Changes in Withdrawal and Craving Scores in Participants Undergoing Opioid Detoxification Utilizing Ibogaine.
Opioid use disorder (OUD) is currently an epidemic in the United States (US) and ibogaine is reported to have the ability to interrupt opioid addiction by simultaneously mitigating withdrawal and craving symptoms. This study examined opioid withdrawal and drug craving scores in 50 participants with OUD undergoing a week-long detoxification treatment protocol with ibogaine. The Addiction Severity Index (ASI) was used for baseline characterization of participants' OUD. Clinical Opioid Withdrawal Scale (COWS), Subjective Opioid Withdrawal Scale (SOWS), and Brief Substance Craving Scale (BSCS) scores were collected at 48 and 24 hours prior to ibogaine administration, as well as 24 and 48 hours after ibogaine administration. At 48 hours following ibogaine administration, withdrawal and craving scores were significantly lowered in comparison to baseline: 78% of patients did not exhibit objective clinical signs of opioid withdrawal, 79% reported minimal cravings for opioids, and 68% reported subjective withdrawal symptoms in the mild range. Ibogaine appears to facilitate opioid detoxification by reducing opioid withdrawal and craving in participants with OUD. These results warrant further research using rigorous controlled trials.


New and fast calculation for incoherent multiple scattering.
To model bidirectional measurements, a numerical method for computing the incoherent light scattered by a diffusing medium is presented. The results are expressed as a function of the incident and the observer angles (theta(i), phi(i)) and (theta(f), phi(f)), in contrast to the N-flux method, which gives no information about the azimuthal-distribution. To solve the multiple-scattering equations, an auxiliary function, expanded on the spherical harmonics, is introduced in the diffusion equation. A set of integral equations on the coefficients are obtained that are well suited for the numerical resolution. The boundary conditions are included in the linear operator of the integral equation, so that each boundary condition is associated with a specific equation. As an illustration, the method is applied to numerical simulations of maps of the light scattered by a thick refractive diffusing layer of refractive index n = 1.5, for two directive phase functions and for several incident collimated-beam angles.


Neonatal morbidity and mortality associated with maternal HELLP syndrome.
The syndrome of hemolysis, elevated liver enzymes and low platelet count (HELLP syndrome) is a severe form of preeclampsia and eclampsia. To compare the impact of HELLP syndrome and hypertension in pregnancy (HIP) on neonatal morbidity and mortality, 11 infants born to mothers with HELLP syndrome were recruited between 1993 and 1997 from neonatal records. They were compared to 11 infants born to mothers with HIP and 11 control infants born to healthy mothers matched for gestational age, postnatal age and gender. Cesarean section rate was higher in the HELLP group than in the controls (p < 0.05). HELLP group infants had lower Apgar scores (54.5% < 1 at 5th min), than controls (9.1%) (p < 0.05). Both HELLP and HIP group infants showed a higher incidence of intrauterine growth retardation (63.6% and 54.5%, respectively) than the controls (9.1%) (p < 0.05). The incidence of respiratory distress syndrome (RDS) was similar in HELLP and HIP groups and was greater than that in controls (p = NS). Additionally, the neonatal death rate was the highest in the HELLP group (p = NS).


Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis.
Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than five-fold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here we sought to define the roles of PAX1 and newly-identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); P=7.07e-11, OR=1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wildtype. By genetic targeting we found that wildtype Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, this suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2, or tamoxifen treatment, significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a Pax1-Col11a1-Mmp3 signaling axis in spinal chondrocytes.


Stable expression of a neuronal dopaminergic progenitor phenotype in cell lines derived from human amniotic fluid cells.
Cells from human amniotic fluid derived from the fetus are considered a source of multipotent cells. Their properties have not been fully exploited, partially because unlike other embryonic sources such as embryonic stem (ES) cells, cell lines from amniocentesis samples have not been generated. We have established and characterized the properties of eight individual cell lines. Flow cytometry using several cell surface markers showed that all cell lines generated consisted of homogeneous populations that lack HLAII antigenicity. Using a combination of immunocytochemistry, Western blotting, and RT-PCR, we found weak expression of Oct4 and nestin and strong expression of tubulin-betaIII, MAP2, and tau. Specific markers for cholinergic, (nor)adrenergic, and GABAergic neurons or glia were weakly expressed or absent, whereas expression of factors implicated in early induction of dopaminergic neurons, TGF-beta3 and beta-catenin were present. Further analysis showed strong expression of EN-1, c-RET, PTX3, and NURR1 essential for induction and survival of midbrain dopaminergic neurons, TH, AADC, and VMAT2 components of dopamine synthesis and secretion, and syntaxin1A and SNAP-25 necessary for neurotransmitter exocytosis. This phenotype was retained throughout passages and up to the current passage 36. Expression of neuronal and dopaminergic markers in individual AF cell lines was comparable to expression in neurons induced from ES cells and in IMR-32 and SH-SY5Y neuroblastomas. Our data show that cell lines can be derived from subcultures of amniocentesis, and are primarily composed of a population of progenitors with a phenotype similar to that of committed mesencephalic dopaminergic neurons.


Multifocal ERG defects associated with insufficient long-term glycemic control in adolescents with type 1 diabetes.
To investigate the relationship between long-term glycemic control and localized neuroretinal function in adolescents with type 1 diabetes (T1D) without diabetic retinopathy (DR). Standard (103 hexagons) and slow-flash (61 hexagons) multifocal ERGs (standard mfERG and sf mfERG) were recorded in 48 patients and 45 control subjects. Hexagons with delayed responses were identified as abnormal. Negative binomial regression analysis was conducted with the number of abnormal hexagons as the outcome variable. Glycated hemoglobin (HbA(1c)) levels, time since diagnosis of T1D, age at diagnosis of T1D, age at testing, and sex were the covariates. Another model replacing HbA(1c) closest to the date of testing with a 1-year average was also generated. There were more abnormal hexagons for mfOPs in patients than in control subjects (P = 0.005). There was no significant difference in the mean number of abnormal hexagons for standard mfERG responses between patients and control subjects (P = 0.11). Negative binomial regression analysis for the standard mfERG data demonstrated that a 1-unit increase in HbA(1c) was associated with an 80% increase in the number of abnormal hexagons (P = 0.002), when controlling for age at testing. Analysis using the 1-year HbA(1c) averages did not result in significant findings. Poor long-term glycemic control is associated with an increase in areas of localized neuroretinal dysfunction in adolescents with T1D and no clinically visible DR. Stricter glucose control during the early stages of the disease may prevent neuroretinal dysfunction in this cohort.


Costs and effects of c7E3 in high risk PTCA patients. An indirect analysis for The Netherlands.
A cost effectiveness study is presented on the use of c7E3 in high risk patients undergoing percutaneous coronary angioplasty (PTCA). The results from the EPIC study have been combined with cost data from The Netherlands. The study took account of the number of survivors without ischaemic events, and the number with neither ischaemic events nor bleeding (both measured after 6 months). It is estimated that the initial costs of c7E3 and the additional costs due to the increased risk of bleeding are almost entirely counterbalanced by the savings, as a result of fewer myocardial infarctions and revascularizations. The additional costs per additional patient without ischaemic events are approximately DFL 5235. The additional costs per additional patient with neither ischaemic events nor bleeding are estimated at DFL 15,685. Both figures are less than the average for similar procedures without c7E3. Sensitivity analysis supports the conclusion that c7E3 treatment is efficient. However, cost effectiveness could be further improved if patients are carefully selected.


pH-Dependent Distribution of Functional Groups on Titanium-Based MXenes.
MXenes are a new rapidly developing class of two-dimensional materials with suitable properties for a broad range of applications. It has been shown that during synthesis of these materials the surfaces are usually functionalized by O, OH, and F and further suggested that controlling the surface allows controlling the material properties. However, a proper understanding of the surface structure is still missing, with a significant discrepancy between computational and experimental studies. Experiments consistently show formation of surfaces with mixed terminations, whereas computational studies point toward pure terminated surfaces. Here, we explain the formation of mixed functionalization on the surface of titanium-based two-dimensional carbides, Ti2C and Ti3C2, using a multiscale modeling scheme. Our scheme is based on calculating Gibbs free energy of formation by a combination of electronic structure calculations with cluster expansion and Monte Carlo simulations. Our calculations show formation of mixtures of O, OH, and F on the surface with the composition depending on pH, temperature, and the work function. On the other hand, our results also suggest a limited stable range of compositions, which challenges the paradigm of a high tunability of MXene properties.


The deafferented reticular thalamic nucleus generates spindle rhythmicity.
The hypothesis that nucleus reticularis thalami (RE) is the generator of spindle rhythmicity during electroencephalogram (EEG) synchronization was tested in acutely prepared cats. Unit discharges and focal waves were extracellularly recorded in the rostral pole of RE nucleus, which was completely disconnected by transections from all other thalamic nuclei. In some experiments, additional transections through corona radiata created a triangular island in which the rostral RE pole survived with the caudate nucleus, putamen, basal forebrain nuclei, prepyriform area, and the adjacent cortex. Similar results were obtained in two types of experiments: brain stem-transected preparations that exhibited spontaneous spindle sequences, and animals under ketamine anesthesia in which transient spindling was repeatedly precipitated during recording by very low doses of a short-acting barbiturate. Both spindle-related rhythms (7- to 16-Hz waves grouped in sequences that recur with a rhythm of 0.1-0.3 Hz) are seen in focal recordings of the deafferented RE nucleus. The presence of spindling rhythmicity in the disconnected RE nucleus contrasts with total absence of spindles in cortical EEG leads and in thalamic recordings behind the transection. Oscillations within the same frequency range as that of spontaneous spindles can be evoked in the deafferented RE nucleus by subcortical white matter stimulation. In deafferented RE cells, the burst structure consists of an initially biphasic acceleration-deceleration pattern, eventually leading to a long-lasting tonic tail. Quantitative group data show that the burst parameters of disconnected RE cells are very similar to those of RE neurons with intact connections. In the deafferented RE nucleus, spike bursts of RE neurons recur periodically (0.1-0.3 Hz) in close time-relation with simultaneously recorded focal spindle sequences. The burst occurrence of deafferented RE cells is greatly reduced after systemic administration of bicuculline. The preservation of both spindle-related rhythms in the disconnected RE nucleus, together with our recent experiments showing abolition of spindle oscillations in thalamic nuclei after lesions of RE nucleus (24), demonstrate that RE nucleus is the generator of spindle rhythms.


[Clinical studies with amoxicillin (Pasetocin) (author's transl)].
This paper describes briefly the results obtained with AMPC (Pasetocin) administered by oral route to 21 patients with infection of the respiratory tract. 1. There was no difference in therapeutic effect on infection of the respiratory tract between daily dosages of 1,000 mg and 750 mg (the former was orally given in 4 divided doses every 6 hours a day and the latter in 3 divided doses after meal). The response of the patients to AMPC was remarkable or satisfactory. 2. Acute aggravation symptoms associated with chronic infection of the respiratory tract showed similar improvement to single acute infection of the respiratory tract. 3. The patients presenting acute aggravation symptoms received treatment for chronic stage consisting of consecutive oral administration of AMPC (500 approximately 750 mg a day) and their prognosis was favorable. Side effects attributable to prolonged treatment were not noted. 4. The incidence of side effects can be reduced largely by rejecting form AMPC therapy the patients who are hypersensitive to drugs including penicillins.


Preferred hearing aid gain in everyday environments.
Thirty-three hearing-impaired individuals were each fitted with three hearing aids. The instruments conformed to three frequency-gain prescriptions, differing by a total of 8 dB/octave, with the middle prescription derived using the MSU version 3.0 procedure. The subjects were divided into three matched groups of eleven. Each group used the fitted hearing aids in one of three everyday listening environments representing quiet, reverberant, and noisy situations, respectively. In each listening environment, preferred hearing aid gain for conversationally produced speech was measured in each hearing aid condition for each subject. Preferred gain in daily listening situations was compared to prescribed gain. Results indicated that: (1) preferred gain averaged across all three environments was about equal to prescribed gain, (2) mean preferred gain in each separate environment was substantially different from the prescribed level, (3) volume control adjustments of about +/- 8 dB relative to the prescribed level would be necessary to accommodate the preferred gain settings of the typical hearing aid wearer in daily life. Guidelines are presented for establishing recommended volume control settings for hearing aid users who may be unable to set the volume control independently.


Pentacam characterization of corneas with Fuchs dystrophy treated with Descemet membrane endothelial keratoplasty.
To characterize central corneal thickness, curvature, and posterior surface elevation in eyes with Fuchs dystrophy that underwent Descemet membrane endothelial keratoplasty (DMEK) for endothelial decompensation and to compare these characteristics with those in normal eyes. Pre- and postoperative corneal tomography was prospectively evaluated using Pentacam (Oculus Optikgeräte GmbH) imaging on 29 eyes with Fuchs dystrophy treated with DMEK. Results were compared with data from a separate cohort of 198 normal eyes. In the Fuchs cohort, the mean preoperative central corneal thickness was 656 μm (range: 574 to 731 μm). This significantly exceeded the mean thickness of 542 μm in the normal cohort (range: 439 to 611 μm, P<.0001) although the cohort thickness ranges overlapped. One month after DMEK, mean central corneal thickness decreased significantly to 539 μm (range: 465 to 669 μm, P<.0001) with no further significant decrease between 1 and 3 months after DMEK (mean difference = -4 μm, P=.39). In the Fuchs cohort, keratometry (average Sim K and delta K) did not change significantly after DMEK (P=.41 and P=.44, respectively); pre- and postoperative values were comparable to those in the normal cohort. The mean forward displacement of the posterior surface increased by 69 μm 1 month after DMEK (P<.0001) without further significant change between 1 and 3 months. After DMEK, central corneal thickness in the Fuchs dystrophy cohort decreased significantly and the posterior corneal surface displaced forward, without significant change in anterior keratometric values or keratometric astigmatism. The preoperative central corneal thickness range in eyes with confluent central guttata overlapped the range in normal corneas.


Comparison of first-line chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavourable or advanced stage Hodgkin lymphoma.
There are two different international standards for the treatment of early unfavourable and advanced stage Hodgkin lymphoma (HL): chemotherapy with escalated BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) regimen and chemotherapy with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) regimen. To determine the advantages and disadvantages of chemotherapy including escalated BEACOPP compared to chemotherapy including ABVD in the treatment of early unfavourable or advanced stage HL as first-line treatment. We searched for randomised controlled trials in MEDLINE, CENTRAL and conference proceedings (January 1985 to July 2013 and for the update to March 2017) and Embase (1985 to November 2008). Moreover we searched trial registries (March 2017; www.controlled-trials.com, www.clinicaltrialsregister.eu/ctr-search/search, clinicaltrials.gov, www.eortc.be, www.ghsg.org, www.ctc.usyd.edu.au, www.trialscentral.org/index.html) SELECTION CRITERIA: We included randomised controlled trials examining chemotherapy including at least two cycles of escalated BEACOPP regimens compared with chemotherapy including at least four cycles of ABVD regimens as first-line treatment for patients with early unfavourable stage or advanced stage HL. The effect measures we used were hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS) and freedom from first progression.We used risk ratios (RRs) relative risks to analyse harms: treatment-related mortality, secondary malignancies (including myeloid dysplastic syndrome (MDS) or acute myeloid leukaemia (AML)), infertility and adverse events.Quality of life was not reported in any trial, therefore not analysed. Two review authors independently extracted data and assessed quality of trials. We screened 1796 records and identified five eligible trials in total i.e. one trial could be added on the previous review. These trials included only adults (16 to 65 years of age). We included all five trials with 3427 people in the meta-analyses: the HD9 and HD14 trials were co-ordinated in Germany, the HD2000 and GSM-HD trials were performed in Italy and the EORTC 20012 was conducted in Belgium. The overall risk of performance and detection bias was low for overall survival (OS), but was high for other outcomes, as therapy blinding was not feasible. The remaining 'Risk of bias' domains were low and unclear.All trials reported results for OS and progression-free survival (PFS). In contrast to the our first published review (2011) the addition of results from the EORTC 20012 BEACOPP escalated increases OS (3142 participants; HR 0.74 (95% confidence interval (CI) 0.57 to 0.97; high-quality evidence). This means that only 90 (70 to 117) patients will die after five years in the BEACOPP escalated arm compared to 120 in the ABVD arm. This survival advantage is also reflected in an increased PFS with BEACOPP escalated (3142 participants; HR 0.54 (95% CI 0.45 to 0.64); moderate-quality evidence), meaning that after five years only 144 (121 to 168) patients will experience a progress, relapse or death in the BEACOPP escalated arm compared to 250 in the ABVD arm.There is no evidence for a difference for treatment-related mortality (2700 participants, RR 2.15 (95% CI = 0.93 to 4.95), low-quality evidence).Although the occurrence of MDS or AML may increase with BEACOPP escalated (3332 participants, RR 3.90 (95% CI 1.36 to 11.21); low-quality evidence)), there is no evidence for a difference between both regimens for overall secondary malignancies (3332 participants, RR 1.00 (95% CI 0.68 to 1.48), low-quality evidence). However, the observation time of the studies included in the review is too short to be expected to demonstrate differences with respect to second solid tumours which would not be expected to show significance until around 15 years after treatment.We are very uncertain how many female patients will be infertile due to chemotherapy and which arm might be favoured (106 participants, RR 1.37 (95% CI 0.83 to 2.26), very low-quality evidence). This is a very small sample, and the age of the patients was not detailed. No analysis of male fertility was provided.Five trials reported adverse events and the analysis shows that the escalated BEACOPP regimens probably causes more haematological toxicities WHO grade III or IV ((anaemia: 2425 participants, RR 10.67 (95% CI 7.14 to 15.93); neutropenia: 519 participants, RR 1.80 (95% CI 1.52 to 2.13); thrombocytopenia: 2425 participants, RR 18.12 (95% CI 11.77 to 27.92); infections: 2425 participants, RR 3.73 (95% CI 2.58 to 5.38), all low-quality evidence).Only one trial (EORTC 20012) planned to assess quality of life, however, no results were reported. This meta-analysis provides moderate- to high-quality evidence that adult patients between 16 and 60 years of age with early unfavourable and advanced stage HL benefit regarding OS and PFS from first-line chemotherapy including escalated BEACOPP. The proven benefit in OS for patients with advanced HL is a new finding of this updated review due to the inclusion of the results from the EORTC 20012 trial. Furthermore, there is only low-quality evidence of a difference in the total number of secondary malignancies, as the follow-up period might be too short to detect meaningful differences. Low-quality evidence also suggests that people treated with escalated BEACOPP may have a higher risk to develop secondary AML or MDS. Due to the availability of only very low-quality evidence available, we are unable to come to a conclusion in terms of infertility. This review does for the first time suggest a survival benefit. However, it is clear from this review that BEACOPP escalated may be more toxic that ABVD, and very important long-term side effects of second malignancies and infertility have not been sufficiently analysed yet.


Geological barriers and restricted gene flow in the holarctic skipper Hesperia comma (Hesperiidae).
Patterns of genetic variation within a species may be a consequence of historical factors, such as past fragmentation, as well as current barriers to gene flow. Using sequence data from the mitochondrial cytochrome oxidase subunit II region (COII) and the nuclear gene wingless, we conducted a phylogeographical study of the holarctic skipper Hesperia comma to elucidate patterns of genetic diversity and to infer historical and contemporary processes maintaining genetic variation. One hundred and fifty-one individuals were sampled from throughout North America and Eurasia, focusing on California and adjacent regions in the western United States where morphological diversity is highest compared to the rest of the range. Analyses of sequence data obtained from both genes revealed a well-supported division between the Old and New World. Within western North America, wingless shows little geographical structure, while a hierarchical analysis of genetic diversity of COII sequences indicates three major clades: a western clade in Oregon and Northern California, an eastern clade including the Great Basin, Rocky Mountains and British Columbia, and a third clade in southern California. The Sierra Nevada and the Transverse Ranges appear to be the major barriers to gene flow for H. comma in the western United States. Relatively reduced haplotype diversity in Eurasia compared to North America suggests that populations on the two continents have been affected by different historical processes.


Combined transarterial and transvenous embolization of multi-hole pial arteriovenous fistula with large varix.
Pial arteriovenous fistula (AVF) is a vascular fistulous disease in which the cerebral pial artery and vein are directly connected without the intervening nidus within a sub-pial space. Multi-hole pial AVFs, wherein multiple feeders flow into one drainer, are usually formed with complex angioarchitecture and are difficult to treat. A rare case of an adult patient with hereditary hemorrhagic telangiectasia and multi-hole pial AVF was described. A 23-year-old woman was referred to our hospital. She was previously diagnosed with left cerebellar pial AVF with multiple feeders (bilateral superior cerebellar artery and common trunk of the left anterior inferior cerebellar artery and posterior inferior cerebellar) and large varix that had been untreated for 9 years. The enlargement of the large varix with the new second varix formation was revealed by angiography. Although asymptomatic, considered to be a risk for future hemorrhage was the continuous high hemodynamic stress. Endovascular embolization was performed by securing safe transarterial n-butyl-2-cyanoacrylate injection by transarterial and transvenous coil placement to the shunt points and feeders, resulting in total occlusion of the fistula without any complications. Extensive transvenous coil placement inside the varix allowed safe embolization of the entire fistula with multiple high-flow feeders. Moreover, bidirectional (transarterial and transvenous) retrograde coil embolization enabled firm obliteration of the shunt points. Performing combined transarterial and transvenous embolization in a well-balanced manner was considered to treat multi-hole pial AVF to provide a safe and effective embolization.


Molecular, Structural, Functional, and Pharmacological Sites for Vesicular Glutamate Transporter Regulation.
Vesicular glutamate transporters (VGLUTs) control quantal size of glutamatergic transmission and have been the center of numerous studies over the past two decades. VGLUTs contain two independent transport modes that facilitate glutamate packaging into synaptic vesicles and phosphate (Pi) ion transport into the synaptic terminal. While a transmembrane proton electrical gradient established by a vacuolar-type ATPase powers vesicular glutamate transport, recent studies indicate that binding sites and flux properties for chloride, potassium, and protons within VGLUTs themselves regulate VGLUT activity as well. These intrinsic ionic binding and flux properties of VGLUTs can therefore be modulated by neurophysiological conditions to affect levels of glutamate available for release from synapses. Despite their extraordinary importance, specific and high-affinity pharmacological compounds that interact with these sites and regulate VGLUT function, distinguish between the various modes of transport, and the different isoforms themselves, are lacking. In this review, we provide an overview of the physiologic sites for VGLUT regulation that could modulate glutamate release in an over-active synapse or in a disease state.


Diversity of biosurfactant producing microorganisms isolated from soils contaminated with diesel oil.
Biosurfactant production is a desirable property of hydrocarbon-degrading microorganisms (HDM). We characterized biosurfactant producing microbial populations from a Long Beach soil, California (USA) and a Hong Kong soil (China), contaminated with diesel oil. A total of 33 hydrocarbon-utilizing microorganisms were isolated from the soils. Twelve isolates and three defined consortia were tested for biosurfactant production and emulsification activity. The highest reduction of surface tension was achieved with a consortium of L1, L2 and L3 isolates from a Long Beach soil (41.4mN m(-1)). Isolate L1 (Acinetobacter junii) displayed the highest reduction of surface tension (46.5 mN m(-1)). The emulsifying capacity evaluated by the E24 emulsification index was highest in the culture of isolate L5 (74%). No substantial emulsification was achieved with the cell-free extracts, indicating that the emulsifying activity was not extracellular. Based on surface tension and the E24 index results, isolates F1, F2, F3, F4, L1, L2, L3 and L4 were identified by 16S rRNA gene sequencing as Bacillus cereus, Bacillus sphaericus, B. fusiformis, Acinetobacter junii, a non-cultured bacterium, Pseudomonas sp. and B. pumilus, respectively. Cluster analyses of 16S rRNA gene sequences of the bacterial isolates revealed 70% similarity amongst hydrocarbon-degrading bacterial community present in both soils. Five isolates (isolates F1, F2, F3, F4 and L4) belong to the Firmicutes order, two isolates (L1 and L3) belong to the Proteobacteria order and one isolate (L2) is an Actinomyces sp. Simpson's index (1 - D) and the Shannon-Weaver index (H) revealed more diversity of HDM in the Hong Kong soil, while evenness (E) and the equitability (J) data indicated that there was not a dominant population. Bacterial isolates displaying substantial potential for production of biosurfactants can be applied in the bioremediation of soils contaminated with petroleum hydrocarbons.


Cloning and sequence analysis of cDNA for human cathepsin D.
An 1110-base-pair cDNA clone for human cathepsin D was obtained by screening a lambda gt10 human hepatoma G2 cDNA library with a human renin exon 3 genomic fragment. Poly(A)+ RNA blot analysis with this cathepsin D clone demonstrated a message length of about 2.2 kilobases. The partial clone was used to screen a size-selected human kidney cDNA library, from which two cathepsin D recombinant plasmids with inserts of about 2200 and 2150 base pairs were obtained. The nucleotide sequences of these clones and of the lambda gt10 clone were determined. The amino acid sequence predicted from the cDNA sequence shows that human cathepsin D consists of 412 amino acids with 20 and 44 amino acids in a pre- and a prosegment, respectively. The mature protein region shows 87% amino acid identity with porcine cathepsin D but differs in having nine additional amino acids. Two of these are at the COOH terminus; the other seven are positioned between the previously determined junction for the light and heavy chains of porcine cathepsin D. A high degree of sequence homology was observed between human cathepsin D and other aspartyl proteases, suggesting a conservation of three-dimensional structure in this family of proteins.


Size-selective mortality fosters ontogenetic changes in collective risk-taking behaviour in zebrafish, Danio rerio.
Size-selective mortality is common in fish populations and can operate either in a positive size-selective fashion by harvesting larger-than-average fish or be negatively size-selective by harvesting smaller-than-average fish. Through various mechanisms (like genetic correlations among behaviour and life-history traits or direct selection on behaviour co-varying with growth rate or size-at-maturation), size-selection can result in evolutionary changes in behavioural traits. Theory suggests that both positive and negative size-selection without additional selection on behaviour favours boldness, while evolution of shyness is possible if the largest fish are harvested. Here we examined the impact of size-selective mortality on collective boldness across ontogeny using three experimental lines of zebrafish (Danio rerio) generated through positive (large-harvested), negative (small-harvested) and random (control line) size-selective mortality for five generations and then relaxed selection for 10 generations to examine evolutionarily fixed outcomes. We measured collective risk-taking during feeding (boldness) under simulated aerial predation threat, and across four contexts in presence/absence of a cichlid. Boldness decreased across ontogeny under aerial predation threat, and the small-harvested line was consistently bolder than controls. The large and small-harvested lines showed higher behavioural plasticity as larvae and developed personality earlier compared to the controls. The large-harvested line showed increased variability and plasticity in boldness throughout ontogeny. In the presence of a live predator, fish did not differ in boldness in three contexts compared to the controls, but the large-harvested line showed reduced behavioural plasticity across contexts than controls. Our results confirmed theory by demonstrating that size-selective harvesting evolutionarily alters collective boldness and its variability and plasticity.


The G-protein-coupled estrogen receptor (GPER/GPR30) in ovarian granulosa cell tumors.
Ovarian granulosa cell tumors (GCTs) are thought to arise from cells of the ovarian follicle and comprise a rare entity of ovarian masses. We recently identified the G-protein-coupled estrogen receptor (GPER/GPR30) to be present in granulosa cells, to be regulated by gonadotropins in epithelial ovarian cancer and to be differentially expressed throughout folliculogenesis. Thus, supposing a possible role of GPER in GCTs, this study aimed to analyze GPER in GCTs. GPER immunoreactivity in GCTs (n = 26; n (primary diagnosis) = 15, n (recurrence) = 11) was studied and correlated with the main clinicopathological variables. Positive GPER staining was identified in 53.8% (14/26) of GCTs and there was no significant relation of GPER with tumor size or lymph node status. Those cases presenting with strong GPER intensity at primary diagnosis showed a significant reduced overall survival (p = 0.002). Due to the fact that GPER is regulated by estrogens, as well as gonadotropins, GPER may also be affected by endocrine therapies applied to GCT patients. Moreover, with our data supposing GPER to be associated with GCT prognosis, GPER might be considered as a possible confounder when assessing the efficacy of hormone-based therapeutic approaches in GCTs.


[The morphological basis of vascular (multiinfarct) dementia (author's transl)].
204 patients with an ischaemic stroke were investigated by computertomography. 84 of these patients were demented and 120 had no signs of dementia. Atrophy was significantly more often seen in the computertomograms of the demented patients. A normal computer-tomogram was commoner in the non demented patients. The distribution of infarcts was similar in both groups but bilateral infarcts were significantly more often present in patients with dementia. The combination of a single infarct with atrophy was seen significantly more often in the patients with dementia. Bilateral infarcts, even without atrophy, were significantly more common in the dementia patients. From these findings it was concluded that the bilateral distribution of the lesions is an important factor in vascular dementia.


The Ewing tumor family of peripheral primitive neuroectodermal tumors expresses human gastrin-releasing peptide.
The Ewing tumor family of peripheral primitive neuroectodermal tumors (pPNETs) are characterized by chromosomal translocations leading to EWS-ETS gene fusions. These hybrid genes express chimeric proteins that are thought to act as aberrant transcription factors. We therefore used differential display-PCR to compare gene expression patterns in pPNET cell lines with those of other small round cell tumors (SRCTs) of childhood. This technique detected differential expression of sequences corresponding to human gastrin-releasing peptide (GRP) in pPNET cell lines but not in other SRCT cell lines. Subsequent Northern and reverse transcription-PCR analysis of SRCT cell lines confirmed GRP positivity in all pPNET lines tested. Of primary tumors tested by reverse transcription-PCR, GRP expression was found in 7 (44%) of 16 pPNETs but in no other primary SRCTs examined. Expression of the GRP receptor gene was demonstrable in 55% of pPNET cell lines and 25% of primary pPNET tumors but also in several other SRCTs. Radioimmunoassays and immunohistochemistry confirmed expression of bioactive GRP peptide in pPNET cell lines and primary tumors, respectively. Moreover, in vitro growth of a pPNET cell line was slowed by treatment with a GRP receptor antagonist and accelerated by a GRP receptor agonist. GRP is a known autocrine growth factor in small cell lung cancer and other neuroendocrine tumors. Its expression in pPNETs provides further evidence for a neuroectodermal histogenesis of these tumors and suggests that autocrine growth of this family of tumors may be at least partially regulated by GRP.


Can Public Health Interventions Change Immediate and Long-Term Dietary Behaviours? Encouraging Evidence from a Pilot Study of the U.K. Change4Life Sugar Swaps Campaign.
The aim of this pilot study was to evaluate the effectiveness of the U.K. Change4Life Sugar Swaps campaign for improving nutritional intake in a small sample of families prior to the 2015 nationwide launch. A total of 49 participants from 14 families received information and materials during a two-week intervention period in November 2014 encouraging them to swap high sugar foods and drinks for low sugar alternatives. Daily dietary intake was reported with online food diaries over four stages, each two weeks in length: (i) baseline (no information provided), (ii) intervention when Sugar Swaps materials were accessible, (iii) immediate follow-up, and (iv) one year on from baseline. Data were analysed for sugar, glucose, fructose, sucrose, lactose, fat, saturated fat, carbohydrate, protein, salt, fibre, vitamin C, and energy. During the intervention, significant daily reductions of 32 g sugar, 11 g fat, and 236 kcal for each family member were observed, among others, and 61% of benefits achieved during the intervention period were maintained at immediate follow-up. Encouragingly, for children, reductions in sugar, sucrose, fat, saturated fat, carbohydrate, and energy were observed one year on. The Sugar Swaps Campaign is potentially an effective public health intervention for improving short- and long-term dietary behaviour for the whole family.


Large area and depth-profiling dislocation imaging and strain analysis in Si/SiGe/Si heterostructures.
We demonstrate the combined use of large area depth-profiling dislocation imaging and quantitative composition and strain measurement for a strained Si/SiGe/Si sample based on nondestructive techniques of electron beam-induced current (EBIC) and X-ray diffraction reciprocal space mapping (XRD RSM). Depth and improved spatial resolution is achieved for dislocation imaging in EBIC by using different electron beam energies at a low temperature of ~7 K. Images recorded clearly show dislocations distributed in three regions of the sample: deep dislocation networks concentrated in the "strained" SiGe region, shallow misfit dislocations at the top Si/SiGe interface, and threading dislocations connecting the two regions. Dislocation densities at the top of the sample can be measured directly from the EBIC results. XRD RSM reveals separated peaks, allowing a quantitative measurement of composition and strain corresponding to different layers of different composition ratios. High-resolution scanning transmission electron microscopy cross-section analysis clearly shows the individual composition layers and the dislocation lines in the layers, which supports the EBIC and XRD RSM results.


Meta-analysis of rare events under the assumption of a homogeneous treatment effect.
We studied the performance of several meta-analysis methods in rare event settings, when the treatment effect is assumed to be homogeneous and baseline prevalences are either homogeneous or heterogeneous. We conducted extensive simulations that included the three most common effect sizes with count data: the odds ratio, the relative risk, and the risk difference. We investigated several important scenarios by varying the level of rareness, the value of the trials' arms unbalance, and the size of the treatment effect. We found that the Mantel-Haenszel method and the Binomial regression model provided the best results across all the scenarios investigated. The Peto method performed satisfactorily only when the true effect size was not too large and the degree of unbalance moderate. Inverse variance was the least reliable method. The use of a continuity correction factor slightly improved the performance of the inverse variance method but deteriorated that of the Peto and Mantel-Haenszel methods. A method based on median unbiased estimators of the probabilities provided similar results to those obtained when using the inverse variance method with a continuity correction. Therefore, when the treatment effect can be assumed to be homogeneous and for either homogeneous or heterogeneous baseline prevalences, we highly recommend using the Mantel-Haenszel method without continuity correction (for all the effect sizes) or the Binomial regression model (for the odds ratio only) to meta-analyze the data.


Cytokine profile of patients with chronic immune thrombocytopenia affects platelet count recovery after Helicobacter pylori eradication.
Helicobacter pylori eradication induces platelet recovery in a subgroup of patients with chronic immune thrombocytopenia (cITP), but the mechanisms involved are still not understood. We aimed to evaluate the effect of H. pylori eradication on platelet response and to identify the associated serum cytokine profile in 95 patients with cITP. Serum cytokine concentrations were determined by enzyme-linked immunosorbent assay prior to and 6 months after H. pylori eradication. Remission of cITP was observed in 17 (28·8%) of 59 patients in whom the bacterium was eradicated. Six months after treatment, a significant reduction in the concentrations of T-helper (Th) 1 and Th17 cells and an increase in T regulatory (Treg) and Th2-cell commitment cytokines were observed in patients who recovered, but not in those whose platelet count did not recover. Patients who had a platelet response to eradication of the bacteria had higher pre-treatment serum levels of γ-interferon (IFNG, IFN-γ), transforming growth factor-β (TGFB1, TGF-β) and interleukin 17 (IL17A, IL-17) than patients who did not respond, but only higher pre-treatment TGFB1 levels was independently associated with platelet response. In conclusion, amelioration of cITP after eradication of H. pylori was linked to a more efficient suppression of Th1 and Th17 response and a more pronounced Treg cell response.


Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, including Japan. Although the development of imaging modalities has made the early diagnosis of HCC possible, surgically resectable cases are relatively uncommon because of hepatic function reserve and/or an advanced stage at presentation. Several modalities, such as transcatheter arterial chemoembolization, percutaneous ethanol injection, microwave coagulation therapy and radiofrequency ablation are reportedly useful in treating patients with non-resectable disease. However, unfortunately, many HCC patients have tumor recurrence. The overall prognosis of patients with HCC is very poor, and treatment of the advanced form is still problematic. In this article, we review the clinical efficacy and toxicity of enteric-coated tegafur/uracil in the treatment of patients with advanced non-resectable HCC.


A critical role for suppressor of cytokine signalling 3 in promoting M1 macrophage activation and function in vitro and in vivo.
Macrophages respond to their microenvironment and develop polarized functions critical for orchestrating appropriate inflammatory responses. Classical (M1) activation eliminates pathogens while alternative (M2) activation promotes regulation and repair. M1 macrophage activation is strongly associated with suppressor of cytokine signalling 3 (SOCS3) expression in vitro, but the functional consequences of this are unclear and the role of SOCS3 in M1-macrophage polarization in vivo remains controversial. To address these questions, we defined the characteristics and function of SOCS3-expressing macrophages in vivo and identified potential mechanisms of SOCS3 action. Macrophages infiltrating inflamed glomeruli in a model of acute nephritis show significant up-regulation of SOCS3 that co-localizes with the M1-activation marker, inducible nitric oxide synthase. Numbers of SOCS3(hi) -expressing, but not SOCS1(hi) -expressing, macrophages correlate strongly with the severity of renal injury, supporting their inflammatory role in vivo. Adoptive transfer of SOCS3-short interfering RNA-silenced macrophages into a peritonitis model demonstrated the importance of SOCS3 in driving production of pro-inflammatory IL-6 and nitric oxide, while curtailing expression of anti-inflammatory IL-10 and SOCS1. SOCS3-induced pro-inflammatory effects were due, at least in part, to its role in controlling activation and nuclear accumulation of nuclear factor-κB and activity of phosphatidylinositol 3-kinase. We show for the first time that SOCS3 also directs the functions of human monocyte-derived macrophages, including efficient M1-induced cytokine production (IL-1β, IL-6, IL-23, IL-12), attenuated signal transducer and activator of transcription 3 activity and ability of antigen-loaded macrophages to drive T-cell responses. Hence, M1-associated SOCS3 was a positive regulator of pro-inflammatory responses in our rodent models and up-regulated SOCS3 is essential for effective M1-macrophage activation and function in human macrophages.


Predictive validity of behavioural animal models for chronic pain.
Rodent models of chronic pain may elucidate pathophysiological mechanisms and identify potential drug targets, but whether they predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy, but there are also examples of successful modelling. Significant differences in how methods are implemented and results are reported means that a literature-based comparison between preclinical data and clinical trials will not reveal whether a particular model is generally predictive. Limited reports on negative outcomes prevents reliable estimate of specificity of any model. Animal models tend to be validated with standard analgesics and may be biased towards tractable pain mechanisms. But preclinical publications rarely contain drug exposure data, and drugs are usually given in high doses and as a single administration, which may lead to drug distribution and exposure deviating significantly from clinical conditions. The greatest challenge for predictive modelling is, however, the heterogeneity of the target patient populations, in terms of both symptoms and pharmacology, probably reflecting differences in pathophysiology. In well-controlled clinical trials, a majority of patients shows less than 50% reduction in pain. A model that responds well to current analgesics should therefore predict efficacy only in a subset of patients within a diagnostic group. It follows that successful translation requires several models for each indication, reflecting critical pathophysiological processes, combined with data linking exposure levels with effect on target.


Is inverse association between lipoprotein(a) and diabetes mellitus another paradox in cardiometabolic medicine?
The impact of Type II Diabetes mellitus (T2DM) on cardiovascular disease (CVD) is well-established, while lipoprotein(a) [Lp(a)] has recently emerged as a recognized CVD risk factor. The rising prevalence of T2DM resulting from modern lifestyles and the development of specific Lp(a)-lowering agents brought the association between T2DM and Lp(a) in the forefront. Despite advancements in T2DM treatment, diabetic patients remain at very-high risk of CVD. Lp(a) may, to some extent, contribute to the persistent CVD risk seen in diabetic patients, and the coexistence of T2DM and elevated Lp(a) levels appears to synergistically amplify overall CVD risk. The relationship between T2DM and Lp(a) is paradoxical. On one hand, high Lp(a) plasma concentrations elevate the risk of diabetic microvascular and macrovascular complications. On the other hand, low Lp(a) plasma concentrations have been linked to an increased risk of developing T2DM. Comprehending the association between T2DM and Lp(a) is critical due to the pivotal roles both entities play in overall CVD risk, as well as the unique aspects of their relationship. The mechanisms underlying the inverse association between T2DM and Lp(a) remain incompletely understood, necessitating further meticulous research.


Association Between Frailty and Antiseizure Medication Tolerability in Older Adults With Epilepsy.
Frailty is an important aspect of biological aging, referring to the increased vulnerability of individuals with frailty to physical and psychological stressors. While older adults with epilepsy are an important and distinct clinical group, there are no data on frailty in this population. We hypothesize that frailty will correlate with the seizure frequency and especially the tolerability of antiseizure medications (ASMs) in older adults with epilepsy. We recruited individuals aged 60 years or older with active epilepsy from 4 Canadian hospital centers. We reported the seizure frequency in the 3 months preceding the interview, while ASM tolerability was quantified using the Liverpool Adverse Events Profile (LAEP). We applied 3 measures of frailty: grip strength as a measure of physical frailty, 1 self-reported score (Edmonton frail score [EFS]), and 1 scale completed by a healthcare professional (clinical frailty scale [CFS]). We also administered standardized questionnaires measuring levels of anxiety, depression, functional disability, and quality of life and obtained relevant clinical and demographic data. Forty-three women and 43 men aged 60-93 years were recruited, 87% of whom had focal epilepsy, with an average frequency of 3.4 seizures per month. Multiple linear regression and zero-inflated negative binomial regression models showed that EFS and CFS scores were associated with decreased ASM tolerability, each point increase leading to 1.83 (95% CI: 0.67-4.30) and 2.49 (95% CI: 1.27-2.39) point increases on the LAEP scale, respectively. Neither the EFS and CFS scores nor grip strength were significantly associated with seizure frequency. The EFS was moderately correlated with depression, anxiety, quality of life, and functional disability, demonstrating the best construct validity among the 3 tested measures of frailty. The EFS was significantly, both statistically and clinically, associated with ASM tolerability. It also showed multiple advantages in performance while assessing for frailty in older adults with epilepsy, when compared with the 2 other measures of frailty that we tested. Future studies must focus on what role the EFS during epilepsy diagnosis may play in ASM selection among older adults with epilepsy.


Outcome of surgical treatment of pancreatic, peri-ampullary and ampullary cancer diagnosed in the south of The Netherlands: a cancer registry based study.
To gain insight into the quality of pancreatic cancer surgery in 10 low-volume (median sized) hospitals, each serving 150,000-250,000 people, in the Comprehensive Cancer Centre South (CCCS) area and of referred patients to academic centres to determine the need for further regionalization. The population-based Eindhoven Cancer Registry was used to select all patients in the CCCS area with pancreatic, peri-ampullary and ampullary cancer diagnosed between January 1, 1995 and April 30, 2000 (N = 1130). Of those, 124 patients (11%) underwent surgical resection (of which 40 were treated in university hospitals outside the region). For all pancreatic carcinoma resections, the 3-month survival rate was 82%, varying from 95% for referred patients to 76% for patients treated within the region (p = 0.014). One- and two-year survival rates showed no difference between both groups (p = 0.36 and p = 0.55, respectively). Surgically treated patients who were referred to university hospitals outside the CCCS area were younger, more often male, more often diagnosed with pTNM stage III, exhibited less comorbidity and had a higher socio-economic status than patients surgically treated within the region. Although the results are based on small numbers and patient selection probably influenced these outcomes, these data seem to support further hospital specialisation, to which the surgeons of the CCCS area have committed themselves.


Cysteine cathepsin non-inhibitory binding partners: modulating intracellular trafficking and function.
Cysteine cathepsins play a fundamental role in tumor growth, invasion and migration, angiogenesis, and the metastatic cascade. Evidence of their overexpression in a wide array of human tumors has been well documented. Cysteine cathepsins seem to have a characteristic location-function relationship that leads to non-traditional roles such as those in development and pathology. For example, during tumor development, some cysteine cathepsins are found not just within lysosomes, but are also redistributed into presumptive exocytic vesicles at the cell periphery, resulting in their secretion. This altered localization contributes to non-lysosomal functions that have been linked to malignant progression. Mechanisms for altered localization are not well understood, but do include the interaction of cysteine cathepsins with binding partners that modulate intracellular trafficking and association with specific regions on the cell surface.


Effect of metoprolol on the prognosis for patients with suspected acute myocardial infarction and indirect signs of congestive heart failure (a subgroup analysis of the Göteborg Metoprolol Trial).
The aim of this study is to describe the impact of early treatment with metoprolol on prognosis during 1 year of follow-up in patients with suspected acute myocardial infarction (AMI) and indirect signs of congestive heart failure (CHF). Patients aged 40-74 years who presented within 48 hours of onset of symptoms raising suspicion of AMI were assessed for inclusion. All patients participated in the Göteborg Metoprolol Trial and had indirect indices of CHF according to various clinical criteria. As soon as possible after hospital admission, patients received either placebo or metoprolol (15 mg) divided into 3 intravenous injections, then oral treatment, 200 mg daily for 3 months. Thereafter, most patients in both treatment groups received metoprolol in an open manner. Among the 1,395 randomized patients, 262 (19%) had signs of mild-to-moderate CHF before randomization. Of these, 131 were randomized to metoprolol and 131 to placebo. During the first 3 months, mortality was 10% among patients randomized to metoprolol versus 19% among patients randomized to placebo (p = 0.036). The corresponding figures for the first year were 14% and 27%, respectively (p = 0.0099). Patients randomized to placebo who showed signs of CHF had a 1-year mortality rate of 28% compared with 10% among patients without such signs (p <0.001). The results suggest that early treatment with metoprolol markedly reduces mortality in patients having suspected AMI and signs of CHF.


'The chances are zero': a qualitative study on perceived susceptibility to pregnancy among women experiencing homelessness.
Women experiencing homelessness are at higher risk of unintended pregnancy than women stably housed. The way women perceive their susceptibility to pregnancy may contribute to effective contraceptive use. This study aimed to explore how women experiencing homelessness perceive their susceptibility to pregnancy with and without contraception from a qualitative, emic perspective. Semi-structured interviews (n =19) were conducted from December 2019 to October 2020 among English-speaking, pregnancy-capable (i.e. not sterilised) women, aged 18-45years, experiencing homelessness. Interview questions included perceived susceptibility to pregnancy with and without contraception, attitudes toward pregnancy, and pregnancy intention. Interviews were audio-transcribed and coded to consensus using a seven-step coding process. Themes were identified via thematic and framework analysis, stratifying participants by pregnancy desire in the next year: yes (n =4), no (n =9), or don't know (n =6). Seventeen women reported inconsistent or no contraceptive use. Some women found their risk of pregnancy was equal with and without contraception based on perceptions of specific contraception efficacy (e.g. condoms vs pills); fertility and fecundity concerns; and high abstinence self-efficacy themes. In stratified analysis, women who desired pregnancy or were uncertain of pregnancy desire in the next year reported similar perceived susceptibility with and without contraception, compared with women not desiring pregnancy in the next year. Given the need to have higher susceptibility to pregnancy without contraceptive use for consistent contraception uptake, findings may explain the lack of contraceptive behaviours and contraception preferences related to pregnancy desire.


Studies on the interaction of staphylococcal delta-haemolysin with isolated islets of Langerhans.
delta-Haemolysin, a small surface-active polypeptide purified from the culture media of Staphylococcus aureus, was observed to stimulate the release of insulin from isolated rat islets of Langerhans. This effect was dose-dependent and saturable, with the half-maximal response elicited by a delta-haemolysin concentration of 10 micrograms/ml. Stimulation of insulin release by delta-haemolysin (10 micrograms/ml) was not dependent on the presence of glucose in the incubation medium, but was augmented by increasing concentrations of the sugar. The release of insulin in response to delta-haemolysin could be inhibited by depletion of extracellular Ca2+ or by adrenaline (epinephrine) (10 microM) and was readily reversible when delta-haemolysin was removed from the medium. In addition, the response was potentiated by incubation with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.2 mM). These observations suggest that delta-haemolysin induced a true activation of the beta-cell secretory mechanism. Stimulation of islets of Langerhans with delta-haemolysin was found to be associated with a modest increase in intracellular cyclic AMP levels, although the adenylate cyclase activity of islet homogenates was not increased by delta-haemolysin. delta-Haemolysin was observed to induce a dose-dependent net accumulation of 45Ca2+ by islet cells and to stimulate the efflux of 45Ca2+ from preloaded islets. The efflux of 45Ca2+ was modest in size and short-lived, but dramatically increased in medium depleted fo 40Ca2+. Incubation in the presence of verapamil augmented delta-haemolysin-induced 45Ca2+ efflux and insulin secretion. delta-Haemolysin was found to be a potent 45Ca2+-translocating ionophore in an artificial system. This response was dose-dependent and could be augmented by verapamil. In addition, phosphatidylcholine (25 micrograms/ml) was found to inhibit both delta-haemolysin induced 45Ca2+ translocation and insulin release in a precisely parallel manner. These studies suggest that the ability of delta-haemolysin to stimulate insulin release may be due, in part, to the facilitation of Ca2+ entry into the beta-cells of islets of Langerhans, mediated directly by an ionophoretic mechanism.


Role of follicle wall in meiosis reinitiation induced by insulin in Rana pipiens oocytes.
The involvement of the ovarian follicle wall in insulin induction of Rana pipiens oocyte maturation in vitro was examined. Complete removal of the follicle wall significantly decreased, but did not obliterate, oocyte maturation (i.e., germinal vesicle breakdown, GVBD) induced by insulin. Dose-response studies of GVBD induction revealed that oocytes within intact follicles were at least 100 times more sensitive to insulin than denuded oocytes. Addition of cyanoketone, a steroid biosynthesis inhibitor, to intact follicles also suppressed insulin-induced GVBD. Inhibitory effects of either follicle wall removal or cyanoketone were not observed when denuded oocytes were treated with progesterone. Addition of either progesterone or pregnenolone to insulin-treated denuded oocytes augmented the oocyte GVBD response compared to either steroid alone and essentially replaced the effect of the follicle wall. In summary, steroidogenesis in the follicle wall appears to be a major factor contributing to the ability of insulin to induce GVBD. However, whether insulin stimulates follicle wall steroidogenesis or simply augments the biological activity of endogenous basal steroid levels is unresolved. The in vitro results show that oocyte maturation can be modulated by the combined actions of several hormones. Such steroid-insulin interactions may also be relevant to understanding the control of oocyte maturation in amphibians and other vertebrates, including mammals, under physiological conditions in vivo.


Topic Modeling Reveals Distinct Interests within an Online Conspiracy Forum.
Conspiracy theories play a troubling role in political discourse. Online forums provide a valuable window into everyday conspiracy theorizing, and can give a clue to the motivations and interests of those who post in such forums. Yet this online activity can be difficult to quantify and study. We describe a unique approach to studying online conspiracy theorists which used non-negative matrix factorization to create a topic model of authors' contributions to the main conspiracy forum on Reddit.com. This subreddit provides a large corpus of comments which spans many years and numerous authors. We show that within the forum, there are multiple sub-populations distinguishable by their loadings on different topics in the model. Further, we argue, these differences are interpretable as differences in background beliefs and motivations. The diversity of the distinct subgroups places constraints on theories of what generates conspiracy theorizing. We argue that traditional "monological" believers are only the tip of an iceberg of commenters. Neither simple irrationality nor common preoccupations can account for the observed diversity. Instead, we suggest, those who endorse conspiracies seem to be primarily brought together by epistemological concerns, and that these central concerns link an otherwise heterogenous group of individuals.


Why do people follow social norms?
Norms prescribe how to make decisions in social situations and play a crucial role in sustaining cooperative relationships and coordinating collective action. However, following norms often requires restricting behavior, demanding to curtail selfishness, or suppressing personal goals. This raises the question why people adhere to norms. We review recent theories and empirical findings that aim at explaining why people follow norms even in private, when violations are difficult to detect and are not sanctioned. We discuss theories of norm internalization, social and self-image concerns, and social learning (i.e. preferences conditional on what others do/believe). Finally, we present two behavioral, incentivized tasks that can be used to elicit norms and measure the individual propensity to follow them.


Can we omit systematic biopsies in patients undergoing MRI fusion-targeted prostate biopsies?
Magnetic resonance imaging (MRI)-targeted prostate biopsy is the recommended investigation in men with suspicious lesion(s) on MRI. The role of concurrent systematic in addition to targeted biopsies is currently unclear. Using our prospectively maintained database, we identified men with at least one Prostate Imaging-Reporting and Data System (PI-RADS) ≥3 lesion who underwent targeted and/or systematic biopsies from May 2016 to May 2020. Clinically significant prostate cancer (csPCa) was defined as any Gleason grade group ≥2 cancer. Of 545 patients who underwent MRI fusion-targeted biopsy, 222 (40.7%) were biopsy naïve, 247 (45.3%) had previous prostate biopsy(s), and 76 (13.9%) had known prostate cancer undergoing active surveillance. Prostate cancer was more commonly found in biopsy-naïve men (63.5%) and those on active surveillance (68.4%) compared to those who had previous biopsies (35.2%; both P < 0.001). Systematic biopsies provided an incremental 10.4% detection of csPCa among biopsy-naïve patients, versus an incremental 2.4% among those who had prior negative biopsies. Multivariable regression found age (odds ratio [OR] = 1.03, P = 0.03), prostate-specific antigen (PSA) density ≥0.15 ng ml-2 (OR = 3.24, P < 0.001), prostate health index (PHI) ≥35 (OR = 2.43, P = 0.006), higher PI-RADS score (vs PI-RADS 3; OR = 4.59 for PI-RADS 4, and OR = 9.91 for PI-RADS 5; both P < 0.001) and target lesion volume-to-prostate volume ratio ≥0.10 (OR = 5.26, P = 0.013) were significantly associated with csPCa detection on targeted biopsy. In conclusion, for men undergoing MRI fusion-targeted prostate biopsies, systematic biopsies should not be omitted given its incremental value to targeted biopsies alone. The factors such as PSA density ≥0.15 ng ml-2, PHI ≥35, higher PI-RADS score, and target lesion volume-to-prostate volume ratio ≥0.10 can help identify men at higher risk of csPCa.


Assessing options for the development of surface water flood warning in England and Wales.
This paper explores the technical options for warning of surface water flooding in England and Wales and presents the results of an Environment Agency funded project. Following the extensive surface water flooding experienced in summer 2007 a rainfall threshold-based Extreme Rainfall Alert (ERA) was piloted by the Met Office and Environment Agency providing initial steps towards the establishment of a warning for some types of surface water flooding. The findings of this paper are based primarily on feedback on technical options from a range of professionals involved in flood forecasting and warning and flood risk management, about the current alerts and about the potential options for developing a more targeted surface water flood warning service. Providing surface water flooding warnings presents a set of technical, forecasting and warning challenges related to the rapid onset of flooding, the localised nature of the flooding, and the linking of rainfall and flood forecasts to flood likelihood and impact on the ground. Some examples of rainfall alerting and surface water flood warning services from other countries are evaluated, as well as a small number of recently implemented local services in England and Wales. Various potential options for implementation of a service are then explored and assessed. The paper concludes that development of a surface water flood warning service for England and Wales is feasible and is likely to be useful to emergency responders and operational agencies, although developing such a service for the pluvial components of this type of flooding is likely to be feasible sooner than for other components of surface water flooding such as that caused by sewers. A targeted surface water flood warning service could be developed for professional emergency responders in the first instance rather than for the public for whom such a service without further operational testing and piloting would be premature.


[Leukocyte cytoskeleton under normal and pathological conditions].
Like other cells, leukocytes have the cellular skeleton comprising microtubules, actine, myosine, and intermediate filaments. Elements of the cellular skeleton are connected with receptors on the plasma membrane surface and determine the distribution density of these receptors. There is functional relationship between microtubules and actine filaments, in particular, microtubules determine uniform distribution of actine filaments in the cell cytoplasm. The basic principle of functioning of the cellular skeleton consists of the process of polymerization and reversible depolymerization of proteins forming components of the cellular skeleton. These processes are regulated by Ca2+, calmoduline, as well as by the ratio of cyclic adenosine monophosphate and guanidine monophosphate in the cell. The cellular skeleton determines the most important functions of leukocytes: their mobility, binding and absorption of various substances, processes of degranulation, fusion of granules with phagocytic vacuole. Cellular skeleton defects are accompanied by recurrent bacterial infections. Several such defects are known: leukocyte actine dysfunction syndrome, Chediak-Higashi syndrome, syndrome with marked increase in the content of cGMP and microtubules in leukocytes. In these syndromes, the therapeutic effect is achieved with the substances which regulate the level of cyclic nucleotides in leukocytes, among them large doses of ascorbic acid.


Mass incarceration can explain population increases in TB and multidrug-resistant TB in European and central Asian countries.
Several microlevel studies have pinpointed prisons as an important site for tuberculosis (TB) and multidrug-resistant TB in European and central Asian countries. To date, no comparative analyses have examined whether rises in incarceration rates can account for puzzling differences in TB trends among overall populations. Using longitudinal TB and cross-sectional multidrug-resistant TB data for 26 eastern European and central Asian countries, we examined whether and to what degree increases in incarceration account for differences in population TB and multidrug-resistant TB burdens. We find that each percentage point increase in incarceration rates relates to an increased TB incidence of 0.34% (population attributable risk, 95% C.I.: 0.10-0.58%, P < 0.01), after controlling for TB infrastructure; HIV prevalence; and several surveillance, economic, demographic, and political indicators. Net increases in incarceration account for a 20.5% increase in TB incidence or nearly three-fifths of the average total increase in TB incidence in the countries studied from 1991 to 2002. Although the number of prisoners is a significant determinant of differences in TB incidence and multidrug-resistant TB prevalence among countries, the rate of prison growth is a larger determinant of these outcomes, and its effect is exacerbated but not confounded by HIV. Differences in incarceration rates are a major determinant of differences in population TB outcomes among eastern European and central Asian countries, and treatment expansion alone does not appear to resolve the effect of mass incarceration on TB incidence.


Long-term results of isolated tricuspid valve replacement.
The long-term outcome of isolated tricuspid valve replacement is unclear because this procedure is rare and usually performed in combination with replacement of other valves. The results of all 31 isolated tricuspid valve replacements carried out in 23 patients in Kyushu University Hospital between 1975 and 2004 were retrospectively reviewed. A bioprosthesis was used in 27 cases and a mechanical valve in 4. There were 2 operative deaths and 4 late deaths. One patient with a mechanical prosthesis needed redo tricuspid valve replacement due to valve thrombosis 6 months after surgery. The mean cardiothoracic ratio and functional class improved significantly postoperatively. At 15 years after tricuspid valve replacement, actuarial survival was 75.6% and freedom from valve-related events was 84.9%. For bioprostheses, freedom from structural valve deterioration at 5, 10 and 15 years was 95.2%, 95.2% and 85.7%, respectively. The long-term results of tricuspid valve replacement are considered satisfactory, and a bioprosthesis can be recommended due to its good outcome and no need for anticoagulation. We should not wait until the development of endstage cardiac impairment before carrying out tricuspid valve surgery.


Sirolimus Long-Term Tolerability and Impact on Kidney Function in Lung Transplantation: A Single-Center Experience.
After lung transplant, 2 common complications are calcineurin inhibitor (CNI) induced nephrotoxicity and bronchiolitis obliterans syndrome. The objective of this study was to investigate the long-term effects of sirolimus conversion after lung transplantation. This was a retrospective cohort study of patients who had undergone lung transplantation at a single center from June 2003 to December 2016. We compared patients converted to a sirolimus-based regimen to those maintained on our standard tacrolimus-based regimen. Kidney function, pulmonary function, and immunosuppression concentrations were compared between the groups. Additionally, indications, toxicity monitoring parameters, and discontinuation rates for sirolimus were collected. During the study period, 176 of the 205 patients who underwent lung transplants were converted to a sirolimus-containing regimen (86%). The most common reason for sirolimus initiation was impairment of kidney function or CNI-associated neurotoxicity. Sirolimus was initiated at a median of 150 days post-transplantation and continued for a medium time of 5.02 (2.27-7.85) years. Of those patients converted to sirolimus, 39 (22%) had sirolimus subsequently discontinued secondary to an adverse event. No difference in pulmonary function was found between the groups at 1- and 3-years post-transplantation. In the sirolimus group, the median estimated glomerular filtration rate improved by 8.6 mL/min/1.73 m2 at 3 months post-conversion (P < .001), which was maintained at both 1 and 3 years (P = .014 and .025, respectively). Sirolimus is a viable immunosuppressant option after lung transplant, which successfully allows for the reduction or withdrawal of the CNI, resulting in sustained improvement in kidney function.


Bradykinin blocks angiotensin II-induced hypertrophy in the presence of endothelial cells.
Angiotensin-converting enzyme inhibitors block left ventricular hypertrophy in vivo. A component of this effect has been attributed to tissue accumulation of bradykinin. Little is known regarding the effect of bradykinin on cardiomyocytes. The objectives of the present study were to define the effects of bradykinin on isolated ventricular cardiomyocytes (from adult and neonatal rat hearts) and to determine the extent to which bradykinin blocks hypertrophy in vitro. Bradykinin was found to be a hypertrophic agonist, as defined by increased protein synthesis and atrial natriuretic peptide secretion and expression. Bradykinin (10 micromol/L) increased [3H]phenylalanine incorporation by 23+/-3% in adult and by 36+/-10% in neonatal cardiomyocytes. Constitutive atrial natriuretic peptide secretion by neonatal myocytes was increased 357+/-103%. All effects of bradykinin were abolished by the B2-kinin receptor antagonist Hoe 140. These increases were similar in magnitude to those observed with phenylephrine (20 micromol/L) and angiotensin II (1 micromol/L). However, in cardiomyocytes cocultured with endothelial cells, bradykinin did not increase protein synthesis. Angiotensin II increased [3H]phenylalanine incorporation by 24+/-3% in adult cardiomyocytes in monoculture and by 22+/-2% in adult rat cardiomyocytes cocultured with endothelial cells. Bradykinin abolished this angiotensin II-induced hypertrophy in myocytes cultured with endothelial cells but not in myocytes studied in the absence of endothelial cells. In conclusion, bradykinin has a direct hypertrophic effect on ventricular myocytes. The presence of endothelial cells is required for the antihypertrophic effects of bradykinin. The results suggest that the increase in local concentration of bradykinin associated with angiotensin-converting enzyme inhibition is an important mechanism by which hypertrophy can be blocked. Manifestation of this mechanism appears to require bradykinin-stimulated release of paracrine factor(s) from endothelial cells, which are also able to block the hypertrophic effects of Ang II.


Emodin attenuated severe acute pancreatitis via the P2X ligand‑gated ion channel 7/NOD‑like receptor protein 3 signaling pathway.
Acute pancreatitis (AP) is an aseptic inflammation characterized with an annual incidence rate, and ~20% patients progressing to severe AP (SAP) with a high mortality rate. Although Qingyi decoction has been frequently used for SAP treatment over the past 3 decades in clinic, the actual mechanism of its protective effects remains unknown. As the major active ingredient of Qingyi decoction, emodin was selected in the present study to investigate the effect of emodin against severe acute pancreatitis (SAP) in rats through NOD‑like receptor protein 3 (NLRP3) inflammasomes. The rats were randomly divided into a sham operation group, an SAP model group induced by a standard retrograde infusion of 5.0% sodium taurocholate into the biliopancreatic duct, and low‑dose (30 mg/kg) and high‑dose (60 mg/kg) emodin‑treated groups. At 12 h after the event, the plasma amylase, lipase, interleukin (IL)‑1β, IL‑18 and myeloperoxidase (MPO) activities were examined. Furthermore, the pathological scores of pancreases were evaluated by hematoxylin and eosin staining. The expression levels of P2X ligand‑gated ion channel 7 (P2X7), NLRP3, apoptosis‑associated speck‑like protein containing a C‑terminal caspase recruitment domain and caspase‑1 were also analyzed by western blot analysis. The data demonstrated that, compared with the SAP group, emodin could significantly relieve the pancreatic histopathology and acinar cellular structure injury, and notably downregulate the plasma amylase and lipase levels, as well as the MPO activities in pancreatic tissues, in a dose‑dependent manner. Furthermore, emodin inhibited the P2X7/NLRP3 signaling pathway followed by the decrease of pro‑inflammatory factors, and the latter is beneficial for the recovery of SAP. Collectively, the data indicated that emodin may be an efficient candidate natural product for SAP treatment.


Is music enriching for group-housed captive chimpanzees (Pan troglodytes)?
Many facilities that house captive primates play music for animal enrichment or for caregiver enjoyment. However, the impact on primates is unknown as previous studies have been inconclusive. We conducted three studies with zoo-housed chimpanzees (Pan troglodytes) and one with group-housed chimpanzees at the National Centre for Chimpanzee Care to investigate the effects of classical and pop/rock music on various variables that may be indicative of increased welfare. Study one compared the behaviour and use of space of 18 animals when silence, classical or pop/rock music was played into one of several indoor areas. Overall, chimpanzees did not actively avoid the area when music was playing but were more likely to exit the area when songs with higher beats per minute were broadcast. Chimpanzees showed significantly fewer active social behaviours when music, rather than silence, was playing. They also tended to be more active and engage in less abnormal behaviour during the music but there was no change to either self-grooming or aggression between music and silent conditions. The genre of music had no differential effects on the chimpanzees' use of space and behaviour. In the second study, continuous focal observations were carried out on three individuals with relatively high levels of abnormal behaviour. No differences in behaviour between music and silence periods were found in any of the individuals. The final two studies used devices that allowed chimpanzees to choose if they wanted to listen to music of various types or silence. Both studies showed that there were no persistent preferences for any type of music or silence. When taken together, our results do not suggest music is enriching for group-housed captive chimpanzees, but they also do not suggest that music has a negative effect on welfare.


Characterization of a Pseudomonas putida ABC transporter (AatJMQP) required for acidic amino acid uptake: biochemical properties and regulation by the Aau two-component system.
We describe an ATP-binding cassette (ABC) transporter in Pseudomonas putida KT2440 that mediates the uptake of glutamate and aspartate. The system (AatJMQP, for acidic amino acid transport) is encoded by an operon involving genes PP1071-PP1068. A deletion mutant with inactivated solute-binding protein (KTaatJ) failed to grow on Glu and Gln as sole sources of carbon and nitrogen, while a mutant lacking a functional nucleotide-binding domain (KTaatP) was able to adapt to growth on Glu after an extended lag phase. Uptake of Glu and Asp by either mutant was greatly impaired at both low and high amino acid concentrations. The purified solute-binding protein AatJ exhibited high affinity towards Glu and Asp (K(d)=0.4 and 1.3 muM, respectively), while Gln and Asn as well as dicarboxylates (succinate and fumarate) were bound with much lower affinity. We further show that the expression of AatJMQP is controlled by the sigma(54)-dependent two-component system AauRS. Binding of the response regulator AauR to the aat promoter was examined by gel mobility shift assays and DNase I footprinting. By in silico screening, the AauR-binding motif (the inverted repeat TTCGGNNNNCCGAA) was detected in further P. putida KT2440 genes with established or putative functions in acidic amino acid utilization, and also occurred in other pseudomonads. The products of these AauR-responsive genes include the H(+)/Glu symporter GltP, a periplasmic glutaminase/asparaginase, AnsB, and phosphoenolpyruvate synthase (PpsA), a key enzyme of gluconeogenesis in Gram-negative bacteria. Based on these findings, we propose that AauR is a central regulator of acidic amino acid uptake and metabolism in pseudomonads.


GAL08, an Uncultivated Group of Acidobacteria, Is a Dominant Bacterial Clade in a Neutral Hot Spring.
GAL08 are bacteria belonging to an uncultivated phylogenetic cluster within the phylum Acidobacteria. We detected a natural population of the GAL08 clade in sediment from a pH-neutral hot spring located in British Columbia, Canada. To shed light on the abundance and genomic potential of this clade, we collected and analyzed hot spring sediment samples over a temperature range of 24.2-79.8°C. Illumina sequencing of 16S rRNA gene amplicons and qPCR using a primer set developed specifically to detect the GAL08 16S rRNA gene revealed that absolute and relative abundances of GAL08 peaked at 65°C along three temperature gradients. Analysis of sediment collected over multiple years and locations revealed that the GAL08 group was consistently a dominant clade, comprising up to 29.2% of the microbial community based on relative read abundance and up to 4.7 × 105 16S rRNA gene copy numbers per gram of sediment based on qPCR. Using a medium quality threshold, 25 single amplified genomes (SAGs) representing these bacteria were generated from samples taken at 65 and 77°C, and seven metagenome-assembled genomes (MAGs) were reconstructed from samples collected at 45-77°C. Based on average nucleotide identity (ANI), these SAGs and MAGs represented three separate species, with an estimated average genome size of 3.17 Mb and GC content of 62.8%. Phylogenetic trees constructed from 16S rRNA gene sequences and a set of 56 concatenated phylogenetic marker genes both placed the three GAL08 bacteria as a distinct subgroup of the phylum Acidobacteria, representing a candidate order (Ca. Frugalibacteriales) within the class Blastocatellia. Metabolic reconstructions from genome data predicted a heterotrophic metabolism, with potential capability for aerobic respiration, as well as incomplete denitrification and fermentation. In laboratory cultivation efforts, GAL08 counts based on qPCR declined rapidly under atmospheric levels of oxygen but increased slightly at 1% (v/v) O2, suggesting a microaerophilic lifestyle.


[Are the newer antihypertensive agents better and more effective than diuretics?].
In recent years, the expenses for medical antihypertensive therapy have increased considerably, the main reason being the switchover to newer and more expensive antihypertensive drugs. Several recent studies which have compared the efficacy of the older, conventional drugs (thiazid diuretics and beta-blockers) with the newer agents (calcium blockers, angiotensin-converting enzyme (ACE) inhibitors), have shown that they are almost equipotent with regard to effects on blood pressure, morbidity and mortality. At lower doses, the metabolic effects of thiazide diuretics are minimal and probably without clinical significance, and the risk of developing diabetes mellitus type 2 does not seem to be increased. The cheaper thiazide diuretics are still valuable drugs in the treatment of hypertension. If more than one agent is necessary to reduce blood pressure to the desired level, they can be combined with other antihypertensive agents.


Substance use and addictive disorders in DSM-5 and ICD 10 and the draft ICD 11.
The present review compares and contrasts the diagnostic entities and taxonomy of substance use and addictive disorders in the beta draft of the Eleventh Revision of the International Classification of Diseases (ICD 11), which was released in November 2016, and the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), which was published in mid-2013. Recently published papers relevant to these two classification systems are examined. New initiatives in diagnosis and assessment including the addictions neuroclinical assessment are noted. The draft ICD 11 retains substance dependence as the 'master diagnosis' in contrast to the broader and heterogeneous concept of substance use disorder in DSM-5 and there is empirical support for the coherence of substance dependence for alcohol, cannabis, and prescribed opioids. Both systems now include gambling disorder in the addictive disorders section, with it being transferred from the impulse control disorders section. The new diagnosis of Internet gaming disorder is included in DSM-5 as a condition for further study, and gaming disorder is grouped with the substance and gambling disorders in the draft ICD 11. Initiatives from the U.S. National Institutes of Health (NIH) are highlighting the importance of capturing the neurobiological phases of the addictive cycle in clinical diagnosis and assessment. Although most of the changes in the draft ICD 11 and DSM-5 are incremental, the contrast between DSM-5 substance use disorder and substance dependence in the draft ICD 11, and the inclusion of gambling disorder and gaming disorder will generate much discussion and research.


Treating posttraumatic stress disorder with MDMA-assisted psychotherapy: A preliminary meta-analysis and comparison to prolonged exposure therapy.
Since the wars in Iraq and Afghanistan, posttraumatic stress disorder (PTSD) has become a major area of research and development. The most widely accepted treatment for PTSD is prolonged exposure (PE) therapy, but for many patients it is intolerable or ineffective. ±3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy (MDMA-AP) has recently re-emerged as a new treatment option, with two clinical trials having been published and both producing promising results. However, these results have yet to be compared to existing treatments. The present paper seeks to bridge this gap in the literature. Often the statistical significance of clinical trials is overemphasized, while the magnitude of the treatment effects is overlooked. The current meta-analysis aims to provide a comparison of the cumulative effect size of the MDMA-AP studies with those of PE. Effect sizes were calculated for primary and secondary outcome measures in the MDMA-AP clinical trials and compared to those of a meta-analysis including several PE clinical trials. It was found that MDMA-AP had larger effect sizes in both clinician-observed outcomes than PE did (Hedges' g=1.17 vs. g=1.08, respectively) and patient self-report outcomes (Hedges' g=0.87 vs. g=0.77, respectively). The dropout rates of PE and MDMA-AP were also compared, revealing that MDMA-AP had a considerably lower percentage of patients dropping out than PE did. These results suggest that MDMA-AP offers a promising treatment for PTSD.


An analysis of weekly instructional input hours and student work hours in occupational therapy fieldwork.
A detailed analysis was made of individual agency practices, and of average across agencies, in weekly instructional hours and student work hours attributed to the Level II fieldwork program during one 12-week assignment. The study is based upon data collected on daily log sheets from students and agency staff and related to their activities for instruction and agency work for that period. Questions addressed were related to whether services by affiliating students offset instructional efforts by staff, and whether assignment of experiences was primarily for student education or for agency expediency. It was found that agencies typically incurred large "losses" during the first 3 to 4 weeks of the assignment, while they gained a substantial sum of "benefits" for the remaining 8 to 9 weeks. Further, it was found that large agencies could absorb initial instructional efforts with minimal negative impact, but that smaller agencies often found it necessary to develop student schedules that met agency needs.


Epigenetics and the evolution of virulence.
A feature of pathogenic and invasive organisms is their adaptability when confronted with host and environmental challenges. Recent studies have demonstrated that plant pathogens rely on epigenetic processes for this purpose. Epiallelic variation of effector genes that results in evasion of host immunity is one emerging phenomenon. Another is the epigenetically induced reprogramming and diversification of transcriptional patterns by de-repression of transposable elements. These observations indicate that epigenetic control of gene expression provides a versatile means of generating phenotypic diversity that is adaptable and heritable across generations.


Neuroprotective effect of MK-801 against intra-striatal quinolinic acid induced behavioral, oxidative stress and cellular alterations in rats.
Huntington's Disease (HD) is a common neurodegenerative disorder characterized by motor disturbances, subcortical dementia and psychiatric disturbances. Pathogenesis of HD revolves so far around excitatory amino acids as the primary cause of neuronal loss. However, number of recent reports suggests the involvement of excitotoxicity and oxidative damage. In the present study, first the dose of quinolinic acid that mimics the symptoms of HD was standardized and then the neuroprotective effect of MK-801 (noncompetitive NMDAr antagonist) was evaluated against intrastriatal quinolinic acid induced behavioral, oxidative stress and cellular alterations in rats. A single unilateral (ipsilateral striatum) injections of quinolinic acid (100, 200 and 300 nM) were made in to striatum. Animals were tested for motor functions using actophotometer and rotarod apparatus. Quinolinic acid (300 nM) significantly reduced the body weight and caused motor in-coordination and produced oxidative damage in the cortex and striatum as indicated by raised lipid peroxidation, nitrite concentration, depletion of superoxide dismutase, catalase and different glutathione levels. Beside, quinolinic acid (300 nM) significantly altered the mitochondrial enzymes complex levels and caused histopathological alterations in the striatum. MK-801(0.02, 0.04, 0.08 mg/kg, ip) treatment significantly improved body weight, behavioral alterations (locomotor activity and rotarod performance) and attenuated oxidative damage and mitochondrial enzymes complex dysfunction. Besides, MK-801 treatment significantly reversed histopathological alterations in striatum. The results suggest antioxidant and neuroprotective action of MK-801 against the quinolinic acid induced Huntington's like behavioral, oxidative stress and cellular alterations in rats.


A comparative analysis of methamphetamine use: black gay and bisexual men in relation to men of other races.
We investigated the patterns and correlates of methamphetamine use among Black gay and bisexual men who participated in a large-scale study of club drug use, and sexual behavior in combination with club drug use in New York City. Almost half of the Black men (49%) in the sample indicated use of methamphetamine in the 4 months prior to assessment, a proportion somewhat lower than their White counterparts. In terms of the overall sample, the proportion of the Black men in the study was equivalent to the proportion of methamphetamine users who identified as Black. Black methamphetamine users tended not to reside in neighborhoods considered traditionally gay, were more likely to be HIV-positive, have lower educational attainment, and have lower levels of income than other methamphetamine users. In terms of frequency and reasons for use, Black methamphetamine users did not differ in any substantive way compared to other races and ethnicities. In addition, they did not differ along any key demographic lines from Black non-methamphetamine users. Poly-drug use was common among all Black men in the sample, with almost all methamphetamine users also reporting use of cocaine, but cocaine users not necessarily reporting methamphetamine use. Once a drug that was considered popular only among White gay men, methamphetamine use has been shown to transcend racial and ethnic lines. Because of the synergy that exists between use of the drug, the concentrated levels of HIV in the Black gay population, and the sexual disinhibition engendered with methamphetamine use, this drug presents a potentially mounting public health challenge.


COVID-19 and Black, Asian, and Minority Ethnic Communities: A Complex Relationship Without Just Cause.
Emerging evidence has indicated a negative and disproportionate impact of COVID-19 on Black, Asian, and minority ethnic (BAME) communities. Previous studies have already reported that biological and social risk factors increase disease susceptibility, particularly in BAME communities. Despite frontline workers in ethnic minority communities in the United Kingdom's National Health Service attempting to quell the pandemic, disproportionate numbers of BAME physicians and other health care workers have died of COVID-19. This unprecedented situation highlights ethical and moral implications, which could further augment the impact of the pandemic on their mental health. While the government attempts to mitigate the rate of virus transmission, certain key factors inadvertently augment the negative impact of the pandemic on the mental health and general well-being of BAME communities. This study examined the available literature to explore the association between, and the wider impact of, COVID-19 on BAME communities. Furthermore, this study aims to raise awareness and provide a deeper insight into current scientific discussions.


Virtual reality as a method for evaluation and therapy after traumatic hand surgery.
In the last decade, Virtual Reality has encountered a continuous development concerning medical purposes and there are a lot of devices based on the classic "cyberglove" concept that are used as new therapeutic method for upper limb pathology, especially neurologic problems [1;2;3]. One of the VR devices is Pablo (Tyromotion), with very sensitive sensors that can measure the hand grip strenght and the pinch force, also the ROM (range of motion) for all the joints of the upper limb (shoulder, elbow, wrist) and offering the possibility of interactive games based on Virtual Reality concept with application in occupational therapy programs. We used Pablo in our study on patients with hand surgery as an objective tool for assessment and as additional therapeutic method to the classic Rehabilitation program [4;5]. The results of the study proved that Pablo represents a modern option for evaluation of hand deficits and dysfunctions, with objective measurement replacement of classic goniometry and dynamometry, with computerized data base of patients with monitoring of parameters during the recovery program and with better muscular and neuro-cognitive feedback during the interactive therapeutic modules.