Efficacy and tolerability of a new ibuprofen 200mg plaster in patients with acute sports-related traumatic blunt soft tissue injury/contusion.
Ibuprofen is used for the treatment of non-serious pain. This study assessed the efficacy and safety of a new ibuprofen plaster for the treatment of pain associated with acute sports impact injuries/contusions. In this randomised, double-blind, multi-centre, placebo controlled, parallel group study, adults (n = 130; 18-58 years of age) diagnosed with acute sports-related blunt soft tissue injury/contusion were randomized to receive either ibuprofen 200 mg plaster or placebo plaster. Plasters were administered once daily for five consecutive days. The primary assessment was area under the visual analogue scale (VAS) of pain on movement (POM) over 0 to three days (VAS AUC0-3d). Other endpoints included algometry AUC from 0 to three days (AUC0-3d) and 0 to five days (AUC0-5d), to evaluate improvement of sensitivity at the injured site, and patient and investigator global assessment of efficacy. Safety was monitored throughout the study. The ibuprofen plaster resulted in superior reduction in AUC0-3d compared with placebo; the Least Squares (LS) mean difference was 662.82 mm*h in favour of the ibuprofen 200mg plaster (P = 0.0011). The greater improvement in VAS AUC of POM was also observed after 12 h, 24 h, and five days of therapy. Tenderness also significantly improved with the ibuprofen plaster compared with placebo; LS mean difference in algometry/tenderness AUC0-3d was 1.87 N/cm2*d and AUC0-5d was 1.87 N/cm2*d (P values ≤0.0004). At all study timepoints, a greater percentage of patients and investigators rated the effectiveness of the ibuprofen 200 mg plaster as good/excellent than the placebo plaster. Treatment-emergent adverse events for the ibuprofen plaster were few (≤1.5%) and were mild in severity. The results of this study indicate 200 mg plaster is effective and safe for the treatment of pain due to acute sports-related traumatic blunt soft tissue injury/contusion in adults.


Gamete fertility and ovule number variation in selfed reciprocal F1 hybrid triploid plants are heritable and display epigenetic parent-of-origin effects.
Polyploidy and hybridization play major roles in plant evolution and reproduction. To investigate the reproductive effects of polyploidy and hybridization in Arabidopsis thaliana, we analyzed fertility of reciprocal pairs of F1 hybrid triploids, generated by reciprocally crossing 89 diploid accessions to a tetraploid Ler-0 line. All F1 hybrid triploid genotypes exhibited dramatically reduced ovule fertility, while variation in ovule number per silique was observed across different F1 triploid genotypes. These two reproductive traits were negatively correlated suggesting a trade-off between increased ovule number and ovule fertility. Furthermore, the ovule fertility of the F1 hybrid triploids displayed both hybrid dysgenesis and hybrid advantage (heterosis) effects. Strikingly, both reproductive traits (ovule fertility, ovule number) displayed epigenetic parent-of-origin effects between genetically identical reciprocal F1 hybrid triploid pairs. In some F1 triploid genotypes, the maternal genome excess F1 hybrid triploid was more fertile, whilst for other accessions the paternal genome excess F1 hybrid triploid was more fertile. Male gametogenesis was not significantly disrupted in F1 triploids. Fertility variation in the F1 triploid A. thaliana is mainly the result of disrupted ovule development. Overall, we demonstrate that in F1 triploid plants both ovule fertility and ovule number are subject to parent-of-origin effects that are genome dosage-dependent.


[Combined use of cutaneous electrostimulation of nerve fibers and electrogymnastics of the spine in painful vertebrogenic syndromes].
A combined use of acupunctural cutaneous electrostimulation of neural fibers and electrogymnastics of the vertebral column was tested in 40 patients with vertebral osteochondrosis accompanied by the muscle tonic or compression radical syndrome. Electrostimulation was performed bilaterally in the paravertebral areas at the level of the blocked motor segment, using series of impulses and achieving rhythmical flexing-unflexing movements of a small range in the damaged segment of the spinal column. Positive effect was obtained in all patients with the muscle tonic syndrome and in half the patients with the compression radical syndrome.


Estimated impact of RTS,S/AS01 malaria vaccine allocation strategies in sub-Saharan Africa: A modelling study.
The RTS,S/AS01 vaccine against Plasmodium falciparum malaria infection completed phase III trials in 2014 and demonstrated efficacy against clinical malaria of approximately 36% over 4 years for a 4-dose schedule in children aged 5-17 months. Pilot vaccine implementation has recently begun in 3 African countries. If the pilots demonstrate both a positive health impact and resolve remaining safety concerns, wider roll-out could be recommended from 2021 onwards. Vaccine demand may, however, outstrip initial supply. We sought to identify where vaccine introduction should be prioritised to maximise public health impact under a range of supply constraints using mathematical modelling. Using a mathematical model of P. falciparum malaria transmission and RTS,S vaccine impact, we estimated the clinical cases and deaths averted in children aged 0-5 years in sub-Saharan Africa under 2 scenarios for vaccine coverage (100% and realistic) and 2 scenarios for other interventions (current coverage and World Health Organization [WHO] Global Technical Strategy targets). We used a prioritisation algorithm to identify potential allocative efficiency gains from prioritising vaccine allocation among countries or administrative units to maximise cases or deaths averted. If malaria burden at introduction is similar to current levels-assuming realistic vaccine coverage and country-level prioritisation in areas with parasite prevalence >10%-we estimate that 4.3 million malaria cases (95% credible interval [CrI] 2.8-6.8 million) and 22,000 deaths (95% CrI 11,000-35,000) in children younger than 5 years could be averted annually at a dose constraint of 30 million. This decreases to 3.0 million cases (95% CrI 2.0-4.7 million) and 14,000 deaths (95% CrI 7,000-23,000) at a dose constraint of 20 million, and increases to 6.6 million cases (95% CrI 4.2-10.8 million) and 38,000 deaths (95% CrI 18,000-61,000) at a dose constraint of 60 million. At 100% vaccine coverage, these impact estimates increase to 5.2 million cases (95% CrI 3.5-8.2 million) and 27,000 deaths (95% CrI 14,000-43,000), 3.9 million cases (95% CrI 2.7-6.0 million) and 19,000 deaths (95% CrI 10,000-30,000), and 10.0 million cases (95% CrI 6.7-15.7 million) and 51,000 deaths (95% CrI 25,000-82,000), respectively. Under realistic vaccine coverage, if the vaccine is prioritised sub-nationally, 5.3 million cases (95% CrI 3.5-8.2 million) and 24,000 deaths (95% CrI 12,000-38,000) could be averted at a dose constraint of 30 million. Furthermore, sub-national prioritisation would allow introduction in almost double the number of countries compared to national prioritisation (21 versus 11). If vaccine introduction is prioritised in the 3 pilot countries (Ghana, Kenya, and Malawi), health impact would be reduced, but this effect becomes less substantial (change of <5%) if 50 million or more doses are available. We did not account for within-country variation in vaccine coverage, and the optimisation was based on a single outcome measure, therefore this study should be used to understand overall trends rather than guide country-specific allocation. These results suggest that the impact of constraints in vaccine supply on the public health impact of the RTS,S malaria vaccine could be reduced by introducing the vaccine at the sub-national level and prioritising countries with the highest malaria incidence.


Pharmacokinetics and Pharmacodynamics of Intravenous Immunoglobulin G Maintenance Therapy in Chronic Immune-mediated Neuropathies.
The regimen for IVIg maintenance treatment varies considerably between patients with chronic immune-mediated neuropathies. Although it is widely recognized that treatment regimens should be improved, detailed pharmacokinetics (PK) of IVIg have not yet been established. We aimed to determine the PK of IVIg maintenance treatment in patients with clinically stable, treatment-dependent, chronic immune-mediated neuropathy. Patients received a median IVIg dose of 30 g (range, 15-70 g) every 14 days (range, 7-28 days) resulting in high IgG peak levels (median, 25.9 g/L; range, 16.7-41.0 g/L) and trough levels (median, 16.1 g/L; range, 9.7-23.6 g/L). IgG PK parameters, including half-life (median, 23.1 days; range, 11-60 days), were constant during subsequent courses in the same patients, but varied considerably between patients. The IgG levels at 1 week after infusion correlated with grip strength. These results provide insight into the PK of IVIg maintenance treatment in patients with chronic immune-mediated neuropathies.


Burden of rheumatoid arthritis among US Medicare population: co-morbidities, health-care resource utilization and costs.
The study aimed to assess the burden of RA among the US Medicare population (aged ≥65 years) by comparing co-morbidities, health-care resource utilization (HCRU) and costs against matched non-RA Medicare patients. Data were obtained from the Medicare fee-for-service claims database from 2010 to 2013. RA Medicare patients were identically matched with Medicare patients without RA (controls) based on demographics. Bivariate analyses were conducted to examine differences between cohorts for co-morbidities, HCRU and costs. A generalized linear model was used to test relationships between patient-level characteristics, HCRU and costs. The study population included 115 867 RA patients and 115 867 age-, sex-, race- and region-matched non-RA controls. Mean age was 75.2 years; 79.4% were female. Co-morbidities were greater in RA vs non-RA patients [Charlson Co-morbidity Index (excluding RA): 1.86 vs 1.00; P < 0.0001]. All-cause annual HCRU was greater in RA vs non-RA patients. Total annual health-care costs were ∼3-fold higher in RA vs non-RA patients ($20 919 vs $7197, respectively; P < 0.0001) with the major driver of costs in the RA cohort being outpatient costs. Approximately half of the overall costs in the RA cohort were RA related ($11 587). After controlling for differences in patient characteristics and co-morbidities between cohorts, the adjusted total mean annual costs for RA patients were still more than twice those of non-RA patients ($16 374 vs $6712; P < 0.0001). Among US Medicare patients, those with an RA diagnosis had a significantly greater burden of co-morbidities, HCRU and costs compared with a matched cohort without RA.


Piezoelectric ceramic rectangular transducers in flexural vibration.
Based on the equivalent elastic method and coupled vibration theory, an analytic method is presented to study the flexural vibration of rectangular transducers consisting of piezoelectric ceramic thin plates. By introducing a mechanical coupling coefficient, the flexural vibration of the piezoelectric ceramic rectangular thin plate is reduced to two simple, one-dimensional flexural vibrations of narrow piezoelectric ceramic strips. The resonance frequency equations for the piezoelectric ceramic rectangular thin-plate transducers in flexural vibration are derived under the free and simply supported boundary conditions analytically. The relationship between the resonance frequency and the flexural vibrational order, the geometrical shape, and the dimensions of the piezoelectric ceramic rectangular thin-plate transducer is analyzed. It is demonstrated that the one-dimensional vibrational theory for the flexural vibration of a narrow piezoelectric ceramic strip and the stripe-mode flexural vibrational theory for the piezoelectric ceramic rectangular thin plate can be derived directly from the theory obtained in this paper. Experimental results show that the measured resonance frequencies of the piezoelectric ceramic rectangular thin-plate transducers in flexural vibration under free-boundary conditions are in good agreement with the calculated results. The method presented in this paper can be used in the resonance frequency analysis of vibrating systems in coupled vibration.


Relationship between adequacy of prenatal care utilization index and pregnancy outcomes.
Prenatal care is a comprehensive antepartum care program involving a coordinated approach to medical care and psychosocial support that is optimally offered before conception. Inadequate care during pregnancy can lead to undesirable outcomes, including preterm labor and low birth weight. One of these new, accurate, and comprehensive indicator measurements is adequacy of prenatal care utilization index. This study aimed to assess the adequacy of care and its relationship with preterm labor and low birth weight. This analytic historical cohort study was performed on 420 mothers who referred to health centers in Sari during 2010. Data were collected by interviews and questionnaires. Based on the adequacy of prenatal care utilization, this care was classified into four groups: intensive, adequate, intermediate, and inadequate. Data were analyzed using chi-square test, analysis of variance (ANOVA), Spearman correlation coefficient, and relative risk (RR). Of the 420 mothers who were studied, inadequate care was observed in 151 (36%) cases, which was the highest percentage of care. There was a significant relationship between the adequacy of prenatal care utilization and preterm labor and low birth weight (for both P < 0.05). Performing inadequate care, the rate of preterm labor was RR = 1.36 times and the rate of low birth weight was RR = 1.08 times more than in adequate and intensive care. According to the programs that reduced the number of referrals of pregnant mothers (standardization protocol for mothers in Iran), this study confirms the efficacy of adequacy of prenatal care on reducing preterm labor and low birth weight. This study emphasizes on minimum care performance and the importance of conducting further studies to assess the relationship between quantities of care and other outcomes.


Improved visual sensitivity during smooth pursuit eye movements.
When we view the world around us, we constantly move our eyes. This brings objects of interest into the fovea and keeps them there, but visual sensitivity has been shown to deteriorate while the eyes are moving. Here we show that human sensitivity for some visual stimuli is improved during smooth pursuit eye movements. Detection thresholds for briefly flashed, colored stimuli were 16% lower during pursuit than during fixation. Similarly, detection thresholds for luminance-defined stimuli of high spatial frequency were lowered. These findings suggest that the pursuit-induced sensitivity increase may have its neuronal origin in the parvocellular retino-thalamic system. This implies that the visual system not only uses feedback connections to improve processing for locations and objects being attended to, but that a whole processing subsystem can be boosted. During pursuit, facilitation of the parvocellular system may reduce motion blur for stationary objects and increase sensitivity to speed changes of the tracked object.


Caffeine inhibits callose deposition in the cell plate and the depolymerization of microtubules in the central region of the phragmoplast.
Treatment of tobacco BY-2 cells with 10 mM caffeine that was started after the cells had entered the mitotic phase did not completely inhibit the deposition of callose in the cell plate and allowed the centrifugal redistribution of phragmoplast microtubules. On the other hand, when treatment with caffeine was started before the cells entered the mitotic phase, the deposition of callose was completely inhibited and the redistribution of phragmoplast microtubules was also inhibited. As the inhibition of redistribution of phragmoplast microtubules seems to be caused by the inhibition of depolymerization of microtubules at the central region of the phragmoplast, these results strongly suggest that the deposition of callose in the cell plate is tightly linked with the depolymerization of phragmoplast microtubules. Callose deposition was observed in phragmoplasts isolated from caffeine-treated cells as well as in those isolated from non-caffeine-treated cells, and caffeine did not inhibit callose synthesis in isolated phragmoplast, indicating that caffeine neither inhibits the accumulation of callose synthase at the equatorial regions of the phragmoplast nor arrests callose synthase itself.


Determining chemical activity of (semi)volatile compounds by headspace solid-phase microextraction.
This research introduces a new analytical methodology for measuring chemical activity of nonpolar (semi)volatile organic compounds in different sample matrices using automated solid-phase microextraction (SPME). The chemical activity of an analyte is known to determine its equilibrium concentration in the SPME fiber coating. On this basis, SPME was utilized for the analytical determination of chemical activity, fugacity, and freely dissolved concentration using these steps: (1) a sample is brought into a vial, (2) the SPME fiber is introduced into the headspace and equilibrated with the sample, (3) the SPME fiber is injected into the GC for thermal desorption and analysis, and (4) the method is calibrated by SPME above partitioning standards in methanol. Model substances were BTEX, naphthalene, and alkanes, which were measured in a variety of sample types: liquid polydimethylsiloxane (PDMS), wood, soil, and nonaqueous phase liquid (NAPL). Variable sample types (i.e., matrices) had no influence on sampling kinetics because diffusion through the headspace was rate limiting for the overall sampling process. Sampling time was 30 min, and relative standard deviations were generally below 5% for homogeneous solutions and somewhat higher for soil and NAPL. This type of activity measurement is fast, reliable, almost solvent free, and applicable for mixed-media sampling.


Cation Disorder and Lithium Insertion Mechanism of Wadsley-Roth Crystallographic Shear Phases from First Principles.
Wadsley-Roth crystallographic shear phases form a family of compounds that have attracted attention due to their excellent performance as lithium-ion battery electrodes. The complex crystallographic structure of these materials poses a challenge for first-principles computational modeling and hinders the understanding of their structural, electronic and dynamic properties. In this article, we study three different niobium-tungsten oxide crystallographic shear phases (Nb12WO33, Nb14W3O44, Nb16W5O55) using an enumeration-based approach and first-principles density-functional theory calculations. We report common principles governing the cation disorder, lithium insertion mechanism, and electronic structure of these materials. Tungsten preferentially occupies tetrahedral and block-central sites within the block-type crystal structures, and the local structure of the materials depends on the cation configuration. The lithium insertion proceeds via a three-step mechanism, associated with an anisotropic evolution of the host lattice. Our calculations reveal an important connection between long-range and local structural changes: in the second step of the mechanism, the removal of local structural distortions leads to the contraction of the lattice along specific crystallographic directions, buffering the volume expansion of the material. Niobium-tungsten oxide shear structures host small amounts of localized electrons during initial lithium insertion due to the confining effect of the blocks, but quickly become metallic upon further lithiation. We argue that the combination of local, long-range, and electronic structural evolution over the course of lithiation is beneficial to the performance of these materials as battery electrodes. The mechanistic principles we establish arise from the compound-independent crystallographic shear structure and are therefore likely to apply to niobium-titanium oxide or pure niobium oxide crystallographic shear phases.


Improving early exclusion of acute coronary syndrome in primary care: the added value of point-of-care troponin as stated by general practitioners.
Aim To investigate general practitioners' (GPs') desire and perceived added value of point-of-care (POC) troponin, its effect on referral decisions, and test requirements. Excluding acute coronary syndrome (ACS) in primary care remains a diagnostic challenges for GPs. Consequently, referral rates of chest pain patients are high, while the incidence of a cardiovascular problem is only 8-15%. Previous studies have shown that GPs are interested in a POC troponin test. This test could enhance rapid exclusion of ACS, thereby preventing unnecessary patient distress, without compromising safety and while reducing costs. However, using this test is not recommended in current guidelines due to uncertainty in the test's potential added value, and the lower sensitivity early after symptom onset as compared with troponin tests in a regular laboratory. An online survey containing 34 questions was distributed among 837 Dutch GPs in June 2015. Findings A total of 126 GPs (15.1%) completed at least 75% of the questions. 67.1% of GPs believe that POC troponin tests have moderate to very high added value. Although the availability of a POC test is expected to increase the frequency at which troponin tests are used, it likely decreases (immediate) referral rates. Of the responding GPs, 78.3% only accept 10 min as the maximum test duration, 78.1% think reimbursement of the POC device is required for implementation, and 68.9% consider it necessary that it can be performed with a finger prick blood sample. In conclusion, according to GPs, the POC troponin test can be of added value to exclude ACS early on. Actual test implementation will depend on test characteristics, including test duration, type of blood sample required, and reimbursement of the analyzer.


The effect on the blood lipid profile of soy foods combined with a prebiotic: a randomized controlled trial.
The value of soy protein as part of the cholesterol-lowering diet has been questioned by recent studies. The apparent lack of effect may relate to the absence of dietary factors that increase colonic fermentation and potentiate the cholesterol-lowering effect of soy. Therefore, unabsorbable carbohydrates (prebiotics) were added to the diet with the aim of increasing colonic fermentation and so potentially increasing the hypocholesterolemic effect of soy. Twenty-three hyperlipidemic adults (11 male, 12 female; 58 +/- 7 years old; low-density lipoprotein cholesterol [LDL-C], 4.18 +/- 0.58 mmol/L) completed three 4-week diet intervention phases-a low-fat dairy diet and 10 g/d prebiotic (oligofructose-enriched inulin, a fermentable carbohydrate), a soy food-containing diet (30 g/d soy protein, 61 mg/d isoflavones from soy foods) and 10 g/d placebo (maltodextrin), and a soy food-containing diet with 10 g/d prebiotic--in a randomized controlled crossover study. Intake of soy plus prebiotic resulted in greater reductions in LDL-C (-0.18 +/- 0.07 mmol/L, P = .042) and in ratio of LDL-C to high-density lipoprotein cholesterol (-0.28 +/- 0.11, P = .041) compared with prebiotic. In addition, high-density lipoprotein cholesterol was significantly increased on soy plus prebiotic compared with prebiotic (0.06 +/- 0.02 mmol/L, P = .029). Differences in bifidobacteria, total anaerobes, aerobes, and breath hydrogen did not reach significance. Soy foods in conjunction with a prebiotic resulted in significant improvements in the lipid profile, not seen when either prebiotic or soy alone was taken. Coingestion of a prebiotic may potentiate the effectiveness of soy foods as part of the dietary strategy to lower serum cholesterol.


Sensory phenotypes provide insight into the natural course of diabetic polyneuropathy.
We aimed to investigate the characteristics and longitudinal course of sensory phenotypes identified through Quantitative Sensory Testing in the frame of diabetic polyneuropathy (DSPN). 316 individuals with diabetes mellitus (DM) were examined (78.8% T2DM), of which 250 were follow-up visits 1, 2 and/or 4 (2.88±1.27) years. Allocation into four sensory phenotypes (healthy, thermal hyperalgesia-TH, mechanical hyperalgesia-MH, and sensory loss-SL) at every timepoint was based on QST profiles of the right foot. Cross-sectional analyses demonstrated a gradual worsening of clinical and electrophysiological sensory findings, and increased DSPN prevalence across the groups culminating in SL. Motor nerve impairment was observed solely in SL. Longitudinal analysis revealed a distinct pattern of the phenotype's developmental course (healthy to TH, to MH, to SL). Baseline MH exhibited the highest risk of transition to SL. Regression to healthy was uncommon and mostly observed in TH. Among those without DSPN initially, presence or future occurrence of SL was associated with a three- to fivefold higher likelihood of DSPN development. Our comprehensive longitudinal study of phenotyped patients with DM elucidates the natural course of DSPN. QST-based sensory examination together with other tools for phenotyping may perhaps be useful to determine the natural course of diabetic neuropathy, to identify patients at high risk for DSPN and guide preventive and therapeutic interventions.


Effectiveness of oral prednisone tapering following intravenous methylprednisolone for acute optic neuritis in multiple sclerosis.
Acute optic neuritis treatment lacks standardized protocols. The value of oral prednisone taper (OPT) following intravenous methylprednisolone (IVMP) on visual outcome parameters in optic neuritis (ON) has never been explored. In the present retrospective study, we investigated whether OPT after IVMP affects the structural and functional visual outcomes of inaugural clinically isolated syndrome (CIS)- or multiple sclerosis (MS)-ON. Adult patients with acute, inaugural, unilateral CIS- or MS-ON, treated with IVMP in Germany and Israel were stratified into patients treated with IVMP alone-versus IVMP and OPT. Inclusion criteria were age ≥18, CIS or MS diagnosis according to McDonald criteria 2017, available visual acuity (VA) at nadir before treatment initiation and at follow-up ≥5 months, as well as a spectral domain optic coherence tomography (OCT) data scan at follow-up. Exclusion criteria included recurrent ON, concomitant ophthalmological comorbidities, optical coherence tomography (OCT) of insufficient quality and ON-related escalation therapy after IVMP. The structural outcome was defined as the average retinal nerve fiber layer (RNFL) difference between the ON-affected and the unaffected eye, while the functional outcome was defined as the final high-contrast best-corrected VA (HC-BCVA) at follow-up compared to nadir. The comparative analysis was performed using linear regression analysis, adjusted for sex, age, and days-to-treatment. Fifty-one patients met the inclusion criteria (25% male). The mean age was 33.9 (±10.23) years. Twenty-six patients (51%) received OPT following IVMP. There was no difference in nadir HC-BCVA between the groups (0.39 No OPT; 0.49 With OPT, P = 0.36). Adjusted linear regression analysis did not indicate an influence of OPT on RNFL thickness or on HC-BCVA (beta coefficient for RNFL difference in percentages: 0.51, 95%-CI: [-4.58, 5.59], beta coefficient for logMAR: 0.11, 95%; CI [-0.12, 0.35] at follow-up. In conclusion, the addition of OPT to IVMP did not affect RNFL thickness or the final VA in a retrospective cohort of 51 patients with inaugural acute CIS- or MS-ON. The results of this exploratory study are currently being re-examined in a large-scale, demographically diverse, prospective study.


Effectiveness of small group cognitive behavioural therapy for anxiety and depression in Ebola treatment centre staff in Sierra Leone.
Following the 2014 Ebola outbreak, South London and Maudsley NHS Foundation Trust (SLAM) were commissioned to provide a 'culturally appropriate, effective and sustainable' intervention to address the psychological needs of the Sierra Leonean Ebola Treatment Centre (ETC) staff. The study evaluated the effectiveness of group Cognitive Behavioural Therapy (CBT) developed to treat anxiety, depression and functional impairment amongst a sample of former ETC staff in Sierra Leone. Group comparisons explored whether the effect of the intervention differed dependent on the facilitators that delivered it, as well as whether it differed between former staff of high- and low-risk ETC roles. A sample of 253 former ETC staff attended the group CBT intervention comprised of eight sessions over six weeks. Outcome measures were administered upon entry and within two weeks after the intervention. At post-intervention, anxiety, depression and functional impairment significantly reduced. Reading ability (RA) was introduced as a covariate having impacted the outcomes. The intervention effect differed by facilitators delivering the sessions but not by ETC role risk. The implications of these results are discussed. Group CBT is a promising psychological intervention for treating the anxiety, depression and functional impairment of former ETC staff in Sierra Leone. Furthermore, as part of a stepped-care approach, it may provide a model for psychological support for staff that have worked on the frontline during future epidemics.


Physico-mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide.
The focus of this investigation was to prepare the cocrystal of carbamazepine (CBZ) using nicotinamide as a coformer and to compare its preformulation properties and stability profile with CBZ. The cocrystal was prepared by solution cooling crystallization, solvent evaporation, and melting and cryomilling methods. They were characterized for solubility, intrinsic dissolution rate, chemical identification by Fourier transform infrared spectroscopy, crystallinity by differential scanning calorimetry, powder X-ray diffraction, and morphology by scanning electron microscopy. Additionally, mechanical properties were evaluated by tensile strength and Heckel analysis of compacts. The cocrystal and CBZ were stored at 40°C/94% RH, 40°C/75% RH, 25°C/60% RH, and 60°C to determine their stability behavior. The cocrystals were fluffy, with a needle-shaped crystal, and were less dense than CBZ. The solubility profiles of the cocrystals were similar to CBZ, but its intrinsic dissolution rate was lower due to the high tensile strength of its compacts. Unlike CBZ, the cocrystals were resistant to hydrate transformation, as revealed by the stability studies. Plastic deformation started at a higher compression pressure in the cocrystals than CBZ, as indicated by the high yield pressure. In conclusion, the preformulation profile of the cocrystals was similar to CBZ, except that it had an advantageous resistance to hydrate transformation.


Achieving Superhydrophobicity of Zr-Based Metallic Glass Surfaces with Tunable Adhesion by Nanosecond Laser Ablation and Annealing.
Tuning the surface wettability and adhesion of metallic glasses (MGs) is a promising approach to enrich their engineering applications. In this study, using nanosecond laser ablation in air, hierarchical micro/nanostructures were directly fabricated on a Zr-based MG surface. Following subsequent annealing, the surface exhibited superhydrophobicity (maximum contact angle: 166°, minimum sliding angle: 2°). Furthermore, the superhydrophobic surface could be tuned from low to high surface adhesion force by controlling the laser-ablated spot interval. By analyzing the laser-ablated structures and surface chemical compositions, the superhydrophobicity was related to the formation of hierarchical micro/nanostructures and the absorption of organic compounds with low surface free energy in air, and the change in surface adhesion force was attributed to the difference in surface roughness. The experimental results showed that the superhydrophobic surface with low adhesion force could be used in self-cleaning applications, while the superhydrophobic surfaces with different adhesion forces could be used in no-loss liquid transportation. This study provides an efficient and low-cost way to fabricate superhydrophobic MG surfaces with tunable adhesion, which will broaden the functional applications of MGs.


Sperm cell purification from mock forensic swabs using SOMAmer™ affinity reagents.
We have demonstrated a proof of concept with affinity-based purification of sperm cells from mock forensic samples using SOMAmer™ reagents, DNA-based affinity reagents developed by SomaLogic, Inc. SOMAmer reagents were selected in vitro using whole-cell SELEX to bind specifically with intact, detergent-treated sperm cells. Successful separation of sperm from epithelial cells and their debris was demonstrated using buccal swabs with added semen. Primarily male DNA profiles were generated from sperm cells eluted from the types of cotton swabs typically used for rape kit evidence collection. The quality of sperm DNA isolated from samples purified using SOMAmers is comparable to existing commercially available differential extraction-based methods at higher sperm concentrations. This purification method is simple, offers relatively rapid (<2hr) sperm purification, and can potentially be automated using robotic workstations. This work serves as proof of concept that demonstrates the first use of SOMAmer reagents as affinity ligands to bind sperm cells. With further development, this technique can potentially be used for high-throughput sexual assault forensic casework.


Bloody nipple discharge (BND) in an 8 months old girl and a 9 months old male--rational diagnostic approach.
Bloody nipple discharge in adults is, in men as well as in women, often a symptom of an underlying malignant disease. In respect of this, multiple invasive and mutilating diagnostic procedures have been performed in infants and older children. Apart from individual cases in older and pubertal children, in childhood benign conditions are most common and can be diagnosed by non-invasive diagnostic procedures. Here we discuss a rational diagnostic approach on the basis of 2 patients with bloody nipple discharge at the age of 8 and 9 months which resolved spontaneously without treatment after 3 and 6 months, respectively.


COVID-19 Risk Factors and Mortality Outcomes Among Medicare Patients Receiving Long-term Dialysis.
There is a need for studies to evaluate the risk factors for COVID-19 and mortality among the entire Medicare long-term dialysis population using Medicare claims data. To identify risk factors associated with COVID-19 and mortality in Medicare patients undergoing long-term dialysis. This retrospective, claims-based cohort study compared mortality trends of patients receiving long-term dialysis in 2020 with previous years (2013-2019) and fit Cox regression models to identify risk factors for contracting COVID-19 and postdiagnosis mortality. The cohort included the national population of Medicare patients receiving long-term dialysis in 2020, derived from clinical and administrative databases. COVID-19 was identified through Medicare claims sources. Data were analyzed on May 17, 2021. The 2 main outcomes were COVID-19 and all-cause mortality. Associations of claims-based risk factors with COVID-19 and mortality were investigated prediagnosis and postdiagnosis. Among a total of 498 169 Medicare patients undergoing dialysis (median [IQR] age, 66 [56-74] years; 215 935 [43.1%] women and 283 227 [56.9%] men), 60 090 (12.1%) had COVID-19, among whom 15 612 patients (26.0%) died. COVID-19 rates were significantly higher among Black (21 787 of 165 830 patients [13.1%]) and Hispanic (13 530 of 86 871 patients [15.6%]) patients compared with non-Black patients (38 303 of 332 339 [11.5%]), as well as patients with short (ie, 1-89 days; 7738 of 55 184 patients [14.0%]) and extended (ie, ≥90 days; 10 737 of 30 196 patients [35.6%]) nursing home stays in the prior year. Adjusting for all other risk factors, residing in a nursing home 1 to 89 days in the prior year was associated with a higher hazard for COVID-19 (hazard ratio [HR] vs 0 days, 1.60; 95% CI 1.56-1.65) and for postdiagnosis mortality (HR, 1.31; 95% CI, 1.25-1.37), as was residing in a nursing home for an extended stay (COVID-19: HR, 4.48; 95% CI, 4.37-4.59; mortality: HR, 1.12; 95% CI, 1.07-1.16). Black race (HR vs non-Black: HR, 1.25; 95% CI, 1.23-1.28) and Hispanic ethnicity (HR vs non-Hispanic: HR, 1.68; 95% CI, 1.64-1.72) were associated with significantly higher hazards of COVID-19. Although home dialysis was associated with lower COVID-19 rates (HR, 0.77; 95% CI, 0.75-0.80), it was associated with higher mortality (HR, 1.18; 95% CI, 1.11-1.25). These results shed light on COVID-19 risk factors and outcomes among Medicare patients receiving long-term chronic dialysis and could inform policy decisions to mitigate the significant extra burden of COVID-19 and death in this population.


Antibacterial Activity of Polyaniline Coated Silver Nanoparticles Synthesized from Piper Betle Leaves Extract.
Plants or natural resources have been found to be a good alternative method for nanoparticles synthesis. In this study, polyaniline coated silver nanoparticles (AgNPs) synthesized from Piper betle leaves extract were investigated for their antibacterial activity. Silver nanoparticles were prepared from the reduction of silver nitrate and NaBH4 was used as reducing agent. Silver nanoparticles and extracts were mixed thoroughly and then coated by polyaniline. Prepared nanoparticles were characterized by Visual inspection, Ultraviolet-visible spectroscopy (UV), Fourier transform infrared Spectroscopy (FT-IR), Transmission Electron Microscopy (TEM) techniques. Antibacterial activities of the synthesized silver nanoparticles were tested against Staphylococcus aureus ATCC 25923, Salmonella typhi ATCC 14028, Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853. UV-Vis spectrum of reaction mixture showed strong absorption peak with centering at 400 nm. The FT-IR results imply that Ag-NPs were successfully synthesized and capped with bio-compounds present in P. betle. TEM image showed that Ag-NPs formed were well dispersed with a spherical structures and particle size ranging from 10 to 30 nm. The result revealed that Ag-Extract NPs showed 32.78±0.64 mm zone of inhibition against S. aureus, whereas norfloxacin (positive control) showed maximum 32.15±0.40 mm zone of inhibition for S. aureus. Again, maximum zone of inhibition 29.55±0.45 mm was found for S. typhi, 27.12±0.38 mm for E. coli and 21.95±0.45 mm for P. aeruginosa. The results obtained by this study can't be directly extrapolated to human; so further studies should be undertaken to established the strong antimicrobial activity of Ag-Extract NPs for drug development program.


Establishing Foundational Nonarbitrary Distinctive and Categorical Relational Responding in Children with Autism.
The present study sought to evaluate a sequence of training procedures on the emergence of foundational relational responses that underly more complex distinctive (i.e., difference) and hierarchical (i.e., categorical) relational frames. In a multiple baseline design, an initial baseline period with three children with autism showed that the participants did not select nonidentical stimuli from an array when presented the contextual cue "different." Simple discrimination training was efficacious in establishing this response and the skill transferred to a novel set of stimuli without reinforcement. In a second baseline period, participants did not demonstrate conditional identical/nonidentical relational responses when provided the contextual cues "same" and "different." Conditional discrimination training with all three participants was again efficacious in establishing the conditional reflexive and distinctive responses and the skill transferred to untrained stimuli. In a third baseline period, participants did not demonstrate correct conditional categorization/sorting. Like in the prior two training conditions, training was efficacious in establishing the target response with a generalized transfer to untrained stimuli.


GABA in the endocrine pancreas: cellular localization and function in normal and diabetic rats.
Gamma amino butyric acid (GABA) and its related enzymes have been demonstrated in pancreatic beta cells of normal rat. Antibodies against GABA-synthesizing enzymes have been implicated in the pathogenesis of Type I diabetes. In spite of the importance of GABA in the aetiology of diabetes mellitus, detailed morphological data on the pattern of distribution of GABA in the pancreas of normal and diabetic rats are lacking. Diabetes mellitus (DM) was induced by a single dose of streptozotocin (STZ) given intraperitoneally (60 mg kg body weight(-1)). Four weeks after the induction of DM, normal (n = 6) and diabetic (n = 6) rats were anesthetized with chloral hydrate and their pancreata were removed and processed for the localization and effect of GABA on insulin secretion using immunohistochemistry and radioimmunoassay techniques. The number of GABA-like immunoreactive (GABA-LIR) cells in the pancreatic islets of STZ-diabetic rats decreased significantly (P<0.0001) when compared to non-diabetic control rats. The pattern and percentage distribution of GABA in the islet of Langerhans of normal and diabetic rat was similar to that of insulin. GABA induced a significant (P<0.0007) increase in insulin secretion from the pancreas of normal rats. In diabetic pancreas, GABA evoked a higher but not significant (P<0.1) increase in insulin secretion. These findings showed that the number of GABA-LIR cells is reduced significantly in diabetes. Moreover, GABA is a strong secretagogue of insulin from the pancreas of normal rat.


Vaginal algometer: development and application of a device to monitor vaginal wall pressure pain threshold.
We describe a device (which we have named a vaginal algometer) which can measure the pressure pain threshold (PPT) on the lateral walls of the vagina. The device was assessed in 63 healthy women and a normal range for this measurement was established. Each woman had her vaginal wall PPT measured and was asked about the acceptability of the procedure. We demonstrate that the vaginal algometer can provide a quantitative assessment of vaginal PPT and that the procedure is acceptable to most women.


ONLAY VERSUS RIVES-STOPPA TECHNIQUES IN THE TREATMENT OF INCISIONAL HERNIAS.
In the surgical correction of large incisional hernias, the use of a prosthesis is essential in most cases regardless of the technique chosen. The preference is for the polypropylene prosthesis. To compare the onlay and Rives-Stoppa techniques in the correction of incisional hernias, their immediate results, complications, advantages, and disadvantages. Two groups of patients with incisional hernias were analyzed, submitted to the onlay (19 patients) and Rives-Stoppa (17 patients) techniques, and that used polypropylene prostheses. General epidemiological variables, perioperative data variables, and postoperative complications were assessed. The patients' epidemiologic profile was similar between both groups. The majority were women (58.4%), with a mean age of 65.5 years and a previous mean body mass index of 41.5 kg/m². The Rives-Stoppa technique was employed in most patients (52.7%). Those submitted to the onlay technique had longer abdominal drainage time and longer hospital stay, as well as a higher incidence of seromas and surgical wound infection. The incisional herniorrhaphy technique with the placement of a pre-peritoneal polypropylene mesh by the Rives-Stoppa technique was superior to the onlay due to lower rates of drain use, hospital stay, and postoperative complications.


One motif to bind them: A small-XXX-small motif affects transmembrane domain 1 oligomerization, function, localization, and cross-talk between two yeast GPCRs.
G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors in mammals and facilitate a range of physiological responses triggered by a variety of ligands. GPCRs were thought to function as monomers, however it is now accepted that GPCR homo- and hetero-oligomers also exist and influence receptor properties. The Schizosaccharomyces pombe GPCR Mam2 is a pheromone-sensing receptor involved in mating and has previously been shown to form oligomers in vivo. The first transmembrane domain (TMD) of Mam2 contains a small-XXX-small motif, overrepresented in membrane proteins and well-known for promoting helix-helix interactions. An ortholog of Mam2 in Saccharomyces cerevisiae, Ste2, contains an analogous small-XXX-small motif which has been shown to contribute to receptor homo-oligomerization, localization and function. Here we have used experimental and computational techniques to characterize the role of the small-XXX-small motif in function and assembly of Mam2 for the first time. We find that disruption of the motif via mutagenesis leads to reduction of Mam2 TMD1 homo-oligomerization and pheromone-responsive cellular signaling of the full-length protein. It also impairs correct targeting to the plasma membrane. Mutation of the analogous motif in Ste2 yielded similar results, suggesting a conserved mechanism for assembly. Using co-expression of the two fungal receptors in conjunction with computational models, we demonstrate a functional change in G protein specificity and propose that this is brought about through hetero-dimeric interactions of Mam2 with Ste2 via the complementary small-XXX-small motifs. This highlights the potential of these motifs to affect a range of properties that can be investigated in other GPCRs.


Artificial Intelligence for Segmentation of Bladder Tumor Cystoscopic Images Performed by U-Net with Dilated Convolution.
Background: Early intravesical recurrence after transurethral resection of bladder tumors (TURBT) is often caused by overlooking of tumors during TURBT. Although narrow-band imaging and photodynamic diagnosis were developed to detect more tumors than conventional white-light imaging, the accuracy of these systems has been subjective, along with poor reproducibility due to their dependence on the physician's experience and skills. To create an objective and reproducible diagnosing system, we aimed at assessing the utility of artificial intelligence (AI) with Dilated U-Net to reduce the risk of overlooked bladder tumors when compared with the conventional AI system, termed U-Net. Materials and Methods: We retrospectively obtained cystoscopic images by converting videos obtained from 120 patients who underwent TURBT into 1790 cystoscopic images. The Dilated U-Net, which is an extension of the conventional U-Net, analyzed these image datasets. The diagnostic accuracy of the Dilated U-Net and conventional U-Net were compared by using the following four measurements: pixel-wise sensitivity (PWSe); pixel-wise specificity (PWSp); pixel-wise positive predictive value (PWPPV), representing the AI diagnostic accuracy per pixel; and dice similarity coefficient (DSC), representing the overlap area between the bladder tumors in the ground truth images and segmentation maps. Results: The cystoscopic images were divided as follows, according to the pathological T-stage: 944, Ta; 412, T1; 329, T2; and 116, carcinoma in situ. The PWSe, PWSp, PWPPV, and DSC of the Dilated U-Net were 84.9%, 88.5%, 86.7%, and 83.0%, respectively, which had improved when compared to that with the conventional U-Net by 1.7%, 1.3%, 2.1%, and 2.3%, respectively. The DSC values were high for elevated lesions and low for flat lesions for both Dilated and conventional U-Net. Conclusions: Dilated U-Net, with higher DSC values than conventional U-Net, might reduce the risk of overlooking bladder tumors during cystoscopy and TURBT.


The motor response to intestinal resection: motor activity in the canine small intestine following distal resection.
The mucosal response to intestinal resection has been extensively studied; little is known of the motor response. Our aim was to evaluate motility in the intestinal remnant following distal resection. Motor activity, duodenocecal transit, nutrition, and absorption were studied over a 3-month period in control animals (n = 9) and in groups of dogs who had undergone 25% (n = 6), 50% (n = 5), and 75% (n = 5) distal resection. Diarrhea and steatorrhea developed in each resection group, and the 75% group alone developed true short bowel syndrome. Resection did not affect migrating motor complex frequency or periodicity; phase 1 duration was shorter in the 75% group (control vs. 75%: 22 +/- 4 vs. 6 +/- 2 minutes, P < 0.03). The most striking motor effect was the development of prominent cluster activity in the distal part of the remnant in 25% and 50% resection animals and throughout the remaining intestine in the 75% group. Duodenocecal transit slowed during the study period from 13 +/- 1 to 20 +/- 2 minutes in the 50% and from 10 +/- 2 to 14 +/- 2 minutes in the 75% group (P < 0.05). The initial motor response to major resections of the distal small intestine is dominated by the development of abnormal patterns. This motor disruption may contribute to the symptomatology and clinical features of the short bowel syndrome.


Evidence for the existence of the PAF acetylhydrolase mutation (Val279Phe) in non-Japanese populations: a preliminary study in Turkey, Azerbaijan, and Kyrgyzstan.
Deficiency of plasma platelet-activating factor (PAF) acetylhydrolase resulting from a missense mutation (Val279Phe) in exon 9 of the gene has been described exclusively in the Japanese population with a very high frequency. This study describes the distribution of the mutation in Turkey and two other Turkic nations, Kyrgyzstan in central Asia and Azerbaijan bordering the Caspian Sea. Among 358 unrelated healthy subjects studied from Turkish population, only 3 had the mutation in heterozygous state (0.84%). Family studies also revealed the presence of homozygous individuals in close relatives of one of these subjects. Among 143 healthy subjects studied from Kyrgyzstan, 12 were heterozygous for the mutation (8.4%). No mutation was detected among 100 healthy individuals studied from Azerbaijan. However, it was suggested that the number of subjects was not enough to draw any conclusion about the prevalence of the mutation in the populations studied. Contrary to the previous notions, identification of the mutation in Turkey and Kyrgyzstan shows the existence of the mutation in non-Japanese populations as well.


The benefit of the European User Community from transnational access to national radiation facilities.
Transnational access (TNA) to national radiation sources is presently provided via programmes of the European Commission by BIOSTRUCT-X and CALIPSO with a major benefit for scientists from European countries. Entirely based on scientific merit, TNA allows all European scientists to realise synchrotron radiation experiments for addressing the Societal Challenges promoted in HORIZON2020. In addition, by TNA all European users directly take part in the development of the research infrastructure of facilities. The mutual interconnection of users and facilities is a strong prerequisite for future development of the research infrastructure of photon science. Taking into account the present programme structure of HORIZON2020, the European Synchrotron User Organization (ESUO) sees considerable dangers for the continuation of this successful collaboration in the future.


Copy Number Variations in Hereditary Spastic Paraplegia-Related Genes: Evaluation of an Iranian Hereditary Spastic Paraplegia Cohort and Literature Review.
In human genetic disorders, copy number variations (CNVs) are considered a considerable underlying cause. CNVs are generally detected by array-based methods but can also be discovered by read-depth analysis of whole-exome sequencing (WES) data. We performed WES-based CNV identification in a cohort of 35 Iranian families with hereditary spastic paraplegia (HSP) patients. Thirty-five patients whose routine single-nucleotide variants (SNVs) and insertion/deletion analyses from exome data were unrevealing underwent a pipeline of CNV analysis using the read-depth detection method. Subsequently, a comprehensive search about the existence of CNVs in all 84 known HSP-causing genes was carried out in all reported HSP cases, so far. CNV analysis of exome data indicated that 1 patient harbored a heterozygous deletion in exon 17 of the SPAST gene. Multiplex ligation-dependent probe amplification analysis confirmed this deletion in the proband and his affected father. Literature review demonstrated that, to date, pathogenic CNVs have been identified in 30 out of 84 HSP-causing genes (∼36%). However, CNVs in only 17 of these genes were specifically associated with the HSP phenotype. Among them, CNVs were more common in L1CAM, PLP1, SPAST, SPG7, SPG11, and REEP1 genes. The identification of the CNV in 1 of our patients suggests that WES allows the detection of both SNVs and CNVs from a single method without additional costs and execution time. However, because of intrinsic issues of WES in the detection of large rearrangements, it may not yet be exploited to replace the CNV detection methods in standard clinical practice.


Perceived risks to independent living: the views of older, community-dwelling adults.
The purpose of the present study was to gather the perceptions of older, community-dwelling adults about factors they considered essential for them to remain living within the community. In-depth interviews were conducted with 103 men and women over the age of 65 years who were living in their own home or apartment, within an urban center. Factors such as finances, health, family support, a sense of identity, and a feeling of independence were perceived by older adults to contribute to their ability to remain living in the community. Importantly, older adults viewed threats to this continued independent living as both (a) factors connected to losses and maintenance of capability, but also (b) as impediments to further growth of their personal well-being.


New Insights into the Chemistry of Lithium Carbamoyls: Characterization of an Adduct (R(2)NC(O)CLi(OLi)NR(2)).
Studies of the reaction of lithium dicyclohexylamide with N,N-dibutylformamide, 1-formylpiperidine, and 4-formylmorpholine indicate that the equilibria resulting from these compounds are shifted toward the formation of an adduct, which quickly collapses to dicyclohexylamine and the lithiated carbamoyl anion derived from the initial disubstituted formamide. Further reactions of the lithium carbamoyl lead to a new adduct where a lithiated carbon is bounded to N, O, and a carbonyl functionality. The (13)C NMR analysis of the reaction mixtures showed the presence of similar intermediates in all cases: adducts of this type have not been reported before. These dilithiated intermediates were trapped with methyl iodide giving the corresponding doubly methylated derivatives. Isolation of substituted glyoxylamides and quantitative determination of the products yields constitute further evidence of the whole reaction scheme proposed.


TRANSITION IN ENDOCRINOLOGY: Hypogonadism in adolescence.
Puberty is a remarkable developmental process with the activation of the hypothalamic-pituitary-gonadal axis culminating in reproductive capacity. It is accompanied by cognitive, psychological, emotional, and sociocultural changes. There is wide variation in the timing of pubertal onset, and this process is affected by genetic and environmental influences. Disrupted puberty (delayed or absent) leading to hypogonadism may be caused by congenital or acquired etiologies and can have significant impact on both physical and psychosocial well-being. While adolescence is a time of growing autonomy and independence, it is also a time of vulnerability and thus, the impact of hypogonadism can have lasting effects. This review highlights the various forms of hypogonadism in adolescence and the clinical challenges in differentiating normal variants of puberty from pathological states. In addition, hormonal treatment, concerns regarding fertility, emotional support, and effective transition to adult care are discussed.


Myxoid Pseudotumor Changes Affecting the Distal Ureter Associated With Urothelial Carcinoma In Situ.
Myxoid pseudotumor is a pseudoneoplastic fibroblastic proliferation that has been described in the perinephric and renal sinus fat tissue. It is characterized by the presence of a myxoid matrix, intermingled with the adipocytes, and a hypocellular population of spindle-shaped and stellate cells. We report a myxoid pseudotumor involving the distal ureter, which broadens the spectrum of possible localizations of this lesion around the urinary tract. It occurred in an 80-year-old patient who underwent a nephroureterectomy indicated after an incidental radiological finding of a thickening of the distal left ureter wall which suggested a ureteral neoplasm. He had two voided urine and one ureteroscopic sample cytologies diagnosed as high-grade urothelial carcinoma, as well as a retrograde ureteroscopy ureteral biopsy which was diagnosed as urothelial carcinoma in situ. This emphasizes the problem of the possible misdiagnosis of myxoid pseudotumor as a ureteral infiltrative carcinoma due to the radiological findings being badly interpreted, compounded by the preoperative cytohistologic data on malignancy. A diffuse urothelial carcinoma in situ was seen in our specimen without infiltrative or papillary tumors. This would not support an obstructive pathogenetic mechanism as has been hypothesized for myxoid pseudotumor.


Role of the S layer in morphogenesis and cell division of the archaebacterium Methanocorpusculum sinense.
Thin sections, freeze-etched, and negatively stained preparations of Methanocorpusculum sinense cells reveal a highly lobed cell structure with a hexagonally arranged surface layer (S layer). Digital image processing of negatively stained envelope fragments show that the S layer forms a porous but strongly interconnected network. Since the S layer is the exclusive cell envelope component outside the cytoplasmic membrane it must have a cell shape determining and maintaining function. Although lattice faults such as disclinations and dislocations are a geometrical necessity on the surface of a closed protein crystal, our data indicate that they also play important roles as sites for the incorporation of new morphological units, in the formation of the lobed cell structure, and in the cell division process. In freeze-etched preparations of intact cells numerous positive and negative 60 degree wedge disclinations can be detected which form pentagons and heptagons in the hexagonal array. Complementary pairs of pentagons and heptagons are the termination points of edge dislocations. They can be expected to function both as sites for incorporation of new morphological units into the lattice and as initiation points for the cell division process. The latter is determined by the ratio between the increase of protoplast volume and the increase in actual S-layer surface area during cell growth. We postulate that this mode of cell fission represents a common feature in lobed archaebacteria which possess an S layer as the exclusive wall component.


RNA2DNAlign: nucleotide resolution allele asymmetries through quantitative assessment of RNA and DNA paired sequencing data.
We introduce RNA2DNAlign, a computational framework for quantitative assessment of allele counts across paired RNA and DNA sequencing datasets. RNA2DNAlign is based on quantitation of the relative abundance of variant and reference read counts, followed by binomial tests for genotype and allelic status at SNV positions between compatible sequences. RNA2DNAlign detects positions with differential allele distribution, suggesting asymmetries due to regulatory/structural events. Based on the type of asymmetry, RNA2DNAlign outlines positions likely to be implicated in RNA editing, allele-specific expression or loss, somatic mutagenesis or loss-of-heterozygosity (the first three also in a tumor-specific setting). We applied RNA2DNAlign on 360 matching normal and tumor exomes and transcriptomes from 90 breast cancer patients from TCGA. Under high-confidence settings, RNA2DNAlign identified 2038 distinct SNV sites associated with one of the aforementioned asymetries, the majority of which have not been linked to functionality before. The performance assessment shows very high specificity and sensitivity, due to the corroboration of signals across multiple matching datasets. RNA2DNAlign is freely available from http://github.com/HorvathLab/NGS as a self-contained binary package for 64-bit Linux systems.


Familial Mediterranean Fever.
Familial Mediterranean Fever is a genetic disorder frequently diagnosed among the Arabs. It is also prevalent among Jews, Armenians and Turks. The clinical picture consists of febrile and painful attacks that differ in quality across patients and even within the same patient. There may be accompanying joint pain, chest pain, skin manifestations and other findings, and amyloidosis may occur in some patients as a complication. The primary treatment is Colchicine, which decreases the frequency of the attacks and prevents the occurrence of amyloidosis. The gene responsible for Familial Mediterranean Fever, MEFV, has been mapped and cloned and mutations were identified within its coding sequence. It encodes a protein that is expected to be a down regulator of inflammation. The spectrum of mutations in the Arabic population is partially studied. There are still several issues to be solved before we fully understand the disorder, and to enable us to confront it and decrease the morbidity and mortality inflicted by it.


Usefulness of pulsed-wave tissue Doppler echocardiography for the assessment of the left and right ventricular function in patients with clinical hypothyroidism.
Clinical hypothyroidism (HT) is often associated with cardiovascular disorders, such as endothelial and myocardial dysfunction. Previous studies have explored left ventricular (LV) function using pulsed-wave tissue Doppler echocardiography (TDE) in HT. However, no study has utilized this technique in the assessment of right ventricular (RV) function in HT. Accordingly, we investigated the effects of clinical HT on LV and RV function by TDE. The study subjects included 35 newly diagnosed HT patients and 32 healthy normal controls. For each subject, serum FT3, FT4, TT3, TT4, and thyroid stimulating hormone (TSH) levels were measured, and standard echocardiography and TDE were performed. No statistically significant difference was found between patients and controls with regard to age, gender, body mass index, heart rate, and blood pressure. Compared to controls, TSH levels were significantly higher, and TT4 and FT4 levels were significantly lower. TDE showed that patients had significantly lower early diastolic tricuspid annular velocity (Ea) and early/late (Ea/Aa) diastolic tricuspid annular velocity ratio (P < 0.001 and P < 0.001, respectively), and significantly longer isovolumetric relaxation time (P < 0.001) than those of the controls. Aa, Sa, isovolumetric contraction time, and ejection time did not significantly differ. In addition, a significant relationship between some TDE indexes, and thyroid hormones (TT4 and FT4) and TSH was observed. We showed that patients with clinical HT are associated with impaired RV diastolic function, in addition to impaired LV diastolic function using TDE.


Getting the most for your education dollar.
Hospitals are spending 33 cents on every dollar for the Patient Focused education of their organizations. By following a few simple guidelines, you can shop smart and get more for your educational dollar. Someone once said, "The greatest learning is through the learning of others." This handful of guidelines represent the collective experiences of hospitals around the country as each strives for an ever more successful yet cost-effective Patient Focused education for their organization. Let their experiences be your best teacher. What about the other 67 cents. In future columns of Dollars and Sense, we will explore ways to help you be a smart shopper of facility renovations, equipment purchases, consulting services, project management and several other categories of typical Patient Focused restructuring expenditures.


Evidence for a TSH-controlled ectophosphotyrosine phosphatase in pig thyroid cultured cells.
In porcine thyroid cells in primary culture, thyrotropin (TSH) provokes important morphological changes associated with specific thyroidal function recovery. TSH influences cell-cell interactions and follicular morphogenesis. In the present report, we identify an ectotyrosine phosphatase activity controlled by chronic treatment with TSH. Specific substrates and various inhibitors allowed us to characterize this activity. This tyrosine phosphatase is located at the outer surface of thyroid cells as demonstrated by phosphotyrosylhistone hydrolysis. Control of cell viability and trypsin treatment confirm this extracellular localization. These data show that TSH activates ectotyrosine phosphatase activity, suggesting a role for surface protein phosphorylation in regulating specific functions of porcine thyroid cells in suspension.


Availability and affordability of essential medicines: exploring the health seeking behaviours and health service utilisation for children under-5 years living in squatter settlement of Karachi, Pakistan.
Child health outcomes in the poor communities are largely affected by the non-availability of essential medicines at government health facilities and non-affordability of prescribed medicines at private retail pharmacies. This phenomenon largely defines health seeking behaviours and health service utilisation patterns of the families of the children. Using observational visits, we examined the shelf-availability of medicines for children less than 5 years of age at a rural health centre and conducted focus group discussions with the mothers to explore the effects of non-availability and non-affordability of medicines. We also validated all information by interviewing the health care providers of the area. We found that erratic and insufficient supply of essential medicines at the government health facility and a limited purchasing power to buy medicines from a retail pharmacy, led to considerable 'financial burden' on the poor people, non-compliance with the treatment, health care seeking from informal health providers and healer shopping. This trend has a serious repercussion on the health seeking behaviours and of course the health outcomes, especially among children. On the users' side, health education and health promotion campaign must be instituted to explain the adverse effects on child health ensure appropriate health care seeking behaviours. For the supply side, the health care authorities must ensure the availability of essential medicines for the children at the government facilities. Local community representatives must be involved in the matters related to medicines stock management at the facility.


Epidermal nevus misinterpreted as child abuse.
Determining what constitutes true child abuse is not always easy. A child with epidermal nevus and multiple café-au-lait spots was erroneously thought to be a victim of abuse. This report details the features of epidermal nevi. We present these findings with the hope that such misdiagnoses can be avoided in the future.


Collagen balls in cervical smears. A previously undescribed finding.
To evaluate several conventional cervical smears obtained from women undergoing routine screening for cervical dysplasia or carcinoma and whose smears contained structures resembling collagen balls. Between 1995 and 1998, cervical smears containing collagen balls were analyzed. The clinical histories of the patients whose smears contained collagen balls, including the gestational history, were reviewed. Histopathologic material from any related surgical specimens was reviewed, with special attention to mesothelial surfaces. Collagen balls were found in 5 of 77,891 Pap smears examined (0.006%). None of the patients had evidence of neoplasms of the genital tract. One of the patients was in the first trimester of pregnancy. We suggest that collagen balls in cervical smear originate in mesothelium-covered organs, from where they are transported via the fallopian tubes into the uterine cavity. Their significance lies in their being mistaken for mucin-distended cells exfoliated from a neoplasm or from detached fragments of a papillary ovarian neoplasm.


Excitatory actions of GABA in the intact neonatal rodent hippocampus in vitro.
The excitatory action of gamma-aminobutyric acid (GABA) is considered to be a hallmark of the developing nervous system. However, in immature brain slices, excitatory GABA actions may be secondary to neuronal injury during slice preparation. Here, we explored GABA actions in the rodent intact hippocampal preparations and at different depths of hippocampal slices during the early post-natal period [post-natal days (P) 1-7]. We found that in the intact hippocampus at P1-3: (i) GABA exerts depolarizing action as seen in cell-attached single GABA(A) channel recordings; (ii) GABA(A) receptor (GABA(A)-R) agonist isoguvacine and synaptic activation of the GABA(A)-Rs increase the frequency of multiple unit activity and the frequency of the network-driven giant depolarizing potentials (GDPs); and that (iii) Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) antagonist bumetanide suppresses GDPs and the excitatory actions of isoguvacine. In the hippocampal slices at P2-5, isoguvacine and synaptic activation of GABA(A)-Rs-evoked excitatory responses at all slice depths, including surface and core. Thus, GABA exerts excitatory actions in the intact hippocampus (P1-3) and at all depths of hippocampal slices (P2-5). Therefore, the excitatory actions of GABA in hippocampal slices during the first post-natal days are not due to neuronal injury during slice preparation, and the trauma-related excitatory GABA actions at the slice surface are a fundamentally different phenomenon observed during the second post-natal week.


Characterization of human immunodeficiency virus type 1 (HIV-1) envelope variation and neutralizing antibody responses during transmission of HIV-1 subtype B.
We analyzed neutralization sensitivity and genetic variation of transmitted subtype B human immunodeficiency virus type 1 (HIV-1) in eight recently infected men who have sex with men and the virus from the six subjects who infected them. In contrast to reports of heterosexual transmission of subtype C HIV-1, in which the transmitted virus appears to be more neutralization sensitive, we demonstrate that in our study population, relatively few phenotypic changes in neutralization sensitivity or genotypic changes in envelope occurred during transmission of subtype B HIV-1. We suggest that limited genetic variation within the infecting host reduces the likelihood of selective transmission of neutralization-sensitive HIV.


[Economic evaluation of healthcare interventions during more than 25 years in Spain (1983-2008)].
Economic evaluation has been promoted as a tool to guide decision-making processes regarding healthcare resources' allocation and in the adoption of healthcare technologies. We analyzed the evolution and the main characteristics of economic evaluations of healthcare interventions done during the period 1983-2008 in Spain. Observational descriptive study. We performed a systematic review in the main bibliographic databases (PubMed/ MEDLINE, SCOPUS, ISI Web of Knowledge, CRD, IME, IBECS) and manually through Internet in journals and public reports. There were predefined inclusion and exclusion criteria, and a set of variables to analyze the characteristics of the selected reports. In total, 477 studies fulfilled the inclusion criteria. Some of the studies characteristics were: cost-effectiveness analysis (62.5%), decision analysis techniques (34.0%), healthcare system perspective (42.1%), therapeutic interventions (70.0%) and non explicit financing (44.0%). The geographical distribution for Spanish regions of the first authors was: Catalonia (29.3%), Community of Madrid (23.7%), Andalusia (6,7%) and Region of Valencia (6.3%). A total of 50.9% of the principal authors were employed at hospital centers. The most common disease conditions were: cardiovascular diseases (15.7%), infectious and parasitic diseases (15.3%) and malignant neoplasms (13.2%). A total of 82.2 % of the reports provided recommendations for decision making. An increasing number of studies was observed. Identified reports combined heterogeneity in the quality of the information brought with regard to analysis methods, data sources, type of interventions, or disease conditions. It is suggested to do more efforts for improving the quantity and quality of reports in public health interventions.


[Forty years of studying angiotensin-converting enzyme: problems and accomplishments].
Questions on the molecular forms multiplicity, certain physical, chemical and catalytical properties, the mechanisms of the activity regulation and biological role of the angiotensin-converting enzyme have been considered. Special attention was paid to the consideration of the angiotensin-converting enzyme role in brain regulative neuropeptide metabolism.


Algorithmic approach in the management of COVID-19 patients with residual pulmonary symptoms.
Coronavirus-19 emerged about 3 years ago and has proven to be a devastating disease, crippling communities worldwide and accounting for more than 6.31 million deaths. The true disease burden of COVID-19 will come to light in the upcoming years as we care for COVID-19 survivors with post-COVID-19 syndrome (PCS) with residual long-term symptoms affecting every organ system. Pulmonary fibrosis is the most severe long-term pulmonary manifestation of PCS, and due to the high incidence of COVID-19 infection rates, PCS-pulmonary fibrosis has the potential of becoming the next large-scale respiratory health crisis. To confront the potentially devastating effects of emerging post-COVID-19 pulmonary fibrosis, dedicated research efforts are needed to focus on surveillance, understanding pathophysiologic mechanisms, and most importantly, an algorithmic approach to managing these patients. We have performed a thorough literature review on post-COVID-19 pulmonary symptoms/imaging/physiology and present an algorithmic approach to these patients based on the best available data and extensive clinical experience.


LABAZ1: A metastatic tumor model for renal cell carcinoma expressing the carbonic anhydrase type 9 tumor antigen.
A metastatic renal cell carcinoma (RCC) tumor model xenograft that expresses the targetable, membrane-bound tumor-associated antigen carbonic anhydrase type 9 (CA IX) is described. The xenograft, established from a high-grade type-2 chromophil RCC (cRCC), has been serially transplanted in immune compromised mice, in which it grows orthotopically under the renal capsule, doubling its size every 9 weeks and sending metastases to the lung and liver at approximately 20 weeks. Tumors were capable of being imaged using a micro-PET (micro-positron emission tomograph) with an 18-fluorodeoxyglucose (18-FDG) tracer. Subsequent xenograft generations have conserved immunohistochemical and ultrastructural properties typical for malignant renal epithelium-derived neoplasia (vimentin+, CK-19+, CA IX+ with hypoxia-inducible factor (HIF)-1 alpha constitutive expression) and have demonstrated extensive proliferation, lack of apoptosis, severe genetic alterations, and molecular expression alterations; transforming growth factor beta 1 (TGF-beta 1), hepatocyte growth factor (HGF), proto-oncogene (c-met), matrix metalloproteinase (MMP)-1, and vascular endothelial growth factor (VEGF) C and D were overexpressed, whereas human epidermal growth factor receptor (HER)-2, MMP-2 and MMP-9, VEGF-R3, p53, and p27 were severely down-regulated, suggesting a proangiogenic environment, local invasiveness, and facilitated lymphatic metastasis. Altogether, LABAZ1 provides a relevant and flexible model to study the biology of cRCC, the role of CA IX in RCC tumorigenesis, progression, and metastasis, and a platform for testing new targeted therapeutic strategies.


Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome.
Enlarged early endosomes have been visualized in Alzheimer's disease (AD) and Down syndrome (DS) using conventional confocal microscopy at a resolution corresponding to endosomal size (hundreds of nm). In order to overtake the diffraction limit, we used super-resolution structured illumination microscopy (SR-SIM) and transmission electron microscopies (TEM) to analyze the early endosomal compartment in DS.By immunofluorescence and confocal microscopy, we confirmed that the volume of Early Endosome Antigen 1 (EEA1)-positive puncta was 13-19% larger in fibroblasts and iPSC-derived neurons from individuals with DS, and in basal forebrain cholinergic neurons (BFCN) of the Ts65Dn mice modelling DS. However, EEA1-positive structures imaged by TEM or SR-SIM after chemical fixation had a normal size but appeared clustered. In order to disentangle these discrepancies, we imaged optimally preserved High Pressure Freezing (HPF)-vitrified DS fibroblasts by TEM and found that early endosomes were 75% denser but remained normal-sized.RNA sequencing of DS and euploid fibroblasts revealed a subgroup of differentially-expressed genes related to cargo sorting at multivesicular bodies (MVBs). We thus studied the dynamics of endocytosis, recycling and MVB-dependent degradation in DS fibroblasts. We found no change in endocytosis, increased recycling and delayed degradation, suggesting a "traffic jam" in the endosomal compartment.Finally, we show that the phosphoinositide PI (3) P, involved in early endosome fusion, is decreased in DS fibroblasts, unveiling a new mechanism for endosomal dysfunctions in DS and a target for pharmacotherapy.


Catalytic mechanism of 6-phosphogluconate dehydrogenase: a theoretical investigation.
Density functional calculations are employed to theoretically explore the mechanism of all elementary reaction steps involved in the catalytic reaction of 6-phosphogluconate dehydrogenase (6PGDH). The model systems we choose for the enzyme contain the essential parts of the cofactor (NADP+), the substrate 6-phosphogluconate (6PG), and some key residues (Lys183 and Glu190) in the active site of sheep liver 6PGDH. The effect of the apoenzyme electrostatic environment on the studied reaction is treated by the self-consistent reaction-field method. Our calculations demonstrate that the first step of the catalytic reaction is the formation of a 3-keto 6PG intermediate, which proceeds through a concerted transition state involving a hydride transfer from 6PG to NADP+, and a proton transfer from 6PG to Lys183. The second step is the elimination of a CO2 molecule from 6-PG, concomitant with a proton transfer from Lys183 to 6-PG. In the final step, a concerted double proton transfer (one from Glu190 to the substrate, another from the substrate to Lys183) results in the final product, the keto form of ribulose 5-phosphate (Ru5P). The rate-limiting step is the formation of a 3-keto 6PG intermediate, with a free energy barrier of 22.7 kcal/mol at room temperature in the protein environment, and all three steps are calculated to be thermodynamically favorable. These results are in good agreement with the general acid/general base mechanism suggested from previous experiments for the 6PGDH reaction.


Operating room organization. Lasers and advanced operative laparoscopy.
Advanced operative laparoscopy and laser surgery require a trained team of physicians, nurses and technicians to be properly carried out. The institution, surgeons, and nursing department must understand this concept if the laparoscopic program is to be successful.


Prolonged cold storage diminishes the 5-hydroxytryptamine- and potassium chloride-mediated contractions of rat thoracic aorta.
Hypothermic preservation of the organ for transplantation causes vascular damage; therefore, the preservation of vascular function is important for the organs to function correctly after transplantation. The aim of the present study is to evaluate the influence of prolonged cold storage (72 hours) on vascular responses to 5-hydroxytryptamine (5-HT) and potassium chloride (KCl), each of which causes receptor-dependent and receptor-independent contractions, respectively. We also examined the protective roles of superoxide dismutase (SOD), L-arginine, the precursor of nitric oxide, iloprost, a synthetic analogue of prostaglandin I(2) with vasodilator functions, or endothelium removal for vascular responses. Endothelium-intact rings were prepared from the rat thoracic aorta, and stored at 4 degrees C for up to 72 hours in Krebs solution alone or Krebs solution that contains SOD, L-arginine or iloprost. The vascular responses were investigated daily. The Analysis of Variance (ANOVA) followed by Dunn test was used for statistical analysis. Being kept in cold in Krebs solution diminished the vascular responses to 5-HT and KCl. The presence of SOD in Krebs solution successfully prevented the decline in these responses, while iloprost or L-arginine partially restored them. In the endothelium-denuded rings, the 5-HT-induced contraction remained protected after 72 hours, whereas the KCl-induced contraction was partially restored. These results indicate that cold preservation declines the 5-HT and KCl-induced vascular responses, which can be partially prevented by iloprost or L-arginine, and can be restored by endothelium removal or SOD. Therefore, superoxide anion and endothelium-derived factors contribute to the decline in the contracting function of the aorta during prolonged cold storage.


Determinants of coronary blood flow after thrombolytic administration. TIMI Study Group. Thrombolysis in Myocardial Infarction.
This study evaluated the determinants of coronary blood flow following thrombolytic administration in a large cohort of patients. Tighter residual stenoses following thrombolysis have been associated with slower coronary blood flow, but the independent contribution of other variables to delayed flow has not been fully explored. The univariate and multivariate correlates of coronary blood flow at 90 min after thrombolytic administration were examined in a total of 2,195 patients from the Thrombolysis in Myocardial Infarction (TIMI) 4, 10A, 10B and 14 trials. The cineframes needed for dye to first reach distal landmarks (corrected TIMI frame count, CTFC) were counted as an index of coronary blood flow. The following were validated as univariate predictors of delayed 90-min flow in two cohorts of patients: a greater percent diameter stenosis (p < 0.0001 for both cohorts), a decreased minimum lumen diameter (p = 0.0003, p = 0.0008), a greater percent of the culprit artery distal to the stenosis (p = 0.03, p = 0.02) and the presence of any of the following: delayed achievement of patency (i.e., between 60 and 90 min) (p < 0.0001 for both cohorts), a culprit location in the left coronary circulation (left anterior descending or circumflex) (p = 0.02, p < 0.0001), pulsatile flow (i.e., reversal of flow in systole, a marker of heightened microvascular resistance, p = 0.0003, p < 0.0001) and thrombus (p = 0.002, p = 0.03). Despite a minimal 16.4% residual stenosis following stent placement, the mean post-stent CTFC (25.8 +/- 17.2, n = 181) remained significantly slower than normal (21.0 +/- 3.1, n = 78, p = 0.02), and likewise 34% of patients did not achieve a CTFC within normal limits (i.e., <28 frames, the upper limit of the 95th percent confidence interval previously reported for normal flow). Those patients who failed to achieve normal CTFCs following stent placement had a higher mortality than did those patients who achieved normal flow (6/62 or 9.7% vs. 1/118 or 0.8%, p = 0.003). Lumen geometry is not the sole determinant of coronary blood flow at 90 min following thrombolytic administration. Other variables such as the location of the culprit artery, the duration of patency, a pulsatile flow pattern and thrombus are also related to slower flow. Despite a minimal 16% residual stenosis, one-third of the patients treated with adjunctive stenting still have a persistent flow delay following thrombolysis, which carries a poor prognosis.


A nonterminal equine mandibular model of bone healing.
To develop a nonterminal large animal bone defect model for assessing the efficacy of regenerative and pharmacologic treatments designed to enhance bone healing. In vivo experimental. Adult gelding horses (n = 6). Under general anesthesia, using radiographic guidance, 13.5 mm diameter bilateral, full thickness mandibular defects were created in 6 horses using a custom surgical jig and coring bit. After 16 weeks, under general anesthesia, 23 mm diameter cores that encompassed the original healing defects and surrounding parent bone material were removed for evaluation. Oxytetracycline was administered 14 days before final core harvest to label bone-forming surfaces. Healing was qualitatively assessed from decalcified hematoxylin and eosin (H&E) stained and undecalcified fluorescent labeled sections. Trabecular to cortical bone fraction (Tb.V/Ct.V), bone volume fraction (BV/TV), tissue mineral density (TMD), and apparent bone mineral density (aBMD) were quantified using microcomputed tomography and compared between left and right sides using Wilcoxon signed rank test. BV/TV was not significantly different between left and right-sided defects. Bone deposition occurred centripetally from the border of the original defect, filling 67% ± 16% (SD) of the defect at 16 weeks. This model has potential use for comparison of regenerative and pharmacologic products aimed to augment bone healing.


Bone Marrow Findings of Immune-Mediated Pure Red Cell Aplasia Following Anti-Programmed Cell Death Receptor-1 Therapy: A Report of Two Cases and Review of Literature.
Immune checkpoint inhibitors have recently emerged as important and effective advanced cancer treatment options. Programmed cell death receptor-1 (PD-1) antagonists such as pembrolizumab and nivolumab have been approved by the US Food and Drug Administration for treatment of many advanced cancers. As anti-PD-1 checkpoint inhibitor use has been increasing, previously unreported rare side effects emerge. These checkpoint inhibitors upregulate humoral and cellular immune responses to tumor antigens. Consequently, they can be associated with immune-related adverse events including hematological-related reactions such as autoimmune hemolytic anemia, immune thrombocytopenia, neutropenia and pancytopenia. However, pure red cell aplasia (PRCA) induced by anti-PD-1 checkpoint inhibitors is rarely reported in the literature. We herein report cases of two patients who developed PRCA during treatment with anti-PD-1 checkpoint inhibitors. In both cases, a peripheral blood smear examination demonstrated reticulocytopenia. Bone marrow biopsies revealed severe erythroid hypoplasia with maturation arrest at the proerythroblast stage, relative granulocytic hyperplasia and lymphocytosis. Flow cytometry and immunohistochemistry revealed that the lymphocytes were predominantly CD8+ T cells. T lymphocytosis, especially in one of the two patients, mimicked a T-cell lymphoproliferative disorder; lack of clonality indicated a reactive process. Our findings, in addition to data presented in the literature, suggest that T cells play a critical role in the pathogenesis of immune-related PRCA. PRCA is an under-recognized immune-mediated adverse event that does not manifest during the clinical trial phase. It is a potentially life-threatening complication, which should be considered in the differential diagnosis of anemia in patients treated with anti-PD-1 checkpoint inhibitors.


The 'Zar' possession syndrome among Ethiopian immigrants to Israel: cultural and clinical aspects.
This article describes a cultural pattern related to altered states of consciousness, observed amongst new immigrants from Ethiopia in Israel. The belief in possession by Zar spirits is one of the most common possession phenomena in Africa and in other continents. Possession by Zar is expressed by a wide range of behaviours, such as involuntary movements (often resembling epileptiform convulsions), mutism and incomprehensible language. Such behaviour can be misinterpreted as representing symptoms of neurologic or psychiatric disorders. Such misinterpretation has led to inappropriate psychiatric admissions and to misdiagnosis of such cases as major psychiatric disorders. The article illustrates the Zar phenomenon by three clinical vignettes and discusses its cultural and anthropological aspects, as well as its clinical implications within a Western society.


Catecholestrogens induce oxidative stress and malignant transformation in human endometrial glandular cells: protective effect of catechol-O-methyltransferase.
Prolonged exposure to unopposed estrogens is a major risk factor for the development of endometrial cancer. Oxidative metabolism of estradiol (E(2)) into the catecholestrogens (CEs), 4-hydroxyestradiol (4-OHE(2)) and 2-hydroxyestradiol (2-OHE(2)), may play an important role in estrogen carcinogenicity. CEs can be oxidized to the corresponding ortho-quinone derivatives with concomitant formation of the reactive oxygen species (ROS). Catechol-O-methyltransferase (COMT) is the major enzyme involved in the detoxification of CEs in extrahepatic tissues. We investigated the potential of E(2), 2-OHE(2) and 4-OHE(2) to induce microsatellite instability (MSI) and neoplastic transformation of immortalized human endometrial glandular (EM) cells. We also investigated the functional significance of COMT gene expression on modulating the effects of E(2) and CEs in EM cells. Our data indicated that E(2) and 4-OHE(2) induce MSI, ROS and neoplastic transformation in EM cells. The capacity of E(2) and its catechol metabolites to induce MSI, ROS and neoplastic transformation in EM cells is ranked as follows: 4-OHE(2) > E(2) > 2-OHE(2). Knockdown of COMT expression in EM cells resulted in increased estrogenic milieu and increased estrogen-induced cell proliferation. More importantly, knockdown of COMT increased the propensity of E(2) or CEs to induce ROS, MSI and neoplastic transformation of EM cells. In contrast, overexpression of COMT in EM cells significantly reduced the cellular estrogenic milieu and protected against E(2)- or CEs-induced, ROS, MSI and neoplastic transformation. The capacity of E(2) or CEs to induce neoplastic transformation of human endometrial glandular cells in vitro may suggest that E(2)-induced endometrial cancer is mediated by its metabolism into CEs. Our study clearly indicates that COMT gene expression plays a critical role in modulating the hormonal and carcinogenic effects of E(2) and CEs and, consequently, modifies the risk for E(2)-induced endometrial cancer. To the best of our knowledge, this is the first study to (i) demonstrate the potential capacity of estrogen and its catechol metabolites to induce neoplastic transformation of immortalized human endometrial glandular cells; and (ii) illustrate the important role of COMT gene expression in protecting against E(2)-induced endometrial cancer.


Three molecular structures cause rhesus D category VI phenotypes with distinct immunohematologic features.
Rhesus D category VI (DVI) is the clinically most important partial D. DVI red blood cells were assumed to possess very low RhD antigen density and to be caused by two RHD-CE-D hybrid alleles. Because there was no population-based work-up, we screened three populations in central Europe for DVI. Twenty-six DVI samples were detected and examined by exon-specific RHD polymerase chain reaction with sequence-specific primers (PCR-SSP). A new genotype, hereby designated D category VI type III, was characterized as a RHD-Ce(3-6)-D hybrid allele by sequencing of the cDNA, parts of intron 1, and by PCR-restriction fragment length polymorphism (PCR-RFLP) of intron 2. Rhesus introns 5 and 6 were sequenced and the 3' breakpoints of all known DVI types shown to be distinct. We differentiated the 5' breakpoints of DVI type I and DVI type II by a newly devised RHD-PCR. Thus, the DVI phenotype originated in at least three independent molecular events. Each DVI type showed distinct immunohematologic features in flow cytometry. The number of RhD proteins accessible on the red blood cells' surface of DVI type III was normal (about 12,000 antigens/cell; DVI type I, 500; DVI type II, 2,400) based on the determination of an RhD epitope density profile. DVI type II and DVI type III occurred as CDe haplotypes, and DVI type I as a cDE haplotype. The distribution of the DVI types varied significantly in three German-speaking populations. Genotyping strategies should take account of allelic variations in partial RhD. The reconsideration of previous serologic and clinical data for partial D in view of the underlying molecular structures may be worthwhile.


[Detoxicating function of the placenta of childbearing women from ecologically unfavorable regions of the Ukraine].
A study of placental detoxifying activity was undertaken using as the investigated indices glutathione transferase and glutathione reductase activities and total amount of SH-groups and those of low-molecular weight thiols. Malonic dialdehyde content was used as a measure of lipid peroxidation. The placental samples were obtained in several regions of the Ukraine judged either "clean", chemically polluted or radioactively contaminated. In the samples from the "clean" region glutathione transferase and glutathione reductase activities as well as the total amount of SH-groups were higher than corresponding indices in ecologically unfavorable regions of the Ukraine. At radioactively heavily exposed women low glutathoione transferase activity combined with low content of SH-groups and pronounced increase of malonic dialdehyde. In the regions with the lower summary effective equivalent annual expositional doses the indices of placental glutathione status are more close to those characteristic for placenta from "clean" regions. The consequences of the more intensive but short exposure characteristic for the women evacuated from Pripyat on the second day after catastrophe were less manifest in the indices of the glutathione status. A decrease of glutathione transferase activity at chemically exposed women was in the range of the lowest values obtained for heavily radioactively exposed ones but differ by higher content of total SH-groups and low molecular weight thiols. The glutathione transferase activity of cytosol from the samples of chemically exposed women increased in vitro after their treatment with the reducing agent. More probable the different mechanisms underlie the similar reduce of glutahtione transferase activity in radioactively contaminated and chemically polluted regions of the Ukraine. The decreased activity of glutathione transferase activity in placenta correlated with the increased frequency of complications during the pregnancy and the delivery and with the worsening status of newborns.


Prostatic involution in rats induced by a novel 5 alpha-reductase inhibitor, SK&F 105657: role for testosterone in the androgenic response.
Within the prostate, androgen stimulates glandular cell secretion and proliferation while inhibiting glandular cell death. Due to its predominant nuclear localization, higher affinity for the androgen receptor, and more than 10-fold higher intracellular concentration than testosterone, dihydrotestosterone (DHT), not testosterone, appears to be the active intracellular androgen within the prostate of intact male hosts. The issue has remained unanswered, however, whether testosterone itself, without irreversible conversion to DHT by the 5 alpha-reductase enzyme, is capable of androgenic effects in the prostate. To address this issue, a novel dead end (i.e. product) inhibitor of the 5 alpha-reductase enzyme, SK&F 105657, was administered to intact or castrated male rats treated with either exogeneous testosterone or DHT. When administered twice a day orally at 25 mg/kg.dose, SK&F 105657 reduced the prostatic DHT content of either intact or castrated rats maintained with exogeneous testosterone to the same low level as that produced by surgical castration. Unlike castration, however, such SK&F 105657 treatment increased the prostatic testosterone content by more than 5-fold. The decrease in prostatic DHT coupled with a raise in testosterone are specifically due to the in vivo inhibition of the 5 alpha-reductase activity, since they were not observed in castrated rats maintained with exogeneous DHT. Treatment of intact or castrated male rats with exogeneous testosterone and oral SK&F 105657 (25 mg/kg, twice daily) resulted in a substantial inhibition of prostatic secretion, an inhibition of prostatic glandular cell proliferation, and an increase in prostatic glandular cell death. The magnitude of the changes, however, was not as great as that observed after surgical castration. The results are, however, specific for 5 alpha-reductase inhibition, since they were not observed in castrated rats given exogeneous DHT. These results demonstrate that if the prostatic testosterone content is elevated to sufficient levels, androgenic effects are induced without a requirement for an elevation in prostatic DHT content. Thus, the conversion of testosterone to DHT appears to function as a means of amplifying androgenic stimulation in the prostate.


[Clinico-morphologic results of laser myocardial revascularization in ischemic heart disease].
Transmyocardial laser revascularization was applied in 58 patients with ischemic heart disease. The objective criterion of the method efficiency was an increase in myocardium perfusion due to newly formed blood vessels under influence of laser irradiation. The laser treatment has improved cardiac function and general condition of the patients. The surgery did not exert considerable influence on the contractile capacity of the myocardium in the patients treated.