The natural history of ALS: Baseline characteristics from a multicenter clinical cohort.
Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed. The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant's electronic health record. Participant burden is therefore minimal. Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database. ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants.Key MessagesWhat is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population.What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures.How this study might affect research, practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.


Trichoderma asperellum (T42) and Pseudomonas fluorescens (OKC)-Enhances Resistance of Pea against Erysiphe pisi through Enhanced ROS Generation and Lignifications.
Plant signaling mechanisms are not completely understood in plant-fungal biotrophic pathogen interactions. Further how such interactions are influenced by compatible rhizosphere microbes are also not well-studied. Therefore, we explored the pea-Erysiphe pisi (obligate biotroph) system to understand the interaction and applied compatible rhizospheric bio-agents Trichoderma asperellum (T42) and Pseudomonas fluorescens (OKC) singly or in combination to assess their influence on the host while under the pathogen challenge. Transcript accumulation pattern of some vital genes in the lignin biosynthetic pathway in pea under E. pisi challenge indicated enhanced activation of the pathway. Interestingly, transcript accumulations were even higher in the bio-agent treated plants compared to untreated plants after pathogen inoculation particularly in co-inoculated treatments. Further, down regulation of the lignifications-associated ABC transporter gene in the pathogen challenged plants possibly is an indication of passive diffusion of monolignols across the membrane from symplast. Additionally, up regulation of NADPH oxidase gene revealed ROS generation in the challenged plants which was confirmed through spectrophotometric estimation of H2O2. Up regulation of laccase and peroxidase along with higher H2O2 generation points out their involvement in lignifications which was further confirmed through cross section analysis of pea stems that showed increased lignifications in pathogen challenged plants co-inoculated with the bioagents. Interestingly, pathogen responsive MAPK homologs MAPK3/MAPK6 and the enzyme serine threonine kinase that activates MAPKs were down regulated and the results possibly indicate non-participation of the MAPK cascade in this interaction. Therefore, it can be concluded that the microbial treatments enhanced pea resistance to E. pisi by generation of ROS and lignifications.


Assessment of ecologic and biologic factors leading to hantavirus pulmonary syndrome, Colorado, U.S.A.
To understand the ecologic parameters of Sin Nombre virus (SNV; family Bunyaviridae, genus Hantavirus) infections in the deer mouse (Peromyscus maniculatus), environmental variables impacting the rodent populations, and the conditions under which SNV is amplified. This may help us understand the antecedents of human risk for developing hantavirus pulmonary syndrome (HPS) as a consequence of SNV infection. Each 6 weeks, we trapped, measured, tagged, bled, and released rodents at three widely spaced sites in Colorado, USA: Fort Lewis (1994-2001), Molina (1994-2001), and Pinyon Canyon Maneuver Site (1995-2001). The ELISA method was used to test rodent blood samples for IgG antibody to SNV antigen. Where rodent species richness was high, the prevalence of infection of deer mice (as determined by the presence of antibody) with SNV was low, and vice versa. There was a higher prevalence of antibody to SNV in male than in female rodents, and seasonal differences were observed in acquisition of SNV between male and female deer mice. Long-lived infected deer mice served as transseasonal, over-winter reservoirs for the virus, providing the mechanism for its survival. Prevalence of rodent infection appears to be associated with fluctuations in deer mouse populations and, indirectly, with timing and amount of precipitation and the resulting biologic events (a trophic cascade). Together with information regarding transseasonal maintenance of SNV, seasonal differences in acquisition of SNV between sexes, group foraging, and various other factors may expand our understanding of the risk factors for acquiring HPS. Taken together and applied, we anticipate developing methods for preventing this disease as well as diseases caused by other rodent-borne viruses.


Modeling the inhibition of the bacteral reduction of U(VI) by beta-MnO2(s).
Pyrolusite (beta-MnO2(s)) was used to assess the influence of a competitive electron acceptor on the kinetics of reduction of aqueous uranyl carbonate by a dissimilatory metal-reducing bacterium (DMRB), Shewanella putrefaciens strain CN32. The enzymatic reduction of U(VI) and beta-MnO2(s) and the abiotic redox reaction between beta-MnO2(s) and biogenic uraninite (UO2(s)) were independently investigated to allow for interpretation of studies of U(VI) bioreduction in the presence of beta-MnO2(s). Uranyl bioreduction to UO2(s) by CN32 with H2 as the electron donor followed Monod kinetics, with a maximum specific reduction rate of 110 M/h/10(8) cells/mL and a half-saturation constant of 370 microM. The bioreduction rate of beta-MnO2(s) by CN32 was described by a pseudo-first-order model with respect to beta-MnO2(s) surface sites, with a rate constant of 7.92 x 10(-2) h(-1)/10(8) cells/mL. Uraninite that precipitated as a result of microbial U(VI) reduction was abiotically reoxidized to U(VI) by beta-MnO2(s), with concomitant reduction to Mn(II). The oxidation of biogenic UO2(s) coupled with beta-MnO2(s) reduction was well-described by an electrochemical model. However, a simple model that coupled the bacterial reduction of U(VI) and beta-MnO2(s) with an abiotic redox reaction between UO2(s) and beta-MnO2(s) failed to describe the mass loss of U(VI) in the presence of beta-MnO2(s). Transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS) revealed that the particle size and spatial distribution of the biogenic UO2(s) changed dynamically in systems with, as compared to without, beta-MnO2(s)). These observations suggested that the surface properties and localization of UO2(s) in relation to the cell and beta-MnO2(s) surfaces was an important factor controlling the abiotic oxidation of UO2(s) and, thus, the overall rate and extent of U(VI) bioreduction. The coupled model that was modified to account for the "effective" contact surface area between UO2(s) and beta-MnO2(s) significantly improved the simulation of microbial reduction of U(VI) in the presence of beta-MnO2(s).


miR‑24 may be a negative regulator of menin in lung cancer.
The incidence of lung cancer in China increases annually, and effective targets for the diagnosis and treatment of lung cancer are urgently needed. miRNAs are currently considered to be involved in the regulation of tumor development and growth. miR‑24 has been found to contribute to the development of several tumors. Menin is a key tumor suppressor gene, and its expression is generally low in lung cancer. The effects of miR‑24 on the biological behavior of lung cancer cells were detected by MTT and Transwell assays. In the present study, miR‑24 was found to be associated with menin, affecting the activity of the SMAD3 pathway in lung cancer by inhibiting menin expression. miR‑24 may promote the growth and metastasis and inhibit the apoptosis of lung cancer cells by targeting menin. Therefore, the aim of the present study was to provide a new theoretical basis for the targeted therapy of lung cancer.


Multimodality imaging assessment of mitral valve anatomy in planning for mitral valve repair in secondary mitral regurgitation.
Secondary mitral regurgitation (MR) is frequent valvular heart disease and conveys worse prognostic. Therapeutic surgical or percutaneous options are available in the context of severe symptomatic secondary MR, but the best approach to treat these patients remains unclear, given the lack of clear clinical evidence of benefit. A comprehensive evaluation of the mitral valve apparatus and the left ventricle (LV) has the ability to clearly define and characterize the disease, and thus determine the best option for the patient to improve its clinical outcomes, as well as quality of life and symptoms. The current report reviews the mitral valve (MV) anatomy, the underlying mechanisms associated with secondary MR, the related therapeutic options available, and finally the usefulness of a multimodality imaging approach for the planning of surgical or percutaneous mitral valve intervention.


Effect of passive immunization against corticotropin-releasing factor (CRF) on the postadrenalectomy changes of CRF binding sites in the rat anterior pituitary gland.
The concentration of corticotropin-releasing factor (CRF)-binding sites decreases in the rat anterior pituitary after adrenalectomy; this change may be related either to a direct effect of the circulating glucocorticoids at the pituitary level or to a desensitization of CRF receptors through an increased CRG release in hypophysial portal blood. In order to examine the latter possibility we have measured plasma adrenocorticotropin hormone (ACTH) levels and the number of anterior pituitary CRF binding sites in sham-operated and 24-hour adrenalectomized rats after blockade of endogenous CRF by passive immunization with an antiserum anti-rat CRF (CRF-AS), or after injection of normal rabbit serum (NRS). In NRS-injected rats, after sham operation, plasma ACTH concentration increased (227 +/- 34 vs. 118 +/- 19 pg/ml in controls) without change in CRF-binding sites capacity (20.7 +/- 2.6 vs. 24.6 +/- 3.5 fmol/mg protein in controls). Adrenalectomy induced a large rise in plasma ACTH (785 +/- 89 pg/ml) and a decrease in the number of CRF-binding sites (12.2 +/- 1.7 fmol/mg protein). After CRF-AS injection, plasma ACTH was normalized in sham-operated animals (149 +/- 24 pg/ml) and significantly reduced in adrenalectomized rats (472 +/- 76 pg/ml); the adrenalectomy-induced decrease in the number of CRF-binding sites was unaffected by the CRF-AS administration (12.2 +/- 1.7 fmol/mg protein). The administration of dexamethasone to adrenalectomized rats significantly reduced plasma ACTH concentrations (23.3 +/- 10.6 pg/ml) and prevented the loss in CRF-binding sites capacity (20.7 +/- 1.3 fmol/mg protein).(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibition of P-glycoprotein and recovery of drug sensitivity of human acute leukemic blast cells by multidrug resistance gene (mdr1) antisense oligonucleotides.
To overcome the problem of multidrug resistance, we investigated the effectiveness of phosphrothioate antisense oligonucleotides (MDR1-AS) in suppressing multidrug resistance gene (mdr1) expression in drug-resistant acute myelogenous leukemia (AML) blast cells and the K562 adriamycin-resistant cell line K562/ADM. The percentage of cells with the mdr1 gene product P-glycoprotein (P-gp) was decreased from 100% to 26% by 20 micromol/L MDR1-AS in the K562/ADM cells, and from 48.1% to 10.2% by 2.5 micromol/L MDR1-AS in the AML blast cells. Western blot analysis also showed a decrease in the amount of P-gp in the MDR1-AS-treated K562/ADM cells. This effect was specific to MDR1-AS, and not observed with sense or random control oligonucleotides. The expression of mdr1 mRNA in K562/ADM and AML blast cells treated with MDR1-AS was decreased compared with the random control. Intracellular rhodamine retention and [3H]daunorubicin also increased after antisense treatment. Chemosensitivity to daunorubicin increased in MDR1-AS-treated blast cells up to 5.9-fold in the K562/ADM cells and 3.0- to 6.4-fold in the AML blast cells. The expression of mdr1 mRNA derived from colony cells decreased in the MDR1-AS-treated groups. No inhibitory effect of the oligonucleotides on normal bone marrow progenitors was observed. These findings suggest that MDR1-AS is useful to overcome multidrug resistance in the treatment of leukemia.


Magnetically driven second-harmonic generation with phase matching in MnWO₄.
Phase matching is known to enhance the nonlinear optical response in materials with a non-centrosymmetric crystallographic or electronic structure. In contrast, phase-matched frequency doubling driven by non-centrosymmetric magnetism that induces acentricity in otherwise centrosymmetric structures has not been reported yet. In our study we demonstrate the emergence of magnetically driven second-harmonic generation (SHG) with phase matching in MnWO4. The phase-matched wavelength for SHG can be tuned continuously between 450 nm to 630 nm with the conversion efficiency being determined by the refractive indices and their dispersion. Our findings reveal a new strategy towards magnetism-based conversion-materials and a route for controlling the nonlinear signal yield by acting primarily on the material's spin degree of freedom rather than employing its electronic or structural properties.


Cell adhesion behavior of chitosan surface modified by bonding 2-methacryloyloxyethyl phosphorylcholine.
2-Methacryloyloxyethyl phosphorylcholine (MPC)-bonded chitosan was prepared by Michael addition of MPC to the amino groups of chitosan. The modified surfaces were characterized by static contact angle and electron spectroscopy for chemical analysis (ESCA). The water contact angle of chitosan decreased with the MPC bonding and the rate of decrease depended on the amount of MPC bonding. ESCA analysis results proved that MPC had been bonded on the chitosan surface and the chitosan modified directly by MPC had a much higher concentration of MPC on the surface compared with that of MPC on chitosan modified indirectly by MPC. Cell adhesion tests indicated that a low concentration of MPC bonded chitosan was more favorable to cell adhesion while a high concentration of MPC bonded chitosan inhibited cell attachment.


Chemical constituents of the style of Zea mays L. with glycation inhibitory activity.
A new sesquiterpene along with 15 known compounds were isolated from the style of Zea mays L. These structures were elucidated on the basis of spectroscopic analysis. The ability of these compounds to inhibit glycation in vitro was analyzed. This allowed determination of chemical functional groups required for the inhibition of glycation.


Porous metal-organic truncated octahedron constructed from paddle-wheel squares and terthiophene links.
A metal-organic truncated octahedron (termed MOP-28) has been constructed from six rigid square-shaped Cu2(CO2)4 paddle-wheel building units and twelve 2,2':5',2' '-terthiophene-5,5' '-dicarboxylate (TTDC) linkers. TTDC linker in the cis,cis conformation provides the critical 90 degrees linkage for this unique construction. The porous structure of MOP-28 is maintained even after the removal of guest species, as evidenced by this compound's nitrogen sorption isotherm of Type I characteristics and unprecedented surface area (Langmuir surface area 1100 m2/g, BET surface area 914 m2/g) among materials composed of discrete molecules.


Production of cellulose microfibrils by Rhizobium.
Electron microscope examination of Rhizobium spp. revealed microfibrils produced by flocculating strains but not by nonflocculating strains. The microfibrils from R. trifolii (NA30) were isolated and identified as cellulose by enzymatic, X-ray diffraction, and infrared spectral analyses. Both infective and noninfective strains of R. trifolii flocculated and produced microfibrils. More infection threads were observed in clover root hairs growing in the presence of flocs in comparison with root hairs where single bacterial cells predominated.


Sodium-glucose co-transporter 2 inhibitors and Sarcopenia: A controversy that must be solved.
Diabetes mellitus is a risk factor for muscle loss and sarcopenia. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) or "gliflozins" are one of the newest anti-hyperglycemic drugs. They reduce blood glucose levels by inhibiting renal glucose reabsorption in the early proximal convoluted tubule. Various randomized trials showed that SGLT2i have cardio-protective and reno-protective action. SGLT2i also affect body composition. They usually decrease body fat percentage, visceral and subcutaneous adipose tissue. However, regarding the muscle mass, there are conflicting findings some studies showing detrimental effects and others showed neutral or beneficial effects. This issue is extremely important not only because of the wide use of SGLT2i around globe; but also skeletal muscle mass consumes large amounts of calories during exercise and is an important determinant of resting metabolic rate and skeletal muscle loss hinders energy consumption leading to obesity. In this systematic review, we extensively reviewed the experimental and clinical studies regarding the impact of SGLT2i on muscle mass and related metabolic alterations. Importantly, studies are heterogeneous and there is unmet need to highlight the alterations in muscle during SGLT2i use.


BCR mediated signal transduction in immature and mature B cells.
Ligation of B cell receptors (BCR) on immature B cells may induce apoptosis, while in mature B cells it stimulates cell activation and growth. The signaling pathway regulating the differential functional response, death or survival of the B cell is not fully characterized. We have tested the intracellular signaling requirement of these processes using B cells isolated from the spleen of irradiated auto-reconstituted (transitional immature B cells) and untreated mice (mature B cells), respectively. We compared the BCR induced intracellular [Ca2+] transient, protein tyrosine phosphorylation and ERK phosphorylation, furthermore, the activation of Elk-1 and CREB transcription factors. The BCR induced rise of intracellular [Ca2+] did not significantly differ in the two populations, only a slight difference in the late phase of the response was observed. Immature B cells responded with a maximum tyrosine phosphorylation to a five times lower dose of anti-IgM compared to the mature population. Most importantly, we have found a significant difference in the tyrosine phosphorylation of the Gab family adaptor proteins, Gab1/2. In contrast to mature B cells, crosslinking of BCR on immature B cells did not induce tyrosine phosphorylation of Gab2, thus the Gab2-organized signal amplification complex could not be produced. Furthermore, we detected a significant difference in the kinetics of BCR induced ERK, Elk-1 and CREB phosphorylation. In immature B cells, ERK was transiently phosphorylated, ceasing after 120 min, while in mature cells, ERK phosphorylation was sustained. Elk-1 and CREB activation was also transient in immature B cells, followed the kinetics of ERK phosphorylation. The lack of sustained Erk1/2 activation suppresses the transcription factors necessary for the proliferation signal. Since ERK is regulated by the phosphorylated Gab1/2, these data demonstrate that BCR triggered phosphorylation and signal amplification of Gab1/2 is a critical step in a life or death decision of B cells.


Effect of multiple application of dentin bonding agent on marginal integrity of resin composite.
The purpose of the present study was to examine the effect of multiple application of dentin bonding agent to the adhesive surface on the marginal integrity of resin composite. The effect of multiple applications was evaluated by measuring the wall-to-wall polymerization contraction gap and by SEM observation. Multiple application of dentin bonding agent was found to prevent formation of the contraction gap. Although monomer penetration into the enlarged collagen network has been widely discussed as the possible mechanism of the dentin bonding agent and dentin primer, the true detailed mechanism of the dentinal bonding agent and dentin primer should be consistently explained by the prevention of monomer diffusion into the dentin and water contamination of the adhesive interface.


Potential of eye movement desensitization and reprocessing therapy in the treatment of post-traumatic stress disorder.
Post-traumatic stress disorder (PTSD) continues to attract both empirical and clinical interest due to its complex symptom profile and the underlying processes involved. Recently, research attention has been focused on the types of memory processes involved in PTSD and hypothesized neurobiological processes. Complicating this exploration, and the treatment of PTSD, are underlying comorbid disorders, such as depression, anxiety, and substance use disorders. Treatment of PTSD has undergone further reviews with the introduction of eye movement desensitization and reprocessing (EMDR). EMDR has been empirically demonstrated to be as efficacious as other specific PTSD treatments, such as trauma-focused cognitive behavioral therapy. There is emerging evidence that there are different processes underlying these two types of trauma treatment and some evidence that EMDR might have an efficiency advantage. Current research and understanding regarding the processes of EMDR and the future direction of EMDR is presented.


Lipid mobility and order in bovine rod outer segment disk membranes. A spin-label study of lipid-protein interactions.
Lipid-protein interactions in bovine rod outer segment disk membranes have been studied by using a series of eight stearic acid spin-label probes which were labeled at different carbon atom positions in the chain. In randomly oriented membrane dispersions, the electron spin resonance (ESR) spectra of the C-8, C-9, C-10, C-11, C-12, C-13, and C-14 atom positional isomers all apparently consist of two components. One of the components corresponds closely to the spectra obtained from dispersions of the extracted membrane lipids, and the other, which is characterized by a considerably greater degree of motional restriction of the lipid chains, is induced by the presence of the protein. Digital subtraction has been used to separate the two components. The proportion of the motionally restricted lipid component is approximately constant, independent of the position of the spin-label group, and corresponds to 30-40% of the total spin-label spectral intensity. The hyperfine splitting of the outer maxima in the difference spectra of the motionally restricted component decreases, and concomitantly, the line widths increase with increasing temperature but change relatively little with increasing distance of the spin-label group from the polar head-group region. This indicates that the corresponding chain motions of the protein-interacting lipids lie in the slow-motion regime of spin-label ESR spectroscopy (tau R approximately 10(-8) S) and that the mobility of these lipids increases with increasing temperature but does not vary greatly along the length of the chain. The data from the hyperfine splittings also suggest the existence of a polarity gradient immediately adjacent to the protein surface, as observed in the fluid lipid regions of the membrane. The more fluid lipid component is only slightly perturbed relative to the lipids alone (for label positions 5-14, inclusive), indicating the presence of chain motions on the nanosecond time scale, and the spectra also reveal a similar polarity profile in both lipid and membrane environments. ESR spectra have also been obtained as a function of magnetic field orientation with oriented membrane samples. For the C-14 atom positional isomer, the motionally restricted component is observed to have a large hyperfine splitting, with the magnetic field oriented both parallel and perpendicular to the membrane normal. This indicates that the motionally restricted lipid chains have a broad distribution of orientations at this label position.(ABSTRACT TRUNCATED AT 400 WORDS)


Virus-like particle formation of Drosophila copia through autocatalytic processing.
Northern blot and nucleotide sequence analyses of copia RNA from a transfectant made by introducing a genomic copia into copia-free cells showed that the 2 kb RNA, one of the major transcripts of copia, is generated through splicing. Using the polymerase chain reaction (PCR), we have also found that the position of the splice sites used in Drosophila larvae and cultured cells originally containing copia is the same as that used in the transfectant. To investigate the function of the 2 kb RNA, we constructed mutant copias which harboured a single point mutation at the splice site or approximately 3 kb deletion of the internal region corresponding to the spliced out sequence. Analyses of transfectants made by introducing these mutant copias into copia-free cells demonstrated that the spliced 2 kb RNA contains sufficient information to make copia virus-like particles (VLPs). Furthermore, when copia RNA corresponding to the spliced RNA was translated in vitro, the major VLP protein was found to be released autocatalytically from its own precursor. A single amino acid substitution at the putative protease active site in the precursor prevented the processing, and resulted in accumulation of the mutant precursor in vitro. From these results, we conclude that copia VLPs are produced through autocatalytic processing of the precursor polyprotein encoded by the spliced copia RNA.


HLA antigens in methotrexate-induced liver cirrhosis.
HLA typing was carried out in 20 psoriatics with methotrexate-induced liver cirrhosis and 44 methotrexate-treated psoriatics who at the time of investigation had not developed cirrhosis. The data were compared with results from tissue typing of 1291 healthy individuals. The antigen combination A1, B8 was found to be increased among patients with cirrhosis vis-à-vis methotrexate-treated psoriatics who did not develop liver cirrhosis. This finding is similar to data on chronic active hepatitis type A and drug-associated chronic active hepatitis. Findings of the antigen combination A1, B8 should--just as with other predisposing factors--lead to caution in liver control in psoriatics on methotrexate therapy.


Susceptibility of Escherichia coli to nitroxoline, an option for uncomplicated urinary tract infections - the first report from Croatia.
Nitroxoline (NTX), 5-nitro-8-hydroxyquinoline is an oral antibiotic with mechanism of bacteriostatic activity that is based on chelation of divalent cations required for bacterial RNA polymerase. Susceptibility to NTX of 100 Escherichia coli urine isolates was determined at the Department of Clinical and Molecular Microbiology, University Hospital Centre Zagreb during September and October 2017. Antimicrobial susceptibility was tested by disc diffusion and the results were interpreted according to the European Committee for Antimicrobial Susceptibility Testing (EUCAST) standards. All E. coli isolates, including ESBL-positive ones, were fully susceptible to imipenem, meropenem, amikacin, fosfomycin and NTX. This is the first report from Croatia about sensitivity of E. coli isolates to NTX. Besides fosfomycin, NTX was the only antimicrobial drug available for peroral administration demonstrating the sensitivity for all tested isolates. The results of the study demonstrated the potential of NTX as an additional therapeutically applicable option for the treatment of uncomplicated UTI.


Intravesical anesthesia for bladder tissue biopsies. Comparison of two methods.
To estimate the level of analgesia which can be obtained with simple intravesical instillation of ropivacaine in comparison to the combination of both instillation and subepithelial injection of the same agent. Fifty-two patients were randomized in order that half (26) of them received simple intravesical instillation of ropivacaine (100 mL solution of ropivacaine in a concentration of 2 mg/mL) (Group A), whereas the other 26 patients received both intravesical instillation and subepithelial injection of 2 mL (4 mg) at the site of biopsy (Group B). In both groups, tissue samples were obtained from urinary bladder (number of biopsies from 3 to 4). The pain during the procedure was estimated by using the Visual Analogue Scale (VAS) which ranged from 0 to 10. The entire procedure was integrated with success in 50 out of 52 patients. The VAS score for the Group A ranged from 4 to 6 (mean 5.08), whereas for Group B from 1 to 3 (mean 1.6). (p<0.0001). Higher values of VAS score were recorded in males in both Groups (p<0.05). When complications of this method produced a slight bleeding (hematuria) in 6 patients (2 from group B and 4 from group A), they were treated with oral administration of fluids. Allergic reactions were not recorded. Hospitalization did not exceed 3 hours after the procedure. The analgesic effect that was obtained with the combination of intravesical instillation and subepithelial injection of ropivacaine provides a safe method of anesthesia for transurethral bladder biopsy.


Appraising Nigeria's approach to combating antimicrobial resistance.
Antibiotic consumption has increased dramatically in recent years, and this increase is predominantly fuelled by low- and middle-income countries. This is a worrying report, as antimicrobial resistance (AMR) is primarily driven by antibiotic consumption. To combat AMR, the Nigerian Ministry of Health established the Antimicrobial Resistance Technical Working Group (AMR-TWG), which developed and implemented the National Action Plan on Antimicrobial Resistance. This study aims to identify and appraise the current situation in the fight against AMR in Nigeria. This study contains a qualitative descriptive assessment of the advancements and the present status of efforts to combat AMR in Nigeria following the execution of the 2017-2022 National Action Plan (NAP) for AMR. The data for this study is soured primarily from the official national policy document on AMR and the responses of the Tracking AMR Country Self-assessment Survey (TrACSS). The results from this study reveal that there have been significant efforts aimed at addressing AMR in Nigeria. These efforts have been focused on improving public awareness of AMR, improving One Health surveillance of AMR, improving infection prevention and control, improving antimicrobial stewardship practices in the country, and investing in research on AMR. However, significant gaps still exist in each of these focus areas that can potentially undermine the attempts that have been made hitherto. Nigeria's commitment to the fight against AMR, as exemplified by the 2017-2022 National Action Plan, needs to be sustained and reinforced to safeguard public health and promote responsible antimicrobial use.


Combinatorial gene regulation by modulation of relative pulse timing.
Studies of individual living cells have revealed that many transcription factors activate in dynamic, and often stochastic, pulses within the same cell. However, it has remained unclear whether cells might exploit the dynamic interaction of these pulses to control gene expression. Here, using quantitative single-cell time-lapse imaging of Saccharomyces cerevisiae, we show that the pulsatile transcription factors Msn2 and Mig1 combinatorially regulate their target genes through modulation of their relative pulse timing. The activator Msn2 and repressor Mig1 showed pulsed activation in either a temporally overlapping or non-overlapping manner during their transient response to different inputs, with only the non-overlapping dynamics efficiently activating target gene expression. Similarly, under constant environmental conditions, where Msn2 and Mig1 exhibit sporadic pulsing, glucose concentration modulated the temporal overlap between pulses of the two factors. Together, these results reveal a time-based mode of combinatorial gene regulation. Regulation through relative signal timing is common in engineering and neurobiology, and these results suggest that it could also function broadly within the signalling and regulatory systems of the cell.


On the relationship between pinning control effectiveness and graph topology in complex networks of dynamical systems.
This paper concerns pinning control in complex networks of dynamical systems, where an external forcing signal is applied to the network in order to align the state of all the systems to the forcing signal. By considering the control signal as the state of a virtual dynamical system, this problem can be studied as a synchronization problem. The main focus of this paper is to study how the effectiveness of pinning control depends on the underlying graph. In particular, we look at the relationship between pinning control effectiveness and the complex network asymptotically as the number of vertices in the network increases. We show that for vertex balanced graphs, if the number of systems receiving pinning control does not grow as fast as the total number of systems, then the strength of the control needed to effect pinning control will be unbounded as the number of vertices grows. Furthermore, in order to achieve pinning control in systems coupled via locally connected graphs, as the number of systems grows, both the pinning control and the coupling among all systems need to increase. Finally, we give evidence to show that applying pinning control to minimize the distances between all systems to the pinned systems can lead to a more effective pinning control.


Management of Choledochal Cysts at a Tertiary Care Centre: A Nine-Year Experience from India.
Although choledochal cyst disease is seen predominantly in childhood, it is becomingly increasingly diagnosed in adult patients. Data of 36 patients with choledochal cysts managed in our institute between January 2010 and December 2018 were retrospectively analyzed. Median age at presentation was 37 years (range: 13-72 years). Female-to-male ratio was 3.5 : 1. All patients were symptomatic, and abdominal pain was the most common symptom. 72.2% had other associated conditions. There was a considerable delay from the onset of symptoms to referral, median duration being 348 days. There were 28 cases of type I (77.8%), 5 cases of type IVA (13.9%), and 3 cases of type IVB (8.3%). Cyst excision with Roux-en-Y hepaticojejunostomy was performed in 29 (80.55%) cases. This procedure was combined with a left lateral sectionectomy, left hepatectomy, and radical cholecystectomy in 1, 2, and 1 cases, respectively. Lilly's technique was used in 2 cases, and cyst excision with hepaticoduodenostomy was performed in 1 case. Early complications were seen in 21 patients (58.3%), and late complications were seen in 5 patients (13.8%). 2 patients were found to have associated malignancies. One patient was detected to have cholangiocarcinoma in the resected liver incidentally, and another patient was diagnosed to have gall bladder cancer intraoperatively. Choledochal cysts should be considered in the differential diagnosis of adults presenting with epigastric or right hypochondrium pain or jaundice. A thorough preoperative evaluation is required. Cyst excision with Roux-en-Y hepaticojejunostomy forms the standard treatment in most cases. Long-term follow-up is essential for management of complications and early detection of malignant change.


Evaluation of Broadly Neutralizing Antibody Sensitivity by Genotyping and Phenotyping for Qualifying Participants to HIV Clinical Trials.
HIV envelope (env) diversity represents a significant challenge for the use of broadly neutralizing antibodies (bNAbs) in HIV treatment and cure studies. Screening for viral sensitivity to bNAbs to select eligible trial participants will be important to improve clinical efficacy; however, no universal approach has been established. Pre-antiretroviral therapy plasma virus from participants in the Zurich Primary HIV Infection (ZPHI) study was genotyped and phenotyped for sensitivity to the bNAbs elipovimab (EVM, formerly GS-9722) and 3BNC117. The genotyping and phenotyping assessments were performed following the Clinical Laboratory Improvement Amendments of 1988 guidelines as required for entry into clinical trials. The genotypic-based prediction of bNAb sensitivity was based on HIV env amino acid signatures identified from a genotypic-phenotypic correlation algorithm using a subtype B database. Genotyping the plasma virus and applying env sensitivity signatures, ZPHI study participants with viral sensitivity to EVM and 3BNC117 were identified. ZPHI study participants with virus sensitive to EVM and 3BNC117 were also identified by phenotyping the plasma virus. Comparison of the genotypic and phenotypic sensitivity assessments showed strong agreement between the 2 methodologies. The genotypic assessment was found to be as predictive as the direct measurement of bNAb sensitivity by phenotyping and may, therefore, be preferred because of more rapid turnaround time and assay simplicity. A significant number of the participants were predicted to have virus sensitive to EVM and 3BNC117 and could, thus, be potential participants for clinical trials involving these bNAbs.


Adipose tissue dysfunction as a central mechanism leading to dysmetabolic obesity triggered by chronic exposure to p,p'-DDE.
Endocrine-disrupting chemicals such as p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), are bioaccumulated in the adipose tissue (AT) and have been implicated in the obesity and diabetes epidemic. Thus, it is hypothesized that p,p'-DDE exposure could aggravate the harm of an obesogenic context. We explored the effects of 12 weeks exposure in male Wistar rats' metabolism and AT biology, assessing a range of metabolic, biochemical and histological parameters. p,p'-DDE -treatment exacerbated several of the metabolic syndrome-accompanying features induced by high-fat diet (HF), such as dyslipidaemia, glucose intolerance and hypertension. A transcriptome analysis comparing mesenteric visceral AT (vAT) of HF and HF/DDE groups revealed a decrease in expression of nervous system and tissue development-related genes, with special relevance for the neuropeptide galanin that also revealed DNA methylation changes at its promoter region. Additionally, we observed an increase in transcription of dipeptidylpeptidase 4, as well as a plasmatic increase of the pro-inflammatory cytokine IL-1β. Our results suggest that p,p'-DDE impairs vAT normal function and effectively decreases the dynamic response to energy surplus. We conclude that p,p'-DDE does not merely accumulate in fat, but may contribute significantly to the development of metabolic dysfunction and inflammation. Our findings reinforce their recognition as metabolism disrupting chemicals, even in non-obesogenic contexts.


Nanomechanical Encoding Method Using Enhanced Thermal Concentration on a Metallic Nanobridge.
We present a fast, energy-efficient nano-thermomechanical encoding scheme for digital information storage and retrieval. Digital encoding processes are conducted by the bistable electrothermal actuation of a scalable nanobridge device. The electrothermal energy is highly concentrated by enhanced electron/phonon scattering and heat insulation in a sub-100 nm metallic layer. The efficient conversion of electrothermal energy into mechanical strain allows digital switching and programming processes within 60 ns at 0.75 V with a programming energy of only 54 pJ. Furthermore, this encoding scheme together with the thermally robust design enables data retention at temperatures up to 400 °C. These results suggest that the proposed nano-thermomechanical encoding method could contribute to low-power electronics and robust information storage/retrieval systems.


Double-looped Mach-Zehnder interferometer for achieving multiple ring-down interferograms.
We put forward a double-looped Mach-Zehnder interferometer for acquiring continuous ring-down interferograms with two fiber-loop cavities with slightly different optical path lengths. Each group of pulses through the sample and reference loops creates a ring-down pulse train with equal time intervals in Vernier fashion, and interferes with each other to produce multiple ring-down interferograms successively by scanning of a delay line. The system requires a scanning range of only a few millimeters to obtain multiple ring-down interferograms. In a proof-of-concept demonstration, the intrinsic losses of two loops are estimated. The measured combined-loss of both loops is compared to the sum of the loop losses measured separately with a conventional fiber-loop ring-down system. The result obtained using the proposed system exhibits a difference of only 0.06 dB with that of the reference system.


[Gender and medical communication--a review].
Communication is a central part of physicians' professional activities. Encounters with good physician-patient communication have been shown to be associated with a higher degree of exchange of information, patient satisfaction, compliance and a more favourable symptoms'course, and with a lower frequency of wrong diagnoses. Gender differences in verbal behaviour and language use have been observed among physicians with regard to form and content of questions, informational manner, partnership building in the physician-patient relation, emotionally focused talk, as well as with regard to length of speech and of visits. Patient gender is associated with the readiness to discuss health issues, with experiencing health and diseases, and with variability of symptom descriptions. Gender constellations have an impact on content and interaction of discourse. Introducing a "second gender thought" on whether patient gender or own gender representations may have influenced diagnostic or therapeutic decisions might help to eventually modify such impact.


Type 2 diabetes with hypertensive patients results in changes to features of adipocytokines: Leptin, Irisin, LGR4, and Sfrp5.
The incidence of hypertension and diabetes is increasing, it is reported that adipocytokines might be involved in the pathogenesis of diabetes and hypertension. We aimed to investigate the features of adipocytokines, included of Leptin, Irisin, LGR4, and Sfrp5 in type 2 diabetes mellitus (T2DM) patients with hypertension, simultaneously analyzed the connection of the alteration of adipocytokines with blood pressure and glucose. 424 patients with T2DM and 90 healthy subjects were included in the study. The patients with T2DM were divided into 4 groups based on the blood pressure. The levels of adipocytokines (Leptin, Irisin, LGR4, and Sfrp5) were determined by enzyme-linked immunosorbent assay (ELISA). Significantly higher levels of Leptin and lower levels of Irisin, LGR4 and Sfrp5 were seen in patients with diabetes compared with non-diabetes (P < 0.05), the mean values of Leptin level was ascending and Irisin, LGR4, and Sfrp5 levels were declining with promoting of blood pressure in hypertension as compared to the non-hypertension with diabetic patients. Multiple stepwise linear regression analysis showed that the concentrations of Leptin, Irisin, Sfrp5, and LGR4 were found to be closely associated with the control of blood pressure and glucose. Conclusion: Four adipocytokines might play different roles and closely relate to the occurrence and development of diabetes and hypertension.


Breast-feeding experiences of women of African heritage in the United Kingdom.
This article explores the breast-feeding experiences of women of African descent in the United Kingdom. Although there is a limited evidence base that describes the breast-feeding experiences of these women, the small number of studies on this topic suggest that a tradition of breast-feeding exists within African communities in the United Kingdom. Cultural materialism is adopted as a theoretical framework to explore the sociocultural influences on breast-feeding in the United Kingdom for this group. The invisibility of this group is examined in relation to the health care research and policy agenda in the United Kingdom, and arguments are made for the urgent need to address this paucity of information to promote evidence-based nursing and midwifery practice.


Identification of cytochrome P450 enzymes involved in the metabolism of 4'-methoxy-alpha-pyrrolidinopropiophenone (MOPPP), a designer drug, in human liver microsomes.
1. The metabolism of 4'-methoxy-alpha-pyrrolidinopropiophenone (MOPPP), a novel designer drug, to its demethylated major metabolite 4'-hydroxy-pyrrolidinopropio-phenone (HO-PPP) was studied in pooled human liver microsomes (HLM) and in cDNA-expressed human hepatic cytochrome P450 (CYP) enzymes. 2. CYP2C19 catalysed the demethylation with apparent Km and Vmax values of 373.4 +/- 45.1 microM and 6.0 +/- 0.3 pmol min(-1) pmol(-1) CYP, respectively (mean +/- SD). Both CYP2D6 and HLM exhibited clear biphasic profiles with apparent K(m,1) values of 1.3 +/- 0.4 and 22.0 +/- 6.5 microM, respectively, and V(max,1) values of 1.1 +/- 0.1 pmol min(-1) pmol(-1) CYP and 169.1 +/- 20.5 pmol min(-1) mg(-1) protein, respectively. 3. Percentages of intrinsic clearances of MOPPP by particular CYPs were calculated using the relative activity factor (RAF) approach with (S)-mephenytoin-4'-hydroxylation or bufuralol-1'-hydroxylation as index reactions for CYP2C19 or CYP2D6, respectively. 4. MOPPP, HO-PPP and the standard 3',4'-methylenedioxy-pyrrolidinopropio-phenone (MDPPP) were separated and analysed by liquid chromatography-mass spectrometry in the selected-ion monitoring (SIM) mode. 5. The CYP2D6 specific chemical inhibitor quinidine (3 microM) significantly (p<0.0001) inhibited HO-PPP formation by 91.8 +/- 0.5% (mean +/- SEM) in incubation mixtures with HLM and 2 microM MOPPP. 6. It can be concluded from the data obtained from kinetic and inhibition studies that polymorphically expressed CYP2D6 is the enzyme mainly responsible for MOPPP demethylation.


pS6K1 as an efficacy marker of GnRH agonist with premenopausal breast cancer.
Estradiol is a key factor for tumorigenesis and prognosis of hormone receptor-positive breast cancer. Adipocytes are one source of estradiol in patients with breast cancer. Recent studies have shown that phosphorylated ribosomal protein S6 kinase-1 plays a critical role in adipogenesis. Therefore, estrogen depletion therapy might have beneficial effects in phosphorylated ribosomal protein S6 kinase-1-positive breast cancer. This study was conducted to evaluate the value of phosphorylated ribosomal protein S6 kinase-1 as a marker for gonadotropin-releasing hormone agonist treatment, a form of estrogen depletion therapy, for premenopausal patients with HR-positive, human epidermal growth factor receptor 2-negative breast cancer. We reviewed the medical records of 296 premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary invasive breast cancer treated between 2008 and 2015. Phosphorylated ribosomal protein S6 kinase-1 positivity was defined by immunohistochemical staining scores of 1+, 2+ and 3+, whereas a score of 0 was considered negative. Phosphorylated ribosomal protein S6 kinase-1-positive tumors were found in 74.0% of the patients. In the phosphorylated ribosomal protein S6 kinase-1-positive group, disease-free survival of patients treated with a gonadotropin-releasing hormone agonist was significantly longer than that of patients treated without a gonadotropin-releasing hormone agonist (mean 106.7 months vs mean 91.1 months, P = 0.018). Phosphorylated ribosomal protein S6 kinase-1 is a potential biomarker for predicting the efficacy of gonadotropin-releasing hormone agonist therapy in premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer.


Liposarcoma of pleural cavity with recurrence as malignant fibrous histiocytoma.
The case of a 54-year-old male, with a massive right pleural liposarcoma weighing over 3200 g, is presented. The tumor was found by light and electron microscopy to be of well-differentiated and pleomorphic subtypes, and it apparently represents the sixth reported case of liposarcoma primary to the pleura. Two years after excision of the primary tumor, it recurred as a neoplasm with histologic and ultrastructural features characteristic of malignant fibrous histiocytoma. The histogenetic and pathologic implications of the above findings are discussed, and the literature regarding intrathoracic liposarcoma and malignant fibrous histiocytoma is reviewed.


Global metabolome changes induced by cyanobacterial blooms in three representative fish species.
Cyanobacterial blooms induce important ecological constraints for aquatic organisms and strongly impact the functioning of aquatic ecosystems. In the past decades, the effects of the cyanobacterial secondary metabolites, so called cyanotoxins, have been extensively studied in fish. However, many of these studies have used targeted approaches on specific molecules, which are thought to react to the presence of these specific cyanobacterial compounds. Since a few years, untargeted metabolomic approaches provide a unique opportunity to evaluate the global response of hundreds of metabolites at a glance. In this way, our study provides the first utilization of metabolomic analyses in order to identify the response of fish exposed to bloom-forming cyanobacteria. Three relevant fish species of peri-urban lakes of the European temperate regions were exposed for 96h either to a microcystin (MC)-producing or to a non-MC-producing strain of Microcystis aeruginosa and metabolome changes were characterized in the liver of fish. The results suggest that a short-term exposure to those cyanobacterial biomasses induces metabolome changes without any response specificity linked to the fish species considered. Candidate metabolites are involved in energy metabolism and antioxidative response, which could potentially traduce a stress response of fish submitted to cyanobacteria. These results are in agreement with the already known information and could additionally bring new insights about the molecular interactions between cyanobacteria and fish.


Psychiatric illness in female physicians. Are high rates of depression an occupational hazard?
More than half of female physicians may experience a psychiatric illness during their lifetime. Depression is by far the most common such disorder, and the suicide rate is alarmingly high. However, female physicians appear to be at lower risk for substance abuse than male physicians. The medical profession could benefit from increased awareness of depression among female physicians and removal of barriers to treatment, such as stigma and discrimination against those with psychiatric illness.


Fourth-order analysis of a diffusive lattice Boltzmann method for barrier coatings.
We examine the applicability of diffusive lattice Boltzmann methods to simulate the fluid transport through barrier coatings, finding excellent agreement between simulations and analytical predictions for standard parameter choices. To examine more interesting non-Fickian behavior and multiple layers of different coatings, it becomes necessary to explore a wider range of parameters. However, such a range of parameters exposes deficiencies in such an implementation. To investigate these discrepancies, we examine the form of higher-order terms in the hydrodynamic limit of our lattice Boltzmann method. We identify these corrections to fourth order and validate these predictions with high accuracy. However, it is observed that the validated correction terms do not fully explain the bulk of observed error. This error was instead caused by the standard finite boundary conditions for the contact of the coating with the imposed environment. We identify a self-consistent form of these boundary conditions for which these errors are dramatically reduced. The instantaneous switching used as a boundary condition for the barrier problem proves demanding enough that any higher-order corrections meaningfully contribute for a small range of parameters. There is a large parameter space where the agreement between simulations and analytical predictions even in the second-order form are below 0.1%, making further improvements to the algorithm unnecessary for such an application.


[Genetic genesis of choriocarcinoma].
To distinguish choriocarcinoma from gestational or non-gestational choriocarcinoma and also identify the causative pregnancy of gestational choriocarcinoma by the genetic origin through molecular genetic analysis. Twelve patients with choriocarcinoma, who had experienced surgery prior to chemotherapy were enrolled in this study. All 12 cases were diagnosed pathologically as choriocarcinoma. Peripheral venous blood samples and formalin-fixed paraffin-embedded blocks of choriocarcinoma tissue microdissected from haematoxylin and eosin-stained sections of tissue by microdissection method were available from the patient and (or) her husband. DNA was then prepared from the couples' blood samples and choriocarcinoma tissue by using standard techniques. PCR amplification and fluorescent microsatellite genotyping were performed by using DNA from the couples and captured choriocarcinoma tissues. The genetic contributions to the choriocarcinoma tissue were determined by comparing the fragments of genes from the choriocarcinoma tissue to those from blood samples of the couples. The primary lesion was ovary in 7 cases, but only 4 of them had the maternal contribution, indicating a non-gestational origin; the other three were gestational choriocarcinoma. The primary lesion was uterus in 5 cases, which were all gestational choriocarcinoma confirmed by genetic analyses. The causative pregnancies of the 8 cases with gestational choriocarcinoma were identified as androgenetic complete hydatidiform mole (AnCHM) in six cases and normal pregnancies in two cases, respectively. Microsatellite polymorphism analysis is a molecular approach for distinguishing the non-gestational choriocarcinoma from the gestational one, and also be used to identify the causative pregnancy of gestational choriocarcinoma.


Accurate Determination of Trace Water in Organic Solution by Quantitative Nuclear Magnetic Resonance.
A new method accompanied by a derived equation for accurate determination of trace water was developed by using quantitative 1H nuclear magnetic resonance (qNMR) spectroscopy. Given that the response for each chemically distinct moiety is uniformly proportional to the number of the corresponding resonant nuclei within the analyte, it is practicable to directly quantify the water content via its proton number using qNMR. In this study, three water standards with known water contents (e.g., 10.02, 1.006, and 0.103 mg/g), which were accurately determined by a well-established Coulometric Karl Fischer (CKF) titration method, were measured by using the developed qNMR method. An excellent agreement between the results from these two methods was obtained. Then, the water content of Sudan I was determined by high-field NMR (HF-NMR) spectroscopy, and the water contents of acetone and bioethanol were measured by low-field NMR (LF-NMR) spectroscopy. These results were compared with the water content measured by the CKF method to confirm the applicability of the established qNMR method. The developed method can eliminate the influences of environmental humidity and background water in the solvent; subsequently, the results calculated by the derived equation were comparable to the nominal values. Under the optimal conditions, the limit of quantitation of this method was as low as 6.7 μg. The recommended sample sizes for practical samples with various water contents (e.g., 10.02, 1.006, and 0.103 mg/g) were determined to be 5, 50, and 60 mg, respectively, which are much smaller than those required for the CKF method. The new method has a static and stable process without any side reactions, and the traceability to the SI unit can be directly achieved through the NMR internal standard. This method overcomes the limitations of the CKF method, especially for measuring methanol-insoluble substances.


Smoking and pulmonary diffusing capacity.
The pulmonary diffusing capacity (DLCO SB) and its two components, the capillary blood volume (Vc) and the diffusing capacity of the membrane (DMCO), expressed in absolute values and per litre of alveolar volume (VA'), were measured at rest and on exercise in healthy male smokers and nonsmokers of similar age and height, and with identical values for haemoglobin and spirographic data. DLCO, DLCO/VA', DMCO and DMCO/VA' are significantly lower in smokers, at rest and on exercise; the decrease in Vc and thetaVc/VA' in smokers at rest is due to a higher level of carboxyhaemoglobin. The decrease of DLCO, DLCO/VA', DMCO and DMCO/VA' is apparently not due to carboxyhaemoglobin or distributional factors but to anatomical lesions, probably of emphysematous nature, altering the pulmonary membrane. Formulas predicting DLCO, DMCO, Vc, DLCO/VA', DMCO/VA' and thetaVc/VA' in terms of age and height were established in smokers and in nonsmokers.


Acute suppurative thyroiditis: a ten-year review in a Taiwanese hospital.
12 patients with acute suppurative thyroiditis were treated over a 10-year period. Their ages ranged from 2-81 years. Eight of them had a pre-existing thyroid mass. A piriform sinus fistula was demonstrated in one of the 2 patients with a history of recurrent infections. Cultures of the pus taken from the infected glands grew Gram-positive streptococci in 4 patients, Gram-negative bacteria in 4, and anaerobic bacteria in 1; the other 3 were sterile. Both patients who grew Klebsiella pneumonia were diabetic. Most of the patients received drainage in addition to systemic antibiotics. Only 2 patients had recurrence during the follow-up period. We present a review of our experience with this uncommon infection.


Interactions of nucleic acids with fluorescent dyes: spectral properties of condensed complexes.
Interaction of cations with nucleic acids (NA) often results in condensation of the product. The driving force of aromatic cation-induced condensation is the cooperative interaction between ligand and single-stranded (ss) NA. This type of reaction is highly specific with regard to the primary and secondary structure of NA, and results in destabilization of the latter. The spectral properties of fluorescent intercalating and non-intercalating ligands [acridine orange, pyronin Y(G), DAPI, Hoechst 33258, and Hoechst 33342]-NA complexes were studied in both the relaxed and condensed form. The changes in absorption, excitation, and fluorescence emission spectra and fluorescence yield that followed the condensation were examined. Although some of these effects can be explained by changes in solvation of the fluorophore and its interaction with NA bases and the solvent, the overall effect of condensation on spectral properties of the complex is unpredictable. In particular, no correlation was found between these effects and the ds DNA binding mode of these ligands. Nevertheless, the spectral data associated with polymer condensation can yield information about the composition and structure of NA and can explain some nonspecific interactions of these probes.


Impact of hibernating and viable myocardium on improvement in perfusion and left ventricular ejection fraction after coronary artery bypass graft.
The association between the extent and degree of perfusion-metabolism mismatch and improvement in perfusion and left ventricular ejection fraction (LVEF) after revascularization was assessed. The secondary aim was to identify the best precoronary artery bypass graft surgery (pre-CABG) PET parameter, if any, to predict the improvement in the perfusion and LVEF after CABG. Overal, 31 patients (mean age: 58+8.3 years) with ischemic left ventricle dysfunction underwent NH3 and F-FDG PET for the assessment of myocardial viability. CABG was performed in these patients and after a mean interval of 3 months, NH3 PET was repeated. The percentages of viable myocardium (VM), hibernating myocardium, degree of mismatch, and LVEF in pre-CABG PET were calculated. These were compared, the median [INCREMENT]LVEF and percent increase in perfusion being 5 (interquartile range: 3-9) and 78.7 (interquartile range: 51.3-100), respectively. No significant association was observed between the severity or extent of perfusion defect/mismatch and improvement in perfusion or LVEF after CABG. Patients with at least 65% VM predicted a 5-unit increase in LVEF at 88.9% sensitivity (P=0.1). There was no significant relation between the severity and extent of perfusion-metabolism mismatch with improvement in perfusion and LVEF after CABG. After CABG for ischemic left ventricle dysfunction, VM shows a tendency toward better improvement in LVEF.


Potential Therapeutic Implications of Caffeic Acid in Cancer Signaling: Past, Present, and Future.
Caffeic acid (CA) has been present in many herbs, vegetables, and fruits. CA is a bioactive compound and exhibits various health advantages that are linked with its anti-oxidant functions and implicated in the therapy and prevention of disease progression of inflammatory diseases and cancer. The anti-tumor action of CA is attributed to its pro-oxidant and anti-oxidant properties. CA's mechanism of action involves preventing reactive oxygen species formation, diminishing the angiogenesis of cancer cells, enhancing the tumor cells' DNA oxidation, and repressing MMP-2 and MMP-9. CA and its derivatives have been reported to exhibit anti-carcinogenic properties against many cancer types. CA has indicated low intestinal absorption, low oral bioavailability in rats, and pitiable permeability across Caco-2 cells. In the present review, we have illustrated CA's therapeutic potential, pharmacokinetics, and characteristics. The pharmacological effects of CA, the emphasis on in vitro and in vivo studies, and the existing challenges and prospects of CA for cancer treatment and prevention are discussed in this review.


Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is characterised by alveolar inflammation, exaggerated release of oxidants, and subnormal concentrations of the antioxidant glutathione in respiratory epithelial lining fluid (ELF). Glutathione (600 mg twice daily for 3 days) was given by aerosol to 10 patients with IPF. Total ELF glutathione rose transiently, ELF oxidised glutathione concentrations increased, and there was a decrease in spontaneous superoxide anion release by alveolar macrophages. Thus, glutathione by aerosol could be a means of reversing the oxidant-antioxidant imbalance in IPF.


Identifying patterns of adolescent drinking: a tri-ethnic study.
The present study was designed to identify common patterns of adolescent drinking in a tri-ethnic sample and to identify which patterns may be the most problematic in each ethnic group. Students (N = 1,874, 60% female) in 9th through 12th grade (653 African Americans, 722 European Americans and 499 Mexican Americans), recruited from six high schools in a large metropolitan school district in the Southwest, completed questionnaires on their drinking practices, self-esteem and involvement in antisocial behaviors. Cluster analyses performed on 950 students identified eight common adolescent drinking patterns: Light, Parent, Family Occasion, Date, Moderate-Friend, Party, Outdoor and Heavy Multiple-Context drinkers. As predicted, Light, Parent and Family Occasion drinkers showed the highest levels of self-esteem and the lowest levels of drinking consequences, drinking reasons and antisocial behavior. Heavy Multiple-Context drinkers showed low self-esteem and high levels of antisocial behavior, drinking reasons and drinking consequences. Party and Date drinkers generally fell between these two groups on the drinking and adjustment variables, with the exception that Date drinkers were as likely to engage in antisocial behaviors as were drinkers in the Heavy Multiple-Context group. Among all of the drinking groups, Outdoor drinkers showed the highest levels of self-esteem, high levels of antisocial behavior and moderate levels of drinking reasons and consequences. Follow-up analyses showed that the differences between the groups on adjustment and consequences were not simply a function of the frequency and quantity of consumption. These findings, taken together, help identify patterns of normative, problem and at-risk drinking, which should be useful in the assessment of adolescent drinking and in future research on the consequences of adolescent alcohol use.


Cardiopulmonary bypass time: every minute counts.
This study was conducted to examine the impact of CPB times on postoperative outcomes. We sought to determine the optimum cut-offs of CPB per graft time and cumulative CPB time and their predictive accuracy for mortality in conjunction with EuroSCORE II. The de-identified data of 1960 patients who had undergone isolated on-pump CABG from 2009 to 2014 were analyzed. The risk strata of cardiopulmonary bypass (CPB)/graft and cumulative CPB times, identified with a decision tree, were added into an augmented model for predicting short- and intermediate-term postoperative clinical events. Prolonged cumulative CPB time (>180 minutes) was significant in predicting mortality while adjusting for EuroSCORE II, postoperative complications, prolonged ICU stay and prolonged mechanical ventilation. Whereas prolonged CPB/graft time (>56 minutes) was marginally non-significant in terms of its direct effects, its indirect effect on mortality could be manifested through enhanced risks of complications, prolonged ICU stay (>48 hours) and prolonged mechanical ventilation (>24 hours). Prolonged CPB times could predict postoperative clinical events, in particular mortality. To minimize the occurrence of unfavorable adverse outcomes, it is recommended that the CPB/graft time and cumulative CPB time be kept below 56 minutes and 180 minutes respectively.


Characterization of the complete mitochondrial genome of Laomedia astacina De Haan, 1841 (Decapoda: Laomediidae) and its phylogenetic implications.
In this study, we determined the complete mitochondrial genome (mitogenome) of Laomedia astacina De Haan, 1841 using next-generation sequencing technology. The total length of the mitogenome sequence of L. astacina is 14,795 base pairs, including 13 protein-coding genes (PCGs), 22 transfer RNA genes, and two ribosomal RNA genes. The overall composition of the mitogenome is estimated to be 35.3% A, 38.0% T, 13.8% C, and 12.9% G, indicating that the L. astacina mitogenome is rich in A + T (73.3%). The phylogenetic relationships of 13 decapod species were constructed based on the 13 PCGs by the maximum-likelihood approach using IQtree software.


Evidence for the presence of pro-oxytocin/neurophysin-converting enzyme in the human ovary.
The activity of pro-oxytocin/neurophysin (pro-OT/Np)-processing enzymes was determined in human granulosa cells, follicular fluids and purified secretory granules of corpora lutea. We detected the presence of an endoprotease which releases OT-Gly10-Lys11-Arg12 on cleavage of the synthetic pro-OT/Np(1-20) peptide after the dibasic Lys11-Arg12 doublet. This endoprotease was inhibited by EDTA, but was not affected by phenylmethanesulfonyl fluoride and pepstatin. Enzymatic activity was markedly reduced by replacement of L-Arg by D-Arg in the basic amino acid doublet of the substrate. The molecular weight of this enzyme was estimated to be 60 kDa. These features closely resembled those of the endoprotease identified in the bovine pituitary. The endoprotease is a metalloenzyme, specific for the Lys-Arg doublet. We also detected a carboxypeptidasic activity, inhibited by guanidinoethane-mercaptosuccinic acid. In the light of our previous detection of the processing intermediates, OT-Gly-Lys-Arg, OT-Gly-Lys and OT-Gly, in human ovary, these observations are in favour of a pro-OT/Np-processing pathway in the human ovary comparable with that in the bovine ovary. Moreover, these results confirm that oxytocin post-translational processing occurs in the human ovary and strongly suggest that pro-OT/Np is synthesized locally.


Measuring Protein Binding to F-actin by Co-sedimentation.
Filamentous actin (F-actin) organization within cells is regulated by a large number of actin-binding proteins that control actin nucleation, growth, cross-linking and/or disassembly. This protocol describes a technique - the actin co-sedimentation, or pelleting, assay - to determine whether a protein or protein domain binds F-actin and to measure the affinity of the interaction (i.e., the dissociation equilibrium constant). In this technique, a protein of interest is first incubated with F-actin in solution. Then, differential centrifugation is used to sediment the actin filaments, and the pelleted material is analyzed by SDS-PAGE. If the protein of interest binds F-actin, it will co-sediment with the actin filaments. The products of the binding reaction (i.e., F-actin and the protein of interest) can be quantified to determine the affinity of the interaction. The actin pelleting assay is a straightforward technique for determining if a protein of interest binds F-actin and for assessing how changes to that protein, such as ligand binding, affect its interaction with F-actin.


An intervention to increase cervical cancer screening among women living with HIV: A mixed methods study.
We examined the effectiveness of a behavioral intervention in promoting cervical cancer screening among women living with HIV (WLWH) in Ghana. A Mixed-methods study was conducted involving 83 WLWH, who were randomly assigned to an intervention group (n = 42) to receive voice-recorded messages based on the 3 R model (Reframing, Reprioritizing, and Reforming) or a control group (n = 41) to receive standard care. The primary outcomes were screening uptake and HPV prevalence. Other outcomes were the acceptability, appropriateness, and feasibility of the intervention. The intervention group had a 100% screening rate, and the control group had a 14.63% screening rate. The prevalent rate of high-risk (hr)-HPV genotypes among the women was 67.5% (95%C.I: 0.56-0.77). Over 48% of the participants had multiple hr-HPV genotypes, 64.29% had HPV16/18/45%, and 73.21% had HPV 31/33/45/52/58. Of the women (89.30%) who screened positive, 60% of them were diagnosed and treated for pre-cancer lesions. The intervention messages were acceptable (encourage proactive behavior), feasible (simple, easy to understand), and appropriate (helpful, informative). Facilitators and barriers to self-sampling were identified. Combining the 3 R model with self-sampling increases cervical cancer screening among WLWH. Healthcare professionals and policymakers can use this model to increase cervical cancer screening.


Comparison of antimicrobial efficacy of multiple beef hide decontamination strategies to reduce levels of Escherichia coli O157:H7 and Salmonella.
This study involved a comparison of the antimicrobial efficacy of several beef hide decontamination interventions to identify those that more effectively reduced levels of Escherichia coli O157:H7 and Salmonella. Whole beef hides were inoculated with E. coli O157:H7 and Salmonella and decontaminated with sprays of solutions of acetic acid (AA; 10%, 55 degrees C), lactic acid (LA; 10%, 55 degrees C), sodium hydroxide (SH; 3%, 23 degrees C), sodium metasilicate (SM; 4%, 23 degrees C), or sodium hydroxide (1.5%), followed by high-pressure washing with chlorinated (0.02%) water (SHC; both applied at 23 degrees C) or water (W; 23 degrees C) or by deluging with solutions of potassium cyanate (PC; 2.4%, 30 degrees C) or sodium sulfide (SS; 6.2%, 30 degrees C). All spraying treatments (AA, LA, SH, SM, and SHC) resulted in removal of visual organic material, whereas the dehairing treatments (PC and SS) successfully removed hair along with visual organic material. The PC, SS, and SHC treatments resulted in the greatest reductions of E. coli O157:H7 (P < 0.05), by 5.1, 4.8, and 5.0 log CFU/cm2, respectively. The SS and SHC treatments decreased Salmonella by 4.2 and 4.4 log CFU/cm2, respectively, compared with the water treatment, which reduced levels by 1.7 log CFU/cm2 (P < 0.05). The SH, AA, and LA treatments also lowered both E. coli O157:H7 and Salmonella by at least 2.0 log CFU/cm2. The treatments that were effective in this study deserve further consideration for commercial implementation as hide decontamination interventions.


Repair of formamidopyrimidines in DNA involves different glycosylases: role of the OGG1, NTH1, and NEIL1 enzymes.
The oxidatively induced DNA lesions 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) and 4,6-diamino-5-formamidopyrimidine (FapyA) are formed abundantly in DNA of cultured cells or tissues exposed to ionizing radiation or to other free radical-generating systems. In vitro studies indicate that these lesions are miscoding, can block the progression of DNA polymerases, and are substrates for base excision repair. However, no study has yet addressed how these lesions are metabolized in cellular extracts. The synthesis of oligonucleotides containing FapyG and FapyA at defined positions was recently reported. These constructs allowed us to investigate the repair of Fapy lesions in nuclear and mitochondrial extracts from wild type and knock-out mice lacking the two major DNA glycosylases for repair of oxidative DNA damage, OGG1 and NTH1. The background level of FapyG/FapyA in DNA from these mice was also determined. Endogenous FapyG levels in liver DNA from wild type mice were significantly higher than 8-hydroxyguanine levels. FapyG and FapyA were efficiently repaired in nuclear and mitochondrial extracts from wild type animals but not in the glycosylase-deficient mice. Our results indicated that OGG1 and NTH1 are the major DNA glycosylases for the removal of FapyG and FapyA, respectively. Tissue-specific analysis suggested that other DNA glycosylases may contribute to FapyA repair when NTH1 is poorly expressed. We identified NEIL1 in liver mitochondria, which could account for the residual incision activity in the absence of OGG1 and NTH1. FapyG and FapyA levels were significantly elevated in DNA from the knock-out mice, underscoring the biological role of OGG1 and NTH1 in the repair of these lesions.


Depth imaging denoising of photon-counting lidar.
Photon-counting lidar systems have difficulty reconstructing target depth images due to ambient noise. In this paper, we propose a novel way of using correlative photons and spatial correlations to reduce the false alarm probability. Experimental results show that the root mean square error of the depth image reconstructed by the proposed algorithm can be 1.68 times and 1.11 times better than that of the fast depth imaging denoising algorithm and log-matched filter estimation. The experimental results show that the proposed algorithm can effectively improve the reconstructed image of photon-counting lidar.


Noninvasive in vivo monitoring of methemoglobin formation and reduction with broadband diffuse optical spectroscopy.
We present noninvasive, quantitative in vivo measurements of methemoglobin formation and reduction in a rabbit model using broadband diffuse optical spectroscopy (DOS). Broadband DOS combines multifrequency frequency-domain photon migration (FDPM) with time-independent near infrared (NIR) spectroscopy to quantitatively measure bulk tissue absorption and scattering spectra between 600 nm and 1,000 nm. Tissue concentrations (denoted by brackets) of methemoglobin ([MetHb]), deoxyhemoglobin ([Hb-R]), and oxyhemoglobin ([HbO2]) were determined from absorption spectra acquired in "real time" during nitrite infusions in nine pathogen-free New Zealand White rabbits. As little as 30 nM [MetHb] changes were detected for levels of [MetHb] that ranged from 0.80 to 5.72 microM, representing 2.2 to 14.9% of the total hemoglobin content (%MetHb). These values agreed well with on-site ex vivo cooximetry data (r2= 0.902, P < 0.0001, n = 4). The reduction of MetHb to functional hemoglobins was also carried out with intravenous injections of methylene blue (MB). As little as 10 nM changes in [MB] were detectable at levels of up to 150 nM in tissue. Our results demonstrate, for the first time, the ability of broadband DOS to noninvasively quantify real-time changes in [MetHb] and four additional chromophore concentrations ([Hb-R], [HbO2], [H2O], and [MB]) despite significant overlapping spectral features. These techniques are expected to be useful in evaluating dynamics of drug delivery and therapeutic efficacy in blood chemistry, human, and preclinical animal models.


Identifying barriers to emergency care services.
This paper aims to present a review of published evidence of barriers to emergency care, with attention towards both financial and other barriers. With the keywords (financial) accessibility, barriers and emergency care services, citations in PubMed were searched and further selected in the context of the objective of this article. Forty articles, published over a period of 15 years, showed evidence of significant barriers to emergency care. These barriers often tend to persist, despite the fact that the evidence was published many years ago. Several publications stressed the importance of the financial barriers in foregoing or delaying potentially life-saving emergency services, both in poor and rich countries. Other publications report non-financial barriers that prevent patients in need of emergency care (pre-hospital and in-patient care) from seeking care, from arriving in the proper emergency department without undue delay or from receiving proper treatment when they do arrive in these departments. It is clear that timely access to life-saving and disability-preventing emergency care is problematic in many settings. Yet, low-cost measures can likely be taken to significantly reduce these barriers. It is time to make an inventory of these measures and to implement the most cost-effective ones worldwide.


Lysine Methyltransferase SMYD1 Regulates Myogenesis via skNAC Methylation.
The SMYD family is a unique class of lysine methyltransferases (KMTases) whose catalytic SET domain is split by a MYND domain. Among these, Smyd1 was identified as a heart- and skeletal muscle-specific KMTase and is essential for cardiogenesis and skeletal muscle development. SMYD1 has been characterized as a histone methyltransferase (HMTase). Here we demonstrated that SMYD1 methylates is the Skeletal muscle-specific splice variant of the Nascent polypeptide-Associated Complex (skNAC) transcription factor. SMYD1-mediated methylation of skNAC targets K1975 within the carboxy-terminus region of skNAC. Catalysis requires physical interaction of SMYD1 and skNAC via the conserved MYND domain of SMYD1 and the PXLXP motif of skNAC. Our data indicated that skNAC methylation is required for the direct transcriptional activation of myoglobin (Mb), a heart- and skeletal muscle-specific hemoprotein that facilitates oxygen transport. Our study revealed that the skNAC, as a methylation target of SMYD1, illuminates the molecular mechanism by which SMYD1 cooperates with skNAC to regulate transcriptional activation of genes crucial for muscle functions and implicates the MYND domain of the SMYD-family KMTases as an adaptor to target substrates for methylation.


Continuous production of flexible fibers from transgenically produced honeybee silk proteins.
Flexible and solvent stable fibers are produced after concentrated recombinant honeybee protein solutions are extruded into a methanol bath, dried, drawn in aqueous methanol, then covalently cross-linked using dry heat. Proteins in solution are predominantly coiled coil. Significant levels of non-orientated ß-sheets form during drying or after coagulation in aqueous methanol. Drawing generally aligns the coiled coil component parallel with the fibre axis and ß-sheet component perpendicular to the fiber axis. The fibres are readily handled, stable in the strong protein denaturants, urea and guanidinium, and suitable for a range of applications such as weaving and knitting.


Multifactor stimulation of megakaryocytopoiesis: effects of interleukin 6.
We have previously demonstrated that interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) stimulate various aspects of megakaryocytopoiesis. We have investigated the capacity of interleukin 6 (IL-6) to stimulate megakaryocyte colony formation from both normal Balb/C marrow and light-density marrow extensively depleted of adherent, pre-B, B and T cells. Human recombinant IL-6 (167 ng/ml) stimulated megakaryocyte colony formation from normal marrow (8.6 +/- 1 megakaryocyte colony-forming units [CFU-meg]/10(5) cells) as compared to control (1.5 +/- 4 CFU-meg/10(5) cells) in 16 determinations (p less than 0.01). IL-6 (167 ng/ml) also stimulated CFU-meg formation from depleted marrow (control, 10.8 +/- 4 CFU-meg/10(5) cells versus IL-6, 68 +/- 19 CFU-meg/10(5) cells in 12 determinations, p less than 0.01). IL-6 synergistically augmented IL-3-induced colony formation (139% IL-3 control, 120% calculated IL-3 plus IL-6 control, n = 11, p less than 0.01) in normal marrow and showed an additive effect in depleted marrow (133% IL-3 control, p less than 0.01, 114% of IL-3 plus IL-6, value not significant [NS] at 0.05 level). Studies with recombinant murine IL-6 gave similar results. There was an increasing level of megakaryocyte colony-stimulating activity from G-CSF (16,667 U/ml, 2.47 +/- 0.6 CFU-meg/10(5) cells, n = 17), to IL-6 (167 ng/ml, 8.47 +/- 0.96 CFU-meg/10(5) cells, n = 19), to GM-CSF (52 U/ml, 23 +/- 4 CFU-meg/10(5) cells, n = 14), to IL-3 (167 U/ml, 48 +/- 5 CFU-meg/10(5) cells, n = 20) as compared to media-stimulated marrow (range 1.29-1.86 CFU-meg/10(5) cells). A similar hierarchy was seen with depleted marrow. Combinations of factors (including IL-3, GM-CSF, G-CSF, and IL-6) tested against normal unseparated murine marrow did not further augment CFU-meg numbers over IL-3 plus IL-6 but did increase colony size. These data suggest that IL-6 is an important megakaryocyte regulator, that at least four growth factors interact synergistically or additively to regulate megakaryocytopoiesis, and that combinations of growth factors, possibly in physical association, might be critical in stimulating megakaryocyte stem cells.


Quantitative investigations of idiotypic antibodies. VI. Idiotypic specificity as a potential genetic marker for the variable regions of mouse immunoglobulin polypeptide chains.
Antisera were prepared in rabbits against anti-p-azobenzoate antibodies of an A/J and a BALB/c mouse and anti-p-azophenylarsonate antibodies of an A/J mouse. After appropriate absorption the antisera reacted with the anti-hapten antibody of the donor mouse but, by sensitive quantitative tests, not at all with other components of the hyperimmune serum or with preimmune serum of the donor mouse. The absorbed antiserum therefore appeared to be specific for idiotypic determinants. Nearly all idiotypic specificities identified in the serum of the donor were also present in the serum of other mice of the same strain, immunized against the same hapten group, but not in mice immunized with a different hapten. In each case the antibodies of the donor mouse reacted most effectively on a weight basis with antiidiotypic antiserum. Cross-reactions were observed among different strains of mice but homologous anti-bodies reacted most effectively with antiidiotypic antisera. C57/BL and DBA antisera contained very low concentrations of specificities present in the A/J and BALB/c antibody populations; antibodies of A/J and BALB/c antisera are more closely related to one another. The results indicate that idiotypic specificity may provide a genetic marker for the variable regions of immunoglobulin polypeptide chains.


Cytogenetic activities of tobacco particulate matter (TPM) derived from a low to middle tar British cigarette.
Tobacco particulate matter (TPM) derived from an experimental low to middle tar cigarette was tested for its cytogenetic activity upon a low passage number Chinese hamster pulmonary cell line. Examination of the mitotic profiles (after one cell cycle) revealed no interference by the agent with mitotic spindle formation and/or function. However, complete chromosomes (or parts of them) were seen to dislocate from the mitotic spindles. Such an event was probably the result of the chromosome aberrations, substantial numbers of which were observed in second division cells, or through a process of centromere inactivation. In second division cells there was a reduction in the number of diploid cells accompanied by an increase in both hypodiploidy and polyploidy and there was also a non-dose-related increase in endoreduplication. The results demonstrate that TPM was capable of inducing both structural and numerical chromosome aberrations in cultured mammalian cells.


A randomized crossover study of bee sting therapy for multiple sclerosis.
Bee sting therapy is increasingly used to treat patients with multiple sclerosis (MS) in the belief that it can stabilize or ameliorate the disease. However, there are no clinical studies to justify its use. In a randomized, crossover study, we assigned 26 patients with relapsing-remitting or relapsing secondary progressive MS to 24 weeks of medically supervised bee sting therapy or 24 weeks of no treatment. Live bees (up to a maximum of 20) were used to administer bee venom three times per week. The primary outcome was the cumulative number of new gadolinium-enhancing lesions on T1-weighted MRI of the brain. Secondary outcomes were lesion load on T2*-weighted MRI, relapse rate, disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Guy's Neurologic Disability Scale), fatigue (Abbreviated Fatigue Questionnaire, Fatigue Impact Scale), and health-related quality of life (Medical Outcomes Study 36-Item Short Form General Health Survey). During bee sting therapy, there was no significant reduction in the cumulative number of new gadolinium-enhancing lesions. The T2*-weighted lesion load further progressed, and there was no significant reduction in relapse rate. There was no improvement of disability, fatigue, and quality of life. Bee sting therapy was well tolerated, and there were no serious adverse events. In this trial, treatment with bee venom in patients with relapsing multiple sclerosis did not reduce disease activity, disability, or fatigue and did not improve quality of life.


Intrauterine treatment of idiopathic hydrops fetalis.
Seven fetuses with idiopathic hydrops fetalis (IHF) were treated in utero by injecting albumin into the fetal abdominal cavity and by removal of accumulated fluid from the serous cavities. Signs of hydrops fetalis disappeared in utero in one, and skin edema significantly decreased in another. In the other five, signs of hydrops fetalis remained unchanged in utero. The hourly fetal urine production rate (HFUPR) increased after albumin injection in three of five. The interval between the initial diagnosis and delivery ranged from 3 to 14 weeks. Gestational age at the time of delivery ranged from 33 to 40 weeks. There were no stillbirths. Two of three without pleural effusion survived, but four with pleural effusion died of respiratory failure during the neonatal period due to pulmonary hypoplasia. These results indicate that albumin injection into the fetal abdomen in utero deserves further attention and that other therapeutic methods should be established to enhance the development of the lungs in cases of intrauterine treatment of IHF with pleural effusion.


Normal adrenal gland thickness on computerized tomography in an Asian Indian adult population.
The size and morphology of the adrenal glands are affected by several physiological and pathological conditions. Radiologists need to be aware of the normal thickness of adrenal gland to accurately assess patients with suspected adrenal pathology. However, there is limited data on the normal size of the adrenal glands. Moreover, this has not been studied in our population. To study the normal thickness of adrenal gland on computerized tomography (CT) in Indian adult population. Retrospective study in a tertiary care hospital in Southern India. Our study included 586 adults who underwent a CT abdominal angiogram over 15 months, and excluding patients with clinical or imaging evidence of adrenal disease. The measurements made included: the maximum thickness of the body, medial and lateral limbs, measured perpendicular to the long axis. The median age was 51 (range: 18-85) years. The mean maximum thickness of the adrenal body, medial, and lateral limbs were 7.2 ± 1.8, 4.1 ± 1.1, and 4.3 ± 1.1 mm on the right side and 8.8 ± 1.9, 4.7 ± 1.1, and 4.9 ± 1.3 mm on the left. The cumulative thickness of the body and the limbs were 15.6 ± 3.7 mm and 18.4 ± 3.8 mm on the right and left sides, respectively. There was a statistically significant difference in all the measurements between the right and left adrenal glands (all P values = 0.000) and between men and women, being larger in men (P value <0.05). Among our patients 27% had at least one adrenal gland body measuring ≥10 mm in thickness. Our study has defined the normal range of adrenal gland thickness in an Asian Indian adult population, which may be used as a baseline reference for future research and as a reference for radiological reporting.


Prothrombin G20210A is a bifunctional gene polymorphism.
The G20210A polymorphism has been shown to alter the efficiency of prothrombin mRNA processing. Here we show that the G20210A mutation also alters prothrombin mRNA stability. Three-fold more prothrombin protein and mRNA were produced in NIH-3T3 cells transfected with the prothrombin cDNAs containing the 20210A variant compared to cells expressing the 20210G variant. mRNA stability assays using chimeric globin transcripts harboring the G or A variant of the 97 nt prothrombin 3'-UTR indicated that the 20210G variant conferred greater instability to the globin reporter transcript than the A variant in transfected HepG2 cells. Both variants of the prothrombin 3'-UTR were shown to provide binding sites for a number of cellular proteins including HuR, an RNA binding protein associated with mRNA stability. Our results indicate that the G20210A is a bifunctional polymorphism, as it not only alters the efficiency of mRNA processing, but also the decay rate of prothrombin mRNA.


Th1/Th2 Balance and Th17/Treg-Mediated Immunity in relation to Murine Resistance to Dextran Sulfate-Induced Colitis.
The role of the Th17/Treg balance in the development of experimental colitis remains poorly understood. We exploited the differential response of BALB/c mice and C57BL/6 mice towards drinking water mediated by dextran sulfate sodium (DSS) challenge. DSS-resistant BALB/c mice were characterized by low levels of IFN-γ and TNF-α but high levels of IL-4, IL-6, IL-10, IL-17A, IL-17F, and colon lamina propria and mesenteric lymph node (MLN) CD4+CD25+FoxP3+ T cells when compared to C57BL/6 mice. Collectively, these data indicate the propensity of BALB/c mice towards a Th2/Th17/Treg-polarized immunity protecting these animals against DSS challenge, whereas Th1-polarization of C57BL/6 mice confers sensitivity to DSS-induced colitis. The intrinsic congenital capacity of mouse strains with respect to T cell proliferation determines sensitivity to experimental colitis.


Synthesis and structure of Ag(1-Me-12-SiPh3-CB11F10): selective F12 substitution in 1-Me-CB11F11- and the first Ag(arene)4+ tetrahedron.
The selective substitution of the antipodal F atom in 1-Me-CB(11)F(11)- with a SiPh(3) moiety led to the isolation and structure determination of the cesium(I) and silver(I) salts of the 1-Me-12-SiPh(3)-CB(11)F(10)- anion. The silver salt contains both a nearly trigonal-planar Ag(arene)(3)+ cation and the first example of a Ag(arene)(4)+ cation.


Transitions in Prognostic Awareness Among Terminally Ill Cancer Patients in Their Last 6 Months of Life Examined by Multi-State Markov Modeling.
Developing accurate prognostic awareness, a cornerstone of preference-based end-of-life (EOL) care decision-making, is a dynamic process involving more prognostic-awareness states than knowing or not knowing. Understanding the transition probabilities and time spent in each prognostic-awareness state can help clinicians identify trigger points for facilitating transitions toward accurate prognostic awareness. We examined transition probabilities in distinct prognostic-awareness states between consecutive time points in 247 cancer patients' last 6 months and estimated the time spent in each state. Prognostic awareness was categorized into four states: (a) unknown and not wanting to know, state 1; (b) unknown but wanting to know, state 2; (c) inaccurate awareness, state 3; and (d) accurate awareness, state 4. Transitional probabilities were examined by multistate Markov modeling. Initially, 59.5% of patients had accurate prognostic awareness, whereas the probabilities of being in states 1-3 were 8.1%, 17.4%, and 15.0%, respectively. Patients' prognostic awareness generally remained unchanged (probabilities of remaining in the same state: 45.5%-92.9%). If prognostic awareness changed, it tended to shift toward higher prognostic-awareness states (probabilities of shifting to state 4 were 23.2%-36.6% for patients initially in states 1-3, followed by probabilities of shifting to state 3 for those in states 1 and 2 [9.8%-10.1%]). Patients were estimated to spend 1.29, 0.42, 0.68, and 3.61 months in states 1-4, respectively, in their last 6 months. Terminally ill cancer patients' prognostic awareness generally remained unchanged, with a tendency to become more aware of their prognosis. Health care professionals should facilitate patients' transitions toward accurate prognostic awareness in a timely manner to promote preference-based EOL decisions. Terminally ill Taiwanese cancer patients' prognostic awareness generally remained stable, with a tendency toward developing higher states of awareness. Health care professionals should appropriately assess patients' readiness for prognostic information and respect patients' reluctance to confront their poor prognosis if they are not ready to know, but sensitively coach them to cultivate their accurate prognostic awareness, provide desired and understandable prognostic information for those who are ready to know, and give direct and honest prognostic information to clarify any misunderstandings for those with inaccurate awareness, thus ensuring that they develop accurate and realistic prognostic knowledge in time to make end-of-life care decisions.


The Lifebox Surgical Headlight Project: engineering, testing, and field assessment in a resource-constrained setting.
Poor surgical lighting represents a major patient safety issue in low-income countries. This study evaluated device performance and undertook field assessment of high-quality headlights in Ethiopia to identify critical attributes that might improve safety and encourage local use. Following an open call for submissions (December 2018 to January 2019), medical and technical (non-medical) headlights were identified for controlled specification testing on 14 prespecified parameters related to light quality/intensity, mounting and battery performance, including standardized illuminance measurements over time. The five highest-performing devices (differential illumination, colour rendering, spot size, mounting and battery duration) were distributed to eight Ethiopian surgeons working in resource-constrained facilities. Surgeons evaluated the devices in operating rooms, and in a comparative session rated each headlight in terms of performance and willingness to purchase. Of 25 submissions, eight headlights (6 surgical and 2 technical) met the criteria for full specification testing. Scores ranged from 8 to 12 (of 14), with differential performance in lighting, mounting and battery domains. Only two headlights met the illuminance parameters of more than 35 000 lux during initial testing, and no headlight satisfied all minimum specifications. Of the five headlights evaluated in Ethiopia, daily operation logbooks noted variability in surgeons' opinions of lighting quality (6-92 per cent) and spot size (0-92 per cent). Qualitative interviews also yielded important feedback, including preference for easy transport. Surgeons sought high quality with price sensitivity (using out-of-pocket funds) and identified the least expensive but high-functioning device as their first choice. No device satisfied all the predetermined specifications, and large price discrepancies were critical factors leading surgeons' choices. The favoured device is undergoing modification by the manufacturer based on design feedback so an affordable, high-quality surgical headlight crafted specifically for the needs of resource-constrained settings can be used to improve surgical safety.