[The clinical significance of expression and amplification of FGF3 in bladder transitional cell carcinoma].
To investigate the amplification and expression of FGF3 in bladder transitional cell carcinoma (BTCC) and its clinical significance. Immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH) methods were used to examine the protein expression and amplification of FGF3 in a tissue microarray (TMA) of 100 BTCCs and 30 adjacent normal bladder mucosas, so as to analyze their correlation and association with patient's clinico-pathological features. In this study, none of the normal bladder mucosas were detected FGF3 positivity, while in 89 informative BTCCs, 20 (22%) cases were observed positive expression of FGF3 protein, and it was significantly more frequently to occur in BTCCs of poor-differentiation (Grade 3), later clinical stage (T2-4) and tumor in >or= 3 cm in diameter (P < 0.05). In FISH study, 10 of the 63 (16%) informative BTCCs were observed amplification of FGF3 and it was significantly associated with BTCC's tumor size and clinical stage (P < 0.05). In addition, 10 BTCCs with amplification of FGF3 in this study were all detected positive expression of FGF3 protein, while in the remaining 53 BTCCs without amplification of FGF3, only 3 (6%) cases were observed FGF3 protein positivity. The up-regulated expression of FGF3 in BTCC was associated closely with tumor's malignant clinical phenotypes, and it might be involved in the malignant progression of parts of BTCC. The amplification of FGF3 gene might be a predominant mechanism of increased expression of FGF3 protein in BTCC.


Seven cases of human nocardiosis caused by Nocardia farcinica.
Twelve nocardia strains isolated from Danish human patients have been examined and compared with reference strains of Nocardia asteroides and N. farcinica using Tsukamura's (1969) simple method of identification. Seven of these strains, recovered from human lesions compatible with nocardioisis, were identified as N. farcinica. These investigations suggest that N. farcinica could be a more common cause of human nocardiosis in Denmark than N. asteroides and other nocardias. N. farcinica might also be the cause of human nocardiosis in other countries.


FINE STRUCTURE OF CHLORIDE CELLS FROM THREE SPECIES OF FUNDULUS.
A MORPHOLOGICAL BASIS FOR OSMOREGULATION IN THE TELEOSTS WAS STUDIED BY COMPARING THE FINE STRUCTURE OF CHLORIDE CELLS FOUND IN EPITHELIA OF THE GILLS OF THREE SPECIES OF FISH: Fundulus heteroclitus which can survive in a wide range of salinities, and F. similis and F. chrysotus which are usually restricted to salt water and fresh water environments, respectively. Gills were removed from F. heteroclitus which had been laboratory adapted to either sea water or pond water. For a comparison, gills were also removed from the marine F. similis and the fresh water F. chrysotus which had been adapted to their natural environments. Gill-filaments were fixed in Millonig's phosphate buffered (pH 7.4), 1 per cent osmium tetroxide and were embedded in Epon. Thin sections of filaments were stained with lead hydroxide. The cytoplasm of chloride cells of all three species of Fundulus is heavily populated with mitochondria and is filled with tubules of the agranular endoplasmic reticulum (ER). An orderly secretory cycle was indicated for chloride cells of salt water adapted F. heteroclitus and the marine F. similis. An amorphous material is observed in the agranular ER. Its density increases towards the apical end of the cell. In the apical cytoplasm, tubules of the agranular ER appear to converge and to discharge the amorphous material into an apical cavity. Except for the actual opening of the apical cavity, the distal end of salt water adapted chloride cells is characteristically shielded from the hypertonic environment by thin cytoplasmic flanges projecting from the neighboring epithelial cells. Chloride cells of the fresh water F. chrysotus resemble chloride cells of pond water adapted F. heteroclitus, in that these cells do not have apical cavities with the functional appearance of those in the sea water adapted forms. The distal end of fresh water adapted chloride cells is typically exposed to the free surface of the gill-filament. The possible function of the cell type is discussed.


Dual-Polymer Drops, Contact Lens Comfort, and Lid Wiper Epitheliopathy.
This study compared a new contact lens rewetting drop containing both carboxymethylcellulose and hyaluronic acid (CMC-HA) with a standard drop containing carboxymethylcellulose only (CMC). Symptoms of discomfort typical in lens wear and lid wiper epitheliopathy (LWE) were assessed over a 3-month period in a diverse sample of contact lens wearers. Adapted daily-wear contact lens subjects using hydrogel, silicone hydrogel, or rigid gas permeable lenses were enrolled in this prospective, randomized, double-masked, parallel-group, 90-day study conducted at 15 clinical sites. Subjects were randomized 2:1 to CMC-HA (n = 244) or CMC alone (n = 121) with dosage at least four times per day, along with their habitual lens care system. At baseline and at days 7, 30, 60, and 90, subject-completed questionnaires, bulbar conjunctival staining, LWE, contact lens distance visual acuity (CLDVA), and standard safety measures were assessed. At day 90, CMC-HA performed significantly better than CMC in ocular symptoms including dryness throughout the day (p = 0.006), and burning/stinging throughout the day (p = 0.02) and at the end of the day (p < 0.001). CMC-HA also performed numerically better for dryness at the end of day (p = 0.06). LWE staining was improved in the CMC-HA group at day 90 whereas it increased slightly in the CMC alone group, with a significant between-group difference (p = 0.009). CMC-HA also demonstrated greater reduction in conjunctival staining compared with CMC alone at day 90 (p = 0.08). No differences in CLDVA, contact lens wear time, acceptability, and product use were observed, and safety outcomes were similar between groups. The addition of HA to a standard CMC rewetting drop improves clinical performance. In this comparison of rewetting drop efficacy in contact lens wearers, LWE was a useful clinical sign for differentiating clinical performance.


Acetylcholine modulates I(f) and IK(ACh) via different pathways in rabbit sino-atrial node cells.
The aim of the present study was to examine whether a direct G-protein pathway was necessary to explain the depression of the cardiac pacemaker current (I(f)) by acetylcholine (ACh). Pacemaker current and spontaneous fluctuations of muscarinic K+ current (IK(ACh)) were simultaneously measured in sino-atrial (SA) node cells isolated from rabbit hearts, using cell-attached and outside-out macro-patches. The effects of 1 microM ACh, added to the bathing solution, were compared on I(f) and on IK(ACh), known to be activated via a direct G-protein mechanism. In a cell-attached configuration where cytoplasmic substrates were present, ACh depressed I(f) by a negatively directed shift of the open probability curve of 7.6 +/- 0.3 mV. ACh never induced modifications in spontaneous openings of muscarinic K+ channels. These results indicate that ACh added to the external solution is unable to modulate IK(ACh) recorded in the membrane-delimited mode, via a G-protein pathway. The ACh depressing effect on I(f) is related to changes in second messenger activity. In outside-out conditions, with guanosine triphosphate (GTP) added to the pipette solution. ACh increased the variance of IK(ACh) fluctuations from 1.66 +/- 0.50 pA2 to 6.60 +/- 2.05 pA2 (at -120 mV). indicating direct G-protein action. ACh had no effect on I(f). It is concluded that in SA node cells, the regulation of I(f) by muscarinic receptors does not involve a direct G-protein pathway. ACh depresses I(f) by a mechanism that probably implicates reduction of intracellular cAMP production.


Liver-inherent immune system: its role in blood-stage malaria.
The liver is well known as that organ which is obligately required for the intrahepatocyte development of the pre-erythrocytic stages of the malaria-causative agent Plasmodium. However, largely neglected is the fact that the liver is also a central player of the host defense against the morbidity- and mortality-causing blood stages of the malaria parasites. Indeed, the liver is equipped with a unique immune system that acts locally, however, with systemic impact. Its main "antipodal" functions are to recognize and to generate effective immunoreactivity against pathogens on the one hand, and to generate tolerance to avoid immunoreactivity with "self" and harmless substances as dietary compounds on the other hand. This review provides an introductory survey of the liver-inherent immune system: its pathogen recognition receptors including Toll-like receptors (TLRs) and its major cell constituents with their different facilities to fight and eliminate pathogens. Then, evidence is presented that the liver is also an essential organ to overcome blood-stage malaria. Finally, we discuss effector responses of the liver-inherent immune system directed against blood-stage malaria: activation of TLRs, acute phase response, phagocytic activity, cytokine-mediated pro- and anti-inflammatory responses, generation of "protective" autoimmunity by extrathymic T cells and B-1 cells, and T cell-mediated repair of liver injuries mainly produced by malaria-induced overreactions of the liver-inherent immune system.


Benchmarking the future generalist workforce.
Previous workforce analyses by the Council on Graduate Medical Education (COGME) have concluded that the United States has too few, or just enough, generalists. However, recent trends suggest that more physicians are entering primary care, raising the possibility of a future surplus. To project the future supply of generalists relative to future requirements. We developed a model that projects the supply of generalists into the future on the basis of the annual number of physicians entering and leaving the workforce. We calculated the number of clinically active generalists from the physician master-files of the American Medical Association and American Osteopathic Association. The number of graduating trainees entering the generalist workforce was calculated from the 1999 to 2000 AMA Annual Survey of GME. The number leaving was calculated by using age- and sex-specific rates or physician death and retirement provided by the Bureau of Health Professions. Projected per capita number of clinically active generalists to the year 2025, relative to physician requirements suggested by COGME and several regional benchmarks of physician supply. The supply of generalists is projected to grow from its current level of 69 per 100,000 to nearly 88 per 100,000 by the year 2025. Adjusting for the changing age-sex structure of the physician workforce decreases the "effective" supply to 85 generalists per 100,000. By the year 2025, the effective supply of generalists will exceed COGME's upper estimate of generalist requirements (80 per 100,000), resulting in an excess of about 18,000 full-time equivalent generalists. The future supply of generalists will also exceed most current regional benchmarks of generalist supply. At current levels of training, the supply of generalists will grow substantially and soon exceed several benchmarks for generalist requirements.


Evaluation of cutaneous side-effects associated with chemotherapeutic use in oncological patients.
Side-effects are frequently encountered in classic chemotherapy. However, the recent development of targeted treatments has resulted in a diminution of these. The most common side-effects are dermatological. To investigate cutaneous changes occurring in patients using classic and targeted chemotherapeutic agents, and the prevalence of these changes in the two groups. One hundred twenty-eight volunteer oncological patients using chemotherapeutic agents were included in this prospective study. Two subgroups were established, patients using classic and those using targeted chemotherapeutic agents. Xerosis was the most common side-effect, being seen in 93 (72.7%) of the 128 patients. Other common side-effects included alopecia, pruritus, mucositis, skin pigmentation, and palmar-plantar erythema. The most common side-effects in the classic chemotherapeutic group were xerosis seen in 71 (75.5%) patients, pruritus in 50 (53.2%), alopecia in 49 (52.1%), and nail changes in 43 (45.7%). The most common side-effects in the targeted chemotherapeutic group were xerosis seen in 22 (64.7%) patients, nail changes in 17 (50%), alopecia in 15 (44.1%), and pruritus in 13 (38.2%). The most common cutaneous side-effects were less prevalent in the patient group using targeted chemotherapeutic agents than in the classic group. Various side-effects associated with chemotherapeutic use which had not been previously reported were also identified in this study. Classic chemotherapeutic agents caused more serious side-effects requiring discontinuation of treatment than targeted chemotherapeutic agents.


Correlation analysis of VHL and Jade-1 gene expression in human renal cell carcinoma.
The aim of this study was to investigate the correlation of von Hippel-Lindau tumor suppressor (VHL) mRNA expression and jade family PHD finger 1 (Jade-1) gene expression in patients with renal cell carcinoma (RCC). Another aim of this study was to analyze the relationship of these two genes with clinicalpathological features of the RCC patients. A total of 75 RCC patients who received surgically therapy in our hospital were included. All patients had complete pathological data. The expression of VHL/Jade-1 was determined by real-time polymerase chain reaction (RT-PCR). VHL and Jade-1 were both obviously downregulated in RCC tissues than that of the matched normal tissues, and both negatively correlated with tumor size as well as tumor grade. And we found a fine association of VHL gene expression with Jade-1. VHL/Jade-1 exhibited significantly decreased expression in RCC tissues and was closely related to the clinical prognosis of patients. The finding of VHL expression positively correlated with Jade-1 expression shed light and provided crucial evidence on the connection of VHL protein with Wnt/b-catenin pathway.


Vectorial transport of nucleoside analogs from the apical to the basolateral membrane in double-transfected cells expressing the human concentrative nucleoside transporter hCNT3 and the export pump ABCC4.
The identification of the transport proteins responsible for the uptake and the efflux of nucleosides and their metabolites enables the characterization of their vectorial transport and a better understanding of their absorption, distribution, and elimination. Human concentrative nucleoside transporters (hCNTs/SLC28A) are known to mediate the transport of natural nucleosides and some nucleoside analogs into cells in a sodium-dependent and unidirectional manner. On the other hand, several human multidrug resistance proteins [human ATP-binding cassette transporter, subfamily C (ABCC)] cause resistance against nucleoside analogs and mediate transport of phosphorylated nucleoside derivatives out of the cells in an ATP-dependent manner. For the integrated analysis of uptake and efflux of these compounds, we established a double-transfected Madin-Darby canine kidney (MDCK) II cell line stably expressing the human uptake transporter hCNT3 in the apical membrane and the human efflux pump ABCC4 in the basolateral membrane. The direction of transport was from the apical to the basolateral compartment, which is in line with the unidirectional transport and the localization of both recombinant proteins in the MDCKII cells. Recombinant hCNT3 mediated the transport of several known nucleoside substrates, and we identified 5-azacytidine as a new substrate for hCNT3. It is of interest that coexpression of both transporters was confirmed in pancreatic adenocarcinomas, which represent an important clinical indication for the therapeutic use of nucleoside analogs. Thus, our results establish a novel cell system for studies on the vectorial transport of nucleosides and their analogs from the apical to the basolateral compartment. The results contribute to a better understanding of the cellular transport characteristics of nucleoside drugs.


Robust composite repetitive control with disturbance observer for high-precision tracking of piezo-actuated nano-stages with measurement delays.
In this paper, a robust composite control strategy in the framework of unified infinite-dimensional H∞ optimal control is developed to support nano-scale periodic tracking with improved non-harmonic disturbance attenuation of piezo-actuated nano-stages with sensor-induced measurement delays. In particular, we analyze the electromechanical coupled dynamics and derive a multi-perturbation model, where an extended Youla-Kucera parameterization-based repetitive controller with a disturbance observer is constructed to optimize control performances on high-precision tracking and perturbation rejection. The controller parameters are solved by using a unified infinite-dimensional H∞ optimization method. Comprehensive experiments on a piezo-actuated stage are conducted, where comparative results with representative methods, such as the conventional repetitive control and proportional-integral-derivative control, demonstrate significant performance improvements in hysteresis compensation, trajectory tracking, and disturbance suppression of the proposed method.


Weighted parallel contributions of binocular correlation and match signals to conscious perception of depth.
Binocular disparity is detected in the primary visual cortex by a process similar to calculation of local cross-correlation between left and right retinal images. As a consequence, correlation-based neural signals convey information about false disparities as well as the true disparity. The false responses in the initial disparity detectors are eliminated at later stages in order to encode only disparities of the features correctly matched between the two eyes. For a simple stimulus configuration, a feed-forward nonlinear process can transform the correlation signal into the match signal. For human observers, depth judgement is determined by a weighted sum of the correlation and match signals rather than depending solely on the latter. The relative weight changes with spatial and temporal parameters of the stimuli, allowing adaptive recruitment of the two computations under different visual circumstances. A full transformation from correlation-based to match-based representation occurs at the neuronal population level in cortical area V4 and manifests in single-neuron responses of inferior temporal and posterior parietal cortices. Neurons in area V5/MT represent disparity in a manner intermediate between the correlation and match signals. We propose that the correlation and match signals in these areas contribute to depth perception in a weighted, parallel manner.This article is part of the themed issue 'Vision in our three-dimensional world'.


A radiobiological model of metastatic burden reduction for molecular radiotherapy: application to patients with bone metastases.
Skeletal tumour burden is a biomarker of prognosis and survival in cancer patients. This study proposes a novel method based on the linear quadratic model to predict the reduction in metastatic tumour burden as a function of the absorbed doses delivered from molecular radiotherapy treatments. The range of absorbed doses necessary to eradicate all the bone lesions and to reduce the metastatic burden was investigated in a cohort of 22 patients with bone metastases from castration-resistant prostate cancer. A metastatic burden reduction curve was generated for each patient, which predicts the reduction in metastatic burden as a function of the patient mean absorbed dose, defined as the mean of all the lesion absorbed doses in any given patient. In the patient cohort studied, the median of the patient mean absorbed dose predicted to reduce the metastatic burden by 50% was 89 Gy (interquartile range: 83-105 Gy), whilst a median of 183 Gy (interquartile range: 107-247 Gy) was found necessary to eradicate all metastases in a given patient. The absorbed dose required to eradicate all the lesions was strongly correlated with the variability of the absorbed doses delivered to multiple lesions in a given patient (r = 0.98, P < 0.0001). The metastatic burden reduction curves showed a potential large reduction in metastatic burden for a small increase in absorbed dose in 91% of patients. The results indicate the range of absorbed doses required to potentially obtain a significant survival benefit. The metastatic burden reduction method provides a simple tool that could be used in routine clinical practice for patient selection and to indicate the required administered activity to achieve a predicted patient mean absorbed dose and reduction in metastatic tumour burden.


Combined photothermal and photodynamic therapy by hyaluronic acid-decorated polypyrrole nanoparticles.
To develop a nanoparticle-based platform using polypyrrole and IR-780 for effective combined photothermal and photodynamic therapy. IR-780 was loaded in a poly(lactic-co-glycolic acid) core, decorated with polypyrrole shells and hyaluronic acid (IPPH). Physicochemical properties and in vitro and in vivo anticancer effects of these nanoparticles were evaluated. The resulting IPPHs were spherical, small and negatively charged. Under near-infrared laser irradiation, the IPPHs generated reactive oxygen species and heat and synergistically improved therapeutic efficacy. The antitumor effects were confirmed by in vitro cellular reactive oxygen species detection and cytotoxicity assays, and in vivo in a xenograft tumor model, with no damage to body organs. Our results indicate the potential of applying IPPH in oncology nanomedicine.


Poly(ADP-ribose) Polymerase in Neurodegeneration: Radiosynthesis and Radioligand Binding in ARC-SWE tg Mice.
We report the synthesis, radiosynthesis, and characterization of a radioligand for poly(ADP-ribose) polymerase (PARP). PARP is of central importance in cell homeostasis, neuroplasticity, and neurodegeneration in the brain. A radiolabeled PARP inhibitor was developed and used for autoradiographic quantification of PARP protein concentration in wild-type and transgenic rodent brains ex vivo in high resolution. The binding of [3H]rucaparib was found to be confined to PARP-expressing domains, for example, cerebellar cortex or hippocampal regions in both models. Saturation binding experiments confirmed selective and reversible binding to a single site ( Kd = 1.1 ± 0.2 nM).


Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus.
The inter-organ flux of substrates after a protein-rich meal was studied in seven healthy subjects and in eight patients, with diabetes mellitus. Arterial concentrations as well as leg and splanchnic exchange of amino acids, carbohydrate substrates, free fatty acids (FFA), and ketone bodies were examined in the basal state and for 3 h after the ingestion of lean beef (3 g/kg body wt). Insulin was withheld for 24 h before the study in the diabetic patients. In the normal subjects, after protein ingestion, there was a large amino acid release from the splanchnic bed predominantly involving the branched chain amino acids. Valine, isoleucine, and leucine accounted together for more than half of total splanchnic amino acid output. Large increments were seen in the arterial concentrations of the branched chain amino acids (100-200%) and to a smaller extent for other amino acids. Leg exchange of most amino acids reverted from a basal net outut to a net uptake after protein feeding which was most marked for the branched chain amino acids. The latter accounted for more than half of total peripheral amino acid uptake...


MosaiCatcher v2: a single-cell structural variations detection and analysis reference framework based on Strand-seq.
Single-cell DNA template strand sequencing (Strand-seq) allows a range of various genomic analysis including chromosome length haplotype phasing and structural variation (SV) calling in individual cells. Here, we present MosaiCatcher v2, a standardized workflow and reference framework for single-cell SV detection using Strand-seq. This framework introduces a range of functionalities, including: an automated upstream Quality Control (QC) and assembly sub-workflow that relies on multiple genome assemblies and incorporates a multistep normalization module, integration of the single-cell nucleosome occupancy and genetic variation analysis SV functional characterization and of the ArbiGent SV genotyping modules, platform portability, as well as a user-friendly and shareable web report. These new features of MosaiCatcher v2 enable reproducible computational processing of Strand-seq data, which are increasingly used in human genetics and single-cell genomics, toward production environments. MosaiCatcher v2 is compatible with both container and conda environments, ensuring reproducibility and robustness and positioning the framework as a cornerstone in computational processing of Strand-seq data. MosaiCatcher v2 is a standardized workflow, implemented using the Snakemake workflow management system. The pipeline is available on GitHub: https://github.com/friendsofstrandseq/mosaicatcher-pipeline/ and on the snakemake-workflow-catalog: https://snakemake.github.io/snakemake-workflow-catalog/?usage=friendsofstrandseq/mosaicatcher-pipeline. Strand-seq example input data used in the publication can be found in the Data availability statement. Additionally, a lightweight dataset for test purposes can be found on the GitHub repository.


Sub-nanosecond micro laser passively Q-switched by a GaAs saturable absorber.
A Nd:GdVO4/GaAs passively Q-switched laser has been demonstrated based on a microchip design. Under high pump power, the high optical intensity inside the laser cavity triggered the two photon absorption of GaAs, and the pulse duration was shortened to sub-nanosecond level. The shortest pulse of 690 ps was obtained, which we believe is the shortest pulse ever generated with a pure GaAs saturable absorber. The maximum average output power, highest repetition rate, largest pulse energy, and highest peak power were 1 W, 190 kHz, 7.5 μJ, and 10.8 kW, respectively. The results indicated that GaAs is a promising passively Q-switched saturable absorber and still has potential to explore.


[General anesthesia for a patient with pulmonary hypertension, bronchial asthma and obesity].
The management of the patient with pulmonary hypertension is a challenge for the anesthesiologists because the risk of right-sided heart failure is markedly increased. We experienced a case of general anesthesia for a patient with pulmonary hypertension (mean pulmonary arterial pressure 39 mmHg), bronchial asthma and obesity. A 31-year-old woman was scheduled for arytenoid rotation for left recurrent nerve palsy. We applied routine monitors (noninvasive blood-pressure, five-lead electrocardiogram, pulse oximeter), and direct blood pressure monitoring through the radial artery. Anesthesia was induced with midazolam 4 mg, fentanyl 100 microg and sevoflurane 5%, and maintained with sevoflurane (1-2%) and nitrous oxide in oxygen. Surgery was completed in 100 minutes without any complications. We could successfully perform general anesthesia in a patient complicated by pulmonary hypertension, bronchial asthma and obesity, without invasive right-sided heart catheterization.


Extended left hepatectomy for intrahepatic cholangiocarcinoma: hepatic vein reconstruction with in-situ hypothermic perfusion and extracorporeal membrane oxygenation.
Liver resection for intrahepatic cholangiocarcinoma (ICC) with invasion of the inferior vena cava (IVC) and hepatic veins (HV) is a challenging procedure. We report a case of a 63-year-old woman with a 6-cm, centrally located liver mass. Her biochemistry results were normal except for a Ca19-9 level of 1199 U/ml. The liver biopsy was consistent with ICC and 60% macrosteatosis. Abdominal CT scans revealed a large central mass invading the left HV, middle HV and right HV, infringing on their junction with the vena cava. An operation was planned using a 3-dimensional (3D) computer simulation model using dedicated software. We also describe a novel veno-portal-venous extracorporeal membrane oxygenation (VPV-ECMO) support with in-situ hypothermic perfusion (IHP) during this procedure. We aimed to perform an extended left hepatectomy and reconstruct 3 right HV orifices with an interposition jump graft to the IVC with total vascular exclusion (TVE) and IHP A supplemental video describing the preoperative planning, the operative procedure with the postoperative follow-up in detail is presented. After the patient was discharged, she developed a hepatic venous outflow obstruction 3 months postoperatively, which was effectively managed with hepatic venous stenting by interventional radiology. She is currently symptom free and without tumour recurrence at the 1-year follow-up. This report demonstrates that extended left hepatectomy for IHC with IHP and VPV-ECMO is safe and feasible under the supervision of a highly experienced team.


The study of H. pylori putative candidate factors for single- and multi-component vaccine development.
Helicobacter pylori has grown to colonize inside the stomach of nearly half of the world's population, turning into the most prevalent infections in the universe. Medical care failures noticeably confirm the need for a vaccine to hinder or deal with H. pylori. This review is planned to discuss the most known factors as a vaccine candidate, including single (AhpC, BG, CagA, KatA, Fla, Hsp, HWC, Lpp, LPS, NAP, OMP, OMV, SOD, Tpx, Urease, VacA) and multi-component vaccines. Many promising results in the field of single and multivalent vaccine can be seen, but there is no satisfactory outcome and neither a prophylactic nor a therapeutic vaccine to treat or eradicate the infection in human has been acquired. Hence, selecting suitable antigen is an important factor as an appropriate adjuvant. Taken all together, the development of efficient anti-H. pylori vaccines relies on the fully understanding of the interactions between H. pylori and its host immune system. Therefore, more work should be done on epitope mapping, analysis of molecular structure, and determination of the antigen determinant region as well due to design a vaccine, preferably a multi-component vaccine to elicit specific CD4 T-cell responses that are required for H. pylori vaccine efficacy.


Concordance of ompA types in children re-infected with ocular Chlamydia trachomatis following mass azithromycin treatment for trachoma.
The chlamydial major outer membrane protein, encoded by the ompA gene, is a primary target for chlamydial vaccine research. However, human studies of ompA-specific immunity are limited, and prior studies have been limited in differentiating re-infection from persistent infection. The purpose of this study was to assess whether children living in trachoma-endemic communities with re-infections of ocular chlamydia were more likely to be infected with a different or similar genovar. The study included 21 communities from a trachoma-hyperendemic area of Ethiopia that had been treated with a mass azithromycin distribution for trachoma. Conjunctival swabbing was offered to all children younger than 5 years of age at baseline (i.e., pre-treatment), and then at follow-up visits 2 and 6 months later. Swabs were subjected to polymerase chain reaction (PCR) to detect C. trachomatis. A random sample of 359 PCR-positive swabs, stratified by study visit and study community, was chosen for ompA sequencing. In addition, ompA sequencing was performed on all swabs of 24 children who experienced chlamydial re-infection (i.e., positive chlamydial test before treatment, negative test 2 months following mass distribution of azithromycin, and again a positive test 6 months post-treatment). ompA sequencing was successful for 351 of 359 swabs of the random sample and 44 of 48 swabs of the re-infection sample. In the random sample, ompA types clustered within households more than would be expected by chance. Among the 21 re-infected children with complete ompA data, 14 had the same ompA type before and after treatment. The high frequency of ompA concordance suggests incomplete genovar-specific protective immunity and the need for multiple antigens as vaccine targets.


Day-night differences in neural activation in histaminergic and serotonergic areas with putative projections to the cerebrospinal fluid in a diurnal brain.
In nocturnal rodents, brain areas that promote wakefulness have a circadian pattern of neural activation that mirrors the sleep/wake cycle, with more neural activation during the active phase than during the rest phase. To investigate whether differences in temporal patterns of neural activity in wake-promoting regions contribute to differences in daily patterns of wakefulness between nocturnal and diurnal species, we assessed Fos expression patterns in the tuberomammillary (TMM), supramammillary (SUM), and raphe nuclei of male grass rats maintained in a 12:12 h light-dark cycle. Day-night profiles of Fos expression were observed in the ventral and dorsal TMM, in the SUM, and in specific subpopulations of the raphe, including serotonergic cells, with higher Fos expression during the day than during the night. Next, to explore whether the cerebrospinal fluid is an avenue used by the TMM and raphe in the regulation of target areas, we injected the retrograde tracer cholera toxin subunit beta (CTB) into the ventricular system of male grass rats. While CTB labeling was scarce in the TMM and other hypothalamic areas including the suprachiasmatic nucleus, which contains the main circadian pacemaker, a dense cluster of CTB-positive neurons was evident in the caudal dorsal raphe, and the majority of these neurons appeared to be serotonergic. Since these findings are in agreement with reports for nocturnal rodents, our results suggest that the evolution of diurnality did not involve a change in the overall distribution of neuronal connections between systems that support wakefulness and their target areas, but produced a complete temporal reversal in the functioning of those systems.


Efficacy of a brief web-based tonic immobility psychoeducation intervention among trauma-exposed adults: A randomized clinical trial.
Tonic immobility (TI) is a defensive response that may occur during traumatic events. Although TI is adaptive in certain circumstances, it has been shown to contribute to increased trauma-related symptoms and poorer recovery. However, current frontline treatments for posttraumatic stress disorder (PTSD) have not focused significant attention on the experience of TI. Thus, the aim of this study was to develop and test the impact of a brief TI-focused psychoeducation (TIP) intervention on posttraumatic cognitions and PTSD symptoms relative to a health education control intervention. The sample included 46 adults with elevated PTSD symptoms who endorsed prior TI episodes. After providing informed consent, participants were randomly assigned to either the active or control intervention and completed self-report questionnaires including the tonic immobility questionnaire (TIQ-R), Life Events Checklist for DSM-5 (LEC-5), Posttraumatic Stress Checklist for DSM-5 (PCL-5), Posttraumatic Cognitions Inventory (PTCI), and Positive and Negative Affect Schedule (PANAS) at baseline, 1-week, and 1-month follow-up assessments. Results from linear mixed effects models indicated that participants in the TIP condition reported significantly larger reductions in posttraumatic cognitions and PTSD symptoms at 1-week, ds = 0.48 and 0.84, respectively, and 1-month, ds = 0.67 and 0.74. The findings suggest that TIP is a promising intervention that may be used to reduce posttraumatic cognitions and PTSD symptoms associated with TI. Given the ease of access, TIP could be used as a standalone intervention or as an add-on to existing evidence-based treatments for PTSD.


Findings of retinitis on gadolinium-enhanced turbo fluid-attenuated inversion recovery images.
This study sought to determine the findings of retinal inflammation on gadolinium-enhanced turbo fluid-attenuated inversion recovery (tFLAIR) images. Five patients with retinal abnormalities (acquired immunodeficiency syndrome complicated by cytomegalovirus retinitis, two patients; lymphoma complicated by Herpes zoster retinitis, one patient; and diabetic retinopathy, two patients) were identified on routine brain magnetic resonance imaging examinations performed with gadolinium-enhanced tFLAIR; five healthy subjects were retrospectively reviewed for comparison. Retinal signal features and thickness were evaluated comparing gadolinium-enhanced tFLAIR with turbo spin-echo T2-weighted and spin-echo T1-weighted images with and without gadolinium. Abnormal retinal thickening and hyperintensity were most conspicuous on gadolinium-enhanced tFLAIR images. Unenhanced T1-weighted images failed to demonstrate any abnormalities. In the enhanced tFLAIR and T1-weighted images, retinal thickness greater than 1.2 mm was abnormal. Abnormal retinal contour and signal was most apparent on the tFLAIR images. Of the sequences studied, gadolinium-enhanced tFLAIR images were found to be the best in identifying incidental retinitis and diabetic retinopathy discovered on routine brain magnetic resonance imaging examinations.


Evaluation of a multi-agent chemotherapy protocol combining lomustine, procarbazine and prednisolone (LPP) for the treatment of relapsed canine non-Hodgkin high-grade lymphomas.
The standard of care treatment for canine lymphoma is multi-agent chemotherapy containing prednisolone, cyclophosphamide, vincristine and an anthracycline such as doxorubicin (CHOP) or epirubicin (CEOP). Lomustine, vincristine, procarbazine, and prednisone (LOPP) has been evaluated as a rescue, with encouraging results; however, resistance to vincristine is likely in patients relapsing on CHOP/CEOP, and this agent may enhance LOPP toxicity without improving efficacy. The aim of this study was to evaluate responses to a modified-LOPP protocol that does not include vincristine (LPP) and is administered on a 21-day cycle. Medical records of dogs with high-grade multicentric lymphoma from 2012 to 2017 were reviewed. Dogs with relapsed lymphoma that received LPP as a rescue protocol were enrolled. Response, time from initiation to discontinuation (TTD) and toxicity of LPP were assessed. Forty-one dogs were included. Twenty-five dogs (61%) responded to LPP including 12 complete responses (CR) and 13 partial responses (PR). Responders had a significantly longer TTD (P < .001) compared to non-responders with 84 days for CR and 58 days for PR. Neutropenia was documented in 20 dogs (57%): 12 grade I to II, 8 grade III to IV. Thrombocytopenia was infrequent (20%): 5 grade I to II, 2 grade III to IV. Twelve dogs developed gastrointestinal toxicity (30%): 10 grade I to II and 2 grade III. Nineteen dogs had elevated ALT (59%): 9 grade I to II, 10 grade III to IV. Treatment was discontinued due to toxicity in 8 dogs (19%). The LPP protocol shows acceptable efficacy and toxicity-profile and minimizes in-hospital procedures.


Developing visibility for aging in social work: the first NGSWC.
In March 2001, the Council on Social Work Education's (CSWE) Strengthening Aging and Gerontology Education for Social Work (SAGE-SW) project published an action agenda for social work and aging (CSWE/SAGE-SW, 2001). CSWE SAGE-SW, funded by the John A. Hartford Foundation from 1998 to 2004, had several charges in the first phase of funding, including the gathering of data through a thorough review of literature, focus groups, surveys and a variety of activities to garner expert input. This agenda, often referred to as the Blueprint, identified a number of serious issues regarding the lack of attention, preparation, leadership and interest in aging within the social work profession. It also provided some recommended actions to address these issues and help set the stage for the creation of the National Gerontological Social Work Conference. What were the issues at hand and why might a National Gerontological Social Work Conference (NGSWC) address some of these issues?


Cytochrome P450 2B1 immunoreactivity in bronchiolar and alveolar epithelial cells after exposure of rats to ozone.
Pulmonary cytochrome P450 (P450) plays an important role in the metabolism of xenobiotics. We have previously demonstrated that exposure to ozone (O3), a major oxidant of photochemical smog, increases P450 content and xenobiotic metabolizing activities in the rat lung. Therefore, it is conceivable that O3 exposures modify the pattern and potency of xenobiotic metabolism. The aim of this study is to examine the effect of O3 exposure on localization of P450 in the lung. After exposure of rats to 0.4 ppm O3 for 14 days, the concentration of P450 2B1, the main isozyme of P450 in the lung, increased to 214% of the control value. By immunohistochemical analyses, O3 exposure caused hypertrophy and hyperplasia of P450 2B1-positive non-ciliated bronchiolar epithelial (Clara) cells, showing an increase in the cell number to 128% of the control level. At the proximal alveoli, O3 exposure induced hypertrophic epithelial cells that presented immunoreactivity to P450 2B1 and morphological characteristics of both type 1 and type 2 cells. These hypertrophic cells had lamellar inclusion bodies, microvilli, and extended cytoplasm. Typical type 2 cells did not react with anti-P450 2B1 antibody even after O3 exposure. These data suggest that O3 exposure may activate the P450-mediated xenobiotic metabolism in the pulmonary epithelial cells, and that expression of P450 2B1 in the pulmonary epithelial cells might be regulated by the factors involved in the process of the differentiation from type 2 to type 1 cells.


Effectiveness of a web-based self-help tool to reduce problem gambling: A randomized controlled trial.
Problem gambling constitutes a public health concern associated with psychopathological comorbidity, substance use, and financial difficulties. Most individuals with gambling problems avoid counseling services due to perceived stigma and their preference for self-reliance. Treatment accessibility could be improved through web-based interventions. We recruited 360 individuals with gambling problems and randomized them to a web-based intervention (n = 185) or an active control group consisting of a self-help manual for problem gambling (n = 175). The primary outcome was the number of days of gambling in the last 30 days. Secondary outcomes included money spent in the last 30 days, time gambling in the last 7 days, gambling-related problems, consumption of alcohol and cigarettes, and psychopathological comorbidity measured at posttreatment and 6-month follow-up. The primary outcome decreased significantly for both groups, with no significant difference between the groups. There were significant group × time interactions according to the Gambling Symptom Assessment Scale (F = 8.83, p <0 .001), the Problem Gambling Severity Index (F = 3.54, p = 0.030), for cigarettes smoked in the last 7 days (F = 26.68, p < 0.001), the Patient Health Questionnaire-9 (F = 19.41, p <0 .001), and the Generalized Anxiety Disorder-7 (F = 41.09, p <0 .001) favoring the intervention group. We experienced an overall high dropout rate (76%). Win Back Control seems to be an effective low-threshold treatment option for individuals with gambling problems that might otherwise be unapproachable for outpatient treatment services. Nevertheless, the high dropout rate should be considered when interpreting the study results, as they may have introduced a degree of variability.


Do nurses really use standard care plans?
The authors studied the use of standard care plans in one institution to determine whether and to what extent nurses were actually using them as tools for patient care. The study produced interesting results and suggestions for improvement. After reading this article, nursing administrators may want to promote similar studies in their own institutions. Improvements made as a result of the findings can pave the way for the next step: determining the effect of standard care plans on the quality of nursing practice and patient outcomes.


Effect of iron on antibacterial immunity in vaccinated mice.
The effect of iron on resistance to Salmonella typhimurium was investigated in mice inoculated with vaccines prepared from live and avirulent (SL3770) or killed and virulent (SR11 or LT2) bacteria. It has been found that mice vaccinated with SL3770 vaccine develop an immunity which can be neutralized with iron. Iron promoted the development of lethal infections by serving as a growth-essential nutrilite for infecting bacteria and by neutralizing the acquired immunity. The titration of this dual effect of iron showed that more iron was needed to neutralize the immunity in vaccinated animals than to promote bacterial growth in normal animals. In the presence of a sufficient amount of exogenous iron, as few as 10 bacteria caused lethal infections in normal and immune mice with the same effectiveness. This iron-sensitive immunity could be changed to iron-resistant immunity by the immunological stimulation of SL3770-vaccinated mice with a sonicated vaccine prepared from heat-killed SR11 or LT2 bacteria. In distinction to iron-sensitive immunity, iron-resistant immunity could be transferred from SR11- or LT2-stimulated to normal mice with serum. Although effective in the transfer of antibacterial immunity, sera of SR11- or LT2-stimulated mice supported the growth of virulent bacteria as well as did sera of normal mice. The absorption of immune serum with either SR11 or LT2 bacteria removed its protective quality, but the sensitized bacteria remained as infectious as untreated bacteria for iron-treated normal mice. Only in SL3770-vaccinated mice were the immune serum-sensitized bacteria not able to cause the infection in spite of daily treatment with iron. These results suggest that iron-resistant immunity is due to the synergistic action of specific antibody and phagocytes of immunologically stimulated animals.


Is bupropion useful in the treatment of post-stroke thalamic apathy? A case report and considerations.
Post-stroke apathy is considered to be one of the clinical consequences of lesions affecting the structures of the prefrontal cortex, basal ganglia, thalamus and limbic system. However, there is no current consensus on the treatment of post-stroke apathy, which mainly depends on the underlying etiology and comorbidities. A 62-year-old man, affected by hemorrhagic stroke in the left thalamus, presented with mood depression, anhedonia, hyporexia and marked apathy. The patient underwent clinical evaluation before and after receiving two different pharmacological therapies: escitalopram and bupropion. Only after treatment with the latter drug did the patient show changes: high motivation and willingness to pursue activities, greater interest in the external environment and social life activities, and an overall reduction of apathy. On the basis of our observations in this case, we hypothesize that the thalamic lesion resulted in disconnection of the fronto-striatal-thalamic circuits, and that loss of the dopaminergic striatal innervation caused the patient's apathetic state. The resolution of the apathetic disorder may be attributable to the action of the dopaminergic drug bupropion on the mesocortical pathway.


The impact of the COVID-19 pandemic on microbial keratitis presentation patterns.
Microbial keratitis (MK) is the most common non-surgical ophthalmic emergency, and can rapidly progress, causing irreversible sight-loss. This study explored whether the COVID-19 (C19) national lockdown impacted upon the clinical presentation and outcomes of MK at a UK tertiary-care centre. Medical records were retrospectively reviewed for all patients with presumed MK requiring corneal scrapes, presenting between 23rd March and 30th June in 2020 (Y2020), and the equivalent time windows in 2017, 2018 and 2019 (pre-C19). In total, 181 and 49 patients presented during the pre-C19 and Y2020 periods, respectively. In Y2020, concurrent ocular trauma (16.3% vs. 5.5%, p = 0.030) and immunosuppression use (12.2% vs 1.7%, p = 0.004) were more prevalent. Despite proportionately fewer ward admissions during the pandemic (8.2% vs 32.6%, p<0.001), no differences were observed in baseline demographics; presenting visual acuity (VA; median 0.6 vs 0.6 LogMAR, p = 0.785); ulcer area (4.0 vs 3.0mm2, p = 0.520); or final VA (0.30 vs 0.30 LogMAR, p = 0.990). Whilst the overall rates of culture positivity were similar in Y2020 and pre-C19 (49.0% vs. 54.7%, p = 0.520), there were differences in the cultures isolated, with a lower rate of poly-microbial cultures in Y2020 (8.3% vs. 31.3%, p = 0.022). Patient characteristics, MK severity and final visual outcomes did not appear to be affected in the first UK lockdown, despite fewer patients being admitted for care. Concurrent trauma and systemic immunosuppression use were greater than in previous years. The difference in spectra of isolated organisms may relate to behavioural changes, such as increased hand hygiene.


Bright Bose-Einstein gap solitons of atoms with repulsive interaction.
We report on the first experimental observation of bright matter wave solitons for 87Rb atoms with repulsive atom-atom interaction. This counterintuitive situation arises inside a weak periodic potential, where anomalous dispersion can be realized at the Brillouin zone boundary. If the coherent atomic wave packet is prepared at the corresponding band edge, a bright soliton is formed inside the gap. The strength of our system is the precise control of preparation and real time manipulation, allowing the systematic investigation of gap solitons.


Role of syntrophic microbial communities in high-rate methanogenic bioreactors.
Anaerobic purification is a cost-effective way to treat high strength industrial wastewater. Through anaerobic treatment of wastewaters energy is conserved as methane, and less sludge is produced. For high-rate methanogenesis compact syntrophic communities of fatty acid-degrading bacteria and methanogenic archaea are essential. Here, we describe the microbiology of syntrophic communities in methanogenic reactor sludges and provide information on which microbiological factors are essential to obtain high volumetric methane production rates. Fatty-acid degrading bacteria have been isolated from bioreactor sludges, but also from other sources such as freshwater sediments. Despite the important role that fatty acid-degrading bacteria play in high-rate methanogenic bioreactors, their relative numbers are generally low. This finding indicates that the microbial community composition can be further optimized to achieve even higher rates.


Comprehensive Evaluation of Cancer Treatment-Related Cardiac Dysfunction by Ultrasound Myocardial Strain: A Network Meta-Analysis.
Anticancer treatment regimens are effective but may lead to cardiac dysfunction. The meaning of this statement is that myocardial strain can be a good indicator of cancer treatment-related cardiac dysfunction. We used Bayesian network meta-analysis to compare and rank these regimens to comprehensively evaluate their influence on the heart. We searched multiple databases to identify relevant studies. Global longitudinal strain (GLS), global radial strain, global circumferential strain, and other parameters were collected at baseline (T0), from baseline to 3 months of follow-up (T3), from 3 months to 6 months of follow-up (T6), and from 6 months to 12 months or longer of follow-up (T12). The weight mean differences (WMD) with 95% confidence intervals (CI) were used to express continuous variables. Direct and indirect comparison and ranking of different regimens based on the forest plots and the surface under the cumulative ranking area. A total of 4613 subjects were included in 33 studies. Anthracycline-based chemotherapy (ANT), trastuzumab, paclitaxel plus carboplatin or clofarabine, and radiotherapy (RT) were more likely to reduce GLS and global circumferential strain at T3 and T12. In particular, ANT+RT resulted in a more significant decrease in GLS than ANT alone at T12 (WMD 1.15; 95% CI, 0.05-2.26). Interestingly, cardioprotective treatment regimens, such as anthracycline plus bisoprolol plus angiotensin-converting enzyme inhibitors (ANT+BB+ACEIs) (WMD -2.79; 95% CI, -5.06 to -0.52), and ANT plus rosuvastatin (STATINs) (WMD -2.92; 95% CI, -5.54 to -0.29), were more likely to improve GLS than ANT at T12. The included anticancer regimens, especially ANT+RT, reduced GLS at T12, but their combination with cardioprotective drugs improved them. These results will help clinicians choose the best therapy regimens.


Cytomegalovirus reactivation in ICU patients.
Approximately 20 years have passed since we reported our results of histologically proven cytomegalovirus (CMV) pneumonia in non-immunocompromised ICU patients. Even if there are more recent reports suggesting that CMV may worsen the outcomes for ICU patients, there is no definite answer to this question: is CMV a potential pathogen for ICU patients or is it simply a bystander? We will describe the pathophysiology of active CMV infection and the most recent insights concerning the epidemiological aspects of these reactivations. Cytomegalovirus can be pathogenic by a direct organ insult (such as for the lung), by decreasing host defences against other microorganisms and/or by enhancing the body's inflammatory response (as in acute respiratory distress syndrome). The incidence of active CMV infection is dependent on the diagnostic method used. Using the most sophisticated available biological tools, the incidence can reach 15-20% of ICU patients (20-40% in ICU patients with positive CMV serology). In adequately powered cohorts of patients, active CMV infection appears to be associated with worse outcomes for mechanically ventilated ICU patients. There is no absolute direct proof of a negative impact of active CMV infection on the health outcomes of mechanically ventilated patients. Prospective randomized trials are lacking. Future trials should examine the potential benefits for health outcomes of using antiviral treatments. Such treatments could be prophylactic, pre-emptive or used only when there is an end-organ disease. Cytomegalovirus infection may affect health outcomes for ICU patients. Additional prospective trials are necessary to confirm this hypothesis.


[Spontaneous bladder perforation--a rare complication of neurogenic bladder dysfunction].
Spontaneous rupture of the urinary bladder which is not associated with trauma is uncommon. A case of spontaneous bladder perforation (triggered by an episode of urinary retention) and peritonitis in a 69-year old male patient with neurogenic bladder dysfunction is reported. The latter was due to disseminated sclerosis and was complicated by recurrent urinary tract infection and two bladder calculi. The etiology, diagnosis and treatment of spontaneous bladder perforation is briefly discussed. The diagnosis spontaneous bladder perforation should be considered in patients with non-characteristic acute abdominal conditions and voiding symptoms, especially if they have neurogenic bladder dysfunction and a history of recurrent lower urinary tract infections and/or bladder calculi. We recommend that bladder stones should be removed--also in asymptomatic cases.


A statistical model for iTRAQ data analysis.
We describe biological and experimental factors that induce variability in reporter ion peak areas obtained from iTRAQ experiments. We demonstrate how these factors can be incorporated into a statistical model for use in evaluating differential protein expression and highlight the benefits of using analysis of variance to quantify fold change. We demonstrate the model's utility based on an analysis of iTRAQ data derived from a spike-in study.


High-power operation of silica-based Raman fiber amplifier at 2147 nm.
We demonstrated a 2147 nm silica-based Raman fiber amplifier with output power of 14.3 W directly pumped with a 1963 nm CW thulium-doped all-fiber MOPA. The 1963 nm thulium-doped all-fiber MOPA is seeded with a 2147 nm thulium-doped all-fiber laser at the same time. The Raman Stokes power shift from 1963 nm to 2147 nm is accomplished in a piece of 50 m silica-based highly nonlinear fiber (HNLF). The conversion efficiency was 38.5% from 1963 nm to 2147 nm in the HNLF. The output power achieved was only currently limited by available 1963 nm input power and the architecture has significant scaling potential. To the best of our knowledge, this is the highest power operation of a Raman fiber amplifier at >2 µm wavelength region.


White and black adolescent females differ in profiles and longitudinal patterns of alcohol, cigarette, and marijuana use.
Emerging research suggests that white youth are more likely to show continuity of alcohol use in the year after drinking onset, compared with black youth. Little is known, however, regarding racial differences in year-to-year continuity of alcohol, cigarette, and marijuana use during adolescence, particularly among females, who are at greater risk for certain substance-related harm than males. This study used latent class/transition analysis to identify profiles of past year alcohol, cigarette, and marijuana use at ages 13-17 in a community sample of 1076 adolescent females (57% black, 43% white). Three profiles of past year substance use were identified in separate analyses by race: "no use," "alcohol only," and "polydrug use." Although similar labels describe the profiles, the probability of endorsing use of a particular substance for a given profile differed by race, precluding direct comparison. Latent transition analyses of five annual waves covering ages 13-17 indicated that an intermittent pattern of use (e.g., use in one year, but not the next) was relatively low at all ages among white girls, but among black girls, an intermittent pattern of use began to decline at age 15. Among black girls, conduct problems at age 12 predicted substance using profiles at age 13, whereas among white girls, intentions to use alcohol and cigarettes at age 12 predicted substance using profiles at age 13. Racial differences in girls' substance use profiles suggest the potential utility of culturally tailored interventions that focus on differences in risk for specific substances and relatively distinct early patterns of use.


Does subjective improvement in adults with intracranial arachnoid cysts justify surgical treatment?
OBJECTIVE Subjective improvement of patients who have undergone surgery for intracranial arachnoid cysts has justified surgical treatment. The current study aimed to evaluate the outcome of surgical treatment for arachnoid cysts using standardized interviews and assessments of neuropsychological function and balance. The relationship between arachnoid cyst location, postoperative improvement, and arachnoid cyst volume was also examined. METHODS The authors performed a prospective, population-based study. One hundred nine patients underwent neurological, neuropsychological, and physiotherapeutic examinations. The arachnoid cysts were considered symptomatic in 75 patients, 53 of whom agreed to undergo surgery. In 32 patients, results of the differential diagnosis revealed that the symptoms were due to a different underlying condition and were unrelated to an arachnoid cyst. Neuropsychological testing included target reaction time, Grooved Pegboard, Rey Auditory Verbal Learning, Rey Osterrieth complex figure, and Stroop tests. Balance tests included the extended Falls Efficacy Scale, Romberg, and sharpened Romberg with open and closed eyes. The tests were repeated 5 months postoperatively. Cyst volume was pre- and postoperatively measured using OsiriX software. RESULTS Patients who underwent surgery did not have results on balance and neuropsychological tests that were different from patients who declined or had symptoms unrelated to the arachnoid cyst. Patients with a temporal arachnoid cyst performed within the normal range on the neuropsychological tests. Seventy-seven percent of the patients who underwent surgery reported improvement, yet there were no differences in test results before and after surgery. Arachnoid cysts in the temporal region and posterior fossa did not influence the preoperative results of neuropsychological and motor tests. The arachnoid cyst volume decreased postoperatively (p < 0.0001), but there was no relationship between volume reduction and clinical improvement. CONCLUSIONS The results of this study speak against objectively verifiable improvement following surgical treatment in adults with intracranial arachnoid cysts.


Worker dose analysis based on real time dosimetry.
Real time dosimetry was used to analyze nuclear medicine technologist dose from performing positron emission tomography clinical imaging procedures. The purpose was to identify which tasks in the procedure were the greatest contributors to dose. Results identified the patient positioning task as the single largest source of technologist dose, followed by measurement and administration of the radioactive drug. The dosimetry method appears suitable for any work situation where it is not clear whether task modification or installation of shielding will better reduce worker dose.


Covid-19 pandemic impact on colonoscopy service and suggestions for managing recovery.
Background and aim As the post-peak phase of the epidemic is approaching, there is an urgent need of an action plan to help resume endoscopy activity. To manage the Covid-19 pandemic-imposed backlog of postponed colonoscopy examinations, an efficient approach is needed. The practice of on-demand sedation with benzodiazepines and/or opiates will allow most patients to complete a water-aided examination with minimal or no sedation. Other methods reported to minimize patient discomfort during colonoscopy can be used, in addition to water-aided techniques. Unsedated or minimally sedated patients who do not require recovery or require a shorter one allow rapid turnaround. The practice obviates the need for assistance with deep sedation from anesthesiologists, who may be in short supply. Trainee education in water-aided colonoscopy has been demonstrated to confer benefits. This review provides some insights into the impact of Covid-19 on endoscopy services, challenges ahead, and possible solutions to help recovery of colonoscopy work and training.


Biological Significance of microRNA Biomarkers in ALS-Innocent Bystanders or Disease Culprits?
MicroRNAs (miRNAs) represent potential biomarkers for neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). However, whether expression changes of individual miRNAs are simply an indication of cellular dysfunction and degeneration, or actually promote functional changes in target gene expression relevant to disease pathogenesis, is unclear. Here we used bioinformatics to test the hypothesis that ALS-associated miRNAs exert their effects through targeting genes implicated in disease etiology. We documented deregulated miRNAs identified in studies of ALS patients, noting variations in participants, tissue samples, miRNA detection or quantification methods used, and functional or bioinformatic assessments (if performed). Despite lack of experimental standardization, overlap of many deregulated miRNAs between studies was noted; however, direction of reported expression changes did not always concur. The use of in silico predictions of target genes for the most commonly deregulated miRNAs, cross-referenced to a selection of previously identified ALS genes, did not support our hypothesis. Specifically, although deregulated miRNAs were predicted to commonly target ALS genes, random miRNAs gave similar predictions. To further investigate biological patterns in the deregulated miRNAs, we grouped them by tissue source in which they were identified, indicating that for a core of frequently detected miRNAs, blood/plasma/serum may be useful for future profiling experiments. We conclude that in silico predictions of gene targets of deregulated ALS miRNAs, at least using currently available algorithms, are unlikely to be sufficient in informing disease pathomechanisms. We advocate experimental functional testing of candidate miRNAs and their predicted targets, propose miRNAs to prioritise, and suggest a concerted move towards protocol standardization for biomarker identification.


TRAF6 Promoted Tumor Glycolysis in Non-Small-Cell Lung Cancer by Activating the Akt-HIFα Pathway.
TRAF6 has been reported to be associated with poor prognosis in non-small-cell lung cancer (NSCLC). However, its precise role in tumor development has not been elaborated. In the present study, the function and the mechanism by which TRAF6 contributes to development were intensively investigated. TRAF6 was found to be overexpressed in primary NSCLC tumor tissue and all tested cell lines. Knockdown of TRAF6 with shRNA substantially attenuated NSCLC cell proliferation and anchorage-independent growth. Moreover, tumor glycolysis, such as glucose consumption and lactate production, also significantly impaired. In TRAF6-deficient cells, hexokinase-2 expression was significantly reduced, which was caused by the decrease of HIF-1α transcriptional activity. Further investigations demonstrated that TRAF6 played an important role in the regulation of Akt activation, and exogenous overexpression of constitutively activated Akt substantially rescued glycolysis suppression in TRAF6 knockdown cells. The results of the xenograft model confirmed that downregulation of TRAF6 in NSCLC tumor cells dramatically restrained tumor growth in vivo. Taken together, our studies revealed the mechanism by which TRAF6 exerts its role in NSCLC development and suggested TRAF6 maybe was a promising candidate target for lung cancer prevention and therapy.


Real Men Love Babies: Protest Speech and Masculinity at Abortion Clinics in the Southern United States.
This article examines the politicized space outside the abortion clinic as a site where gender ideologies about male roles and responsibilities in abortion are contested, using anti-abortion protest rhetoric that targets men accompanying women. Protesters attempt to elicit reactions from men using gendered stereotypes, in hopes that men will change their minds about or prevent an abortion. Anti-abortion protest speech uses mixed messages about masculinity, strength, and fatherhood to shame male companions for their support of abortion. Protesters' rhetoric constructs men as inherently responsible for preventing abortion, where only by leaving the clinic space can these men gain power, controlling their reproductive futures by controlling their female companion's. However, men reacted in different ways to the words shouted by protesters: by ignoring them, agreeing with them, or occasionally by initiating physical or verbal altercations. I find that male companions often employ tropes of patriarchal masculinity within attempts to perform supportive masculinity in response to protest speech, while protesters simultaneously use patriarchal masculinity and contemporary gender ideologies on responsible fatherhood in attempts to prevent abortion. These conflicting rhetorical themes and diverse reactions are indicative of larger struggles in the U.S. pro-choice and pro-life movements about the role of men in abortion.


Autoantibodies reacting with poly(ADP-ribose) and with a zinc-finger functional domain of poly(ADP-ribose) polymerase involved in the recognition of damaged DNA.
Poly(ADP-Ribose) polymerase (PARP) is a chromatin-associated enzyme that specifically binds to DNA strand breaks in a zinc-dependent manner. We describe here the presence of IgG antibodies reacting with recombinant human PARP in the serum of patients with systemic lupus erythematosus (SLE) and primary and secondary Sjögren's syndrome (pSS and sSS). The reactivity of patients' sera was further studied in ELISA with a synthetic peptide of 44 residues corresponding to the second zinc finger (F2) present in the DNA-binding domain of PARP and which was shown to effectively bind 65Zn. Thirty-five percent of SLE sera (n = 97), 42% of pSS sera (n = 67), and 56% of sSS sera (n = 16) were found to contain raised levels of IgG antibodies reacting with peptide F2 which corresponds to the domain in PARP that is directly involved in the specific recognition of single and double strand breaks in DNA. Antibodies reacting with the whole enzyme and/or peptide F2 occurred independently from antibodies reacting with poly(ADP-ribose) which is rapidly synthesized in vivo by PARP from NAD and then degraded in response to DNA strand breaks.


Association between Oral Health Status and Diabetic Nephropathy-Related Indices in Japanese Middle-Aged Men.
Oral health status is known to be associated with lifestyle-related diseases such as diabetes and chronic kidney disease. In Japan, around 40% of hemodialysis cases are patients with diabetic nephropathy. The aim of this study was to clarify the association between oral health status and diabetic nephropathy-related indices in Japanese middle-aged men. Sixty-six men (age range: 55-64 years) with ≥20 remaining teeth and who received public medical checkups and oral examinations were enrolled. We examined correlations of age, body mass index, HbA1c, HDL-C, LDL-C, neutral fat, serum creatinine, and the estimated glomerular filtration rate (eGFR) with the number of remaining teeth or the community periodontal index (CPI) score (periodontal pocket < 4 mm: 0, 4-6 mm: 1, ≥6 mm: 2). A positive correlation between the CPI score and serum creatinine and a negative correlation between CPI score and eGFR (Spearman's rank correlation coefficient, r = 0.459, p < 0.01, and r = -0.460, p < 0.01, respectively) were observed. The mean eGFR in the CPI score 0 group was significantly higher than that in the CPI score 1/2 group (82.6 vs. 70.7, Student's t-test, p < 0.01). Logistic regression analysis using eGFR as a dependent variable and age, CPI score, body mass index, HbA1c, and neutral fat as independent variables suggested that low eGFR (<60) could be attributed to CPI score (OR = 3.169, 95% CI: 1.031-9.742, p = 0.044). These results suggest a possible association between periodontal status and renal function in Japanese middle-aged men. Periodontal condition is controlled by oral prophylaxis, and periodontal disease and chronic kidney disease have some common risk factors. Thus, periodontal management can contribute to the prevention of severe chronic kidney disease.


Simultaneous consideration of multiple candidate protein biomarkers for long-term risk for cardiovascular events.
Although individual protein biomarkers are associated with cardiovascular risk, rarely have multiple proteins been considered simultaneously to identify which set of proteins best predicts risk. In a nested case-control study of 273 death/myocardial infarction (MI) cases and 273 age- (within 10 years), sex-, and race-matched and event-free controls from among 2023 consecutive patients (median follow-up 2.5 years) with suspected coronary disease, plasma levels of 53 previously reported biomarkers of cardiovascular risk were determined in a core laboratory. Three penalized logistic regression models were fit using the elastic net to identify panels of proteins independently associated with death/MI: proteins alone (Model 1); proteins in a model constrained to retain clinical variables (Model 2); and proteins and clinical variables available for selection (Model 3). Model 1 identified 6 biomarkers strongly associated with death/MI: intercellular adhesion molecule-1, matrix metalloproteinase-3, N-terminal pro-B-type natriuretic peptide, interleukin-6, soluble CD40 ligand, and insulin-like growth factor binding protein-2. In Model 2, only soluble CD40 ligand remained strongly associated with death/MI when all clinical risk predictors were retained. Model 3 identified a set of 6 biomarkers (intercellular adhesion molecule-1, matrix metalloproteinase-3, N-terminal pro-B-type natriuretic peptide, interleukin-6, soluble CD40 ligand, and insulin-like growth factor binding protein-2) and 5 clinical variables (age, red-cell distribution width, diabetes mellitus, hemoglobin, and New York Heart Association class) strongly associated with death/MI. Simultaneously assessing the association between multiple putative protein biomarkers of cardiovascular risk and clinical outcomes is useful in identifying relevant biomarker panels for further assessment.


[Specific antigen prostatic changes during treatment with finasteride or dutasteride for benign prostatic hyperplasia].
The aim of this paper was to compare and analyze the therapeutic effects and PSA variation levels with treatment with finasteride-tamsulosin and dutasteride-tamsulosin for benign prostatic hyperplasia for 2 years and the risk to developing prostate cancer for patients with PSA<4 ng/mL. We retrospectively investigated 288 patients who suffered from BPH and PSA>4 ng/mL between January 2003 and July 2010. For treatment groups, we divided the patients into two groups: one was treated with tamsulosin and finasteride and the other with tamsulosin and dutasteride. At the beginning of treatment, the patients underwent transrectal ultrasonography and prostate mapping, measurement of urine flow rate, PSA, and International Prostate Symptom Score (IPSS). A total of 288 patients were able to be. Both finasteride and dutasteride rduced PSA and prostate volume significantly. The comparison between the 2 groups showed a significant difference at 3 months for IPSS; uroflussimetry and prostate volume in the dutasteride group, but at 6 months did not differ significantly between the groups. Patients with a PSA reduction more than half presented a good response and didn't request surgical theraphy. 5 alpha Reductase inhibitors for BPH treatment reduced PSA and prostate volume significantly after 6 months of theraphy and after 3 months only for dutasteride. PSA reduction is directly correlated with response to theraphy. Didn't were evidenced statistically differences on prostate cancer presence during theraphy.


Allergic rhinitis: diagnosis and management.
Allergic rhinitis affects up to 20 per cent of the pediatric population and occurs in children of all ages. Secondary infection, dental malocclusion and a variety of other sequelae may complicate the primary disorder. The diagnosis of allergic rhinitis is based on historic features, physical findings and selected laboratory investigations. Treatment may involve antigen avoidance programs and immunotherapy. However, pharmacotherapy with antihistamines, sympathomimetics and, in severe cases, corticosteroids, is most frequently used.


Genome-wide organization, evolutionary diversification of the COMMD family genes of amphioxus (Branchiostoma belcheri) with the possible role in innate immunity.
The COMMD (COpper Metabolism gene MURR1 Domain) gene family with ten members participates in various biological processes, such as the regulation of copper and sodium transport, NF-κB activity and cell cycle progression. However, studies on the COMMD gene family in amphioxus (Branchiostoma belcheri) are yet largely unknown. In this study, we have identified and characterized the ten COMMD family members from amphioxus (designated as AmphiCOMMDs). Firstly, we clone the full length of AmphiCOMMDs, and all AmphiCOMMD proteins contain the conserved COMM domain with two NES (Nuclear Export Signal) motifs. Secondly, the genomic structure analysis demonstrates that genes of the COMMD family have undergone intron loss and gain during the process of divergence from amphioxus to vertebrates. Thirdly, phylogenetic analysis indicates that AmphiCOMMDs are more closely related to vertebrates, implying the AmphiCOMMDs may be the ancestor of the vertebrate COMMDs. Fourthly, AmphiCOMMDs are ubiquitously and differentially expressed in five investigated tissues (muscles, gills, intestine, heaptic cecum and notochord). Finally, our results show that expression levels of AmphiCOMMD genes are fluctuating after LPS stimulation to some different extent. Taken together, our studies have elaborated the evolutionary dynamic and the innate immune role of the COMMD family genes in amphioxus.


History of cryotherapy.
Cryotherapy refers to the use of cold temperature to treat disease and is a mainstay therapeutic modality for a wide variety of skin conditions. This article reviews the early history of development of cryotherapy in dermatology.


Development of light and pH-dual responsive self-quenching theranostic SPION to make EGFR overexpressing micro tumors glow and destroy.
Drug resistant and undetectable tumors easily escape treatment leading metastases and/or recurrence of the lethal disease. Therefore, it is vital to diagnose and destroy micro tumors using simple yet novel approaches. Here, we present fluorescence-based detection and light-based destruction of cancer cells that are known to be resistant to standard therapies. We developed a superparamagnetic iron oxide nanoparticle (SPION)-based theranostic agent that is composed of self-quenching light activated photosensitizer (BPD) and EGFR targeting ligand (Anti-EGFR ScFv or GE11 peptide). Photosensitizer (BPD) was immobilized to PEG-PEI modified SPION with acid-labile linker. Prior to stimulation of the theranostic system by light its accumulation within cancer cells is vital since BPD phototoxicity and fluorescence is activated by lysosomal proteolysis. As BPD is cleaved, the system switches from off to on position which triggers imaging and therapy. Targeting, therapeutic and diagnostic features of the theranostic system were evaluated in high and moderate level EGFR expressing pancreatic cancer cell lines. Our results indicate that the system distinguishes high and moderate EGFR expression levels and yields up to 4.3-fold increase in intracellular fluorescence intensity. Amplification of fluorescence signal was as low as 1.3-fold in the moderate or no EGFR expressing cell lines. Anti-EGFR ScFv targeted SPION caused nearly 2-fold higher cell death via apoptosis in high EGFR expressing Panc-1 cell line. The developed system, possessing advanced targeting, enhanced imaging and effective therapeutic features, is a promising candidate for multi-mode detection and destruction of residual drug-resistant cancer cells.


Multiplex assay for detection of strain-specific antibodies against the two variable regions of the G protein of respiratory syncytial virus.
The role of strain differences in respiratory syncytial virus (RSV) disease has not been clearly defined. To investigate the possibility that strain differences contribute to susceptibility to repeat infections, we developed assays to detect antibodies to the two variable regions of the RSV G protein by cloning and expressing the internal variable region at amino acids (aa) 60 to 172 (g1) and the carboxy-terminal variable region at aa 193 to the carboxy terminus (g2) from different genotypes of RSV. The purified proteins were covalently linked to beads with different proportions of red and orange fluorescent dyes and reacted against serum specimens. Antibody reacting against the differently colored beads, and thus against different G polypeptides, was detected by use of flow cytometry and the Luminex system. This assay system detected group- and, to some extent, genotype-specific responses to RSV infection and can be used to investigate the role of strain differences in RSV disease.


The role of surgical resection when combined with chemotherapy and radiation in the management of pelvic rhabdomyosarcoma.
With the development of combined chemotherapy and radiation therapy for embryonal rhabdomyosarcoma, the role and extent of surgical resection of these pelvic tumors need to be defined. Thirty-six children with pelvic genitourinary rhabdomyosarcoma seen at St. Jude Children's were managed on protocols combining surgical resection and radiation, and chemotherapy. Ten children presented with cervical-vaginal tumors, which were managed with combined therapy; the surgical resection was histovaginectomy in eight and pelvic exenteration in one. Eight of the ten are free of disease from 1 to 14 years. Twelve children presented with bladder and prostate tumors, which were resected with segmental cystectomy in four cases, biopsy in five, and pelvic exenteration in three. All received combination therapy and six of the twelve are surviving free of disease from 6 months to 16 years. Fourteen children presented with paratesticular rhabdomyosarcoma. Chemotherapy was combined with radical orchiectomy in all cases. Retroperitoneal node dissection was done in nine and five had inguinal node dissection. Nine of the 14 are surviving NED from 2 to 16 years. One patient died, free of disease, with complications of combination therapy. The results of this review supports the approach of combining chemotherapy, radiation, and complete surgical resection.


A systematic review of assessment tools for adults used in traumatic brain injury research and their relationship to the ICF.
Good assessment is an essential component of effective patient management. Yet the sheer volume of available assessment instruments presents a barrier for the clinician or researcher to (a) be knowledgeable about suitable measures and (b) keep up-to-date with new measures that are published. In order to create a resource of currently-used measures, we conducted a systematic review of assessment tools used in the research literature on traumatic brain injury (TBI). We used two electronic databases (Medline and PsycINFO) to identify full-length, English-language articles published between 2000 and 2012 in which outcome in adults with TBI was assessed with behavioural tests or questionnaires. The searches yielded 5,735 articles and after deletion of duplicates (n = 1,383) and articles not meeting selection criteria (n = 1,759), 2,593 articles were further examined. The articles contained 910 behavioural instruments, with a final set of 728 unique instruments. Each instrument was classified against the International Classification of Functioning, Disability and Health (ICF). Half of the instruments (n = 370, 50.8%) evaluated the mental functions domain of the ICF body functions component, with a substantially smaller proportion (n = 64, 8.8%) examining specific motor-sensory and other body functions. Instruments also covered domains of activities/participation (n = 109, 15.0%), environmental factors (n = 22, 3.0%) and personal factors (n = 36, 4.9%). A substantial number of scales (n = 93, 12.8%) were multidimensional across the body function domains (n = 32), as well as the functioning and disability part of the ICF (n = 60). The remaining 5% of instruments addressed concepts not covered by the ICF, including quality of life (n = 19, 2.6%) and rehabilitation process tools (such as therapeutic alliance). The 728 instruments were listed and more than 70 of the most common, spread across 20 domains, were highlighted. These data provide a comprehensive and up-to-date resource that gives the researcher or clinician a very large selection of assessment instruments covering the major areas of function pertinent to TBI.


Study of the HIV-1 receptors CD4, CXCR4, CCR5 and CCR3 in the human and rat testis.
Sexual transmission of HIV is one of the main routes of transmission of AIDS. Despite the fact that the virus has been found in the semen and germ cells of patients with HIV, little is known about how the virus infects the cells of the genital tract. We studied the cellular distribution of CD4, a receptor necessary for HIV infection, and the major HIV co-receptors CCR3, CCR5 and CXCR4 in the rat and human testis. We used RT-PCR, Northern blotting and immunohistochemistry to demonstrate that CCR3 is absent from the testes of both species, whereas CCR5 and CXCR4 are present on the resident testicular macrophages in the interstitial space but not in the germ cell line. All of the human testicular macrophages expressed the markers CD45 and MAC387 and most also expressed CD4. Thus, our data suggest that macrophages in the testis may be infected by HIV and that these macrophages may be a site of early viral localization and a potential HIV reservoir. This may in turn alter the activity of Leydig cells and subsequently affect spermatogenesis.


Children's adaptation to insulin dependent diabetes mellitus: a critical review of the literature.
A preventive health care context is important in managing children with insulin dependent diabetes mellitus (IDDM). Specific risk factors can make adaptation to IDDM more difficult. These include older age, female gender, family stress, and non-intact family structure. Factors which enhance child adaptation, also called resistance factors, include family cohesion and adaptability, positive coping strategies, younger age, and social support. Children having a chronic illness face many challenges, including changes in lifestyle, such as regimented scheduling of everyday life, readjustment of roles in the family, and potential activity alterations. An important role of health care professionals is to guide and counsel both children who are newly diagnosed with a chronic illness and their families about ways to normalize their lives as much as possible, even while realizing that their lives will never be the same as before diagnosis. Throughout the course of an illness, children and families rely on nurses to provide information about health promotion and illness management. Nurses coordinating the care of children adapting to insulin dependent diabetes mellitus (IDDM) must recognize the significance the diagnosis has on the child. Furthermore, identification of those factors that place the child at risk for poor adaptation is critical so that the nurse can assist with the process of adaptation and recruit other psychological or social support resources as early as possible.


A case of complete androgen insensitivity syndrome with a novel androgen receptor mutation.
We report a case of a 14-year-old girl with primary amenorrhea and phenotypic as well as hormonal features of complete androgen insensitivity syndrome (CAIS), who tested positive for a novel missense androgen receptor gene mutation resulting in serine-to-isoleucine change at position 703 in exon 4 in the ligand-binding domain. The interesting features of this case include a persistence of Müllerian derivatives, Sertoli cell adenoma, Tanner III pubic hair, and a normal bone mineral density. These features are not typically described in CAIS. This novel mutation associated with a unique clinical presentation serves to significantly enrich the literature on this rare and fascinating disorder of androgen insensitivity syndrome.


Relationship between angiogenic squamous dysplasia and bronchogenic carcinoma in patients undergoing white light bronchoscopy.
To better understand the characteristic morphology of angiogenic squamous dysplasia (ASD) and its association with different types of common bronchogenic carcinomas using routine white light bronchoscopy. Using a case-control design, 186 formalin-fixed paraffin-embedded blocks of bronchial tissue (136 cases, 50 controls) obtained from patients who underwent routine nonfluorescence bronchoscopy between 2004 and 2005 were studied. ASD occurred at a higher frequency in patients with neoplastic lesions compared with those without neoplastic lesions (28 of 136 versus one of 50). ASD was also more prevalent in patients with squamous cell carcinoma compared with other neoplasms. Seventy six per cent of the ASD patients (22 of 29) smoked cigarettes. The morphology of ASD on hematoxylin and eosin- and CD31-stained sections was characterized by prominent microvasculature and capillary projections closely juxtaposed to variable degrees of dysplasia in all of the bronchogenic carcinoma specimens, and to metaplasia in one case in the control group. ASD is a unique morphological entity that should be considered by pathologists even on bronchoscopic biopsies from patients who undergo white light bronchoscopy. The presence of ASD may represent a risk biomarker of bronchogenic carcinoma in screening programs and in chemoprevention of lung cancer.


Drug interactions between direct-acting oral anticoagulants and calcineurin inhibitors during solid organ transplantation: considerations for therapy.
Introduction: There is a high incidence of venous thromboembolism (VTE) in solid organ transplant recipients. The safety and efficacy of direct-acting oral anticoagulants (DOAC) have been well established in clinical practice for the prevention and treatment of VTE in broad populations. However, the management of VTE in the setting of solid organ transplantation remains a challenge to clinicians due to limited evidence of DOAC usage with calcineurin inhibitors. Areas covered: The current literature available on the pharmacokinetic-pharmacodynamic interaction between DOACs and calcineurin inhibitors is presented. A comprehensive review was undertaken using PubMed, Embase, drug product labeling, and drug product review conducted by the US Food and Drug Administration using Drugs@FDA. The potential for mitigation strategies and clinical management using extant knowledge is explored. Expert opinion: Immunosuppression therapy is necessary to prevent graft rejection by the host. The sparsity of data together with the lack of well-designed prospective studies of DOAC use in solid organ transplant recipients presents a unique challenge to clinicians in determining the clinical relevance of possible drug interactions. Existing evidence suggests that with attention to concomitant drug use and renal function, the co-administration of DOACs and calcineurin inhibitors is safe and effective.


A large-scale hole in the ionosphere caused by the launch of skylab.
A dramatic ionospheric phenomenon, unique in magnitude and in spatial and temporal extent, occurred along the Atlantic Coast of North America after the launch of the NASA Skylab Workshop on 14 May 1973. The effect was a large and rapid decrease in the total number of ionospheric electrons within a distance of 1000 kilometers of the burning engines of the Saturn V launch vehicle. The observations are interpreted in terms of exceptionally enhanced chemical loss rates due to the molecular hydrogen and water vapor contained in the Saturn second-stage exhaust plume.


What is it to practise good medical ethics? A Muslim's perspective.
Good medical ethics should aim at ensuring that all human beings enjoy the highest attainable standard of health. With the development of medical technology and health services, it became necessary to expand the four basic principles of medical ethics and link them to human rights. Despite the claim of the universality of those ethical principles, their perception and application in healthcare services are inevitably influenced by the religious background of the societies in which those services are provided. This paper highlights the methodology and principles employed by Muslim jurists in deriving rulings in the field of medical ethics, and it explains how ethical principles are interpreted through the lens of Islamic theory. The author explains how, as a Muslim obstetrician-gynaecologist with a special interest in medical ethics, including international consideration of reproductive ethics issues, he attempts to 'practise good medical ethics' by applying internationally accepted ethical principles in various healthcare contexts, in ways that are consistent with Islamic principles, and he identifies the evidence supporting his approach. He argues that healthcare providers have a right to respect for their conscientious convictions regarding both undertaking and not undertaking the delivery of lawful procedures. However, he also argues that withholding evidence-based medical services based on the conscientious objection of the healthcare provider is unethical as patients have the right to be referred to services providing such treatment.


Degradation of piperazine by Paracoccus sp. TOH isolated from activated sludge.
Piperazine is widely used as an intermediate in the manufacture of insecticides, rubber chemicals, corrosion inhibitors, and urethane. In this study, a highly effective piperazine-degrading bacteria strain, TOH, was isolated from the acclimated activated sludge of a pharmaceutical plant. This strain, identified as Paracoccus sp., utilises piperazine as the sole source of carbon, nitrogen and energy for growth. The optimal pH and temperature for the growth of TOH were 8.0 and 30°C, respectively. The effects of co-substrates and heavy metals on the degradation efficiency of piperazine were investigated. The results indicated that exogenously supplied glucose promoted the degradation of piperazine, while the addition of ammonium chloride slightly inhibited piperazine degradation. Metal ions such as Ni(2+) and Cd(2+) inhibited the degradation of piperazine, whereas Mg(2+) increased it. In addition, metabolic intermediates were identified by mass spectrometry, allowing a degradation pathway for piperazine to be proposed for the first time.


The Emerging Roles of Heparan Sulfate 3-O-Sulfotransferases in Cancer.
Alteration in the expression of heparan sulfate (HS)-modifying enzymes has been frequently observed in cancer. Consequently, dysregulation of the HS biosynthetic machinery results in dramatic changes in the HS structure, thereby impacting a range of pivotal cellular processes involved in tumorigenesis and cancer progression including proliferation, migration, apoptosis, and immune escape. HS 3-O-sulfotransferases (HS3STs) catalyse the maturation step of glucosaminyl 3-O-sulfation within HS chains. Although seven HS3ST isozymes have been described in human, 3-O-sulfation is a rare modification and only a few biological processes have been described to be influenced by 3-O-sulfated HS. An aberrant expression of HS3STs has been reported in a variety of cancers. Thus, it was suggested that changes in the expression of these enzymes as a result of tumorigenesis or tumor growth may critically influence cancer cell behavior. In accordance with this assumption, a number of studies have documented the epigenetic repression of HS3ST2 and HS3ST3A in many cancers. However, the situation is not so clear, and there is accumulating evidence that HS3ST2, HS3ST3A, HS3ST3B, and HS3ST4 may also act as tumor-promoting enzymes in a number of cancer cells depending on their phenotypes and molecular signatures. In this mini-review, we focus on the recent insights regarding the abnormal expression of HS3STs in cancer and discuss the functional consequences on tumor cell behavior. In term of clinical outcome, further investigations are needed to explore the potential value of HS3STs and/or their 3-O-sulfated products as targets for therapeutic strategies in cancer treatment.


Glucocorticoid receptors in cultured skin fibroblasts of normal and adrenocorticoid disorders.
Glucocorticoid receptors (GR) in cultured fibroblasts obtained by forearm skin biopsy were characterized and GR in patients with hyper- and hypo-cortisolism were compared. Scatchard analysis of specific whole cell [3H]-dexamethasone binding showed a single class of high affinity receptors with a mean (+/- SD) binding capacity (R0) of 126,800 +/- 21,600 sites/cell and mean (+/- SD) apparent dissociation constant (Kd) of 2.9 +/- 0.4 nM in 6 normal subjects. Competition study of various steroids revealed that glucocorticoids were the most potent competitors. The order of the strength of competition was dexamethasone greater than betamethasone greater than prednisolone greater than hydrocortisone. Sucrose density gradient analysis revealed a specific 8.6 S binding peak in cytosol and 3.6 S in nuclear extracts. Dexamethasone showed the dose-dependent suppressive effect on thymidine incorporation. An inverse linear correlation between CI50 and % inhibition of thymidine incorporation by glucocorticoids was observed. There were no significant differences in parameters of whole cell GR among healthy controls, Cushing's disease (n = 4, R0 = 131,225 +/- 29,950/cell, Kd = 3.1 +/- 0.6 nM) and Addison's disease (n = 2, R0 = 131,600 +/- 25,600/cell, Kd = 3.2 +/- 0.2 nM). In one additional patient of hypercortisolism without clinical symptoms of Cushing's disease, R0 (144,000 +/- 12,960) was the same as control, but Kd (5.0 +/- 1.2 nM) was higher than the control.


Online health promotion, early identification of difficulties, and help seeking in young people.
To examine the use and impact of a dedicated health information Web site for adolescents. Five hundred fifty-eight (27.2%) of all students in grades 7 through 12 from 4 schools logged onto the Web site; 1775 (86.4%) of all students in these grades completed a year-end health survey, with 455 (81.5%) of the students who used the Web site completing the survey. Dependent variables were help seeking and satisfaction ratings plus visits to specific Web site sections. Predictor variables were demographic characteristics, mental health, and psychosocial difficulties assessed at years' end. Students logged on >11,000 times during the year. Female students, students wanting professional help, those scoring higher on depressive vulnerability measures, and students reporting more severe mood problems were related to logging on frequently over longer periods of time, as well as viewing information sheets, posting and viewing questions and answers, and completing the symptom screen. Students accessing the Web site from 1 to 7 A.M. reported higher levels of distress than did students who accessed the Web site at other times of the day. Visits to the Web site were positively associated with visits to school health centers and guidance counselors and referrals to a health professional. Results are consistent with a health-needs model of utilization of this Internet-based health resource. A school-based health information Web site holds significant promise for health promotion and early self-identification for emotional problems.