Volume blood flow, static pressure ratio and venous conductance in native arterio-venous fistulae: three surveillance methods compared.
Dialysis venous pressure monitoring has been widely recommended as a surveillance method but has not been shown to improve access outcomes in randomised controlled trials. The method has been impaired by the need to either turn off the blood pump or to derive the static venous pressure from the venous pressure measured with the dialysis pump running. We have developed a unique algorithm which converts Doppler-shifted spectral information derived from unscaled pulsatile blood flow waveforms into an estimate of mean blood pressure (MBP) at the point of ultrasound insonation. We have devised the unique expression shown here: MBP = MAP/(1 + Pff/Vff) where MAP is the mean arterial pressure, Pff = (systolic - diastolic)/MAP measured on the contralateral arm and Vff = spectral maximum - minimum/mean. Venous conductance (VC) can be measured by combining this pressure data with Duplex ultrasound blood flow data. A new device BlueDop™ has been used to illustrate the potential clinical value of non-invasive static pressure ratio (SPRn) in a monitoring role. Duplex and BlueDop™ technology were tested in an arterio-venous fistula (AVF) study in which VC, Q and SPRn were compared. Thresholds used for detection of ≥60% venous stenosis were VC <10 mL min-1 mm Hg-1, Q <500 mL min-1, SPRn >0.56. The following accuracy was achieved: VC = 96%, Q = 92%, SPRn = 76% with similar accuracy in predicting premature thrombosis. A new algorithm has been described and its in vivo accuracy in estimating mean 'pressure from flow' has been confirmed. Two new variables and a new dedicated instrument BlueDop™ have been demonstrated in clinical use.


Factors relating to the development of hypertension after cardiopulmonary bypass.
Paroxysmal hypertension after cardiac surgery is a phenomenon of physiological and clinical significance. The possible preoperative and intraoperative factors that may predict its occurrence were studied in 81 consecutive patients undergoing coronary artery surgery (n = 58) or valve replacement (n = 27), of whom 45 (56%) developed postoperative hypertension. Hypertension occurred significantly more often in those patients who received beta adrenergic blocking agents preoperatively and who underwent coronary artery surgery. Patients with hypertension had significantly higher mean left ventricular ejection fractions preoperatively (52%) than those without (41%) and required phentolamine significantly more often and isoprenaline significantly less often intraoperatively. It is suggested that the significance of preoperative beta adrenergic blockade, the type of operation, and the intraoperative requirement for phentolamine in patients who developed post-operative hypertension may indicate the role of enhanced sympathetic activity and disturbance of cardiac receptors during surgery. Preoperative myocardial performance and the method of myocardial protection during surgery are likely to influence the occurrence of the hypertensive phenomenon.


Characterisation of indole alkaloids and phenolic acids from wild mushroom Tropicoporus linteus and its chemical profiles compared with other Sanghuang mushrooms.
Two new indole alkaloids, 1-methylindole-7-methoxy-3-carboxaldehyde (2) and 7-methoxyindole-3-carboxaldehyde (4), together with 7-methoxyindole-3-carboxylic acid methyl ester (1) and 1-methylindole-3-carbaldehyde (3) were isolated from the fruiting bodies of wild Sanghuang mushroom Tropicoporus linteus (TL663). TLC, 1H-NMR and LC-MS chemical profiles of this mushroom compared with other three genera of wild Sanghuang mushroom extracts were investigated. The TLC, 1H-NMR and LC-MS profiles of TL663 and Sanghuangporus sanghuang (SS664) were similar and significantly different from other mushrooms. These two samples indicated the same TLC chromatograms by showing prominent bands of 1 - 4 when observed under UV 254 nm and having sharp aldehyde proton signals of 3-carboxaldehyde indole type in 1H-NMR spectra. From LC-MS analyses, peaks of isolated compounds 1 - 4 and indole-3-carboxaldehyde (5) in TL663 extract and peaks of protocatechuic acid (6), caffeic aldehyde (7), caffeic acid (8) and 3,4-dihydroxybenzalacetone (9) phenolic acids in TL663 fraction were identified.


Synthesis and biological evaluation of cruentaren A analogues.
The complex macrolide cruentaren A is a highly selective and potent inhibitor of F-ATPase (F-type adenosine triphosphatase). As it shows some resemblance to benzolactone enamides like apicularen A, it was of interest to perform some structure-activity studies to delineate the key functional groups that are responsible for the activity. Building upon our previously developed route to cruentaren A, which is based on a ring-closing alkyne metathesis reaction (RCAM), several cruentaren analogues were prepared. Replacement of the 3-hydroxy hexanoic part with acids that lack the hydroxy group function resulted in a significant drop in cytotoxicity and F-ATPase inhibition. Furthermore, two enamide analogues 23 and 50 were synthesized. However, these compounds were only cytotoxic in the micromolar range. Under the conditions for cleavage of the C3 aromatic methyl ether, the enamide function was transformed to the corresponding oxazinanone, resulting in analogues 25 and 52.


Liver scanning in malignant genitourinary tumours.
To assess the value of liver scanning as a routine pretreatment screening test for metastatic spread in patients with malignant genitourinary tumours, the authors reviewed the records of 68 such patients who underwent liver scanning. Of 74 scans obtained, 10 gave positive results. There was a 6% false-positive rate and in five of six true-positive scans other clinical and laboratory data indicated the presence of distant metastatic spread. The liver scan provided new information in only one case. The authors conclude that routine liver scanning before treatment is not warranted in patients with malignant genitourinary tumours.


Draft genome sequence of Halomonas lutea strain YIM 91125(T) (DSM 23508(T)) isolated from the alkaline Lake Ebinur in Northwest China.
Species of the genus Halomonas are halophilic and their flexible adaption to changes of salinity and temperature brings considerable potential biotechnology applications, such as degradation of organic pollutants and enzyme production. The type strain Halomonas lutea YIM 91125(T) was isolated from a hypersaline lake in China. The genome of strain YIM 91125(T) becomes the twelfth species sequenced in Halomonas, and the thirteenth species sequenced in Halomonadaceae. We described the features of H. lutea YIM 91125(T), together with the high quality draft genome sequence and annotation of its type strain. The 4,533,090 bp long genome of strain YIM 91125(T) with its 4,284 protein-coding and 84 RNA genes is a part of Genomic Encyclopedia of Type Strains, Phase I: the one thousand microbial genomes (KMG-I) project. From the viewpoint of comparative genomics, H. lutea has a larger genome size and more specific genes, which indicated acquisition of function bringing better adaption to its environment. DDH analysis demonstrated that H. lutea is a distinctive species, and halophilic features and nitrogen metabolism related genes were discovered in its genome.


Intestinal microorganisms do not supply associated gnotobiotic rats with conjugated linoleic acid.
Conjugated linoleic acid (CLA) is produced from linoleic acid (LA) by bacteria in the rumen of herbivores. CLA enters the human diet mainly via milk fat and fatty beef; it acts as an effective anticarcinogen and exhibits other important physiological effects. The objective of the current study was to investigate the capability of a LA-conjugating bacterial community isolated from a human volunteer and associated with germ-free rats to supply the host with CLA. Gnotobiotic rats were fed a diet enriched with esterified LA in the form of sunflower-seed oil. The control group was fed the same diet and remained germ-free. Bacterial cell counts, in vitro LA-conjugation activities, and CLA concentration in feces and in the contents of various intestinal segments were determined. After 10 wk, various tissues were analyzed for CLA concentrations. LA-conjugation activity was found only in feces, cecum and colon content samples from associated rats, but CLA accumulation in various body tissues did not differ significantly between the two groups. The ratio of CLA to LA in feces and in cecal and colonic contents did not differ between groups, indicating that the microorganisms in the cecum and the colon do not synthesize substantial amounts of CLA in vivo and therefore, do not contribute to the CLA supplementation of the host.


Channel-opening kinetics of GluR6 kainate receptor.
GluR6 is an ionotropic glutamate receptor subunit of the kainate subtype. It plays an essential role in synaptic plasticity and epilepsy. We expressed this recombinant receptor in HEK-293 cells and characterized the glutamate-induced channel-opening reaction, using a laser-pulse photolysis technique with the caged glutamate (gamma-O-(alpha-carboxy-2-nitrobenzyl)glutamate). This technique permits glutamate to be liberated photolytically from the caged glutamate with a time constant of approximately 30 micros. Prior to laser photolysis, the caged glutamate did not activate the GluR6 channel, nor did it inhibit or potentiate the glutamate response. At the transmembrane voltage of -60 mV, pH 7.4 and 22 degrees C, the channel-opening and -closing rate constants were determined to be (1.1 +/- 0. 4) x 10(4) and (4.2 +/- 0.2) x 10(2) s(-1), respectively. The intrinsic dissociation constant of glutamate and the channel-opening probability were found to be 450 +/- 200 microM and 0.96, respectively. These constants are derived from a minimal kinetic mechanism of the channel activation involving the binding of two glutamate molecules. This mechanism describes the time course of the open-channel form of the receptor as a function of glutamate concentration. On the basis of the channel-opening rate constants obtained, the shortest rise time (20-80% of the receptor current response) or the fastest time by which the GluR6Q channel can open is predicted to be 120 micros. The open-channel form of the receptor determines the transmembrane voltage change, which in turn controls synaptic signal transmission between two neurons. The comparison of the channel-opening kinetic rate constants between GluR6Q and GluR2Q(flip), reported in the companion paper, suggests that at a glutamate concentration of 100 microM, for instance, the integrated neuronal signal will be dominated by a slower GluR6Q receptor response, as compared to the GluR2Q(flip) component.


Protocol: Remote care as the 'new normal'? Multi-site case study in UK general practice.
Following a pandemic-driven shift to remote service provision, UK general practices offer telephone, video or online consultation options alongside face-to-face. This study explores practices' varied experiences over time as they seek to establish remote forms of accessing and delivering care. This protocol is for a mixed-methods multi-site case study with co-design and national stakeholder engagement. 11 general practices were selected for diversity in geographical location, size, demographics, ethos, and digital maturity. Each practice has a researcher-in-residence whose role is to become familiar with its context and activity, follow it longitudinally for two years using interviews, public-domain documents and ethnography, and support improvement efforts. Research team members meet regularly to compare and contrast across cases. Practice staff are invited to join online learning events. Patient representatives work locally within their practice patient involvement groups as well as joining an online patient learning set or linking via a non-digital buddy system. NHS Research Ethics Approval has been granted. Governance includes a diverse independent advisory group with lay chair. We also have policy in-reach (national stakeholders sit on our advisory group) and outreach (research team members sit on national policy working groups). We expect to produce rich narratives of contingent change over time, addressing cross-cutting themes including access, triage and capacity; digital and wider inequities; quality and safety of care (e.g. continuity, long-term condition management, timely diagnosis, complex needs); workforce and staff wellbeing (including non-clinical staff, students and trainees); technologies and digital infrastructure; patient perspectives; and sustainability (e.g. carbon footprint). By using case study methods focusing on depth and detail, we hope to explain why digital solutions that work well in one practice do not work at all in another. We plan to inform policy and service development through inter-sectoral network-building, stakeholder workshops and topic-focused policy briefings.


Soyoligosaccharide increases fecal bifidobacteria counts, short-chain fatty acids, and fecal lipid concentrations in young Korean women.
The effects of soyoligosaccharide intake on human fecal characteristics were investigated by measuring the fecal water content, bifidobacteria counts, pH, and concentrations of short-chain fatty acids (SCFAs) and lipids. Sixteen young women were randomly assigned to one of two groups: (1) 1.5 g/day soyoligosaccharide intake group [low soyoligosaccharide (LSO)] or (2) 3 g/day soyoligosaccharide intake group [high soyoligosaccharide (HSO)]. The experimental period was 30 days, and fecal samples were collected every 7 days. The number of bifidobacteria in feces was increased significantly in the HSO group. Of the fecal SCFAs, propionate and butyrate concentrations were significantly increased in the HSO group. The excretions of total lipids in feces were significantly increased in both the LSO and HSO groups. These results demonstrate that a soyoligosaccharide intake of 3 g/day increases fecal bifidobacteria counts, SCFA concentrations, and fecal lipid output in Korean young women.


Experimental autoimmune keratitis induced in rats by anti-cornea T-cell lines.
Idiopathic inflammation of the cornea, keratitis, has been proposed to result from an autoimmune process, but thus far no convenient animal model of keratitis exists. An attempt was made to establish an animal model for keratitis, to investigate possible autoimmune mechanisms. T-cell lines were established from lymph node cells removed from rats immunized with bovine corneal epithelium (BCE) extract. After restimulation in vitro with BCE or a specific corneal antigen, the cells were transferred by intraperitoneal injection into naive rats, rats subjected to total body irradiation, or rats in which only one eye was irradiated. Neither direct immunization with corneal antigens nor transfer of activated anti-corneal T-cells into naive rats gave any signs of keratitis. Irradiation alone did not induce corneal inflammation. Transfer of corneal-specific activated T cells into irradiated rats produced keratitis starting around day 4 and culminating around day 8. The disease was self-limiting and the severity dependent on the dose and site of radiation. Keratitis was characterized by corneal haze, conjunctival and episcleral hyperemia, episcleral hemorrhages, chemosis, corneal infiltrates, and vascularization. Immunohistochemistry showed T-cell and macrophage infiltration of epithelium and stroma in the affected corneas. Thus, keratitis may be produced by T cells reactive to corneal antigens, provided that the target tissue has been made susceptible by irradiation. The effectiveness of T-cell vaccination in preventing adoptive keratitis suggests that systemic as well as local tissue factors may regulate the disease process.


Intersex related gene expression profiles in clams Scrobicularia plana: Molecular markers and environmental application.
Intersex, the appearance of female characteristics in male gonads, has been identified in several aquatic species. It is a widespread phenomenon in populations of the bivalve, Scrobicularia plana, from the southwest coast of the U.K. Genes previously identified as differentially expressed (ferritin, testicular haploid expressed gene, THEG, proliferating cell nuclear antigen, PCNA; receptor activated protein kinase C, RACK; cytochrome B, CYB; and cytochrome c oxidase 1, COX1) in intersex clams relative to normal male clams, were selected for characterisation and an environmental survey of the Channel region. Transcripts were significantly differentially expressed at sites with varying intersex incidence and contaminant burdens. Significant correlations between specific gene expressions, key contaminants and sampling locations have been identified, though no single gene was associated with intersex incidence. The results highlight the difficulty in understanding the intersex phenomenon in molluscs where there is still a lack of knowledge on the control of normal reproduction.


[Intestinal microflora in workers of harmful industry].
Prolonged work in industry under unhealthy working conditions leads to disturbances in the normal intestinal microflora in employees. The content of bifidobacteria decreases simultaneously with an increase in the amount of opportunistic microorganisms. The degree of disturbances in intestinal microbiocenosis correlates with the length of service.


Effects of polyamines on the ultrafiltration of plasmid DNA.
It is well established that the structure of plasmid DNA is a strong function of solution ionic conditions due to changes in intramolecular electrostatic interactions between the charged phosphate groups along the DNA backbone. Multivalent cations like spermine and spermidine play a critical role in compacting and controlling the structure of supercoiled DNA in living cells. The objective of this work was to investigate the effects of these polyamines on the ultrafiltration of plasmid DNA, including possible opportunities to use these polycations to enhance the purification of specific plasmid isoforms. Data were obtained using a wide range of spermine and spermidine concentrations to evaluate DNA transmission through Biomax polyethersulfone ultrafiltration membranes. Spermine has a very strong effect on DNA transmission, with the sieving coefficient of the supercoiled plasmid decreasing by more than an order of magnitude upon addition of only 15 μM spermine. A comparable change in DNA transmission required >300 μM of the trivalent spermidine. The polyamines were able to significantly increase the selectivity for the separation of DNA from a model protein, but they were unable to provide a significant increase in the selectivity for separating DNA isoforms under the conditions examined in this study. The results do demonstrate that both spermine and spermidine can be used to control the extent of DNA transmission/purification during ultrafiltration. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 35: e2765, 2019.


Evaluation of methods for assigning causes of death from verbal autopsies in India.
Physician-coded verbal autopsy (PCVA) is the most widely used method to determine causes of death (COD) in countries where medical certification of death is low. Computer-coded verbal autopsy (CCVA), an alternative method to PCVA for assigning the COD is considered to be efficient and cost-effective. However, the performance of CCVA as compared to PCVA is yet to be established in the Indian context. We evaluated the performance of PCVA and three CCVA methods i.e., InterVA 5, InSilico, and Tariff 2.0 on verbal autopsies done using the WHO 2016 VA tool on 2,120 reference standard cases developed from five tertiary care hospitals of Delhi. PCVA methodology involved dual independent review with adjudication, where required. Metrics to assess performance were Cause Specific Mortality Fraction (CSMF), sensitivity, positive predictive value (PPV), CSMF Accuracy, and Kappa statistic. In terms of the measures of the overall performance of COD assignment methods, for CSMF Accuracy, the PCVA method achieved the highest score of 0.79, followed by 0.67 for Tariff_2.0, 0.66 for Inter-VA and 0.62 for InSilicoVA. The PCVA method also achieved the highest agreement (57%) and Kappa scores (0.54). The PCVA method showed the highest sensitivity for 15 out of 20 causes of death. Our study found that the PCVA method had the best performance out of all the four COD assignment methods that were tested in our study sample. In order to improve the performance of CCVA methods, multicentric studies with larger sample sizes need to be conducted using the WHO VA tool.


Hedgehog Signaling: Implications in Cancers and Viral Infections.
The hedgehog (SHH) signaling pathway is primarily involved in embryonic gut development, smooth muscle differentiation, cell proliferation, adult tissue homeostasis, tissue repair following injury, and tissue polarity during the development of vertebrate and invertebrate organisms. GLIoma-associated oncogene homolog (GLI) family of zinc-finger transcription factors and smoothened (SMO) are the signal transducers of the SHH pathway. Both SHH ligand-dependent and independent mechanisms activate GLI proteins. Various transcriptional mechanisms, posttranslational modifications (phosphorylation, ubiquitination, proteolytic processing, SUMOylation, and acetylation), and nuclear-cytoplasmic shuttling control the activity of SHH signaling pathway proteins. The dysregulated SHH pathway is associated with bone and soft tissue sarcomas, GLIomas, medulloblastomas, leukemias, and tumors of breast, lung, skin, prostate, brain, gastric, and pancreas. While extensively studied in development and sarcomas, GLI family proteins play an essential role in many host-pathogen interactions, including bacterial and viral infections and their associated cancers. Viruses hijack host GLI family transcription factors and their downstream signaling cascades to enhance the viral gene transcription required for replication and pathogenesis. In this review, we discuss a distinct role(s) of GLI proteins in the process of tumorigenesis and host-pathogen interactions in the context of viral infection-associated malignancies and cancers due to other causes. Here, we emphasize the potential of the Hedgehog (HH) pathway targeting as a potential anti-cancer therapeutic approach, which in the future could also be tested in infection-associated fatalities.


Production of ribosome-released nascent proteins with optimal physical properties.
The growing interest in protein folding under physiologically relevant conditions has prompted investigations requiring direct comparisons between ribosome-bound and ribosome-released nascent proteins. Such studies, involving the ad hoc release of newly synthesized proteins from stalled ribosomes, demand a release agent able to produce nonaggregated native proteins and preserve the overall nature of the medium. Here, we explore hydroxylamine, a reactant rarely used to release nascent chains, and compare it to other ribosome-release agents: puromycin, RNase A/EDTA, and sodium hydroxide. Ribosome-bound nascent chains corresponding to the sequence of apoHmpH, the Escherichia coli N-terminal domain of Hmp, were used as a model system. Fluorescence anisotropy decays were employed to probe the self-association and overall physical properties of nascent proteins. Gel electrophoresis and RNA chip microfluidic capillary electrophoresis yielded information on the integrity of nascent peptidyl-tRNAs and ribosomes, respectively. Of the four reagents examined, only hydroxylamine releases nascent apoHmpH without causing extensive aggregation or degradation of the ribosome. Hydroxylamine does not introduce large hydrophobic C-terminal modifications and functions at nearly physiological pH. It is therefore a suitable reagent for the ad hoc release of nascent proteins from the ribosome.


Rad54 protein stimulates heteroduplex DNA formation in the synaptic phase of DNA strand exchange via specific interactions with the presynaptic Rad51 nucleoprotein filament.
RAD54 is an important member of the RAD52 group of genes that carry out recombinational repair of DNA damage in the yeast Saccharomyces cerevisiae. Rad54 protein is a member of the Snf2/Swi2 protein family of DNA-dependent/stimulated ATPases, and its ATPase activity is crucial for Rad54 protein function. Rad54 protein and Rad54-K341R, a mutant protein defective in the Walker A box ATP-binding fold, were fused to glutathione-S-transferase (GST) and purified to near homogeneity. In vivo, GST-Rad54 protein carried out the functions required for methyl methanesulfonate sulfate (MMS), UV, and DSB repair. In vitro, GST-Rad54 protein exhibited dsDNA-specific ATPase activity. Rad54 protein stimulated Rad51/Rpa-mediated DNA strand exchange by specifically increasing the kinetics of joint molecule formation. This stimulation was accompanied by a concurrent increase in the formation of heteroduplex DNA. Our results suggest that Rad54 protein interacts specifically with established Rad51 nucleoprotein filaments before homology search on the duplex DNA and heteroduplex DNA formation. Rad54 protein did not stimulate DNA strand exchange by increasing presynaptic complex formation. We conclude that Rad54 protein acts during the synaptic phase of DNA strand exchange and after the formation of presynaptic Rad51 protein-ssDNA filaments.


A 12-month prospective cohort study of injury in international rowers.
In this study, the injury incidence and association with type and volume of training in international rowers were described. A prospective cohort design was used over a 12-month period. 20 international rowers who were competing as part of the Irish Amateur Rowing Union squad system. The rowers were interviewed monthly, and data were collected regarding their training and competition exposure as well as their injury experience. A mean injury rate of 3.67 per 1000 exposure hours was reported with a total of 44 injuries reported in a 12-month period. The mean number of injuries sustained per athlete was 2.2 (1.24) over the 12-month period. The area where the greatest number of injuries were reported was the lumbar spine (31.82% of total injuries, 95% CI 20 to 50) (fig 2) followed by the knee (15.91% of total injuries, 95% CI 10 to 30) and the cervical spine (11.36% of total injuries, 95% CI 5 to 24). Half of the injuries (22 injuries, 50% of total reported injuries) were to the spine (chi(2) = 30.8, df = 9, p = 0.0003). Ergometer training load was the most significantly associated with injury risk (r = 0.68, p = 0.01). International rowers are at higher risk of injury than most non-contact sports and some contact sports. The high risk of lumbar spine injury and the significant association of high volume of ergometer training merit further research to reduce time and competition lost to injury.


Prognosis of Parkinson's disease in Japan. Tottori University Parkinson's Disease Epidemiology (TUPDE) Study Group.
Therapy for Parkinson's disease (PD) has been progressing. However, the prognosis for patients with PD is still unclear. We studied the course of PD in patients in the San-in Area of Japan over a long time period. The main purpose of this study was to see whether there was a difference in survival between PD patients and the general population. Information on 114 deceased PD patients, who died between 1989 and 1996, was collected from hospitals belonging to the Tottori University Parkinson's Disease Epidemiology Study Group. Although the duration of illness was prolonged, the survival of PD patients was still poorer than that of the general population. The most common cause of death was pneumonia. The main cause of death in young PD patients was also pneumonia. In order to improve the survival of PD patients, PD-related conditions should be treated more extensively, especially pneumonia.


Molecular clock-like evolution of human immunodeficiency virus type 1.
The molecular clock hypothesis states that the rate of nucleotide substitution per generation is constant across lineages. If generation times were equal across lineages, samples obtained at the same calendar time would have experienced the same number of generations since their common ancestor. However, if sequences are not derived from contemporaneous samples, differences in the number of generations may be misinterpreted as variation in substitution rates and hence may lead to false rejection of the molecular clock hypothesis. A recent study has called into doubt the validity of clock-like evolution for HIV-1, using molecular sequences derived from noncontemporaneous samples. However, after separating their within-individual data according to sampling time, we found that what appeared to be nonclock-like behavior could be attributed, in most cases, to noncontemporaneous sampling, with contributions also likely to derive from recombination. Natural selection alone did not appear to obscure the clock-like evolution of HIV-1.


Geographic Variation in Racial Disparities in Mortality From Influenza and Pneumonia in the United States in the Pre-Coronavirus Disease 2019 Era.
In 2018, influenza and pneumonia was the eighth leading cause of death in the United States. Since 1950, non-Hispanic blacks (NHBs) have experienced higher rates of mortality than non-Hispanic whites (NHWs). Previous studies have revealed geographic variation in mortality rates by race. The identification of areas with the greatest disparity in influenza and pneumonia mortality may assist policymakers in the allocation of resources, including for the coronavirus disease 2019 pandemic. Does geographic variation in racial disparity in influenza and pneumonia mortality exist? The Centers for Disease Control and Prevention database for Multiple Cause of Death between 1999 and 2018 for NHB and NHW decedents ≥ 25 years of age with a Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems code for influenza (J09-J11) and pneumonia (J12-J18) was used. Age-adjusted mortality rates (AAMRs) with 95% CIs were computed by race for Health & Human Services (HHS) regions and urbanization in NHBs and NHWs. In 1999 through 2018, there were 540,476 deaths among NHBs and NHWs 25 to 84 years of age. AAMRs were higher in NHBs than NHWs in each age group and in seven of 10 HHS regions. The greatest disparity was in HHS regions 2 (New York and New Jersey) and 9 (Arizona, California, Hawaii, and Nevada). In HHS region 2, NHBs (24.6; 95% CI, 24.1-25.1) were more likely to die than NHWs (15.7; 95% CI, 15.6-15.9). Similarly, in region 9, NHBs (23.2; 95% CI, 22.7-23.8) had higher mortality than NHWs (16.1; 95% CI, 15.9-16.2). Within these regions, disparities were greatest in the core of major metropolitan areas. A very high AAMR in NHBs was noted in large, central metropolitan areas of region 2: 28.2 (95% CI, 27.6-28.9). In 1999 through 2018, the NHB-NHW disparity in AAMRs from influenza and pneumonia was greatest in central metropolitan areas of HHS regions 2 and 9.


The sit-up: complex kinematics and muscle activity in voluntary axial movement.
This paper describes the kinematics and muscle activity associated with the standard sit-up, as a first step in the investigation of complex motor coordination. Eight normal human subjects lay on a force table and performed at least 15 sit-ups, with the arms across the chest and the legs straight and unconstrained. Several subjects also performed sit-ups with an additional weight added to the head. Support surface forces were recorded to calculate the location of the center of pressure and center of gravity; conventional motion analysis was used to measure segmental positions; and surface EMG was recorded from eight muscles. While the sit-up consists of two serial components, 'trunk curling' and 'footward pelvic rotation', it can be further subdivided into five phases, based on the kinematics. Phases I and II comprise trunk curling. Phase I consists of neck and upper trunk flexion, and phase II consists of lumbar trunk lifting. Phase II corresponds to the point of peak muscle contraction and maximum postural instability, the 'critical point' of the sit-up. Phases III-V comprise footward pelvic rotation. Phase III begins with pelvic rotation towards the feet, phase IV with leg lowering, and phase V with contact between the legs and the support surface. The overall pattern of muscle activity was complex with times of EMG onset, peak activity, offset, and duration differing for different muscles. This complex pattern changed qualitatively from one phase to the next, suggesting that the roles of different muscles and, as a consequence, the overall form of coordination, change during the sit-up.


Interleukin-33 regulates intestinal inflammation by modulating macrophages in inflammatory bowel disease.
Interleukin 33 (IL-33) that signals through the ST2 receptor has emerged as a critical modulator in several inflammatory disorders, including inflammatory bowel disease (IBD). However, the precise mechanisms by which IL-33 modulates IBD are controversial. The aim of this study was thus to clarify the role of IL-33 in IBD. The plasma levels of IL-33 were significantly decreased, but soluble ST2 levels were increased in patients with IBD compared to healthy individuals. Moreover, IL-33 restored goblet cell numbers and induced macrophage switching from the M1 to the M2 phenotype. These effects were sufficient to ameliorate colitis in dextran sodium sulfate, trinitrobenzene sulfonic acid, and peritoneal cavity cell transfer models. IL-33 facilitated goblet cell restoration via modulating macrophages toward the M2 phenotype. In addition, wound healing was significantly faster in IL-33-treated human monocyte-derived macrophages than in control cells, which could be attributed to increased polarisation into M2 macrophages. We found that patients with IBD show decreased serum levels of IL-33 compared with healthy individuals and that IL-33 can attenuate colitis and aid tissue repair in mice. The mechanism by which IL-33 exerts these effects appears to involve the stimulation of differentiation of goblet cells and M2 macrophages.


Limbic responsiveness to procaine in cocaine-addicted subjects.
The limbic system plays a critical role in motivation, emotional expression, and memory. The authors investigated whether a state of permanent limbic neuronal hyperexcitability, or sensitization, is present in cocaine addicts as a consequence of repeated cocaine use. Single photon emission computed tomography (SPECT) of regional cerebral blood flow (rCBF) was used to compare the central nervous system response to the limbic stimulus procaine in 10 cocaine-dependent male patients and 10 healthy comparison male subjects. The cocaine-addicted subjects demonstrated bilateral activation of the orbitofrontal cortex after the procaine challenge, whereas the comparison subjects showed activation of the anterior cingulate, bilateral insular, and right amygdalar regions. After receiving placebo, the cocaine-addicted subjects showed markedly lower rCBF in the bilateral orbitofrontal cortex than the comparison subjects. The pattern of hypoperfusion in the placebo state followed by heightened activation with procaine in the cocaine-addicted subjects is similar to the pattern of interictal hypoperfusion and ictal hyperperfusion that has been observed in subjects with epilepsy. The findings for the cocaine-addicted subjects may thus represent evidence of localized (orbitofrontal) sensitization.


Recent developments in oligonucleotide conjugation.
Synthetic oligonucleotides (ONs) are being investigated for various therapeutic and diagnostic applications. The interest in ONs arises because of their capability to cause selective inhibition of gene expression by binding to the target DNA/RNA sequences through mechanisms such as antigene, antisense, and RNA interference. ONs with catalytic activity (ribozymes and DNAzymes) against the target sequences, and ability to bind to the target molecules (aptamers), ranging from small molecules to proteins, are also known. Therefore ONs are considered potentially useful for the treatment of viral diseases and cancer. ONs also find use in the design of DNA microchips (a powerful bio-analytical tool) and novel materials in nanotechnology. However, the clinical success achieved so far with ONs has not been satisfactory, and the major impediments have been recognised as their instability against nucleases, lack of target specificity, and poor uptake and targeted delivery. Tremendous efforts have been made to improve the ON properties by either incorporating chemical modifications in the ON structure or covalently linking (conjugation) reporter groups, with biologically relevant properties, to ONs. Conjugation is of great interest because it can be used not only to improve the existing ON properties but also to impart entirely new properties. This tutorial review focuses on the recent developments in ON conjugation, and describes the key challenges in efficient ON conjugation and major synthetic approaches available for successful ON conjugate syntheses. In addition, an overview on major classes of ON conjugates along with their use in therapeutics, diagnostics and nanotechnology is provided.


The kappa-opioid receptor agonist MR-2034 stimulates the rat hypothalamic-pituitary-adrenal axis: studies in vivo and in vitro.
There is increasing evidence that opiates not only have analgesic properties, but also regulate mechanisms activated during the stress response, such as the hypothalamic-pituitary-adrenal (HPA) axis. Indeed, opioid-containing neurons innervate the paraventricular nucleus and the median eminence, thus modulating inputs to ACTH-controlling neurons. In addition, dynorphin (the endogenous ligand of the kappa-opioid receptor)-like peptides have been found co-localized with corticotrophin-releasing hormone (CRH) and are believed to be co-secreted with it in the hypophyseal portal circulation to modulate ACTH release. In this study, we evaluated the effects of the selective kappa-opioid receptor agonist MR-2034 [(-)-N-(2-tetrahydrofurfuryl)-normetazocine] on the HPA axis in vivo and in vitro. MR-2034 was given intravenously to catheterized, freely moving, male Sprague-Dawley rats and serial blood samples were collected for ACTH and corticosterone (B) measurements. We evaluated also the site of MR-2034 action on the HPA axis in vivo, after the administration of alpha-helical CRH9-41, a CRH receptor antagonist, on hypothalamic CRH, pituitary ACTH, and B release in vitro. MR-2034 increased plasma ACTH and B levels in a dose-related fashion and this effect was antagonized by the selective kappa-opioid receptor antagonist MR-1452. In the presence of alpha-helical CRH9-41, the responses of plasma ACTH and B to MR-2034 were blunted significantly, suggesting that this compound activates the HPA axis through a CRH-dependent mechanism. Accordingly, MR-2034 stimulated hypothalamic CRH release in vitro in a concentration-dependent fashion and this effect was antagonized dose-dependently by MR-1452. However, the stimulatory effect of MR-2034 on plasma ACTH and B in vivo was not completely abolished by alpha-helical CRH9-41, suggesting that an additional, CRH-independent, mechanism was involved. Indeed, MR-2034 was able to stimulate basal ACTH output in a dose-dependent manner and this effect was antagonized by MR-1452 in vitro. On the other hand, MR-2034 did not have any effect on B release from adrenocortical cells or adrenal quarters in vitro. These results show that the benzomorphan MR-2034 stimulates the HPA axis in the rat by acting at the hypothalamic and the pituitary level. We hypothesize that endogenous kappa-opioid peptides not only act at the pituitary level to increase ACTH output, but may also act at the hypothalamic level to increase CRH release through an autocrine and/or ultrashort positive feedback mechanism.


A new coumarin derivative, 4-acetatecoumarin, with antifungal activity and association study against Aspergillus spp.
Fungal infections have become a concern for health professionals, and the emergence of resistant strains has been reported for all known classes of antifungal drugs. Among the fungi causing disease, we highlight those that belong to the genus Aspergillus. For these reasons, the search for new antifungals is important. This study examines the effects of a coumarin derivative, 4-acetatecoumarin (Cou-UMB16) both alone and together with antifungal drugs, and its mode of action against Aspergillus spp. Cou-UMB16 was tested to evaluate its effects on mycelia growth, and germination of Aspergillus spp. fungal conidia. We investigated its possible action on cell walls, on the cell membrane, and also the capacity of this coumarin derivative to enhance the activity of antifungal drugs. Our results suggest that Cou-UMB16 inhibits Aspergillus spp. virulence factors (mycelia growth and germination of conidia) and affects the structure of the fungal cell wall. When applying Cou-UMB16 in combination with azoles, both synergistic and additive effects were observed. This study concludes that Cou-UMB16 inhibits mycelial growth and spore germination, and that the activity is due to its action on the fungal cell wall, and that Cou-UMB16 could act as an antifungal modifier.


Rapid high-temperature treatment of human milk.
Increasing interest in feeding human milk to low-birth-weight infants raises concern about microbial contamination of milk that is pooled or stored. We examined the effect of rapid high-temperature treatment on bacteria and viruses and on the nutritional and immunologic quality of pooled human milk. Growth of endogenous bacteria and infectivity of added cytomegalovirus were undetectable after heating at 72 degrees C for 15 and 5 seconds, respectively. Folic acid and vitamins B1, B2, B6, and C were not affected, whereas bile salt-stimulated lipase was inactivated by these conditions. The concentration of lactoferrin and secretory IgA, and SIgA antibody activity were not changed by heating at 72 degrees C. Lysozyme concentration and enzymatic activity were increased significantly by heat treatment, suggesting that this component may be largely sequestered in milk. Our findings suggest that rapid high-temperature treatment can reduce microbial contamination without destroying the unique nutritional and immunologic qualities of human milk.


Minichromosomes derived from the B chromosome of maize.
Fourteen minichromosomes derived from the B chromosome of maize are described. The centromeric region of the B chromosome contains a specific repetitive DNA element called the B repeat. This sequence was used to determine the transmission frequency of the different types of minichromosomes over several generations via Southern blot analysis at each generation. In general, the minichromosomes have transmission rates below the theoretical 50% frequency of a univalent chromosome. The gross structure of each minichromosome was determined using fluorescence in situ hybridization (FISH) on root tip chromosome spreads. The presence of the B centromeric repeat and of the adjacent heterochromatic knob sequences was determined for each minichromosome. In two cases, the amount of the centromeric knob repeat is increased relative to the progenitor chromosome. Other isolates have reduced or undetectable levels of the knob sequence. Potential uses of the minichromosomes are discussed.


Association between Helicobacter pylori infection and the subsequent risk of end-stage renal disease: a nationwide population-based cohort study.
The association between Helicobacter pylori infection and end-stage renal disease (ESRD) events remains unknown. We assessed the relationship between H. pylori infection requiring hospital admission and the subsequent risks of ESRD. This was a retrospective cohort study in which data from the National Health Insurance system of Taiwan was used. The H. pylori-infected cohort comprised 20,068 patients. Each participant was frequency-matched by age and sex with 4 individuals from the general population without H. pylori-infected. Cox proportional hazards regression analysis was used to estimate the influence of H. pylori infection on the risk of ESRD. The overall incidence of ESRD was 3.72 times greater in the H. pylori-infected cohort than in the non-infected cohort (11.1 vs. 2.96 per 1000 person-years), with an adjusted HR of 2.58 [95% confidence interval (CI)=2.33-2.86]. The risk of ESRD markedly increased in patients with H. pylori infection combined with at least one of the following concomitant comorbidities: hypertension, diabetes, hyperlipidaemia and coronary artery disease. This is currently the largest nation-based study in which the risk of ESRD in H. pylori-infected patients was examined. H. pylori infection was associated with a subsequent risk of ESRD. H. pylori-infected patients with concomitant chronic kidney disease (CKD) or cardiovascular disease (CVD) risk factors were at higher risk of ESRD than were those who had a single CKD or CVD risk factor.


Controlled, double-blind, randomized trial to assess the efficacy and safety of hydroxychloroquine chemoprophylaxis in SARS CoV2 infection in healthcare personnel in the hospital setting: A structured summary of a study protocol for a randomised controlled trial.
SARS-CoV-2 infection presents a high transmission in the group of health professionals in Spain (12-15% infected). Currently there is no accepted chemoprophylaxis but hydroxychloroquine (HDQ) is known to inhibit the coronavirus in vitro. Our hypothesis is that oral administration of hydroxychloroquine to healthcare professionals can reduce the incidence and prevalence of infection as well as its severity in this group. Design: Prospective, single center, double blind, randomised, controlled trial (RCT). Adult health-care professionals (18-65 years) working in areas of high exposure and high risk of transmission of SARS-COV-2 (COVID areas, Intensive Care Unit -ICUs-, Emergency, Anesthesia and all those performing aerosol-generating procedures) will be included. Exclusion criteria include previous infection with SARS CoV2 (positive SARS-CoV-2 PCR or IgG serology), pregnancy or lactation, any contraindication to hydroxychloroquine or evidence of unstable or clinically significant systemic disease. Patients will be randomized (1:1) to receive once-daily oral Hydroxychloroquine 200mg for two months (HC group) or placebo (P group) in addition to the protective measures appropriate to the level of exposure established by the hospital. A serological evaluation will be carried out every 15 days with PCR in case of seroconversion, symptoms or risk exposure. Primary outcome is the percentage of subjects presenting infection (seroconversion and/or PCR +ve) by the SARS-Cov-2 virus during the observation period. Additionally, both the percentage of subjects in each group presenting Pneumonia with severity criteria (Curb 65 ≥2) and that of subjects requiring admission to ICU will be determined. While awaiting a vaccine, hygiene measures, social distancing and personal protective equipment are the only primary prophylaxis measures against SARS-CoV-2, but they have not been sufficient to protect our healthcare professionals. Some evidence of the in vitro efficacy of hydroxychloroquine against this virus is known, along with some clinical data that would support the study of this drug in the chemoprophylaxis of infection. However, there are still no data from controlled clinical trials in this regard. If our hypothesis is confirmed, hydroxychloroquine can help professionals fight this infection with more guarantees. This is a single-center study that will be carried out at the Marqués de Valdecilla University Hospital. 450 health professionals working at the Hospital Universitario Marqués de Valdecilla in areas of high exposure and high risk of transmission of SARS COV2 (COVID hospital areas, Intensive Care Unit, Emergency, Anesthesia and all those performing aerosol-generating procedures) will be included. 1) Health professionals aged between 18 and 65 years (inclusive) at the time of the first screening visit; 2) They must provide signed written informed consent and agree to comply with the study protocol; 3) Active work in high exposure areas during the last two weeks and during the following weeks. 1) Previous infection with SARS CoV2 (positive coronavirus PCR or positive serology with SARS Cov2 negative PCR and absence of symptoms); 2) Current treatment with hydroxychloroquine or chloroquine; 3) Hypersensitivity, allergy or any contraindication for taking hydroxychloroquine, in the technical sheet; 4) Previous or current treatment with tamoxifen or raloxifene; 5) Previous eye disease, especially maculopathy; 6) Known heart failure (Grade III to IV of the New York Heart Association classification) or prolonged QTc; 7) Any type of cancer (except basal cell) in the last 5 years; 6) Refusal to give informed consent; 8) Evidence of any other unstable or clinically significant untreated immune, endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric illness; 9) Antibodies positive for the human immunodeficiency virus; 10) Significant kidney or liver disease; 11) Pregnancy or lactation. Two groups will be analyzed with a 1: 1 randomization rate. 1)Intervention: (n = 225): One 200 mg hydroxychloroquine sulfate coated tablet once daily for two months.2)Comparator (control group) (n = 225): One hydroxychloroquine placebo tablet (identical to that of the drug) once daily for two months MAIN OUTCOMES: The primary outcome of this study will be to evaluate: number and percentage of healthcare personnel presenting symptomatic and asymptomatic infection (see "Diagnosis of SARS CoV2 infection" below) by the SARS-Cov2 virus during the study observation period (8 weeks) in both treatment arms;number and percentage of healthcare personnel in each group presenting with Pneumonia with severity criteria (Curb 65 ≥2) and number and percentage of healthcare personnel requiring admission to the Intensive Care Unit (ICU) in both treatment arms. DIAGNOSIS OF SARS COV2 INFECTION: Determination of IgA, IgM and IgG type antibodies against SARS-CoV-2 using the Anti-SARS-CoV-2 ELISA kit (EUROIMMUN Medizinische Labordiagnostika AG, Germany) every two weeks. In cases of seroconversion, a SARS-CoV-2 PCR will be performed to rule out / confirm an active infection (RT-PCR in One Step: RT performed with mastermix (Takara) and IDT probes, following protocol published and validated by the CDC Evaluation of COVID-19 in case of SARS-CoV-2 infection RANDOMISATION: Participants will be allocated to intervention and comparator groups according to a balanced randomization scheme (1: 1). The assignment will be made through a computer-generated numeric sequence for all participants BLINDING (MASKING): Both participants and investigators responsible for recruiting and monitoring participants will be blind to the assigned arm. Taking into account the current high prevalence of infection in healthcare personnel in Spain (up to 15%), to detect a difference equal to or greater than 8% in the percentage estimates through a two-tailed 95% CI, with a statistical power of 80% and a dropout rate of 5%, a total of 450 participants will need to be included (250 in each arm). The protocol approved by the health authorities in Spain (Spanish Agency for Medicines and Health Products "AEMPS") and the Ethics and Research Committee of Cantabria (CEIm Cantabria) corresponds to version 1.1 of April 2, 2020. Currently, recruitment has not yet started, with the start scheduled for the second week of May 2020. Eudra CT number: 2020-001704-42 (Registered on 29 March 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Lithium chloride prevents interleukin-1β induced cartilage degradation and loss of mechanical properties.
Osteoarthritis is a chronic degenerative disease that affects the articular cartilage. Recent studies have demonstrated that lithium chloride exhibits significant efficacy as a chondroprotective agent, blocking cartilage degradation in response to inflammatory cytokines. However, conflicting literature suggests lithium may affect the physicochemical properties of articular cartilage and thus long-term exposure may negatively affect the mechanical functionality of this tissue. This study aims to investigate the effect of lithium chloride on the biomechanical properties of healthy and interleukin-1β treated cartilage in vitro and examines the consequences of long-term exposure to lithium on cartilage health in vivo. Bovine cartilage explants were treated with lithium chloride for 12 days. Chondrocyte viability, matrix catabolism and the biomechanical properties of bovine cartilage explants were not significantly altered following treatment. Consistent with these findings, long term-exposure (9 months) to dietary lithium did not induce osteoarthritis in rats, as determined by histological staining. Moreover, lithium chloride did not induce the expression of catabolic enzymes in human articular chondrocytes. In an inflammatory model of cartilage destruction, lithium chloride blocked interleukin-1β signaling in the form of nitric oxide and prostaglandin E2 release and prevented matrix catabolism such that the loss of mechanical integrity observed with interleukin-1β alone was inhibited. This study provides further support for lithium chloride as a novel compound for the treatment of osteoarthritis.


Effectiveness of mindfulness meditation on pain and quality of life of patients with chronic low back pain.
Recovery of patients with chronic low back pain (LBP) is depended on several physical and psychological factors. Therefore, the authors aimed to examine the efficacy of mindfulness based stress reduction (MBSR) as a mind-body intervention on quality of life and pain severity of female patients with nonspecific chronic LBP (NSCLBP). Eighty-eight patients diagnosed as NSCLBP by physician and randomly assigned to experimental (MBSR+ usual medical care) and the control group (usual medical care only). The subjects assessed in 3 times frames; before, after and 4 weeks after intervention by Mac Gil pain and standard brief quality of life scales. Data obtained from the final sample analyzed by ANCOVA using SPSS software. The findings showed MBSR was effective in reduction of pain severity and the patients who practiced 8 sessions meditation reported significantly lower pain than patients who only received usual medical care. There was a significant effect of the between subject factor group (F [1, 45] = 16.45, P < 0.001) and (F [1, 45] = 21.51, P < 0.001) for physical quality of life and (F [1, 45] = 13.80, P < 0.001) and (F [1, 45] = 25.07, P < 0.001) mental quality of life respectively. MBSR as a mind-body therapy including body scan, sitting and walking meditation was effective intervention on reduction of pain severity and improvement of physical and mental quality of life of female patients with NSCLBP.


Mannose-binding lectin levels in children with asthma.
Mannose-binding lectin (mbl), one of the important components of innate immunity, can activate the lectin pathway of the complement system. After binding mannose containing carbohydrate structures of foreign antigen, mbl initiates and regulates the inflammatory responses. Asthma is a complex inflammatory disease of the lung involving many components of the immune system. Our objective was to investigate the serum mbl levels of asthmatic children in comparison with healthy controls. Serum mbl levels were determined by nephelometric assay in 72 asthmatic children (5-15 yr old) and 30 healthy age-matched controls. Mbl levels of asthmatic children were measured both during acute attack and after complete remission. There was no significant difference between the mbl levels during acute attack (median 4.1 mg/l) or quiescence of symptoms (median 3.6 mg/l). Serum mbl levels both during acute attack or quiescence of symptoms was significantly higher in asthmatic children than in the healthy controls (median 2.8 mg/l, p < 0.0001 for each). Furthermore, mbl levels of asthmatic children positively correlated with peripheral blood eosinophils (r = 0.377, p < 0.001), which is a systemic component of airway inflammation in asthma. Our findings indicate that mbl may be implicated in the pathogenesis of asthma by contributing to airway inflammation or by increasing the risk of developing asthma.


Posterior cruciate ligament injuries.
Until recently, the function of the posterior cruciate ligament has been poorly understood and the traditional wisdom is that injuries to this ligament do not result in any appreciable functional disability. There is increasing evidence, however, that the natural history may not be as benign as was originally assumed. This review seeks to analyse current knowledge concerning the function, diagnosis, natural history and treatment of this injury.


[Effect of a number of immunostimulating preparations on the intracellular bactericidal systems of peripheral blood neutrophils].
Administration of methyluracil (20 mg/kg), dibasol (2 mg/kg), prodigiosan (5 micrograms/kg) and levamisole (2.5 mg/kg) to rabbits was followed by stimulation of phagocytic activity of peripheral blood neutrophils. As regards the degree of the effect, the drugs might be arranged in the following way: prodigiosan greater than levamisole greater than methyluracil greater than dibazol. The induction effects of levamisole and prodigiosan on the activity of the myeloperoxidase bactericidal system and alkaline phosphatase in leukocytes correlated with an increase in their functional activity. In contrast to the drugs indicated, the phagocytosis-stimulating action of methyluracil on peripheral blood neutrophils was not apparently mediated via the bactericidal systems studied but via other mechanisms one of which might be activation of nucleo- and proteinosynthesis. In the dose indicated dibasol did not produce any essential effect on the phagocytic response and intracellular bactericidal systems of phagocytes. All the drugs under study did not produce any effect on the neutrophil content of non-enzymatic cation proteins.


Traumatic events and symptoms of post-traumatic stress disorder amongst Sudanese nationals, refugees and Ugandans in the West Nile.
To compare the incidence of traumatic events and its association with symptoms of post-traumatic stress disorder in three population groups in northern Uganda and southern Sudan. Household and individual level data collected through a single-round cross-sectional demographic survey. The sub-counties of Yivu, Odupi and Midia in the northern Ugandan district of Arua and of Otogo in Yei River district in southern Sudan. Residents of these Ugandan and Sudanese sub-counties were categorized on the basis of citizenship and refugee status (i.e. as Ugandan nationals, Sudanese nationals or Sudanese refugees). The random sample population consisted of 3,323 adults (mean age: 30 years; 75% female) from 1,831 national and refugee households. Sudanese refugees reported the highest number of violent events experienced or witnessed ever and in the past one year . Witnessing of traumatic events, ever and in the past year , significantly predicted PTSD in surveyed population. Sex, age, education and occupation were also significantly associated with the development of PTSD symptoms. The population prevalence of PTSD was estimated to be 48% for Sudanese stayees, 46% for Sudanese refugees and 18% for Ugandan nationals. Symptoms of PTSD in war-affected Sudanese populations can be partly explained by traumatic event exposures. The high prevalence of violence and symptoms of PTSD in refugee populations highlight the need for better protection and security in refugee settlements. Humanitarian agencies must consider the provision of mental health services for populations affected by war and forced migration.


Increased transendothelial permeability of anti-cancer agent carboplatin with the aid of hyperbaric oxygenation.
1. The objective was to investigate the transport of an anticancer agent carboplatin across the blood-brain barrier in combination with hyperbaric oxygenation treatment. An in vitro well-validated model of bovine brain capillary endothelial cells was used. 2. A transendothelial transport of doxorubicin, a known P-glycoprotein substrate, was enhanced 1.5-fold by verapamil for 2-h incubation at 37 degrees C. A transendothelial permeability coefficient of carboplatin (1.29 x 10(-3)cm min-1) was also increased 1.8-fold by verapamil. 3. Under the hyperbaric oxygenation conditions (at 0.2 MPa for the first 10 min), the transendothelial transport for 2 h of doxorubicin and carboplatin were increased 1.3- to 1.8-fold by hyperbaric oxygenation, like the suppressive effects of verapamil on P-gp function, without increase of the transport of lucifer yellow, a non P-glycoprotein substrate. 4. Combination of hyperbaric oxygenation treatment and verapamil could not further increase the permeability coefficients of these drugs that were already enhanced by either treatment, implying the P-glycoprotein-mediated carboplatin efflux transport similarly as doxorubicin. 5. Together with our reported high efficacy of carboplatin combined with hyperbaric oxygenation therapy on brain tumours, the present results suggest that carboplatin could be transported by P-glycoprotein, but that this efflux mechanism would be reduced by the hyperbaric oxygenation with the consequences of clinical efficacy.


Fliposomes: pH-Sensitive Liposomes Containing a trans-2-morpholinocyclohexanol-Based Lipid That Performs a Conformational Flip and Triggers an Instant Cargo Release in Acidic Medium.
Incorporation of a pH-sensitive conformational switch into a lipid structure enables a drastic conformational flip upon protonation that disrupts the liposome membrane and causes rapid release of cargo specifically in areas of increased acidity. pH-sensitive liposomes containing the amphiphile (1) with trans-2-morpholinocyclohexanol conformational switch, a phospholipid, and a PEG-lipid conjugate were constructed and characterized. The optimized composition-1/POPC/PEG-ceramide (50/45/5)-could be stored at 4 °C and pH 7.4 for up to 1.5 years, and was stable in blood serum in vitro after 48 h at 37 °C. Liposomes loaded with ANTS/DPX or methotrexate demonstrated an unusually quick content release (in a few seconds) at pH below 5.5, which was independent of inter-liposome contact. The pH-titration curve for the liposome leakage paralleled the curve for the acid-induced conformational flip of 1 studied by 1H-NMR. Freeze-fracture electron microscopy images showed budding and division of the bilayer at pH 5.5. A plausible mechanism of pH-sensitivity involves an acid-triggered conformational flip of 1, shortening of lipid tails, and membrane perturbations, which cause the content leakage. The methotrexate-loaded liposomes demonstrated much higher cytotoxicity in HeLa cells than the free drug indicating that they can serve as viable drug delivery systems.


Combined wIRA-Hyperthermia and Hypofractionated Re-Irradiation in the Treatment of Locally Recurrent Breast Cancer: Evaluation of Therapeutic Outcome Based on a Novel Size Classification.
Effective tumor control in patients suffering from unresectable locally recurrent breast cancer (LRBC) in pre-irradiated areas can be achieved by re-irradiation combined with superficial hyperthermia. Using this combined modality, total re-irradiation dose and toxicity can be significantly reduced compared to conventionally fractionated treatment schedules with total doses of 60-66 Gy. Applying contact-free, thermography-controlled water-filtered infrared-A superficial hyperthermia, immediately followed by hypofractionated re-irradiation, consisting of 4 Gy once per week up to a total dose of 20 Gy, resulted in high overall response rates even in large-sized tumors. Comparability of clinical data between different combined Hyperthermia (HT)/Radiotherapy (RT) treatment schedules is impeded by the highly individual characteristics of this disease. Tumor size, ranging from microscopic disease and small lesions to large-sized cancer en cuirasse, is described as one of the most important prognostic factors. However, in clinical studies and analyses of LRBC, tumor size has so far been reported in a very heterogeneous way. Therefore, we suggest a novel, simple and feasible size classification (rClasses 0-IV). Applying this classification for the evaluation of 201 patients with pre-irradiated LRBC allowed for a stratification into distinct prognostic groups.


PARIS, an optogenetic method for functionally mapping gap junctions.
Cell-cell communication via gap junctions regulates a wide range of physiological processes by enabling the direct intercellular electrical and chemical coupling. However, the in vivo distribution and function of gap junctions remain poorly understood, partly due to the lack of non-invasive tools with both cell-type specificity and high spatiotemporal resolution. Here, we developed PARIS (pairing actuators and receivers to optically isolate gap junctions), a new fully genetically encoded tool for measuring the cell-specific gap junctional coupling (GJC). PARIS successfully enabled monitoring of GJC in several cultured cell lines under physiologically relevant conditions and in distinct genetically defined neurons in Drosophila brain, with ~10 s temporal resolution and sub-cellular spatial resolution. These results demonstrate that PARIS is a robust, highly sensitive tool for mapping functional gap junctions and study their regulation in both health and disease.


Mutations in the human SIX3 gene in holoprosencephaly are loss of function.
Holoprosencephaly (HPE) is the most common developmental anomaly of the human forebrain; however, the genetics of this heterogeneous and etiologically complex malformation is incompletely understood. Heterozygous mutations in SIX3, a transcription factor gene expressed in the anterior forebrain and eyes during early vertebrate development, have been frequently detected in human HPE cases. However, only a few mutations have been investigated with limited functional studies that would confirm a role in HPE pathogenesis. Here, we report the development of a set of robust and sensitive assays of human SIX3 function in zebrafish and apply these to the analysis of a total of 46 distinct mutations (19 previously published and 27 novel) located throughout the entire SIX3 gene. We can now confirm that 89% of these putative deleterious mutations are significant loss-of-function alleles. Since disease-associated single point mutations in the Groucho-binding eh1-like motif decreases the function in all assays, we can also confirm that this interaction is essential for human SIX3 co-repressor activity; we infer, in turn, that this function is important in HPE causation. We also unexpectedly detected truncated versions with partial function, yet missing a SIX3-encoded homeodomain. Our data indicate that SIX3 is a frequent target in the pathogenesis of HPE and demonstrate how this can inform the genetic counseling of families.


Diffusion tensor tractography reveals abnormal topological organization in structural cortical networks in Alzheimer's disease.
Recent research on Alzheimer's disease (AD) has shown that the decline of cognitive and memory functions is accompanied by a disrupted neuronal connectivity characterized by white matter (WM) degeneration. However, changes in the topological organization of WM structural network in AD remain largely unknown. Here, we used diffusion tensor image tractography to construct the human brain WM networks of 25 AD patients and 30 age- and sex-matched healthy controls, followed by a graph theoretical analysis. We found that both AD patients and controls had a small-world topology in WM network, suggesting an optimal balance between structurally segregated and integrative organization. More important, the AD patients exhibited increased shortest path length and decreased global efficiency in WM network compared with controls, implying abnormal topological organization. Furthermore, we showed that the WM network contained highly connected hub regions that were predominately located in the precuneus, cingulate cortex, and dorsolateral prefrontal cortex, which was consistent with the previous diffusion-MRI studies. Specifically, AD patients were found to have reduced nodal efficiency predominantly located in the frontal regions. Finally, we showed that the alterations of various network properties were significantly correlated with the behavior performances. Together, the present study demonstrated for the first time that the Alzheimer's brain was associated with disrupted topological organization in the large-scale WM structural networks, thus providing the structural evidence for abnormalities of systematic integrity in this disease. This work could also have implications for understanding how the abnormalities of structural connectivity in AD underlie behavioral deficits in the patients.


Do changing moisture levels during incubation influence phenotypic traits of hatchling snakes (Tropidonophis mairii, Colubridae)?
Phenotypic traits (e.g., size, strength, speed) of hatchlings in many reptile species are influenced by hydric conditions in the nest. Previous experiments have focused on comparisons between eggs maintained under constant (but different) conditions, but eggs in natural nests frequently experience strong temporal shifts in soil water content during incubation. Keelback snakes (Tropidonophis mairii) in the Australian wet-dry tropics nest over most of the year, so early nests experience decreasing water availability during development, late nests experience increases, and others (midyear) remain stable in this respect. We mimicked these three conditions and incubated 54 eggs (nine from each of six clutches) in a split-clutch design to maintain the same average water content but with differing trajectories through incubation. The experimental treatments significantly affected the total amount of water taken up by the eggs (and thus final egg mass), but incubation periods were unaffected. Hatchling size but not strength showed minor but statistically significant effects of incubation regimes. The ability of keelback eggs to take up excess water whenever it becomes available (either early or late in development) and to retain it even when conditions change buffers embryogenesis effectively (but not completely) against fluctuations in soil water conditions.


[Advantages and current limitations of numeric angiography].
Numeric angiography possesses the definite advantages of diminished risks when compared with conventional arteriography, and marked reliability when used for valid indications. It is also economically interesting since hospitalization is avoided. Limitations of the method are currently related to technical and data-processing problems. Insufficient size of the brilliance amplifiers means that several injections of contrast medium are necessary, with increased risks in some patients. Image resolution is insufficient with currently available matrices to study small vessels. The rate of image production, originally insufficient, now with modern equipment enables mobile structures such as the heart to be studied.


The pathophysiology of stress incontinence.
The factors contributing to stress incontinence of urine are reviewed and categorized with respect to their effects on coaptation and compression of the urethra. Intrinsic urethral dysfunction and poor anatomic support are discussed from both a functional and a pathophysiologic approach.


Dependence and psychosis with 4-methylmethcathinone (mephedrone) use.
'Legal highs' are recreational drugs sold over the internet and the so-called 'head shops' all over the UK. They are freely available to buy and use as they are not covered by the Misuse of Drugs Act 1971. Mephedrone (4-methylmethcathinone) was sold as a 'legal high' until 17 April 2010 when it was made a class B drug under the Misuse of Drugs Act 1971. Numerous deaths and self-harm has been associated with mephedrone use. Effects of mephedrone are reported to be empathogenic similar to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and stimulant properties similar to cocaine. Not much is known of the effects of mephedrone on mental health. We present a case of dependence and psychosis in a patient using mephedrone (4-methylmethcathinone). The patient needed inpatient hospital care, was treated with antipsychotic olanzapine and recovered well.


Noninvasive Gamma Sensory Stimulation May Reduce White Matter and Myelin Loss in Alzheimer's Disease.
Patients with Alzheimer's disease (AD) demonstrate progressive white matter atrophy and myelin loss. Restoring myelin content or preventing demyelination has been suggested as a therapeutic approach for AD. Herein, we investigate the effects of non-invasive, combined visual and auditory gamma-sensory stimulation on white matter atrophy and myelin content loss in patients with AD. In this study, we used the magnetic resonance imaging (MRI) data from the OVERTURE study (NCT03556280), a randomized, controlled, clinical trial in which active treatment participants received daily, non-invasive, combined visual and auditory, 40 Hz stimulation for six months. A subset of OVERTURE participants who meet the inclusion criteria for detailed white matter (N = 38) and myelin content (N = 36) assessments are included in the analysis. White matter volume assessments were performed using T1-weighted MRI, and myelin content assessments were performed using T1-weighted/T2-weighted MRI. Treatment effects on white matter atrophy and myelin content loss were assessed. Combined visual and auditory gamma-sensory stimulation treatment is associated with reduced total and regional white matter atrophy and myelin content loss in active treatment participants compared to sham treatment participants. Across white matter structures evaluated, the most significant changes were observed in the entorhinal region. The study results suggest that combined visual and auditory gamma-sensory stimulation may modulate neuronal network function in AD in part by reducing white matter atrophy and myelin content loss. Furthermore, the entorhinal region MRI outcomes may have significant implications for early disease intervention, considering the crucial afferent connections to the hippocampus and entorhinal cortex.


Cytokine Removal in Extracorporeal Blood Purification: An in vitro Study.
Cytokines are among the main target substances that have to be removed effectively in order to improve the patient's health status in the treatment of sepsis, septic shock, and liver diseases. Although there are various medical devices commercially available, the success of their clinical use is limited. The aim of this in vitro study was to compare 3 different medical devices with respect to their clearance for the cytokines interleukin-6 (IL-6), IL-8, IL-1β, and tumor necrosis factor alpha. The medical devices that were tested are the whole blood adsorbent CytoSorb, the high cutoff filter EMiC2, and the hemofilter HemofeelCH 1.8. The study was carried out on the multiFiltrate machine with 1 L human plasma for 8 h. Samples for cytokine quantification were taken at defined time points from the plasma pool. Each experiment was conducted in triplicates, and clearance was calculated for all tested cytokines. All 3 medical devices showed good cytokine removal. The highest clearance for all cytokines was achieved by hemoperfusion with Cytosorb. IL-8 and IL-6 clearance were higher with Hemofeel (continuous venovenous hemodiafiltration) than with EMiC2 (continuous venovenous hemodialysis) because the polymethyl methacrylate (PMMA)-based membrane Hemofeel is able to remove these 2 cytokines by adsorption. Protein and albumin loss was highest withCytosorb and lowest with EMiC2. The mechanisms of cytokine removal by blood purification include convection, diffusion, and adsorption. PMMA-based filters are able to combine all 3 mechanisms for certain cytokines. Cytosorb showed the best adsorption kinetics, while dialysis with polystyrene-based membranes offers the best biocompatibility because they do not show any unspecific adsorption of other plasma components.


Imaging of primary multifocal osseous lymphoma.
To review our experience with primary multifocal osseous lymphoma (PMOL), to characterize its imaging features, before and after treatment, and to correlate these features with clinical outcome. Hospital charts and imaging studies in eight patients with PMOL were reviewed. These included bone radiographs, bone scans, CT and MRI. Number, distribution and appearance of lesions before treatment were evaluated; and post-treatment changes were assessed for evidence of healing or progression, correlated with clinical outcome. A total of 63 lesions were identified by pre-treatment bone scan, 36 by MRI (including 10 not visible on bone scan) and 16 by radiographs. Twenty-one percent of lesions occurred about the knee, and 63% of patients had concomitant skull, distal femoral and proximal tibial lesions. The radiographic appearance ranged from lytic to sclerotic. Lesions were isointense to hematopoietic marrow on T2-weighted MR sequences. Only plain radiographic evidence of healing or progression correlated with clinical outcome. Distribution of PMOL was best assessed by bone scan. However, MRI revealed larger areas of marrow involvement and detected lesions in the pelvis not seen on bone scan. Marrow involvement around the knee was common, and the combination of skull, distal femoral and proximal tibial lesions may suggest the diagnosis. Radiographs underestimate the extent of disease but were the best modality for assessment of treatment response.


Worsening psychological wellbeing of Australian hospital clinical staff during three waves of the coronavirus (COVID-19) pandemic.
Objective This study aimed to assess and compare the psychological wellbeing of Australian hospital clinical staff at three timepoints during the coronavirus disease 2019 (COVID-19) pandemic. Methods An anonymous, online, cross-sectional survey was conducted at three timepoints during the COVID-19 pandemic (T1: May-June 2020; T2: October-December 2020; T3: November 2021-January 2022). The surveys were completed by nurses, midwives, doctors and allied health staff employed at a large metropolitan tertiary health service located in Melbourne, Australia. The Depression, Anxiety and Stress Scale (DASS-21) assessed respondents' psychological wellbeing in the past week. General linear models were used to measure the effects of survey timepoint on DASS-21 subscale scores, adjusting for selected sociodemographic and health characteristics. Results A total of 1470 hospital clinical staff completed at least one survey (T1: 668 (14.7%), T2: 358 (7.9%) and T3: 444 (9.8%)). Respondents' sociodemographic characteristics were similar across the three timepoints and within professional discipline groups. Respondents' psychological wellbeing was worse at T3 compared to the earlier survey timepoints. Adjusting for respondent characteristics, depression, anxiety and stress scores were significantly higher for respondents of the third survey compared to the first (P < 0.001). Conclusions There was a significant and persistent negative impact on the psychological wellbeing of hospital clinical staff in Australia across waves of the COVID-19 pandemic. Hospital clinical staff would benefit from ongoing and continued wellbeing support during and after pandemic waves.


Cultural variation in implicit independence: An extension of Kitayama et al. ().
Previous research shows that European Americans are consistently more independent (or less interdependent) than Japanese when implicit indices are used to assess independence (vs. interdependence). The present work extended this evidence by including a novel implicit association test (IAT), as an index of implicit attitude towards independence and interdependence. Consistent with the previous findings, as compared to Japanese, Americans were significantly higher in multiple indices of implicit independence (vs. interdependence) including personal (vs. social) self-definition, experience of disengaging (vs. engaging) emotions and personal (vs. social) form of happiness. Furthermore, as compared to Japanese, Americans had a significantly more positive implicit attitude towards independence assessed with the IAT. As also observed in the previous research, explicit measures showed inconsistent cross-cultural patterns. Lastly, we observed little statistical within-culture coherence among the implicit measures of independence (vs. interdependence), consistent with a view that the implicit indices capture alternative ways for individuals to achieve the cultural mandate of independence or interdependence.


Classification of neuroleptics: implications for tardive dyskinesia.
The dopamine (DA) receptor blocking effect of neuroleptics is believed to be responsible for their antipsychotic effect. This blockade can be demonstrated in experimental animals by the ability of neuroleptics to antagonize stereotypies induced by DA agonists. Biochemically DA receptor-blocking properties of neuroleptics are illustrated by direct binding to DA receptors or by measuring inhibition of DA-stimulated adenylate cyclase activity. Most pharmacological and biochemical experiments with neuroleptics have concentrated on dopaminergic effects of the compounds both after acute and long-term treatment. After long-term treatment with neuroleptics an increase in DA receptor number and an increase in stereotyped behavior are seen. DA supersensitivity have been implied in the development of tardive dyskinesia (TD) in patients on long-term neuroleptic medication. In search for neuroleptics which would be less prone to induce TD and more effective in treating dyskinesia we have looked at the profile of a series of neuroleptics in in vitro experiments and in acute and long-term in vivo experiments. Since neuroleptics also influence other transmitter systems than the dopaminergic we have investigated interactions with drugs affecting these transmitter systems. According to their differential effects on DA receptors (D1 and D2) and their ability to develop tolerance and supersensitivity, the neuroleptics can be classified into different groups, some of which might be expected to induce less TD and be preferred for treating dyskinesia.


Functional properties of the paracellular pathway in some leaky epithelia.
We here review the functional properties of the paracellular pathway of leaky epithelia such as gallbladder and renal proximal tubule. These epithelia are characterized by leaky terminal bars between adjacent cells which allow small ions, non-electrolytes and water to leak from lumen to interstitial fluid or back. In the past 10 years a great deal of information has been obtained about the properties of the misnamed 'tight' junctions in the terminal bars, by assuming that the overall permeation pattern reflected predominantly the junctional permeation properties. Although recent trans- and intraepithelial impedance analyses indicate that this assumption is not always justified (the contribution of the lateral intercellular space to the paracellular shunt resistance is not negligible, when the spaces are collapsed) it seems that the major conclusions are correct. The properties of the terminal junctions may thus be summarized as follows. (1) Large molecules such as horseradish peroxidase are not able to pass. (2) Passage of lipophilic substances is insignificant, as these substances permeate by the cellular route. (3) Depending on the tissue, ion permeation is either governed by channels with negative fixed charges, or positive fixed charges, or both. As inferred from ion selectivity patterns the channels of different epithelia are either wide and highly hydrated or narrow and poorly hydrated, thus allowing more or less water molecules to pass besides the ions. In narrow channels single-file diffusion may occur. (4) Besides the selective channels a free solution shunt seems to be present in some epithelia. (5) When applied in millimolar concentrations 2,4,6-triaminopyrimidinium and amiloride block negatively charged junctional channels. However these substances do not simply turn leaky epithelia into tight epithelia, because they have additional effects on the cell membranes. (6) As observed in cell cultures, formation of tight junctions requires connecting particles to be present on the cell surface--which seems to be controlled by the cytoskeleton-- and requires the presence of calcium ions as ligands. (7) Cellular control over paracellular permeability may be exerted through changes of intracellular calcium concentration.


[Erythropoietin administration in the predialysis period].
Anemia is recognized as a very important non-traditional risk factor for cardiovascular morbidity and mortality in patients with uremia. Despite many advantages of erythropoietin therapy, the number of patients treated with this drug is modest, particularly during the pre-end stage renal disease. Patients with chronic renal failure are at risk to develop coronary artery disease, left ventricular hypertrophy and chronic heart failure when hemoglobin concentration falls below 10 g/dl and creatinine clearance under 60 ml/min. Early erythropoietin treatment prevents not only cardiovascular morbidity and mortality, but also progression of renal failure towards end-stage renal disease. Anti-oxidant, anti-hypoxic and anti-apoptotic effects of erythropoietin prevent tubular lesions and interstitial fibrosis. There still remains a confusion regarding the optimum target hemoglobin concentration in the pre-dialysis phase. Guidelines in Europe and US are probably not appropriate for all patients and it is important that renal anemia patients are considered as individuals. It may be appropriate to normalize hemoglobin concentration in young patients who have active lifestyles and no severe co-morbidity. In contrast, partial correction is more appropriate for the elderly with significant co-morbidities. Special attention should be paid to patients with diabetes, where anemia starts earlier and is more profound than in other renal patients. There is no risk of early anemia treatment using erythropoietin and this regime does not increase the total cost of treatment. Early referral to a nephrologist is the key how to define underlying renal disease, slow down the progression of renal failure, prevent co-morbid conditions and to prepare patients for end-stage renal disease treatment.


Action observation as a tool for neurorehabilitation to moderate motor deficits and aphasia following stroke.
The mirror neuron system consists of a set of brain areas capable of matching action observation with action execution. One core feature of the mirror neuron system is the activation of motor areas by action observation alone. This unique capacity of the mirror neuron system to match action perception and action execution stimulated the idea that mirror neuron system plays a crucial role in the understanding of the content of observed actions and may participate in procedural learning. These features bear a high potential for neurorehabilitation of motor deficits and of aphasia following stroke. Since the first articles exploring this principle were published, a growing number of follow-up studies have been conducted in the last decade. Though, the combination of action observation with practice of the observed actions seems to constitute the most powerful approach. In the present review, we present the existing studies analyzing the effects of this neurorehabilitative approach in clinical settings especially in the rehabilitation of stroke associated motor deficits and give a perspective on the ongoing trials by our research group. The data obtained up to date showed significant positive effect of action observation on recovery of motor functions of the upper limbs even in the chronic state after stroke, indicating that our approach might become a new standardized add-on feature of modern neurorehabilitative treatment schemes.


Scrutinizing ACGIH risk assessments: the trichloroethylene case.
The American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit values (TLVs) for occupational exposure to chemicals and physical agents have been very influential in the setting of occupational exposure limits in many countries. Three ACGIH risk assessments of the chlorinated solvent trichloroethylene (TCE) [ACGIH (1989): 5th edition; ACGIH (1992): 5th edition. Revised Vol II; ACGIH (1996): Suppl. 6th edition] are compared to 26 other risk assessments made of the same chemical substance. The documents are compared in terms of their overall conclusions and the data selected for assessment. It is shown that these ACGIH risk assessment documents were based on incomplete and biased data sets. The data on which the ACGIH [ACGIH (1996): Suppl. 6th edition] base their TCE risk assessment do not adequately reflect the available scientific knowledge about TCE toxicity and carcinogenicity. This may have influenced their conclusion that TCE is not carcinogenic in either animals or humans which stand out compared to contemporary risk assessments.


Strategies for increasing fruit and vegetable intake in grocery stores and communities: policy, pricing, and environmental change.
Grocery stores and community settings are important and promising venues for environmental, policy, and pricing initiatives to increase fruit and vegetable intake. This article examines supermarket-based and community environmental, policy, and pricing strategies for increasing intake of fruits and vegetables and identifies promising strategies, research needs, and innovative opportunities for the future. The strategies, examples, and research reported here were identified through an extensive search of published journal articles, reports, and inquiries to leaders in the field. Recommendations were expanded with input from participants in the CDC/ACS-sponsored Fruit and Vegetable, Environment Policy and Pricing Workshop held in September of 2002. Four key types of grocery-store-based interventions include point-of-purchase (POP) information; reduced prices and coupons; increased availability, variety, and convenience; and promotion and advertising. There is strong support for the feasibility of these approaches and modest evidence of their efficacy in influencing eating behavior. Church-based programs, child care center policies, and multisectoral community approaches show promise. Both descriptive and intervention research are needed to develop and evaluate more effective environmental strategies to increase F&V intake in grocery stores and communities. Innovative strategies, partnerships, grass roots action involving economic development for low-income communities, and sustainability are important considerations.


X-ray opaque waveguide for dentistry.
The aim of this study is the design, realization, and examination of a new x-ray contrast hollow waveguide which will be suitable for x-ray diagnostics or treatment required in medicine, as dentistry, maxiollofacial surgery or oncology. With the growing usefulness of laser radiation therapeutic interventions, a strong demand for radiation delivery from the laser source to the interaction place has appeared. For more complicated surgery, especially for internal intervention, an x-ray is necessary. In such cases, as a minimum, the end of the delivery system must be x-ray contrasted to distinguish where the interaction of radiation with tissue would take place. Up to now, neither fiber, hollow waveguide, nor other delivery system have been x-ray opaque. A new type of hollow glass waveguide was designed, fabricated, and examined as a delivery system for an endodontic treatment. The system is composed from the cyclic olefin polymer coated silver hollow glass waveguide with special covering for x-ray visibility. The inner diameter of the waveguide was 320 microm, the outer diameter was 630 microm, and its length was 100 mm. After the delivery system was created, the hollow waveguide was checked under an x-ray machine and its opacity was measured. For actual treatment, an Er:YAG laser system generating a mid-infrared radiation was used. The root canals of 10 molars were treated endodontically, and the result of that treatment was compared with the common cleaning methods. During treatment, digital x-ray images were taken with conventional files, using this new designed hollow waveguide. The position of a metal instrument demonstrates the quality of opacity after conventional step-back technique. The hollow waveguide is visible in the left tooth canal. A bone density analysis shows no differences between a left (waveguide) and right (tooth) canal. It was demonstrated that no differences exist between x-ray opacity of the metal instrument used for endodontic treatment and a special hollow waveguide. The digitalized, three-dimensional image helps to detect a precise position of customary instrument or waveguide in root canal.


Persistent effects after trigeminal nerve proprioceptive stimulation by mandibular extension on rat blood pressure, heart rate and pial microcirculation.
The trigemino-cardiac reflex is a brainstem reflex known to lead to a decrement in heart rate and blood pressure, whereas few data have been collected about its effects on the cerebral hemodynamic. In this study we assess the in vivo effects of trigeminal nerve peripheral stimulation by mandibular extension on pial microcirculation and systemic arterial blood pressure in rats. Experiments were performed in male Wistar rats subjected to mandibular extension obtained inserting an ad hoc developed retractor between the dental arches. Mean arterial blood pressure and heart rate were recorded and the pial arterioles were visualized by fluorescence microscopy to measure the vessel diameters before (15 minutes) during (5-15 minutes) and after (80 minutes) mandibular extension. While in control rats (sham-operated rats) and in rats subjected to the dissection of the trigeminal peripheral branches mean arterial blood pressure, heart rate and pial microcirculation did not change during the whole observation period (110 minutes), in rats submitted to mandibular extension, mean arterial blood pressure, heart rate and arteriolar diameter significantly decreased during stimulation. Afterward mean arterial blood pressure remained reduced as well as heart rate, while arteriolar diameter significantly increased evidencing a vasodilatation persisting for the whole remaining observation time. Therefore, trigeminal nerve proprioceptive stimulation appears to trigger specific mechanisms regulating systemic arterial blood pressure and pial microcirculation.


Interleukin-2 initiates metabolic responses associated with critical illness in humans.
The cytokine interleukin-2 is a primary modulator of the immune response that occurs after infection, trauma, and transplant rejection, yet its role as a mediator of associated metabolic changes in surgical illness is unknown. We studied clinical and metabolic responses in eleven tumor-bearing humans with normal renal and hepatic function receiving bolus intravenous (I.V.) interleukin-2 (30,000 U/kg). Additional subjects (n = 6) were pretreated with the cyclooxygenase inhibitor, ibuprofen (1600 mg, orally), before interleukin-2 administration. Serial measurements were made of vital signs, symptoms, hematology, and plasma concentrations of pituitary and stress hormones and selected cytokines. Administration of interleukin-2 resulted in fever, tachyacardia, "flu-like" symptoms, and neurohormonal elaboration. The responses observed were quantitatively similar to those that occurred after endotoxin administration in healthy subjects (n = 13), but differed in the following manner: 1) the onset of fever and endocrine changes occurred after a longer latent interval (180-240 minutes vs. 60-90 minutes after endotoxin), 2) peak responses after the administration of interleukin-2 also occurred later, 3) no increased circulating tumor necrosis factor was detected after administration of interleukin-2 (peak plasma concentration was greater than 35 pg/ml vs. 270 +/- 70 pg/ml after endotoxin administration), and 4) administration of interleukin-2 but not of endotoxin was associated with increased circulating concentrations of gamma interferon (peak plasma concentration 1.7 +/- 0.2 NIH U/ml vs. less than 0.1 NIH U/ml after endotoxin administration). Fever and neurohormonal responses after interleukin-2 administration were greatly attenuated by ibuprofen administration. Interleukin-2 induces other cytokines that exert their effects largely through the cyclooxygenase pathway. Interleukin-2 may be an important signal, initiating the integrated host responses to infection and injury.


Serum immunoglobulins in leukaemia and malignant lymphoma.
The serum immunoglobulin levels were studied in 25 healthy control subjects and 23 cases of leukaemia (6 cases of acute lymphatic leukaemia, 5 cases of acute myeloid leukaemia, 2 cases of chronic lymphatic leukaemia and 10 cases of chronic myeloid leukaemia) and 17 cases of malignant lymphoma (13 cases of Hodgkin's lymphoma and 4 cases of non-Hodgkin lymphoma). The mean levels of IgG, IgA and IgM in 25 control subjects were 1573.56 +/- 91.45 mg/dl, 209.64 +/- 12.55 mg/dl and 109.81 +/- 10.03 mg/dl respectively, those in 23 cases of leukaemia were 1338.23 +/- 109.74 mg/dl, 195.53 +/- 20.72 mg/dl and 127.47 +/- 13.29 mg/dl respectively and those in 17 cases of malignant lymphoma were 996.99 +/- 99.50 mg/dl, 147.47 +/- 19.61 mg/dl and 129.35 +/- 19.95 mg/dl respectively. The mean levels of IgG and IgA were found to be decreased in cases of leukaemia with elevated levels of IgM, however, it was found to be insignificant (p less than 0.4). The mean IgG, IgA and IgM levels were found to be almost identical in different leukaemia irrespective of cytological types except in 2 cases of chronic lymphatic leukaemia which showed low levels of IgG and IgA. The mean levels of IgG and IgA were found to be significantly decreased in malignant lymphoma (p less than 0.02). IgM levels were found to be increased in 3 cases of non-Hodgkin lymphoma.