaemia and trophic changes by the frequency of major amputation, amputation-free survival, and total mortality by combinations of the WIfI classification during a 6-month follow up period. Our retrospective multicentre study enrolled a total of 109 patients, including 60 men and 49 women, with a mean age of 70±7.3 years. The patients were subdivided into 2 groups. Group 1 patients (n=58) received standard conservative therapy without prostaglandin E1 and group 2 patients (n=51) received similar treatment with the use of prostaglandin E1. The statistical analysis (chi-squared test, Fisher criterion, log-rank test) was carried out with regard to stratification of the patients in the groups by the WIfI component combinations. No statistically significant differences between the groups in the frequency of amputation and total mortality were revealed (p=0.094 and p=0.925, respectively). The use of the WIfI classification system made it possible to single out a cohort of patients (with a WIfI combination of 130) for whom the results of administering prostaglandin E1 statistically significantly differed by the frequency of amputation (p=0.042) and by amputation-free survival (p=0.017). No significant differences by these outcomes were obtained for other combinations analysed. A conclusion was drawn that using prostaglandin E1 in comprehensive conservative treatment decreased the frequency of amputation and increased amputation-free survival in patients presenting with unreconstructable critical limb ischaemia and referred to the category with a combination of 130 according to the WIfI classification.


Cloning and expression of the 44-kilodalton major outer membrane protein gene of the human granulocytic ehrlichiosis agent and application of the recombinant protein to serodiagnosis.
A 44-kDa major outer membrane protein of the human granulocytic ehrlichiosis (HGE) agent is an immunodominant antigen in human infection. A gene encoding this protein was cloned and sequenced. Southern blot results revealed the existence of multigenes homologous to the P44 gene in the genome of the HGE agent. The recombinant 44-kDa protein (rP44) was expressed by using expression vector pET30a. The reactivity of the affinity-purified rP44 was evaluated by Western immunoblot analysis and dot blot immunoassay. Western immunoblot analysis showed that mouse anti-rP44 serum reacted with 44- to 42-kDa proteins in six different HGE agent strains tested except strain 2, in which three proteins of 42, 40, and 38 kDa were recognized. Eleven HGE patient serum samples, a horse anti-HGE serum, and a horse anti-Ehrlichia equi serum recognized the rP44 protein. This suggests that rP44 is an HGE-E. equi group-specific antigen. Neither human anti-Ehrlichia chaffeensis serum nor rabbit anti-Borrelia burgdorferi serum reacted with rP44. Sera from two patients coinfected with the HGE agent and B. burgdorferi reacted positively with rP44 and the HGE agent. Sera from 20 HGE patients with indirect fluorescent-antibody (IFA) titers ranging from 1:20 to 1:2,560 gave distinct positive reactions in a dot immunoblot assay. There was a positive correlation between the color densities of the dot reactions and the IFA titers when greater than 50 ng of recombinant antigen per dot was used. The use of the affinity-purified rP44 protein as antigen would provide a more specific, consistent, and simpler serodiagnosis for HGE than the use of whole infected cells or purified HGE agents.


Highly polarization-sensitive far infrared detector based on an optical antenna integrated aligned carbon nanotube film.
Polarization detection is another important way to characterize a light field in addition to intensity and spectrum. This is required for high-fidelity information acquisition and high precision target recognition in the infrared detection region. Single-wall carbon nanotube (SWCNT) films have been investigated for infrared detection with considerable sensitivity at room temperature based on the photothermoelectric effect. In this work, a bowtie antenna integrated aligned SWCNT film is proposed for highly polarization sensitive, far infrared detection. The SWCNT film is shaped into a belt and doped with diverse agents to form a p-n junction at the center. The SWCNTs are arranged perpendicular to the electronic transportation direction. The antenna is aligned at the junction and along the SWCNTs. Based on the following four factors: (1) deep-subwavelength light concentration at the junction, (2) alignment between the SWCNTs and the antenna, (3) anisotropic heat transfer in the aligned SWCNT film, and (4) light field reduction within the gap of the bowtie antenna for the polarization perpendicular to the antenna axis, the ratio between the responsivities for the polarizations parallel and perpendicular to the SWCNTs could be higher than 13 600. By changing the size of the antenna, the resonant frequency could be tuned. Over the range from 0.5 to 1.5 THz, the peak polarization extinction ratios at different resonant frequencies are all bigger than 700, and they are 16 to 320 times higher than that of the aligned SWCNT belt without the antenna. Moreover, the integration of the antenna and the aligned SWCNT belt also enhances the responsivity by 1 to 2 orders of magnitude. Compared to an aligned multi-wall carbon nanotube (MWCNT) film, an aligned SWCNT film integrated with an optical antenna is more favorable for highly polarization sensitive, far infrared detection. The result is based on the numerical simulations of the light and the thermal fields.


Reproductive effort of Mastocarpus papillatus (Rhodophyta) along the California coast.
Species with sexual and asexual life cycles may exhibit intraspecific differences in reproductive effort. The spatial separation of sexual and asexual lineages, called geographic parthenogenesis, is common in plants, animals and algae. Mastocarpus papillatus is a well-documented case of geographic parthenogenesis in which sexuals dominate southern populations, asexuals dominate northern populations, while mixed populations occur throughout central California. We quantified abundances and reproductive effort of sexual and asexual fronds and tetrasporophytes at eight sites in California to test the hypotheses that (1) reduced sexual reproduction at higher latitudes and tidal heights explains the observed geographic parthenogenesis and (2) reproductive effort (spore production per blade area) declines with increasing latitude. Abundances of all phases varied site-specifically. However, there was no geographic pattern of reproductive effort of fronds. Reproductive effort of fronds was greater in 2006 than in 2007 and correlated with sea surface temperatures. Sexual fronds exhibited greater reproductive effort than did asexual fronds and sexual reproductive effort was also inversely correlated with local upwelling index. Tetrasporophytes showed greater reproductive effort in northern sites, but total supply of tetraspores per m2 was greatest in the middle of the sampling range where crusts were more abundant. There was no decline of reproductive effort at higher latitudes. Geographic patterns of fecundity of life stages do not explain geographic parthenogenesis in M. papillatus. Site-specific differences in viability among spores or established thalli of different life cycles may explain their respective geographic distributions, as the sexual and asexual life cycles responded differently to environmental variations.


Interstitial adenosine triphosphate modulates muscle afferent nerve-mediated pressor reflex.
Previous work has shown that muscle contraction elevates interstitial adenosine triphosphate concentration ([ATP]i), which is likely due to the release of ATP from active skeletal muscle. ATP activation of purinergic receptors P2X on thin muscle afferent fibers further enhances cardiovascular responses to contraction. Thus, the purposes of this study were: (1) to examine the mechanisms by which ATP is released from muscle in response to mechanical stimulation; and (2) to study the effects of interstitial ATP concentrations on modulating pressor response to muscle contraction. Static contraction of the triceps surae muscle was evoked by electrical stimulation (at 5 HZ and 2.5 times motor threshold) of the tibial nerve in 9 anesthetized cats. Muscle interstitial ATP samples were collected from microdialysis probes inserted into the muscles. Dialysate ATP concentrations were determined using the luciferin-luciferase assay. In a control experiment, contraction was induced after 0.5 ml of saline was injected into the arterial blood supply of the hindlimb muscles. This increased [ATP]i by 220% (P < 0.05 vs. baseline). After gadolinium (1 mM), a blocker of mechanically sensitive channels, was injected into the muscles, contraction increased [ATP]i by 112% (P < 0.05 vs. control). In contrast, glibenclamide (an inhibitor of the ATP-binding cassette protein), monensin, and brefeldin A, which interfere with vesicular formation (or trafficking) and inhibit exocytosis, did not significantly affect ATP release by muscle contraction. In addition, a regression analysis showed that [ATP]i was linearly related to the pressor response to muscle contraction. The data suggest that ATP release from skeletal muscle is mediated via involvement of mechanosensitive channels. These findings further support a physiological role for release of ATP in modulating cardiovascular responses during static muscle contraction.


The Larynx is Protected from Secondary and Vertical Papillomavirus Infection in Immunocompetent Mice.
Mouse papillomavirus MmuPV1 causes both primary and secondary infections of the larynx in immunocompromised mice. Understanding lateral and vertical transmission of papillomavirus to the larynx would benefit patients with recurrent respiratory papillomatosis (RRP). To test the hypothesis that the larynx is uniquely vulnerable to papillomavirus infection, and to further develop a mouse model of RRP, we assessed whether immunocompetent mice were vulnerable to secondary or vertical laryngeal infection with MmuPV1. Larynges were collected from 405 immunocompetent adult mice that were infected with MmuPV1 in the oropharynx, oral cavity, or anus, and 31 mouse pups born to immunocompetent females infected in the cervicovaginal tract. Larynges were analyzed via polymerase chain reaction (PCR) of lavage fluid or whole tissues for viral DNA, histopathology, and/or in situ hybridization for MmuPV1 transcripts. Despite some positive laryngeal lavage PCR screens, all laryngeal tissue PCR and histopathology results were negative for MmuPV1 DNA, transcripts, and disease. There was no evidence for lateral spread of MmuPV1 to the larynges of immunocompetent mice that were infected in the oral cavity, oropharynx, or anus. Pups born to infected mothers were negative for laryngeal MmuPV1 infection from birth through weaning age. Secondary and vertical laryngeal MmuPV1 infections were not found in immunocompetent mice. Further work is necessary to explore immunologic control of laryngeal papillomavirus infection in a mouse model and to improve preclinical models of RRP. N/a Laryngoscope, 2023.


Testicular lesions other than germ cell tumours: feasibility of testis-sparing surgery.
To review all non-germ-cell testicular lesions presenting at our institution and to determine the feasibility of testis-sparing surgery for these patients. All surgery for testicular masses between June 1995 and June 2005 were reviewed retrospectively. Patients with atrophy, germ cell tumours, infection or torsion were excluded. The study comprised men who had radical orchidectomy for suspected germ-cell tumour but had other final pathology, and those where testis-sparing surgery was attempted for a presumed benign lesion. Thirteen patients with lesions appropriate for the study were identified; all but one had a palpable lesion. The lesions could be categorized as inflammatory (three hyalinized fibrosis, two sarcoidosis, one chronic inflammation), cystic (one epidermoid cyst, one unilocular cyst), benign neoplasms (two adenomatoid tumours, one Leydig cell tumour, one capillary haemangioma) or malignant neoplasms (one lymphoma). Based on the preoperative impression, testis-sparing surgery was attempted in eight of the lesions and was successful in six where it was attempted. In the other five, testis-sparing surgery was not attempted because the preoperative impression was that of a germ cell tumour. Testis-sparing surgery was successful in only six of the 13 patients with these lesions. Testis-sparing surgery might be possible if there is significant suspicion of a benign lesion. If frozen-section analysis is equivocal, a radical orchidectomy is required. Testis-sparing surgery was feasible in highly selected cases.


TFOS DEWS II Tear Film Report.
The members of the Tear Film Subcommittee reviewed the role of the tear film in dry eye disease (DED). The Subcommittee reviewed biophysical and biochemical aspects of tears and how these change in DED. Clinically, DED is characterized by loss of tear volume, more rapid breakup of the tear film and increased evaporation of tears from the ocular surface. The tear film is composed of many substances including lipids, proteins, mucins and electrolytes. All of these contribute to the integrity of the tear film but exactly how they interact is still an area of active research. Tear film osmolarity increases in DED. Changes to other components such as proteins and mucins can be used as biomarkers for DED. The Subcommittee recommended areas for future research to advance our understanding of the tear film and how this changes with DED. The final report was written after review by all Subcommittee members and the entire TFOS DEWS II membership.


[Regulation of dopaminergic neuronal activity by heart-type fatty acid binding protein in the brain].
Haloperidol as a potent dopamine D2 receptor (D2R) antagonist was a major tranquilizer to treat schizophrenia patients. However, the D2R blocking action in dorsal striatum is thought to cause extrapyramidal symptoms as adverse effects. However, the pathophysiological mechanism underlying extrapramidal symptoms induced by chronic treatment of haloperidol remains unclear. We recently found that lacking of heart-type fatty acid binding protein (H-FABP) in the brain aggravate catalepsy behavior induced by haloperidol. Here, we examined neuronal mechanism of augmentation of haloperidol-induced catalepsy in H-FABP null mice. Notably, catalepsy induced by haloperidol, a D2 antagonist, is augmented, whereas catalepsy induced by SCH23390, a D1 antagonist, was not affected in H-FABP null mice. Interestingly, haloperidol-induced acetylcholine (ACh) release in the dorsal striatum was markedly enhanced in H-FABP null mice compared to wild mice. We also defined the co-localization of D2R with H-FABP in the ACh interneurons in the striatum. Taken together, H-FABP regulates dopaminergic neuronal activity through interaction with D2R in rodent brain. The increased ACh release in the striatum accounts for haloperidol-induced catalepsy.


Inference for the difference in the area under the ROC curve derived from nested binary regression models.
The area under the curve (AUC) statistic is a common measure of model performance in a binary regression model. Nested models are used to ascertain whether the AUC statistic increases when new factors enter the model. The regression coefficient estimates used in the AUC statistics are computed using the maximum rank correlation methodology. Typically, inference for the difference in AUC statistics from nested models is derived under asymptotic normality. In this work, it is demonstrated that the asymptotic normality is true only when at least one of the new factors is associated with the binary outcome. When none of the new factors are associated with the binary outcome, the asymptotic distribution for the difference in AUC statistics is a linear combination of chi-square random variables. Further, when at least one new factor is associated with the outcome and the population difference is small, a variance stabilizing reparameterization improves the asymptotic normality of the AUC difference statistic. A confidence interval using this reparameterization is developed and simulations are generated to determine their coverage properties. The derived confidence interval provides information on the magnitude of the added value of new factors and enables investigators to weigh the size of the improvement against potential costs associated with the new factors. A pancreatic cancer data example is used to illustrate this approach.


Clonal CD8 T cells in the leptomeninges are locally controlled and influence microglia in human neurodegeneration.
Recent murine studies have highlighted a crucial role for the meninges in surveilling the central nervous system (CNS) and influencing CNS inflammation. However, how meningeal immunity is altered in human neurodegeneration and its potential effects on neuroinflammation is understudied. In the present study, we performed single-cell analysis of the transcriptomes and T cell receptor repertoire of 72,576 immune cells from 36 postmortem human brain and leptomeninges tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. We identified the meninges as an important site of antigen presentation and CD8 T cell activation and clonal expansion and found that T cell activation in the meninges is a requirement for infiltration into the CNS. We further found that natural killer cells have the potential to negatively regulate T cell activation locally in the meninges through direct killing and are one of many regulatory mechanisms that work to control excessive neuroinflammation.


[Natural immune response and immunological memory in the effects of a 2d unrelated antigen].
In combined administration of two nonaffiliated erythrocytic antigens there can be seen both depression and stimulation of the immunological response to the participating antigens. The end result of the interaction depended on the "power", the dose and the order of administration of the antigens. Distribution of the antigen in the animals whose immune response was depressed as a result of preliminary administration of the nonaffiliated antigen remained unchanged. The factor determining the effect on the immunological response to the other antigen did not serve as an antibody.


NMDA receptor upregulation: molecular studies in cultured mouse cortical neurons after chronic antagonist exposure.
We examined the possibility of changes in gene expression of the NMDA receptor subunits after chronic antagonist treatment. Exposure of neurons to the NMDA antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP-5) produced an increase in the levels of the R2B mRNA subunit. Concomitant exposure of neurons to AP-5 and NMDA reversed the upregulation. Chronic AP-5 treatment increased the R1 polypeptide, whereas no change was observed in the levels of mRNA encoding the R1 subunit. A more pronounced increase was observed in the R2A/B polypeptides. These data demonstrate that chronic treatment with NMDA antagonists selectively upregulates the NMDA receptor mRNAs and polypeptides. Furthermore, antagonist treatment produced a differential regulation of the R1, R2A, and R2B subunits in cortical neurons.


Contribution of solid organ transplant recipients to the pediatric non-hodgkin lymphoma burden in the United States.
Pediatric solid organ transplant recipients have a 100 to 200 times higher risk of non-Hodgkin lymphoma (NHL) than the general pediatric population. Consequently, transplant-related NHL may contribute considerably to the pediatric NHL burden in the United States. A cohort study using a linkage between the US transplant registry and 16 cancer registries was conducted. Cancer incidence rates were calculated for people less than 20 years old in the transplant and general populations. Rates were applied to transplant registry and US census data to estimate pediatric NHL counts for transplant recipients and the general population. During 1990-2012, an estimated 22,270 NHLs were diagnosed in US children and adolescents; they included 628 cases diagnosed in transplant recipients. Thus, 2.82% of pediatric NHL diagnoses in the general population (95% confidence interval [CI], 2.45%-3.19%) occurred in transplant recipients. Among transplant recipients, the most common subtypes were diffuse large B-cell lymphoma (DLBCL; 64.5% of cases) and Burkitt lymphoma (BL; 8.6%). For DLBCL and BL, transplant recipients contributed 7.62% (95% CI, 6.35%-8.88%) and 0.87% (95% CI, 0.51%-1.23%) of diagnoses, respectively. The proportion of NHLs that occurred in transplant recipients was highest among children less than 5 years old (4.46%; 95% CI, 3.24%-5.69%) and in more recent calendar years (3.73% in 2010-2012; 95% CI, 2.07%-5.39%). DLBCL patterns were similar, with transplant recipients contributing 19.78% of cases among children less than 5 years old (95% CI, 12.89%-26.66%) and 11.4% of cases in 2010-2012 (95% CI, 5.54%-17.28%). Among children and adolescents, solid organ transplant recipients contribute a substantial fraction of NHL diagnoses, particularly DLBCL diagnoses. This fraction has increased over time. Prevention efforts targeted toward this group could reduce the overall pediatric NHL burden. Cancer 2017;123:4663-4671. © 2017 American Cancer Society.


Effects of dutasteride on lower urinary tract symptoms: a prospective analysis based on changes in testosterone/dihydrotestosterone levels and total prostatic volume reduction.
This study analyzed the effects of dutasteride on lower urinary tract symptoms based on the association between changes in the total testosterone (TT)/dihydrotestosterone (DHT) levels and total prostate volume (TPV) reduction. Sixty participants diagnosed with benign prostatic hyperplasia were given 0.5 mg of dutasteride daily for 52 weeks. Measures of TT and DHT levels, TPV and uroflowmetry were obtained before and after dutasteride treatment. Forty-three patients demonstrated a TPV reduction of ≥5% (Group 1), whereas the remaining 17 patients demonstrated a TPV reduction of <5% (Group 2). DHT suppression and DHT/TT ratio at baseline were significantly higher in Group 1 than Group 2. International Prostate Symptom Scores (IPSS) and uroflowmetry were significantly improved in both groups. In Group 2, nine patients demonstrated some improvement in IPSS (Group 2A), whereas eight did not (Group 2B). The rate of TT increase and improvement in voiding symptoms were significantly higher in Group 2A than Group 2B. Dutasteride-induced TPV reduction is dependent on individual 5-α reductase inhibitor activity. Some patients demonstrating smaller dutasteride-induced TPV reduction may experience an improvement in voiding symptoms owing to an increased level of testosterone.


The novel signal peptides, pedibin and Hym-346, lower positional value thereby enhancing foot formation in hydra.
Signaling molecules affecting patterning processes are usually proteins and rarely peptides. Two novel peptides, pedibin and Hym-346, that are closely related to one another have been isolated from Hydra vulgaris and Hydra magnipapillata. Several experiments indicate that both cause a reduction in the positional value gradient, the principle patterning process governing the maintenance of form in the adult hydra. The peptides cause an increase in the rate of foot regeneration following bisection of the body column. Treatment of animals with either peptide for an extended period of time resulted in an apical extension of the range of expression of CnNk-2 along the body column. Such an extension is correlated with a decrease in positional value. Transplantation of tissue treated with Hym-346 results in an increase in the fraction forming feet, and aggregates derived from Hym-346 tissue form more feet and fewer heads. The latter two experiments provide a direct measure of the lowering of positional value in the treated tissue. These results suggest that peptides play signaling roles in patterning processes in cnidaria and, plausibly, in more complex metazoans as well.


A tool to assess mobility status in critically ill patients: the Perme Intensive Care Unit Mobility Score.
The benefits of early mobilization for adult patients in the intensive care unit (ICU) are reduced length of ICU and hospital stays, fewer readmissions to the ICU, decreased duration of mechanical ventilation, fewer days of detrimental bedrest, minimal adverse or unsafe events, and improved walking distance. Because there are no available tools to specifically measure mobility status of patients in the ICU setting, there is an urgent need to create a reliable tool that measures and standardizes the assessment of mobility status for these patients. The purpose of this study was to describe the development of this novel ICU-specific tool to assess a patient's mobility status, examine the initial reliability of the tool, and address its clinical application. The Perme ICU Score was quickly and easily administered by physical therapists. Overall, the inter-rater agreement was 94%. A total of six items had kappa values of < .6, and these low scores may have been the result of the procedure to collect inter-rater scores, wherein one rater assisted with the activity while a second rater observed. In order to improve reliability, the authors developed directions to standardize the assessment. The Perme ICU Mobility Score is a tool developed to measure the patient's mobility status starting with the ability to follow commands and culminating in the distance walked in two minutes. Preliminary data suggest that the validity of this tool is supported by expert concurrence, its overall reliability is high, and its clinical use is acceptable.


[Unilateral papilledema in pseudotumor cerebri].
The appearance of unilateral papilledema in the fundus photos of 6 women with pseudotumor cerebri is presented. Associated findings included obesity in 5 and a partially empty sella in 2. The possible explanations for the development of unilateral papilledema in pseudotumor cerebri are reviewed and favor a mechanism that is present at the distal end of the optic nerves.


Heterogeneity of carcinoembryonic antigen. I. Concanavalin A-reactive and -nonreactive CEA.
The use of Con A-Sepharose affinity chromatography for preparation of CEA from two metastatic liver tumors resulted in a separation of two species of CEA. One is concanavalin A-reactive CEA (CEA-M): the other is Con A-nonreactive CEA (CEA-P). Both CEA-M and CEA-P were glycoproteins and have identical antigenicity. However, 4 samples of CEA-M and CEA-P subfractions differed in their protein:carbohydrate ratios. The yield of CEA-M was greater than that of CEA-P. In electrophoresis, both CEA-M and CEA-P migrated at the region of beta-globulin of human blood serum. The isoelectric points of 4 samples of CEA-M and CEA-P subfractions from two different tumor sources differed from each other. In these preparations CEA-M usually showed a larger value of isoelectric point than CEA-P. Ultracentrifugal analysis of these four preparations revealed only a single peak, except CEA-P in case 1. Antigenic activity of CEA-M was almost completely destroyed by beta-N-acetylhexosaminidase treatment but only partly digestion with pronase. A possibility was suggested that N-acetylglucosamine at nonreducing terminal(s) is essential for the antigenic determinant groups of CEA molecule.


Solvent-mediated structural transformations of copper(II) coordination polymers induced by different short-chain alcohols.
A three-dimensional copper(II) coordination polymer (CP), {Cu(L-F)(N3)}n (1), was synthesized by reacting Cu(NO3)2 with 5-fluoronicotinic acid (HL-F) and NaN3 in a water medium. Complex (1) shows a 3D network, in which the 1D [Cu2(COO)N3]n chains are interconnected via L-F ligands. By immersing (1) into different short-chain alcohols (CH3OH, C2H5OH and HOC2H4OH), three different CPs were isolated, including {Cu3(L-F)4(N3)2(CH3OH)2}n (2), {Cu3(L-F)4(N3)2(C2H5OH)2}n (3) and {Cu2.5(L-F)3(N3)2(HOC2H4OH)0.5}n (4). CPs (2) and (3) display a similar structure, in which trinuclear subunit [Cu3(COO)2(N3)2(solvent)2] is generated. Furthermore, such entities are interconnected via L-F ligands to give rise to a 3D network. As for (4), there are trinuclear [Cu3(COO)2(N3)2] and binuclear [Cu2(COO)N3] units, which are interconnected by L-F ligands to generate a 3D network. Notably, in (2) and (3), the coordination modes of CH3OH and C2H5OH solvents are monodentate; whereas for (4), the HOC2H4OH solvent adopts a bridging mode to link two Cu atoms. Of further interest, these processes are solvent-mediated structural transformations, with obvious colour changes in the crystals. Structural changes and mechanisms of transformation are discussed in detail.


Use of alcohol, drugs, inhalants, and smoking tobacco and the long-term risk of depression in men: A nationwide Swedish cohort study from 1969-2017.
The use of alcohol, drugs, inhalants, and smoking tobacco may lead to mood disorders such as depression. However, knowledge on the independent contributions of the use of these substances to the risk of depression is lacking. The study cohort consisted of 24,564 men included in the Swedish national military conscription register who were conscripted in 1969-1970 and followed until 2017. Cox proportional hazard ratios were used to estimate the risk of depression according to alcohol, drug, inhalant, and cigarette consumption, and adjusted for body mass index, verbal comprehension test scores, handgrip strength, and the other main exposures investigated. During an average follow-up period of 44 years, 4500 men were diagnosed with or treated for depression at a mean age of 54 years. A dose-dependent association was found in men who smoked cigarettes, with the highest risk for smoking >20 cigarettes per day, at time of conscription (aHR 1.86, 95 % CI 1.61-2.16, p < 0.001). Independent associations with an increased risk of depression were found for the use of drugs at least once (aHR 1.21, 95 % CI 1.10-1.32, p < 0.001) and >50 times (aHR 1.48, 95 % CI 1.23-1.77, p < 0.001) and the use of inhalants (aHR 1.16, 95 % CI 1.05-1.29). Excessive alcohol intake was not associated with the risk of depression. The results suggest that people who reported to have used cigarettes, alcohol, or drugs at 18 years of age have a moderately increased risk of depression later in life.


Obesity as a Neuroendocrine Disorder.
Obesity is one of the most prevalent diseases in the world. Based on hundreds of clinical and basic investigations, its etiopathogenesis goes beyond the simple imbalance between energy intake and expenditure. The center of the regulation of appetite and satiety lies in the nuclei of the hypothalamus where peripheral signals derived from adipose tissue (e.g., leptin), the gastrointestinal tract, the pancreas, and other brain structures, arrive. These signals are part of the homeostatic control system (eating to survive). Additionally, a hedonic or reward system (eating for pleasure) is integrated into the regulation of appetite. This reward system consists of a dopaminergic circuit that affects eating-related behaviors influencing food preferences, food desires, gratification when eating, and impulse control to avoid compulsions. These systems are not separate. Indeed, many of the hormones that participate in the homeostatic system also participate in the regulation of the hedonic system. In addition, factors such as genetic and epigenetic changes, certain environmental and sociocultural elements, the microbiota, and neuronal proinflammatory effects of high-energy diets also contribute to the development of obesity. Therefore, obesity can be considered a complex neuroendocrine disease, and all of the aforementioned components should be considered for the management of obesity.


Intracellular Ca2+ and the phospholipid PIP2 regulate the taste transduction ion channel TRPM5.
The transduction of taste is a fundamental process that allows animals to discriminate nutritious from noxious substances. Three taste modalities, bitter, sweet, and amino acid, are mediated by G protein-coupled receptors that signal through a common transduction cascade: activation of phospholipase C beta2, leading to a breakdown of phosphatidylinositol-4,5-bisphosphate (PIP2) into diacylglycerol and inositol 1,4,5-trisphosphate, which causes release of Ca2+ from intracellular stores. The ion channel, TRPM5, is an essential component of this cascade; however, the mechanism by which it is activated is not known. Here we show that heterologously expressed TRPM5 forms a cation channel that is directly activated by micromolar concentrations of intracellular Ca2+ (K1/2 = 21 microM). Sustained exposure to Ca2+ desensitizes TRPM5 channels, but PIP2 reverses desensitization, partially restoring channel activity. Whole-cell TRPM5 currents can be activated by intracellular Ca2+ and show strong outward rectification because of voltage-sensitive gating of the channels. TRPM5 channels are nonselective among monovalent cations and not detectably permeable to divalent cations. We propose that the regulation of TRPM5 by Ca2+ mediates sensory activation in the taste system.


Chitosan coatings with different degrees of deacetylation regulate the postharvest quality of sweet cherry through internal metabolism.
In this study, chitosan coatings with different degrees of deacetylation (DD, 88.1 % and 95.2 %) were electrostatically sprayed on sweet cherries to evaluate their impacts on postharvest characteristics and internal metabolism. The results showed that chitosan coating could effectively delay the change of weight, color, firmness, and maintain the content of total phenols, flavonoids and titratable acids, and inhibit the activities of β-galactosidase and polyphenol oxidase during cold storage. The storage qualities and physiological activities of sweet cherry were significantly correlated with the contents of sorbitol, 4-hydroxycinnamic acid, hydrogenated hydroxycinnamic acid, tyrosine, proline, glutamine, phenylalanine, and other metabolites. Chitosan coating may modulate fruit quality by inhibiting the energy metabolism, accelerating the accumulation of carbohydrates, and promoting the metabolism of phenylalanine and flavonoid. Especially, chitosan coating with 88.1 % DD had better wettability on sweet cherry's peel and displayed more obvious preservation effect through stronger metabolic regulation ability.


Assessment of HIV Post-Exposure Prophylaxis Use Among Health Workers of Governmental Health Institutions in Jimma Zone, Oromiya Region, Southwest Ethiopia.
Infection with Human Immunodeficiency Virus is a serious public health problem costing the lives of many people including health workers. Hence, Ethiopia has developed guideline on the prevention of infection in health institutions in July 2004 and also employed the use of post exposure prophylaxis since the implementation of free antiretroviral in January 2005. However in the country, specifically in Jimma zone, published studies showing the clear picture about HIV post exposure prophylaxis in the work place were non-existent. Therefore, this study was conducted to assess the knowledge, practice and factors associated to HIV post-exposure prophylaxis use among health workers of governmental health institutions in the Zone. A cross-sectional survey employing quantitative and qualitative methods was conducted from October to December 2008. Two hundred fifty four health workers participated in the quantitative study. Health workers for focus group discussion and key informants for in-depth interviews were identified with the help of administrators/ HIV/AIDs coordinators of the two administrative health bureaus and institutions included in the study. The quantitative data were entered and cleaned using Epi Info version 6.4 and analysed using SPSS for windows version 11.0. Descriptive statistics and chi-square test was employed to assess association among variables. P-value less than 0.05 was considered statistically significant. Among the total 254 participants, 213 (83.9%) had inadequate knowledge about post exposure prophylaxis of HIV and 174 (68.5%) had ever been exposed to HIV risk conditions. Out of 174 health workers exposed to HIV risk, 105 (60.3%) sustained needle prick/cut by sharps, 77 (44.3%) to blood and 68 (39.1%) exposed to patients' body fluid. Perceived causes of exposure were; high workload 77 (44.3%), lack of protective barriers 58 (33.3%) and lack of knowledge on standard precautions 31 (17.8%). One hundred forty two (81.6%) of those exposed did not use post-exposure prophylaxis. Lack of information about the existence of post-exposure prophylaxis service 48 (33.8%), fear of stigma and discrimination 46 (32.4%), lack of understanding the value of reporting 33 (23.2%) and lack of support and encouragement to report 29 (20.4%) were the reasons for not using. Moreover, formal (separate) HIV post-exposure prophylaxis centre with proper guideline was non-existent in the study areas. In general, findings of the quantitative and qualitative study revealed that the knowledge of health workers about post exposure prophylaxis against HIV is inadequate. Though many of the studied health workers had HIV risk exposure, only few used post-exposure prophylaxis. Therefore, establishing a 24 hours accessible formal post-exposure prophylaxis centre with proper guideline is recommended. Health institutions are also advised to raise awareness of their employees on post exposure prophylaxis.


Integrative genomic analyses on GLI1: positive regulation of GLI1 by Hedgehog-GLI, TGFbeta-Smads, and RTK-PI3K-AKT signals, and negative regulation of GLI1 by Notch-CSL-HES/HEY, and GPCR-Gs-PKA signals.
GLI family members are zinc-finger transcription factors, which are involved in embryogenesis and carcinogenesis through transcription regulation of GLI1, CCND1, CCND2, FOXA2, FOXC2, RUNX2, SFRP1, and JAG2. GLI1 transcription is upregulated in a variety of human tumors, such as basal cell carcinoma, lung cancer, breast cancer, gastric cancer, pancreatic cancer, and esophageal cancer. Hedgehog signaling via Smoothened cascade and receptor tyrosine kinase (RTK) signaling via PI3K-AKT cascade induce stabilization of GLI1 protein, whereas G-protein coupled receptor (GPCR) signaling via Gs-PKA cascade induces degradation of GLI1 protein. Here we report integrative genomic analyses of the GLI1 gene. The GLI1 and ARHGAP9 genes are located in a tail-to-tail manner with overlapping 3'-ends. ARHGAP9 was expressed in bone marrow, spleen, thymus, monocytes, and macrophages, whereas GLI1 was almost undetectable in normal tissues or cells with predominant ARHGAP9 expression. Because overlapping sense and anti-sense transcripts are annealed to each other to give rise to double-stranded RNAs functioning as endogenous RNAi, GLI1 expression might be negatively regulated by ARHGAP9 transcripts. GLI-binding element with one base substitution at the +1589-bp position from the transcriptional start site (TSS) of the human GLI1 gene was completely conserved in chimpanzee GLI1, mouse Gli1, and rat Gli1 genes. Ten Smad-binding elements, double E-boxes for EMT regulators, and double N-boxes for HES/HEY family members within intron 1 of the human GLI1 gene were also conserved in mammalian GLI1 orthologs. GLI1 transcription is upregulated due to Hedgehog, and TGFbeta signaling activation, whereas GLI1 transcription is downregulated due to Snail/Slug, and Notch signaling activation. Together these facts indicate that Hedgehog, TGFbeta, and RTK signals positively regulate GLI1, and that Notch, and GsPCR signals negatively regulate the GLI1.


Amyloid and Tau PET Positivity in Progressive Agrammatic Aphasia and Apraxia of Speech.
The agrammatic variant of primary progressive aphasia (PAA), primary progressive apraxia of speech (PPAOS), or a combination of both (AOS-PAA) are neurodegenerative disorders characterized by speech-language impairments and together compose the AOS-PAA spectrum disorders. These patients typically have an underlying 4-repeat tauopathy, although they sometimes show evidence of amyloid-β and tau deposition on PET, suggesting Alzheimer's disease (AD). Given the growing number of pharmacologic treatment options for AD, it is important to better understand the incidence of AD pathology in these patients. This study aimed to evaluate the frequency of amyloid-β and tau positivity in AOS-PAA spectrum disorders. Sixty-five patients with AOS-PAA underwent a clinical speech-language battery and PiB PET and flortaucipir PET imaging. Global PiB PET standardized uptake value ratios (SUVRs) and flortaucipir PET SUVRs from the temporal meta region of interest were compared between patient groups. For 19 patients who had died and undergone autopsy, their PET and pathology findings were also compared. The results showed that although roughly half of the patients are positive for at least one biomarker, their clinical symptoms and biomarker status were not related, suggesting that AD is not the primary cause of their neurodegeneration. All but one patient in the autopsy subset had a Braak stage of IV or less, despite four being positive on tau PET imaging. Inclusion criteria for clinical trials should specify clinical presentation or adjust the evaluation of such treatments to be specific to disease diagnosis beyond the presence of certain imaging biomarkers.


Treatment of chikungunya musculoskeletal disorders: a systematic review.
Chikungunya virus is amongst the fastest expanding vector transmissible diseases in recent years and has been causing massive epidemics in Africa, Asia, Latin America and the Caribbean. Despite human infection by this virus being first described in the 1950s, there is a lack of adequate therapeutic evaluations to guide evidence-based recommendations. The current guidelines rely heavily in specialists' opinion and experience instead of using higher rated evidence. Areas covered: A systematic review of the literature was performed- not restricted to clinical trials - reporting the therapeutic response against this infection with the intent to gather the best evidence of the treatment options against musculoskeletal disorders following chikungunya fever. The 15 studies included in the analysis were categorized considering the initiation of treatment during the acute, subacute and chronic phase. Expert commentary: This review demonstrates the complexity of chikungunya fever and difficulty of therapeutic management. This review found no current evidence-based treatment recommendations for the musculoskeletal disorders following chikungunya fever. To provide an optimal treatment that prevents perpetuation or progression of chikungunya infection to a potentially destructive and permanent condition without causing more harm is an aim that must be pursued by researchers and health professionals working with this disease.


Novel potential pharmacological applications of dimethyl fumarate-an overview and update.
Dimethyl fumarate (DMF) is an FDA-approved drug for the treatment of psoriasis and multiple sclerosis. DMF is known to stabilize the transcription factor Nrf2, which in turn induces the expression of antioxidant response element genes. It has also been shown that DMF influences autophagy and participates in the transcriptional control of inflammatory factors by inhibiting NF-κB and its downstream targets. DMF is receiving increasing attention for its potential to be repurposed for several diseases. This versatile molecule is indeed able to exert beneficial effects on different medical conditions through a pleiotropic mechanism, in virtue of its antioxidant, immunomodulatory, neuroprotective, anti-inflammatory, and anti-proliferative effects. A growing number of preclinical and clinical studies show that DMF may have important therapeutic implications for chronic diseases, such as cardiovascular and respiratory pathologies, cancer, eye disorders, neurodegenerative conditions, and systemic or organ specific inflammatory and immune-mediated diseases. This comprehensive review summarizes and highlights the plethora of DMF's beneficial effects and underlines its repurposing opportunities in a variety of clinical conditions.


Gene polymorphisms of interleukin 28B and the risk to chronic hepatitis B virus infection in Thai.
In this study, we aimed to evaluate the effect of two single nucleotide polymorphisms (SNPs) of interleukin 28B (IL28B) (rs12979860C/T and rs8099917G/T) on chronic hepatitis B virus (CHB) infection in Thai population. We studied 375 subjects: 83 CHB with hepatocellular carcinoma (HCC) patients, 128 CHB without HCC and 164 individuals with self-limited HBV infection, by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and TaqMan allelic discrimination assay. Results revealed significant risk of IL28B rs8099917T allele associated with CHB without HCC compared with self-limited HBV [odds ratio (OR) (95% confidence interval (CI)) = 2.56 (1.08-6.28), P = 0.019]. The effect of this T allele was similar to that of an autosomal recessive gene in the presence of TT genotype compared with GG and GT genotype [OR (95% CI) = 2.70 (1.11-6.77), P = 0.016, P (logistic regression) = 0.048]. The two locus haplotype analysis of the two IL28B SNP loci did not show any association with CHB (P > 0.05). In conclusion, these results suggested a IL28B rs8099917T allele predispose for susceptibility to chronic HBV infection but not leading to HCC in Thai population.


Automated contour propagation of the prostate from pCT to CBCT images via deep unsupervised learning.
To develop and evaluate a deep unsupervised learning (DUL) framework based on a regional deformable model for automated prostate contour propagation from planning computed tomography (pCT) to cone-beam CT (CBCT). We introduce a DUL model to map the prostate contour from pCT to on-treatment CBCT. The DUL framework used a regional deformable model via narrow-band mapping to augment the conventional strategy. Two hundred and fifty-one anonymized CBCT images from prostate cancer patients were retrospectively selected and divided into three sets: 180 were used for training, 12 for validation, and 59 for testing. The testing dataset was divided into two groups. Group 1 contained 50 CBCT volumes, with one physician-generated prostate contour on CBCT image. Group 2 contained nine CBCT images, each including prostate contours delineated by four independent physicians and a consensus contour generated using the STAPLE method. Results were compared between the proposed DUL and physician-generated contours through the Dice similarity coefficients (DSCs), the Hausdorff distances, and the distances of the center-of-mass. The average DSCs between DUL-based prostate contours and reference contours for test data in group 1 and group 2 consensus were 0.83 ± 0.04, and 0.85 ± 0.04, respectively. Correspondingly, the mean center-of-mass distances were 3.52 mm ± 1.15 mm, and 2.98 mm ± 1.42 mm, respectively. This novel DUL technique can automatically propagate the contour of the prostate from pCT to CBCT. The proposed method shows that highly accurate contour propagation for CBCT-guided adaptive radiotherapy is achievable via the deep learning technique.


Detection of Mycobacterium tuberculosis in clinical specimens from children using a polymerase chain reaction.
We evaluated the usefulness of the polymerase chain reaction (PCR) using the insertion sequence IS6110 as the target for DNA to detect Mycobacterium tuberculosis in clinical specimens from children. This was a prospective, controlled, blinded study comparing PCR on clinical specimens, mycobacterial culture, and clinical diagnosis. Sixty-five hospitalized children were evaluated, 35 with tuberculosis disease and 30 controls. Cases were defined by culture and/or specific clinical criteria. Controls included patients with tuberculosis infection but no detectable disease as well as patients free of tuberculosis infection and disease. Polymerase chain reaction had a sensitivity of 40% and a specificity of 80% compared with clinical diagnosis. Mycobacterial culture had a sensitivity of 37%. The combination of culture and PCR identified 19 of 35 children (54%) with clinically diagnosed tuberculosis. There were six children with false-positive PCR results: One had tuberculosis infection without disease, two had Mycobacterium avium lymphadenitis, and three had diagnoses unrelated to tuberculosis. The sensitivity of PCR is comparable to that of culture for detecting M tuberculosis in children, and may strengthen and hasten the clinical diagnosis in culture-negative patients. However, because of the limitations in specificity, the results of PCR alone are insufficient to diagnose tuberculosis in children. Although ongoing refinements in PCR techniques should improve the specificity of this test, epidemiologic and clinical information continue to be the most important consideration in the diagnosis of tuberculosis in culture-negative children.


The inflammatory microenvironment and microbiome in prostate cancer development.
Chronic inflammation promotes the development of several types of solid cancers and might contribute to prostate carcinogenesis. This hypothesis partly originates in the frequent observation of inflammatory cells in the prostate microenvironment of adult men. Inflammation is associated with putative prostate cancer precursor lesions, termed proliferative inflammatory atrophy. Inflammation might drive prostate carcinogenesis via oxidative stress and generation of reactive oxygen species that induce mutagenesis. Additionally, inflammatory stress might cause epigenetic alterations that promote neoplastic transformation. Proliferative inflammatory atrophy is enriched for proliferative luminal epithelial cells of intermediate phenotype that might be prone to genomic alterations leading to prostatic intraepithelial neoplasia and prostate cancer. Studies in animals suggest that inflammatory changes in the prostate microenvironment contribute to reprogramming of prostate epithelial cells, a possible step in tumour initiation. Prostatic infection, concurrent with epithelial barrier disruption, might be a key driver of an inflammatory microenvironment; the discovery of a urinary microbiome indicates a potential source of frequent exposure of the prostate to a diverse number of microorganisms. Hence, current evidence suggests that inflammation and atrophy are involved in prostate carcinogenesis and suggests a role for the microbiome in establishing an inflammatory prostate microenvironment that might promote prostate cancer development and progression.


[Complementary medicine and health legislation].
This review begins by explaining the meaning and purpose of health law in general. While legal regulations pertinent to mainstream medicine are functioning well, this project focuses on the legal situation that developed in Switzerland as a consequence of the increasing availability and use of services in complementary medicine. There are obvious gaps and deficits in our legislation concerning medical and paramedical providers of services in complementary medicine. Main emphasis of this project, therefore, was placed on the regulations dealing with health professionals in complementary medicine, in particular on standards of training, on licenses to practice, and on the compensation by health insurance funds. The project achieved a comprehensive stock-taking of the great variety of the Swiss federal and the 26 cantonal laws and regulations. It also drew conclusions on the necessity to formulate generally applicable rules and regulations for the field of complementary medicine and finally submitted a list of practical recommendations.


Integrated Environmental Assessment and Management.
Increasing demand for metals used in clean energy technologies, including electric vehicles, has led to an increased demand in certain metals such as Ni, Co, and Mn. This demand has in turn led to an expanding interest in deep-seabed mining (DSM) of polymetallic nodule deposits that contain these exact metals. The main concerns about DSM relate to the incomplete information available about the environmental risks associated with seabed mineral extraction. Key uncertainties need to be systematically addressed to refine environmental impact predictions and establish effective mitigation measures. Adaptive management is an iterative process for reducing the uncertainty that can be applied by both mining companies and regulatory bodies. This Special Series paper reviews the key opportunities and challenges to operationalizing adaptive management in DSM projects and highlights the need for a framework to move from theory to practice. The discussion proposes a systems approach to adaptive management, which could help to guide the environmental management of deep-sea mineral extraction. Integr Environ Assess Manag 2022;18:674-681. © 2021 SETAC.


The role of first use of inhalants within sequencing pattern of first use of drugs among Brazilian university students.
The present study investigated the role of first use of inhalants within a first drug sequencing pattern. In a representative sample of university students from 27 Brazilian capitals (n = 12,711), we analyzed the patterns of transition from/to first use of inhalants to/from the first use of alcohol, tobacco, cannabis, cocaine, hallucinogens, ecstasy, amphetamines, prescription opioids, and tranquilizers. Cox proportional hazards models were used to analyze data. Drugs that were not specified as the pair of drugs tested in each model were included as time-varying covariates in all models. In this sample, first use of inhalants was preceded only by the first use of alcohol and tobacco. However, first use of inhalants preceded first use of cannabis, amphetamines, cocaine, and tranquilizers. First use of inhalants preceded the first use of prescription opioids, and vice versa. This study highlights the need to intervene early with youths who are at risk of or just beginning to use inhalants, because this class of drugs seems to be the first illegal drug in Brazil to be experimented by respondents in our sample. There is also a call for attention to individuals who have already first used inhalants because of their higher chance to experiment with other drugs such as cannabis, cocaine, and prescription drugs. All these findings show an in-transition culture of drug use, which should be tracked through time, because some classical models (i.e., gateway model) might be outdated and might also not fit within different settings.


Induction of the E-selectin promoter by interleukin 1 and tumour necrosis factor alpha, and inhibition by glucocorticoids.
Cytokine-induced expression of the endothelial cell surface adhesion molecule E-selectin is inhibited by glucocorticoids (GCs). To investigate possible mechanisms for steroid inhibition, a reporter gene (ESAP) was constructed, comprising the cytokine responsive region of the E-selectin gene (nt -383 to +81) coupled to alkaline phosphatase (AP). In A549 cells stably transfected with the ESAP gene, AP production was highly responsive to the cytokines interleukin 1beta (IL-1beta) and tumour necrosis factor alpha, with ED50 values of 3 pM and 1000 pM respectively. Furthermore the cytokine-induced AP responses were inhibited by GCs, indicating that both transcriptional activation and GC suppression of the E-selectin gene were mediated via regulatory elements within the same region of the promoter. The relative potencies of GC drugs as inhibitors of IL-1beta (10 pM)-stimulated ESAP-gene activation were fluticasone> beclomethasone>dexamethasone, with IC50 values of 0.13, 1.1 and 2.7 nM respectively. Inhibition by fluticasone was blocked by the GC receptor (GR) antagonist drug mifepristone (Ru486), which is consistent with the suppressive effects of GCs being mediated via the GR. However, because the E-selectin promoter lacks a consensus glucocorticoid responsive element, mechanisms for inhibition independent of GR-DNA binding were investigated. Evidence that GCs also inhibited cytokine activation of a synthetic nuclear factor kappaB (NFkappaB)-driven reporter gene transiently transfected into A549 cells suggested that interference with the activation and/or function of this transcription factor was important for GC inhibition of ESAP. However, in A549-ESAP cells, fluticasone (100 nM) did not affect IL-1beta (10 pM)-induced IkBalpha degradation, NFkappaB-p65 nuclear translocation or the DNA-binding capacity of nuclear NFkappaB complexes, over a period during which cytokine-induced ESAP-gene activation was inhibited. Finally, there was no evidence to suggest that GC enhancement of IkBalpha gene expression contributed to the suppression of the cytokine response. We conclude that interference by GR with the transcriptional activation potential of DNA-bound NFkappaB complexes might contribute to mechanisms underlying the anti-inflammatory effects of GCs.


The economic impact of initiatives to reduce stigma: demonstration of a modelling approach.
This paper seeks to provide a methodology to assess the cost-effectiveness of anti-stigma campaigns for people with mental health problems. The costs of running a national campaign in Scotland were obtained and combined with the number of adults in the Scottish population and the estimated number of people with improved attitudes towards people with mental health problems. A decision model was constructed to estimate the economic impact of a campaign in terms of increased use of services by people with depression and increased work time. If the campaign caused 10% of changed attitudes then it was estimated to cost pound 35 per one less person who felt that people with mental health problems were dangerous and pound 186 per one less person who felt the public needs protection from people with mental health problems. The decision model suggested extra economic benefits (employment gains minus service costs) as a result of an anti-stigma campaign compared to the absence of a campaign. Data on the economic impact of anti-stigma campaigns are scarce and evaluation is intrinsically difficult. We have demonstrated a method to conduct such analyses. The model proposed here should be tested further as data become available.


Development of an mHealth App for Patients With Psoriasis Undergoing Biological Treatment: Participatory Design Study.
In Denmark, patients with psoriasis undergoing biological treatment have regular follow-ups, typically every 3 months. This may pose a challenge for patients who live far away from the hospital. Mobile health (mHealth) is a promising and reliable tool for the long-term management of patients with psoriasis undergoing biological treatment because the disease course can be properly monitored. Despite recent developments in mHealth, the full potential of teledermatology remains to be tapped by newer, more attractive forms of services focused on patients' needs. This study aims to design and develop an mHealth app to support the self-management of patients with psoriasis using a participatory design. Using participatory design, we conducted 1 future workshop, 4 mock-up workshops, and 1 prototype test with patients and health care professionals to co-design a prototype. The process was iterative to ensure that all stakeholders would provide input into the design and outcome; this approach enabled continuous revision of the prototype until an acceptable solution was agreed upon. Data were analyzed according to the steps-plan, act, observe, and reflect-in the methodology of participatory design. Health care professionals and patients emphasized the importance of a more patient-centered approach, focusing on the communication and maintenance of relationships. Patients perceived consultations to be impersonal and repetitive and wanted the opportunity to contribute to the agenda while attending a consultation. Patients also stated they would prefer not to attend visits in person every 3 months. On the basis of these findings, we designed an mHealth app that could replace in-person visits and support patients at in-person visits. Video consultations, self-monitoring, and registration of patient-reported outcome data were embedded in the app. Using participatory design facilitated mutual learning and democratic processes that gave end users a significant influence over the solution. Despite the advantages of using participatory design in developing mHealth solutions, organizational conditions may still represent a barrier to the optimization of solutions.


Application of a Y-type-DNA-functionalized nanogold probe featuring specific telomerase recognition and doxorubicin release in cancer cells.
A Y-type-DNA-functionalized nanogold probe was synthesized to identify telomerase and trigger drug release in cancer cells. This system involved a DNA-functionalized nanogold probe centered on gold nanoparticles with a dense modification of Y-type DNA molecular beacons on the surface. The Y-type DNA molecular beacons consisted of telomerase primers (TPs), a FAM-labeled single-strand DNA (Mismatch-DNA), and a single-strand DNA of two templates (Linker-DNA1 and Linker-DNA2). Doxorubicin (Dox), an anti-cancer drug molecule, was inserted into DNA double strands. When telomerase existed, TP was extended and the Mismatch-DNA was released, leading to the emission of fluorescent light from FAM while releasing Dox. This probe specifically detected cancer cells and did not affect normal cells. This drug delivery system will reduce the tumour size and cause minimal injury to normal tissues.


Ouabain-resistant mutants of Chinese hamster ovary cells are not directly affected in Na+, K+-ATPase.
The nature of biochemical lesions in a number of independent single-step ouabain-resistant (OuaR) mutants of Chinese hamster ovary cells has been examined. The cellular uptake of 86Rb in the mutant cells was found to be resistant to inhibition by ouabain and correlated with the degree of resistance of the mutants to the drug. However, the plasma membrane Na+, K+-ATPase from all five of the OuaR mutants examined showed similar sensitivity to inhibition by ouabain as seen for the enzyme from the parental sensitive cells. These results provide evidence that, contrary to the general assumption, OuaR mutants of Chinese hamster ovary cells, which are widely used for genetic and quantitative mutagenesis studies, are not directly affected in the Na+, K+-ATPase.


The Role of Dopamine D3 Receptor Partial Agonism in Cariprazine-Induced Neurotransmitter Efflux in Rat Hippocampus and Nucleus Accumbens.
Cariprazine is an approved antipsychotic and antidepressant which is a dopamine (DA) D3-preferring D3/D2 receptor partial agonist, serotonin (5-HT) 5-HT1A receptor partial agonist, and 5-HT2B and 5-HT2A receptor antagonist, a profile unique for atypical antipsychotic drugs. The purpose of this study was to clarify the effects of cariprazine and selective D3 receptor ligands on neurotransmitter efflux in the rat nucleus accumbens (NAC) and ventral hippocampus (HIP), brain regions important for reality testing, rewarded behavior, and cognition. In vivo microdialysis was performed in awake, freely moving rats after administration of cariprazine; (+)-PD-128907 [(4aR,10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], a D3 receptor-preferring agonist; and SB-277011A [trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide hydrochloride], a selective D3 receptor antagonist, alone or combined, and extracellular levels of multiple neurotransmitters and metabolites were measured in the NAC and HIP by ultraperformance liquid chromatography with tandem mass spectrometry. Cariprazine increased DA, norepinephrine (NE), and 5-HT efflux in both regions, whereas it increased glycine (Gly) and glutamate efflux only in the NAC and efflux of DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) only in the HIP. Similarly, SB-277011A increased DA, NE, DOPAC, and HVA, but not 5-HT, efflux in the NAC and HIP, and acetylcholine efflux in the HIP. Most of these effects of cariprazine and SB-277011A were fully or partially attenuated by the D3 receptor agonist (+)-PD-128907, suggesting these effects of cariprazine are related to its D3 receptor partial agonism, and that this mechanism, leading to diminished stimulation of D3 receptors, may contribute to its efficacy in both schizophrenia and bipolar disorder. The possible role of Gly in the action of cariprazine is discussed. SIGNIFICANCE STATEMENT: The novel atypical antipsychotic drug cariprazine increased nucleus accumbens and hippocampal neurotransmitter efflux, similar to the actions of the D3 receptor antagonist SB-277011A [trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide hydrochloride]. The D3 receptor-preferring agonist (+)-PD-128907 [(4aR, 10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], diminished the effects of both compounds on neurotransmitter efflux in both regions. These results suggested D3 receptor partial agonist activity of cariprazine, producing functional antagonism, may contribute to its efficacy in schizophrenia and bipolar disorder.


Prenatal ethanol exposure alters the modulation of the gamma-aminobutyric acidA1 receptor-gated chloride ion channel in adult rat offspring.
We examined the effect of prenatal ethanol exposure on gamma-aminobutyric acid (GABA)-stimulated 36Cl- flux. Sprague-Dawley rat dams were fed either a liquid diet containing 5% ethanol, pair-fed an isocalorically equivalent 0% ethanol diet or rat chow ad libitum throughout gestation. Membrane vesicles were prepared from medial frontal cortex, cerebellum and hippocampal formation of adult offspring in each diet group. GABA-stimulated 36Cl- flux was not significantly affected by prenatal ethanol exposure in any of the three brain regions examined. Positive allosteric modulation of GABA-stimulated 36Cl- flux by flunitrazepam or alphaxalone, as well as negative modulation by FG-7142 or pregnenolone, were all diminished in medial frontal cortex of 5% ethanol diet offspring compared with both ad libitum and pair-fed control groups. In cerebellum, prenatal ethanol exposure attenuated the modulatory effects of both benzodiazepines, but did not affect neurosteroid modulation. In hippocampus, prenatal ethanol exposure enhanced the effects of flunitrazepam and alphaxalone, whereas negative modulatory effects were either decreased (FG-7142) or unchanged (pregnenolone). These results indicate that moderate ethanol consumption during gestation can produce long-lasting alterations in neuromodulatory influences on GABAA receptor-mediated inhibitory neurotransmission in adult offspring. In hippocampal formation, the heightened sensitivity to positive modulatory influences may contribute to synaptic plasticity deficits in fetal ethanol-exposed rat offspring. We speculate that these prenatal ethanol-induced changes may be either a consequence of differential GABAA receptor subunit expression or receptor uncoupling in different brain regions. Furthermore, offspring exposed to ethanol in utero may display differential sensitivities to benzodiazepines and possibly other centrally active therapeutic agents.


Dissemination and proliferation of intravenously injected murine, syngeneic T lymphoma cells.
BALB/c mice were inoculated intravenously with syngeneic T lymphoma cells. Dissemination and proliferation of malignant cells in vitro were determined from time of cell injection to the time of death of the animal, using an agar medium in which only tumor cells grew. Tumor cells were detected in kidney from day 7, and in liver, lungs and ovaries from days 9-12. The myeloid-lymphatic system was only sparsely invaded. Three weeks after injection the animals died of general metastases, and colonies could be grown from all organs. Peripheral blood tumor cells colonies were grown in quantities of 1-2% on injected cells during the first hour. They then disappeared from blood, but reappeared 2-3 weeks later. Within the first 15 min after i.v. infections of vitro labelled tritiated-thymidine tumor cells, 45% of the radioactivity was recovered from lungs and 40% from the liver. After this time the activity gradually declined. Only about 1% of the initial activity of the injected cells was found in the spleen, kidney and brain during the first 24 hours. Blood glow of the organs was examined by means of indicator fractionation. Highest flow rates were measured in liver, kidney, brain and lungs. Thus, the sites of metastases after tumor cell injection were determined neither by the initial deposition of tumor cells, nor by blood flow rates through the organs. This result shows that cellular interaction between neoplastic cells and the immediate environment must be major determinants in the development of metastases.


From Toques to Tokes: Two challenges facing nationwide legalization of cannabis in Canada.
In 2015, a new Liberal Government came to power in Canada, elected on a platform that included legalization and regulation of cannabis for recreational purposes. Their legislation, based on recommendations from a Federal Task Force on Marijuana Legalization and Regulation, is due in early April 2017. This commentary utilizes Canadian Federal policy papers, previous literature, and internal and international agreements to examine two key areas critical to the development of a nationwide regulated market for cannabis in Canada; the need to overcome restrictions to legalizing cannabis in United Nations' drug control treaties, and the unique challenges that non-medical cannabis creates for navigating interprovincial trade policies in Canada. Irrespective of UN conventions that appear to prohibit legalization of cannabis the Government is preparing to bring forward legislation as this article goes to print. At the same time significant squabbles impede the selling of even beer and wine inter-provincially in Canada. This paper identifies the challenges facing Canadian legalization efforts, but also shows how the legalization legislation may provide opportunities to engender significant change beyond the simple legalization of a specific drug. This commentary does not argue for any specific course of action for Canada, but rather explores the nuance of legalization absent from the declaration in the Liberal party platform. The paper argues that Canada's efforts may hasten the dismantling of the UN drug control structure, and provide renewed opportunities for intern-provincial trade in Canada.


Involvement of caspases in apoptotic cell death of murine macrophages infected with Actinobacillus actinomycetemcomitans.
Infection of murine macrophages in vitro with periodontopathic bacterium Actinobacillus actinomycetemcomitans induces apoptotic cell death. In this study, we investigated the involvement of caspases in apoptotic cell death of A. actinomycetemcomitans-infected macrophages. Two peptide inhibitors of caspases, benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone (Z-VAD-FMK) and benzyloxycarbonyl-Asp-Glu-Val-Asp (OMe)-fluoromethyl ketone (Z-DEVD-FMK), inhibited apoptotic cell death of murine macrophage cell line J774.1 infected with A. actinomycetemcomitans. During the process of apoptosis, interleukin-1beta (IL-1beta) was detected in the culture supernatants of J774.1 cells. IL-1beta secretion was blocked by the caspase-1 inhibitor, Z-VAD-FMK, indicating that caspase-1 is involved in not only the induction of apoptosis but also the IL-1beta secretion from A. actinomycetemcomitans-infected J774.1 cells. Immunoblot analysis revealed that the infection of A. actinomycetemcomitans to J774.1 cells induced the cleavage of retinoblastoma protein (Rb), suggesting that caspase-3 was activated by A. actinomycetemcomitans infection. The cytosol from A. actinomycetemcomitans-infected J774.1 cells induced Rb proteolysis in vitro, which was inhibited by the caspase-3 inhibitor, Z-DEVD-FMK. Furthermore, caspase-3-like activity was markedly increased in J774.1 cells infected with A.actinomycetemcomitans between 12 h and 24 h, which was subsequently inhibited by the addition of caspase-3 inhibitor, Z-DEVD-FMK. These findings indicate that caspase-3 induces apoptosis in J774.1 cells infected with A. actinomycetemcomitans. Taken together, these results suggest that caspase-1 and caspase-3 are involved in the induction of apoptosis in A. actinomycetemcomitans-infected macrophages.


A flow cytometry-based screen of nuclear envelope transmembrane proteins identifies NET4/Tmem53 as involved in stress-dependent cell cycle withdrawal.
Disruption of cell cycle regulation is one mechanism proposed for how nuclear envelope protein mutation can cause disease. Thus far only a few nuclear envelope proteins have been tested/found to affect cell cycle progression: to identify others, 39 novel nuclear envelope transmembrane proteins were screened for their ability to alter flow cytometry cell cycle/DNA content profiles when exogenously expressed. Eight had notable effects with seven increasing and one decreasing the 4N:2N ratio. We subsequently focused on NET4/Tmem53 that lost its effects in p53(-/-) cells and retinoblastoma protein-deficient cells. NET4/TMEM53 knockdown by siRNA altered flow cytometry cell cycle/DNA content profiles in a similar way as overexpression. NET4/TMEM53 knockdown did not affect total retinoblastoma protein levels, unlike nuclear envelope-associated proteins Lamin A and LAP2α. However, a decrease in phosphorylated retinoblastoma protein was observed along with a doubling of p53 levels and a 7-fold increase in p21. Consequently cells withdrew from the cell cycle, which was confirmed in MRC5 cells by a drop in the percentage of cells expressing Ki-67 antigen and an increase in the number of cells stained for ß-galactosidase. The ß-galactosidase upregulation suggests that cells become prematurely senescent. Finally, the changes in retinoblastoma protein, p53, and p21 resulting from loss of NET4/Tmem53 were dependent upon active p38 MAP kinase. The finding that roughly a fifth of nuclear envelope transmembrane proteins screened yielded alterations in flow cytometry cell cycle/DNA content profiles suggests a much greater influence of the nuclear envelope on the cell cycle than is widely held.


Improving care for urban children with asthma: design and methods of the School-Based Asthma Therapy (SBAT) trial.
The School Based Asthma Therapy (SBAT) trial builds on a pilot study in which we found that school-based administration of preventive asthma medications for inner-city children reduced asthma symptoms. However, the beneficial effects of this program were seen only among children not exposed to environmental tobacco smoke (ETS). The current study is designed to establish whether this intervention can be enhanced by more stringent adherence to asthma guidelines through the addition of symptom-based medication dose adjustments, and whether smoke-exposed children benefit from the intervention when it is combined with an ETS reduction program. The intervention consists of both administration of preventive asthma medications in school (with dose adjustments according to NHLBI guidelines) and a home-based ETS reduction program utilizing motivational interviewing principles. This paper describes the methodology, conceptual framework, and lessons learned from the SBAT trial. Results of this study will help to determine whether this type of comprehensive school-based program can serve as a model to improve care for urban children and reduce disparities.


[Botox in combined treatment of cerebral palsy in children].
Ten patients with cerebral palsy (CP) were treated with botox (botulinum toxin, type A). The next forms of the disease were observed in the patients: a spastic dysplegia, a spastic hemiplegia, a spastic-hyperkinetic form of CP. Botox was injected into the damaged muscles in a dose of 100-300 Units. Therapeutical effect was found in 90% of the patients, an average duration of the medical effect was 6-12 months. Because of the small cohort of the patients treated with botox there was made a preliminary conclusion about the high efficiency and safety of botox for CP treatment. The need of further clinical observations was emphasized.


[A new case of Cohen's syndrome].
We report a detailed description of ocular alterations, especially uveal coloboma, as shown in a patient with Cohen's syndrome. We also report new lesions, not previously described in the revised bibliography: lens and optic head colobomas, hyaloid artery and anterior "vasculosa lentis" tunica vestige. The most characteristic ocular alterations previously described in the bibliography are eyelid antimongoloid fissures, strabismus and myopia.


Suppression of renin secretion by insulin: dependence on extracellular calcium.
The isolated perfused rat kidney was used to examine the effect of insulin on renin release (RR). Insulin produced a dose-dependent reduction of RR when added to the perfusate at concentrations between 10 and 1,000 microU/ml. When kidneys were perfused with a calcium-free perfusate, RR increased nearly fivefold. Insulin (1,000 microU/ml) not only failed to suppress RR in calcium-free perfusions but stimulated it. The addition of verapamil (10(-5) M) to the perfusate likewise prevented the insulin inhibition of RR. Perfusion without potassium reduced RR to one-third of control values. The addition of insulin to kidneys perfused without potassium further suppresses RR. We conclude that at concentrations similar to those found in plasma, insulin modulates renin secretion. This process requires the influx of calcium possibly through insulin receptor-operated channels.


Cytogenomics and gene expression in a case of metachronous bilateral renal cell carcinomas with drop metastasis: Resolving a diagnostic dilemma with molecular technologies.
Metachronous bilateral renal cell carcinomas (RCCs) are rare but well known. We present a case of metachronous bilateral RCCs with a ureter orifice metastasis, for which the pathological diagnosis was confirmed with single nucleotide polymorphism microarray (SNP-M) and gene expression assay (GEA). A 53-year-old man presented with a right ureteral obstruction. A cystoscopy showed a large pedunculated tumor emanating from the right ureteral orifice, consistent with a drop metastasis, which was biopsied. He had a history of a clear cell RCC (ccRCC) 1.5 years prior and a right renal pelvic mass found 8 months later. Histologically, the biopsied right ureteral tumor demonstrated sheets of poorly differentiated cancer cells composed of a mixture of spindled and focal clear cell components. The main differential diagnosis was metastatic RCC versus urothelial carcinoma, but the immunohistochemical profile was not contributory. SNP-M revealed a genomic profile consistent with a metastatic ccRCC with loss of chromosome 3p. GEA showed a gene expression pattern consistent with kidney origin. The cytogenomic array also identified chromosome copy number patterns that were shared between both kidney tumors. This finding suggests that both tumors had a common origin, and thus, the metachronous ccRCC in the contralateral kidney represents a metastasis.


Blood-brain barrier permeability in Alzheimer's disease: a case-control MRI study.
Blood-brain barrier (BBB) dysfunction may contribute to the risk of Alzheimer's disease (AD). Dynamic contrast-enhanced magnetic resonance imaging (MRI) was performed repeatedly nine times before and up to 30 min following a 20 ml Gd-DTPA bolus injection in 15 AD participants and 15 healthy older people. For each participant, small circular regions of interest (size: 9 voxels) were placed to sample widely the deep gray matter (12 regions), cortical gray matter (72 regions), white matter (72 regions) and CSF (8 regions) as well as the basilar and internal carotid arteries (3 regions). Data were analysed using mixed effects models. There was no overall significant difference for AD subjects versus controls, but there was a significant effect for the time-by-AD interaction. Estimated marginal means remained essentially unchanged in AD subjects, but increased slowly after 15 min in healthy controls. An initial rise in gray matter MRI signal intensity followed by a later increase was also seen in AD participants after adjusting for CSF MRI signal intensities. The data suggest that BBB permeability is present even at an early stage of AD. Though the extent of leakage was no greater than that of non-demented people of a similar age in this small sample, the temporal pattern differed, indicating different blood-brain-CSF compartmental kinetics.


The Effect of Self-directed Exercise Using a Task Board on Pain and Function in the Upper Extremities of Stroke Patients.
[Purpose] We evaluated the effect of self-directed exercise using a task board on function and pain in the upper extremities of stroke patients [Subjects and Methods] We used the one group pre-post test design. Seven stroke patients who were selected based on the inclusion criteria participated in the program once a week for 10 weeks. The self-directed exercise comprised 5 stages that were divided according to the level of difficulty. The exercise was performed for 60 minutes using a special task board that we designed. The FMA (Fugl-Meyer Motor Assessment), VAS (Visual Analogue Scale), and speed of stacking were assessed to evaluate the amount of use of the affected arm at before and after intervention. [Results] The scores of the VAS and FMA, but not that of the speed of stacking cups, were improved. There was no significant correlation between the changes in VAS, FMA, and the speed of stacking cups. [Conclusion] The findings suggest that self-directed exercise with the task board could improve the levels of function and pain in the upper extremities. We suggest that self-directed exercise can be utilized as a clinical rehabilitation program and improve therapeutic effects.


Acidosis and coma after hemodialysis.
Ethylene glycol poisoning is a rare yet potentially fatal illness seen most commonly in association with ingestion by alcoholics or in suicide attempts. It is characterized by an elevated anion gap metabolic acidosis, osmolal gap, calcium oxalate crystals in the urine, and a well-defined clinical picture. Prompt treatment is crucial because effective intervention can prevent the neurologic, cardiac, pulmonary, and renal sequelae associated with ethylene glycol poisoning. Hemodialysis offers rapid clearance of ethylene glycol and its toxic metabolites. In this article, the case of a hemodialysis patient who suffered contamination of the dialysate solution with ethylene glycol, leading to altered mental status, coma, and severe anion gap metabolic acidosis, is reported. Despite prolonged dialysis and correction of the acidosis, the patient remained comatose and subsequently died.


A method to analyze the sectoral impact of Fiscal support for COVID-19 affected economies: The case of Oceania.
In this paper, we apply the method of computable general equilibrium (CGE) modeling in economics to ascertain how fiscal support measures such as wage subsidies, small business loans, and finance guarantee schemes have impacted at an economy-wide and sectoral level for 8 COVID-19 affected economies in Oceania. We model our scenarios based on IMF World economic outlook projections, combined with the fiscal stimulus packages offered to counter this global health pandemic's recessionary effect. Our study confirms that the adverse impact of COVID-19 on output is cushioned through a large fiscal stimulus package wherever offered. This package would still be inadequate to avoid unemployment and job losses in tourism and education services in Oceania, with continued support essential for their survival in 2021.•The approach entails steps (1) to (3), as outlined in the paper.•Future researchers will find this method useful in evaluating the adverse impact of not only COVID-19 but any other external shocks to the economy, either directly or indirectly, that involves fiscal support mechanisms.


[Intestinal absorption from therapeutic iron doses (author's transl)].
On a total of 105 persons with normal iron stores, iron depletion, and iron deficiency the intestinal absorption from therapeutic iron doses (100 mg Fe and 50 mg Fe as ferrous glycocoll sulphate) of a special galenic form was measured. The measurements were performed by means of a whole-body counter and preparations labelled with radio-iron (59Fe). Mean values of absorption rates from 100 mg Fe in healthy males were 5.0% and in healthy females 5.6% whereas in latent iron deficiency and in iron deficiency anemia mean values of 10% and 13% were obtained, respectively. The maximum absorption rate of 20 to 25% is reached already in the late stage of latent iron deficiency. Advancing severeness of iron deficiency is not followed by an increase of iron absorption. Investigations on 21 persons showed no significant difference between absorption rates of the galenic preparations used when administered orally before or after breakfast, respectively.


Prenatal air pollution exposure increases the risk of macrosomia: evidence from a prospective cohort study in the coastal area of China.
Effects of prenatal ambient air pollution exposure could increase the risk of adverse pregnancy outcomes, which have been well documented by various studies. However, only very few studies investigated the effects on macrosomia. This study investigated the effects of prenatal air pollution exposure on the risk of macrosomia in a coastal city of China. Data of birth outcomes and air pollution in a coastal city in China between November 1, 2013, and December 31, 2017, were collected. Finally, 58,713 eligible births, including 8159 (13.9%) macrosomia and 50554 (86.1%) normal birth weight (NBW) infants, were included in the analysis. Logistic regression analyses were used to evaluate the effects of prenatal air pollution exposure on macrosomia. In the single-pollutant models, each 10 μg/m3 increase of PM2.5, PM10, and SO2 exposures, during the entire pregnancy or three trimesters, were related to elevated risk of macrosomia (adjusted RR, 95% CI) ranging from 1.018 (1.001, 1.035) to 1.314 (1.188, 1.454). In addition, O3 exposure in the first trimester (adjusted RR =1.034, 95% CI 1.009, 1.059) also increased the macrosomia risk. Prenatal PM2.5, PM10, and SO2 exposure could significantly increase the risk of macrosomia. These findings need to be further verified in more studies with multiple coastal cities included.


Associations between psychiatric symptoms and seclusion use: Clinical implications for care planning.
Findings from an increasing number of studies suggest that incorporating systematic short-term risk assessments in treatment planning could lead to safer practice on psychiatric admissions wards. The aim of the present study was to investigate the associations between the scores of three structured observation tools - the Kennedy Axis V (K-Axis-V), the Brief Psychiatric Rating Scale (BPRS), and the Social Dysfunction and Aggression Scale (SDAS) - and seclusion. In total, 1840 weekly risk assessments with these observation scales were collected over 2342 admission weeks. These assessment scores related to 370 acutely-admitted psychiatric patients and were subjected to a multilevel analysis. It was found that several dynamic and static factors were related to seclusion. Dynamic factors included violent behaviour, current substance abuse, suspiciousness, and negativism. Static factors included ethnicity and having been diagnosed with a substance abuse disorder. The findings suggest that the incorporation of the Kennedy-Axis V, the BPRS, and the SDAS into standard practice might be helpful in identifying patients at high risk of seclusion, and could be supportive to treatment planning and clinical decision-making in the prevention of seclusion use in acute psychiatric settings.


Mucosal correlates of protection in HIV-1-exposed sero-negative persons.
Resistance to HIV-1 infection in HIV-1-exposed sero-negative (HESN) persons offers a promising opportunity to identify mechanisms of 'natural' protection. Unique features of the mucosa in particular may contribute to this protection. Here, we highlight several key issues pertaining to the mucosal correlates of protection in HESN persons, including humoral immune responses, mechanisms of mucosal HIV-1 neutralization, immune cell activation, and role of the microbiota in mucosal responses. We also discuss mucosal model systems that can be used to investigate the mechanisms of resistance in HESN subjects. A clear understanding of the mucosal correlates of protection against HIV-1 in HESN persons will provide critical new insights for the development of effective vaccine and microbicide strategies for the prevention of HIV-1 transmission.


Inhibition of polypeptide chain initiation in Daudi cells by interferons. Evidence that activity of initiation factor eIF-2 and availability of mRNA are unimpaired.
The accompanying paper [McNurlan & Clemens (1986) Biochem. J. 237, 871-876] shows that the inhibition of proliferation of Daudi cells by human interferons is associated with impairment of the overall rate of protein synthesis. We have examined whether two of the mechanisms which are believed to control translation in interferon-treated virus-infected cells may be responsible for the inhibition of protein synthesis during the antiproliferative response in these uninfected cells. Although the rate of polypeptide chain initiation is lower in interferon-treated Daudi cells, as indicated by the disaggregation of polysomes, there is no significant inhibition of activity of initiation factor eIF-2 or of [40 S . Met-tRNAf] initiation complex formation in cell extracts. The phosphorylation state of the alpha subunit of eIF-2 remains unaltered. There is no major decrease in mRNA content as a proportion of total RNA up to 4 days of interferon treatment, as judged by poly(A) content, although the amount of total mRNA/10(6) cells eventually declines. The mRNA present in extracts from interferon-treated cells remains translatable when added to an mRNA-dependent reticulocyte lysate system. We conclude that neither the interferon-inducible eIF-2 protein kinase pathway nor the 2',5'-oligo(adenylate)-ribonuclease L pathway are responsible for the inhibition of polypeptide chain initiation. Rather, the data suggest impairment at the level of formation of [80 S ribosome X mRNA] initiation complexes.


Heat shock protein levels are not elevated in heat-resistant B16 melanoma cells.
Heat-resistant variants have been selected from B16 melanoma cells and from surface mutants previously derived from them. The aim of the present study was to explore the possible role of heat shock proteins in the manifestation of this heat resistance. The major heat shock proteins evident after heating have subunit molecular weights of 68, 70, 89, and 110K on sodium dodecyl sulfate-polyacrylamide gels. The 68-kDa protein is not evident in any of the unheated B16 cell lines while the levels of the other heat shock proteins are elevated after heating. The constitutive levels of the 70, 89, and 110-kDa heat shock proteins were assessed after gel electrophoretic separation of proteins in several of the heat-resistant variants. No major differences were found in the levels of these proteins between the heat-sensitive parent lines and the heat-resistant variants. We therefore conclude that heat shock proteins are not a determining factor in the heat-resistant phenotype of B16 melanoma cells.


Children often present with infantile spasms after herpetic encephalitis.
To determine what epilepsy types occur after herpetic encephalitis and what are the determinant factors for subsequent infantile spasms. We analyzed retrospectively the clinical history of 22 patients, referred to Necker and Saint Vincent de Paul Hospitals (Paris) through the French pediatric epilepsy network from March 1986 to April 2010 and who developed epilepsy some months after herpetic encephalitis. We focused on seizure semiology with video-electroencephalography (EEG) recording, and on neuroradiology and epilepsy follow-up. Fourteen patients developed pharmacoresistant spasms, and eight developed focal epilepsy, but none had both. The patients who developed spasms were more frequently younger than 30 months at age of onset of epilepsy and had herpetic encephalitis earlier (mean 10.6 months of age) than those who developed focal epilepsy (mean 59.7 and 39.6 months, respectively). Epilepsy follow-up was similar in both groups (8.5 and 11 years, respectively). We found 26 affected cerebral areas; none alone was related to the development of epileptic spasms. Risk factors to develop epileptic spasms were to have had herpetic encephalitis early (mean 10 months); to be significantly younger at onset of epilepsy (mean 22.1 months); and to have cerebral lesions involving the insula, the hippocampus, and the temporal pole.


The management of work-related back pain.
This paper describes the Spinal Treatment Program at Columbia Hospital in Milwaukee. The primary goal of the program is to efficiently return the employee with a work-related back injury to the work setting. The two-phase program has been developed to provide treatment of acute injury, patient education, work hardening, and an assessment of the patient's ability to perform job tasks. Preliminary evaluative data are presented for patients treated from 1982 to 1984. The patient's discharge status (returned or did not return to work) was examined as a function of sex, age, educational level, employment category, duration of pain, or worker's compensation status. Results indicated that discharge status was significantly related to sex, employment category, duration of pain, and worker's compensation status.


Inhibition of Plk1 induces mitotic infidelity and embryonic growth defects in developing zebrafish embryos.
Polo-like kinase 1 (Plk1) is central to cell division. Here, we report that Plk1 is critical for mitosis in the embryonic development of zebrafish. Using a combination of several cell biology tools, including single-cell live imaging applied to whole embryos, we show that Plk1 is essential for progression into mitosis during embryonic development. Plk1 morphant cells displayed mitotic infidelity, such as abnormal centrosomes, irregular spindle assembly, hypercondensed chromosomes, and a failure of chromosome arm separation. Consequently, depletion of Plk1 resulted in mitotic arrest and finally death by 6days post-fertilization. In comparison, Plk2 or Plk3 morphant embryos did not display any significant abnormalities. Treatment of embryos with the Plk1 inhibitor, BI 2536, caused a block in mitosis, which was more severe when used to treat plk1 morphants. Finally, using an assay to rescue the Plk1 morphant phenotype, we found that the kinase domain and PBD domains are both necessary for Plk1 function in zebrafish development. Our studies demonstrate that Plk1 is required for embryonic proliferation because its activity is crucial for mitotic integrity. Furthermore, our study suggests that zebrafish will be an efficient and economical in vivo system for the validation of anti-mitotic drugs.