Self-report methodology for quantifying standardized cannabis consumption in milligrams delta-9-tetrahydrocannabinol.
Background: There is currently no format-independent method to determine delta-9-tetrahydrocannabinol (THC) in milligrams for self-report studies.Objectives: Validate self-report method for quantifying mg THC from commercially available cannabis products using product labeling, which includes both net weight and product potency.Methods: 53 adult cannabis users (24 M, 29F), 21-39 years of age (M = 28.38, SD = 4.15), were instructed to report daily use via a weekly survey for two consecutive weeks, provide product label photographs, abstain from use for 24 h, submit a urine sample and complete the Cannabis Use Disorder Identification Test - Revised (CUDIT-R) and the Marijuana Craving Questionnaire - Short Form (MCQ-SF). Milligrams of THC were determined by multiplying quantity of product used by its THC concentration. Urine was analyzed for the urine metabolite 11-nor-carboxy-THC (THC-COOH) via liquid chromatography mass spectroscopy. THC and THC-COOH values were log10 transformed prior to correlational analyses.Results: Median daily THC consumption was 102.53 mg (M = 203.68, SD = 268.13). Thirty-three (62%) of the 53 participants reported using two or more formats over the 2-week period. There was a significant positive correlation between log10 THC-COOH and log10 THC mg (r(41) = .59, p < .001), log10 THC mg and MCQ-SF score (r(41) = .59, p < .001), and log10 THC mg dose and CUDIT-R score, (r(41) = .39, p = .010).Conclusion: Our label-based methodology provides consumption information across all modalities of cannabis use in standard units that can be combined across products for calculation of dose. It is a viable and valid method for quantifying mg of THC consumed and can be utilized in any region where cannabis is legal, and labeling is regulated.


Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders.
Next-generation sequencing and genome-wide association studies represent powerful tools to identify genetic variants that confer disease risk within populations. On their own, however, they cannot provide insight into how these variants contribute to individual risk for diseases that exhibit complex inheritance, or alternatively confer health in a given individual. Even in the case of well-characterized variants that confer a significant disease risk, more healthy individuals carry the variant, with no apparent ill effect, than those who manifest disease. Access to low-cost genome sequence data promises to provide an unprecedentedly detailed view of the nature of the hereditary component of complex diseases, but requires the large-scale comparison of sequence data from individuals with and without disease to deliver a clinical calibration. The provision of informatics support remains problematic as there are currently no means to interpret the data generated. Here, we initiate this process, a prerequisite for such a study, by narrowing the focus from an entire genome to that of a single biological system. To this end, we examine the 'Hemostaseome,' and more specifically focus on DNA sequence changes pertaining to those human genes known to impact upon hemostasis and thrombosis that can be analyzed coordinately, and on an individual basis, to interrogate how specific combinations of variants act to confer disease predisposition. As a first step, we delineate known members of the Hemostaseome and explore the nature of the genetic variants that may cause disease in individuals whose hemostatic balance has become shifted toward either a prothrombotic or anticoagulant phenotype.


Controlling leakage currents: the role of the binding group and purity of the precursors for self-assembled monolayers in the performance of molecular diodes.
This paper describes that the performance of molecular diodes based on self-assembled monolayers (SAMs) depends on the type of anchoring group and purity of the precursors of these SAMs. The SAMs were formed on ultrasmooth template-stripped silver (Ag(TS)) surfaces, which served as the bottom-electrode, and a eutectic alloy of gallium-indium was used as the top-electrode. When these junctions incorporate SAMs of the form S(CH2)11Fc (≡ SC11Fc) derived from HSC11Fc, they are good molecular diodes and rectify currents with rectification ratios R (≡ |J(-1.0 V)|/|J(+1.0 V)|) of ∼1.0 × 10(2). Replacing the thiol by disulfide or thioacetate functionalities in the precursor resulted in molecular diodes with values of R close to unity. Cyclic voltammetry and angle resolved X-ray photoelectron spectroscopy indicated that the SAMs derived from the disulfide or thioacetate precursors have lower surface coverages and are more defective than SAMs derived from thiols. In the junctions these defective SAMs caused defects and increased the leakage currents. The purity of the thiol-precursor is also crucial: 3 or 5% of disulfide present in the thiol caused a 28 or 61% decrease in R, respectively, and >15% of disulfide lowered R to unity, while the yield in nonshorting junctions remained unchanged. Our results show that the type of binding group, and the puritiy of the thiols, are crucial parameters in the experimental design of molecular electronic devices to ensure optimal device performance by keeping leakage currents to a minimum.


Employer demands lower cost.
A case study of premium negotiations between a health maintenance organization (HMO) and an employer group is presented. The employer HMO and employer had a well-established relationship for several years. In the fourth year of consecutive double-digit rate increases, the employer demanded a decrease in premiums. The ensuing negotiations included the employer's mandate of the HMO to make operational changes to effect cost reductions. The HMO was able to provide sufficient evidence supporting its position in the rate increase and subsequently a premium increase of 5 percent was negotiated. The case study is followed in subsequent articles by the opinions and commentary of executives in the managed care industry.


Phosphorylation by Sky1p promotes Npl3p shuttling and mRNA dissociation.
Mammalian SR proteins are currently thought to function in mRNA export as well as splicing. They contain multiple phosphorylated serine/arginine (RS/SR) dipeptides. Although SR domains can be phosphorylated by many kinases in vitro, the physiologically relevant kinase(s), and the role(s) of these modifications in vivo have remained unclear. Npl3 is a shuttling protein in budding yeast that we showed previously to be a substrate for the mammalian SR protein kinase, SRPK1, as well as the related yeast kinase, Sky1. Here we demonstrate that Sky1p phosphorylates only one of Npl3p's eight SR/RS dipeptides. Mutation of the C-terminal RS to RA, or deletion of SKY1, results in the cytoplasmic accumulation of Npl3p. The redistribution of Npl3p is accompanied by its increased association with poly(A)+ RNA and decreased association with its import receptor, Mtr10p, in vivo. We propose that phosphorylation of Npl3p by the cytoplasmically localized Sky1p is required for efficient release of mRNA upon termination of export.


Lead exposure and poisoning of songbirds using the Coeur d'Alene River Basin, Idaho, USA.
Previous studies have found widespread Pb poisoning of waterfowl in the Coeur d'Alene River Basin in northern Idaho, USA, which has been contaminated by mining and smelting activities. We studied the exposure of ground-feeding songbirds to Pb, sampling 204 American robins (Turdus migratorius), song sparrows (Melospiza melodia), and Swainson's thrushes (Catharus ustulatus) throughout the basin. These songbirds had mean blood Pb concentrations (mg/kg, dry weight) of less than 0.19 at a reference area (25 mg Pb/kg soil), 1.09 at moderately contaminated sites (170 to 1300 mg Pb/kg soil), and 2.06 at highly contaminated sites (2000 to 5000 mg Pb/kg soil). Based on guidelines for evaluating blood Pb in birds, 6% of robins from the highly contaminated sites had background concentrations, 24% were subclinically poisoned, 52% were clinically poisoned, and 18% were severely clinically poisoned with Pb. Blood Pb concentrations were lower in song sparrows than in robins and lowest in Swainson's thrushes. More than half of the robins and song sparrows from all contaminated sites and more than half of the Swainson's thrushes from highly contaminated sites showed at least 50% inhibition of the activity of the enzyme δ-aminolevulinic acid dehydratase (ALAD), commonly used as a measure of exposure to Pb. The highest hepatic Pb concentration of 61 mg/kg (dry weight) was detected in a song sparrow. Using Al as a marker for soil in songbird ingesta, we estimated average soil ingestion rates as 20% in robins, 17% in song sparrows, and 0.7% in Swainson's thrushes. Soil Pb in ingesta accounted for almost all of the songbirds' exposure to Pb. Based on these results, it is recommended that ecological risk assessments of ground-feeding songbirds at contaminated sites include soil ingestion as a pathway of exposure to Pb.


Construction of Co2 P-Ni3 S2 /NF Heterogeneous Structural Hollow Nanowires as Bifunctional Electrocatalysts for Efficient Overall Water Splitting.
Designing efficient and stable transition metal-based catalysts for electrocatalytic water splitting is vital for the development of hydrogen production. Herein, a facile synthetic strategy is developed to fabricate transition metal-based heterogeneous structural Co2 P-Ni3 S2 hollow nanowires supported on nickel foam (Co2 P-Ni3 S2 /NF). Owing to the multiple active sites provided by transition metal compounds, large surface area of the unique hollow nanowire morphology, and the synergistic effect of Co2 P-Ni3 S2 heterostructure interfaces, Co2 P-Ni3 S2 /NF requires ultralow overpotentials of 110, 164 mV for HER and 331.7, 358.3 mV for OER at large current densities of 100, 500 mA cm-2 in alkaline medium, respectively. Importantly, the two-electrode electrolyzer assembled by Co2 P-Ni3 S2 /NF displays a cell voltage of 1.54 V at 10 mA cm-2 and operates stably over 24 h at 100 mA cm-2 , which performs better than reported transition metal-based bifunctional electrocatalysts. This work presents a successful fabrication of transition metal-based bifunctional HER/OER electrocatalysts at large-current density and brings new inspiration for developing applicable energy conversion materials.


'Hemostatic pause' in pediatric tonsillectomy?
A randomized prospective study was performed on 101 children undergoing dissection tonsillectomy in two different sequences. In the 'pause' sequence, a period of inactivity lasting 1.5 min ('hemostatic pause') with the Boyle-Davis gag relaxed and the fossae packed with gauze swabs was implemented after the tonsils were excised. Hemorrhage was controlled exclusively by ligatures. The duration of tonsillectomy and the number of ligatures used were accurately recorded. The procedure was identical in the 'no pause' group but the pause period was omitted. No reactionary haemorrhage occurred. There was no significant difference in the operating time between the two groups, but the mean number of ligatures required was significantly reduced in the 'pause' sequence. We conclude that 'hemostatic pause' in tonsillectomy reduces the amount of ligatures needed for satisfactory hemostasis.


Quantitative analysis of abnormal spontaneous behavior and clinical assessment of the stargazer rat.
A new mutant derived from the Zucker rat strain called stargazer (homozygous stg/stg) displays abnormal behavior that is characterized by pronounced arching of the neck ("stargazing"), rapid circling, and conspicuous hyperactivity. Results of serologic assays performed by two independent diagnostic laboratories have indicated that the abnormal behavior in the stargazer is not the result of a viral or bacterial infection. In this report, different groups of stargazer rats and their normal-behaving littermates (heterozygous stg/+) were assessed with regard to spontaneous behaviors, heart rate, blood pressure, and plasma biochemical profiles. Besides frequent stargazing, the predominant behavioral feature of the stargazers was extreme hyperactivity; they had sevenfold greater activity than the normal littermates (P < 0.05), expressed in the form of rapid ambulation and tail-chasing. The stargazers had significantly greater daily calorie and water consumption, despite being significantly smaller in body weight than the littermates (P < 0.05 for all). However, urine output was not different between the two groups. Heart rate and blood pressure also were not different. Stargazers had significantly lower total triglycerides concentration and lower aminotransferase activity than littermates (P < 0.05 for both), a finding probably related to their smaller body size. It is concluded that stargazer rats are extremely hyperactive but normotensive; heterozygous littermates are behaviorally normal, despite being carriers of the stg gene; and routine diagnostic blood testing revealed no important differences between the stargazers and their unaffected littermates.


Protuberant fibro-osseous lesion of the temporal bone: "Bullough lesion".
Primary tumors of the calvarium are infrequent, and with the exception of osteoma, lesions confined to the surface of the skull are very rare. The differential diagnosis includes benign and malignant matrix forming tumors, other mesenchymal tumors, and reactive lesions. Fibro-osseous lesions are characteristically centered within bone and surface fibro-osseous lesions always prompt consideration of parosteal osteosarcoma, which is rare but well documented in the calvarium. We present 2 cases of a distinctive lesion of the temporal bone intimately related to the occipito-mastoid suture and typically presenting as a retroauricular soft tissue mass with calcific densities, confined to the soft tissues on the outer table of the skull without intraosseous involvement. The lesion is characterized histologically by rounded and ovoid zones of ossification within a bland fibrous stroma. The first 2 cases were documented in 1999 as "Protuberant fibroosseous lesion of the temporal bone.:" We present a further 2 cases, 1 of 2 years duration and the other with a 10-year history. This distinctive entity, which must be distinguished from other fibro-osseous lesions, including subtle low-grade parosteal osteosarcoma, seems to behave in a benign fashion and thus far recurrence is not documented. Local excision seems adequate. The pathologic features in the original report were documented by Prof Peter Bullough. As these cases were recognized by him alone we propose calling this entity "Bullough lesion" or, better still, "Bullough's Bump!"


Stable and functional immobilization of histidine-tagged proteins via multivalent chelator headgroups on a molecular poly(ethylene glycol) brush.
We present a generic approach for immobilizing oligohistidine-tagged proteins with high stability and homogeneous functionality onto glass-type surfaces. Multivalent chelator heads (MCH) carrying two and three nitrilotriacetic acid (NTA) moieties were coupled with controlled surface concentration to glass surfaces premodified with an ultrathin two-dimensional polymer brush of a bifunctional poly(ethylene glycol). Low roughness and lateral homogeneity of these surfaces were confirmed by AFM and fluorescence microscopy, respectively. Protein immobilization and interactions at these interfaces were studied by label-free and fluorescence detection. Oligohistidine-tagged proteins bound specifically to NTA loaded with nickel(II) ions and could be eluted with imidazole. More than 90% of the immobilized protein preserved its activity. In contrast to mono-NTA, immobilized multivalent chelator heads bound oligohistidine-tagged proteins stoichiometrically and with high stability, even at very low chelator surface concentrations. Thus, an excess of the metal chelator sites was not necessary, and excessive binding sites could be quantitatively blocked with an indifferent protein. As a consequence, increased functional stability of the immobilized protein and a substantial reduction in nonspecific adsorption were achieved. Binding of histidine-tagged proteins to the MCH-modified surface was efficiently blocked by stoichiometric amounts of soluble MCH, and biomolecular interaction unbiased by the interaction of the histidine tag to the surface-bound MCH was observed. These excellent features and the compatibility with many solid-phase analytical techniques make this surface chemistry beneficial for functional protein analysis.


Toward Next-Generation Biohybrid Catalyst Design: Influence of Degree of Polymerization on Enzyme Activity.
Due to their capacity to conduct complex organic transformations, enzymes find extensive use in medical and industrial settings. Unfortunately, enzymes are limited by their poor stability when exposed to harsh non-native conditions. While a host of methods have been developed to stabilize enzymes in non-native conditions, recent research into the synthesis of polymer-enzyme biohybrids using reversible deactivation radical polymerization approaches has demonstrated the potential of increased enzymatic activity in both native and non-native environments. In this manuscript, we utilize the enzyme lipase, as a model system, to explore the impact that modulation of grafted polymer molecular weight has on enzyme activity in both aqueous and organic media. We studied the properties of these hybrids using both solution-phase enzyme activity methods and coarse-grain modeling to assess the impact of polymer grafting density and grafted polymer molecular weight on enzyme activity to gain a deeper insight into this understudied property of the biohybrid system.


Late abscess formation following indirect hernia repair utilizing silk suture.
Inguinal hernia repair is the most common operation performed by pediatric surgeons. The critical portion of the operation is high ligation of the hernia sac, which is classically performed with silk suture. This foreign body has the potential to serve as a nidus for latent infection/rejection that may result in an abscess long after the operation. This complication has rarely been described in the literature. We have cared for six children who have presented with latent inguinal or pelvic abscesses following high ligation of the inguinal hernia sac with silk suture. The purpose of this report is to examine the varied presentations by which latent complications following herniorraphy may manifest. The pediatric surgeon should recognize that not every inguinal mass following a previous inguinal herniorraphy represents a recurrent hernia! A retrospective review of the charts of six patients with late abscess formation following antecedent inguinal hernia repair was undertaken. The details of the initial and operative endeavors were recorded with specific attention to the details of the initial operative hernia repair as well as the suture material utilized. Inguinal hernia repair continues to be the most common operation performed by pediatric surgeons. Utilization of braided, non-absorbable silk suture may result in latent abscess formation and the need for operative drainage of inguinal or pelvic abscess. Today, as other types of suture material are likely equally efficacious in the ability to effectively close the patent processus vaginalis, pediatric surgeons should consider utilizing non-braided, or absorbable suture material for high ligation of the indirect hernia sac to potentially prevent this complication.


The Loss of Control Over Eating Scale: development and psychometric evaluation.
This study describes the development, content validity, and convergent validity of the Loss of Control over Eating Scale (LOCES). An initial pool of 56 items covering 13 facets of loss-of-control eating was assembled by reviewing qualitative literature, clinical descriptions, and research on binge eating. Eating disorder experts (n = 34) and eating disorder clients (n = 22) rated each proposed item's clarity and relevance to the construct of loss-of-control eating, rated 13 facets for their relevance to the construct, and provided open-ended feedback about the items and facets. Based on the experts' and clients' quantitative and qualitative feedback, scale items were clarified, 28 items were added, and 10 were deleted. University students (n = 476; 70% female, mean age = 20.4 years) completed the resulting 74-item questionnaire, rating how often they had the experience identified in the item while eating in the last 4 weeks. They also completed the measures of eating disturbance, general distress, functional impairment, and general self-control. The resulting 24-item LOCES (Cronbach's α = .96) retained items with highest item-total correlations and coverage of the 12 construct facets that experts rated as important. The LOCES was significantly correlated with eating disturbances, general distress, functional impairment, and general self-control. Three subfactors were identified: behavioral, cognitive/dissociative, and positive/euphoric aspects of loss-of-control eating. A brief, seven-item version of the LOCES was developed and validated. A thorough process of development, content validation, and psychometric evaluation in multiple samples yielded the multifaceted LOCES and its brief form. These instruments may be useful in assessing loss-of-control eating in both clinical and nonclinical settings.


Ectopic phytocystatin expression leads to enhanced drought stress tolerance in soybean (Glycine max) and Arabidopsis thaliana through effects on strigolactone pathways and can also result in improved seed traits.
Ectopic cystatin expression has long been used in plant pest management, but the cysteine protease, targets of these inhibitors, might also have important functions in the control of plant lifespan and stress tolerance that remain poorly characterized. We therefore characterized the effects of expression of the rice cystatin, oryzacystatin-I (OCI), on the growth, development and stress tolerance of crop (soybean) and model (Arabidopsis thaliana) plants. Ectopic OCI expression in soybean enhanced shoot branching and leaf chlorophyll accumulation at later stages of vegetative development and enhanced seed protein contents and decreased the abundance of mRNAs encoding strigolactone synthesis enzymes. The OCI-expressing A. thaliana showed a slow-growth phenotype, with increased leaf numbers and enhanced shoot branching at flowering. The OCI-dependent inhibition of cysteine proteases enhanced drought tolerance in soybean and A. thaliana, photosynthetic CO2 assimilation being much less sensitive to drought-induced inhibition in the OCI-expressing soybean lines. Ectopic OCI expression or treatment with the cysteine protease inhibitor E64 increased lateral root densities in A. thaliana. E64 treatment also increased lateral root densities in the max2-1 mutants that are defective in strigolactone signalling, but not in the max3-9 mutants that are defective in strigolactone synthesis. Taken together, these data provide evidence that OCI-inhibited cysteine proteases participate in the control of growth and stress tolerance through effects on strigolactones. We conclude that cysteine proteases are important targets for manipulation of plant growth, development and stress tolerance, and also seed quality traits.


Feature-based tactile object recognition.
Tactile sensing offers powerful capabilities for robotic perception. Through the use of array-force sensors, precisely located surface information about objects in the workspace is available wherever the robot arm may reach. In order to use this information to identify objects and their placement, interpretation processes should employ proprioceptive information and should use tactile image features which reflect object characteristics. A technique is described for the generation of constraints on object identity and placement such that information from multiple sensor contacts may cooperate towards interpretation.


Infusion of propofol with bispectral index monitoring does not reduce the amount of propofol used during transvaginal oocyte retrieval procedure.
In our study we aimed to investigate whether the use of bispectral index (BIS) monitoring would decrease total propofol consumption during the transvaginal oocyte retrieval procedure. This was a prospective, randomized, controlled, parallel-group clinical trial. The study was conducted in the operating room, and postoperative recovery room. One hundred and thirty, American Society of Anesthesiologists (ASA) I-II patients, over age 18, undergoing transvaginal oocyte retrieval were included in this study. All patients were administered 2 μg/kg fentanyl, and 2 mg/kg propofol for the induction of anesthesia. The patients were divided into two groups. Patients in the group bolus were given 0.5 mg/kg of propofol when necessary, according to the observer's range of motion. Patients in the group BIS were given 10 mg/kg/h propofol infusion adjusted to keep the BIS value between 40 and 60. The primary outcome was the total dose of propofol administered per patient. The secondary outcomes were the time to reach the value of 5 on the Modified Observer's Assessment of Alertness Sedation Scale (MOASs), the time to reach Post Anesthetic Discharge Scoring System (PADSS) ≥ 9 of the patients, satisfaction of the patient, and the gynecologist. The amount of total propofol was higher in the group BIS than in the group bolus administered according to the patient's clinic. There was no difference in the time to reach the value of 5 on the MOASs between the groups. The time to reach PADSS ≥ 9 was longer in the group BIS than in the group bolus. There was no difference between the two groups in terms of the satisfaction of the patient and the gynecologist. Administration of propofol as an infusion with BIS monitoring did not reduce the amount of propofol administered to patients during transvaginal oocyte retrieval.Clinical trial registration number: NCT05631925-30/11/2022.


Loneliness, HIV-related stigma, and condom use among a predominantly rural sample of HIV-positive men who have sex with men (MSM).
Most previous studies of the sexual behaviors of men who have sex with men (MSM) living with HIV are based on samples recruited within relatively urban and suburban areas of the United States. Using an internet-based questionnaire, we assessed HIV-related stigma, loneliness, and event-level sexual behaviors in a sample of HIV positive MSM (n = 100) residing within a largely rural area in the Midwestern United States. HIV-related stigma was correlated with loneliness (r = 0.619, p < 0.01). Loneliness was negatively associated with condom usage with the most recent partner of unknown status (p < 0.05). Namely, a 1-unit increase in the UCLA loneliness score was met with a 10% decrease in odds of condom usage. Further studies are warranted that explore loneliness, within the context of HIV-related stigma, among HIV-positive MSM residing in rural areas. More refined data will inform clinical and social service practice, as they provide much-needed information on sexual health outcomes and experiences of an often underserved and under studied population.


[Antimicrobial action of Lentinus edodes juice on human microflora].
The action of the juice of Shiitake mushroom (L. edodes) on pathogenic and opportunistic microorganisms, detected in cases of considerable dysbiotic changes (Escherichia coli O-114, Staphylococcus aureus, Enterococcus faecalis, Candida albicans), as well as on some bacterial eubiotic producer strains (Escherichia coli M-17, Bifidobacterium spp., Lactobacillus spp.). The juice of this mushroom at a concentration of 5% from the volume of the nutrient medium was found to produce a pronounced antimicrobial effect with respect to C. albicans, S. aureus, E. faecalis, E. coli O-114 and to stimulate the growth of E. coli M-17. Bifidobacteria and lactobacteria exhibited resistance to the action of L. edodes juice.


Coordinated regulation of NK receptor expression in the maturing human immune system.
NK cells are responsible for recognizing and killing transformed, stressed, and infected cells. They recognize a set of non-Ag-specific features termed "altered self" through combinatorial signals from activating and inhibitory receptors. These NKRs are also expressed on CD4(+) and CD8(+) T cells, B cells, and monocytes, although a comprehensive inventory of NKR expression patterns across leukocyte lineages has never been performed. Using mass cytometry, we found that NKR expression patterns distinguish cell lineages in human peripheral blood. In individuals with high levels of CD57, indicative of a mature immune repertoire, NKRs are more likely to be expressed on non-NK cells, especially CD8(+) T cells. Mature NK and CD8(+) T cell populations show increased diversity of NKR surface expression patterns, but with distinct determinants: mature NK cells acquire primarily inhibitory receptors, whereas CD8(+) T cells attain a specific subset of both activating and inhibitory receptors, potentially imbuing them with a distinct functional role. Concurrently, monocytes show decreased expression of the generalized inhibitory receptor leukocyte Ig-like receptor subfamily b member 1, consistent with an increased activation threshold. Therefore, NKR expression is coordinately regulated as the immune system matures, resulting in the transfer of "altered self" recognition potential among leukocyte lineages. This likely reduces Ag specificity in the mature human immune system, and implies that vaccines and therapeutics that engage both its innate and adaptive branches may be more effective in the settings of aging and chronic infection.


What can bibliographic software offer you?
This article provides an introduction to bibliographic software products, common uses for bibliographic software, and some suggestions on how to choose the right software product. The focus of this article is on software for individual, rather than institutional, use. Bibliographic software is designed to allow information to be catalogued and retrieved with ease. Bibliographic software products range from catalogue database software to more specialized bibliographic database and management software products. Each type of product meets the needs of a specific user group.


Fatal spontaneous Clostridium septicum gas gangrene: a possible association with iatrogenic gastric acid suppression.
The long-term use of proton pump inhibitors has been linked to an increased risk for the development of gastric polyps, hip fractures, pneumonia, and Clostridium difficile colitis. There is evidence that chronic acid suppression from long-term use of proton pump inhibitors poses some risk for the development of C difficile-associated diarrhea by decreasing the elimination of pathogenic microbes before reaching the lower gastrointestinal tract. Here we present a case of a 51-year-old woman with a recent history of abdominal pain and fever who presented to the emergency department with rapidly progressive spontaneous necrotizing fasciitis and gas gangrene and died within hours of presentation. Postmortem examination confirmed spreading tissue gas gangrene and myonecrosis. In addition, multiple intestinal ulcers containing Clostridium septicum were present at autopsy. This case illustrates a possible association between proton pump inhibitor therapy and fatal C septicum infection.


Real-life burden of adverse reactions to biological therapy in inflammatory bowel disease: a single-centre prospective case series.
Biologics represent a key therapeutic option in inflammatory bowel disease (IBD), but are associated with several side effects. Post-marketing surveillance, through a spontaneous adverse drug reactions (ADRs) monitoring system, is essential to assess the safety profile of biologics. The aim of the study was to prospectively evaluate the occurrence of ADRs in IBD patients treated with biologics from a single centre in Southern Italy. Data from patients with Crohn's Disease (CD) and Ulcerative Colitis (UC) who underwent biological therapy were prospectively collected. ADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA®). Overall, 68 (54% male, 68% with UC and 32% with CD) biologic-naïve IBD patients underwent biological therapy. Mean follow-up was 11.7 ± 6.2 months. As a results of switches, for 68 patients we obtained 96 biologic prescriptions. Overall, 45 ADRs occurred in 36 (53%) patients, distributed as follows (ADRs/prescriptions): 19/37 with IFX-Remicade, 5/12 with IFX-Remsima, 8/9 with GOL, 11/26 with ADA, and 2/12 with VDZ. Mild ADRs were 29 (64%), moderate 15 (34%) and 1 (2%) severe. General disorders and administration related reactions were the most frequent ADRs (35%), followed by skin and subcutaneous tissue disorders (20%), infections (15%), musculoskeletal (11%), respiratory (6%) blood (4%), gastrointestinal (4%), and vascular disorders (2%). In 9 cases (20%) the ADRs resulted in definitive discontinuation of biologic therapy. In a prospective cohort of IBD patients, more than half experienced ADRs during biologic therapy. General disorders and administration related reactions were the most common ADRs, while infections were less common and rarely led to discontinuation of therapy. Findings underline the importance of surveillance in management of IBD patients during biologic therapy and implementing safety protocols with data from real-life settings.


Recall and recognition measures of paired associate learning in healthy aging.
Associate-recognition has received little attention as a potential clinical tool for detecting early Alzheimer's disease (AD). As an important preliminary stage to investigating the paradigm's diagnostic utility, we designed and administered a verbal associate-recognition task to healthy elderly participants (n = 62) and compared their performance to that on traditional cued-recall PAL. In both test conditions, the stimulus list comprised of a mixture of highly imageable and less imageable word pairs. Overall, performance on the associate-recognition task was superior to that on the cued-recall analogue. This 'recognition advantage' was not attributable to the higher baseline or chance guessing rate in the associate-recognition condition, as the size of the recognition advantage varied across learning trials and stimulus imageability. In comparison to performance on the imageable stimuli, performance on the less imageable stimuli was poor in both associate-recognition and cued-recall conditions. Across the delay, performances were more likely to drop in the cued-recall condition than the associate-recognition condition. These results suggest that verbal associate-recognition may be clinically efficacious and better tolerated in elderly populations than traditional cued-recall paradigms. Although these results are encouraging, further research is required to examine the utility of associate-recognition in clinical populations, particularly early AD.


Transcriptional networks and cellular senescence in human mammary fibroblasts.
Senescence, the molecular program that limits the finite proliferative potential of a cell, acts as an important barrier to protect the body from cancer. Techniques for measuring transcriptome changes and for modulating their expression suggest that it may be possible to dissect the transcriptional networks underlying complex cellular processes. HMF3A cells are conditionally immortalized human mammary fibroblasts that can be induced to undergo coordinated senescence. Here, we used these cells in conjunction with microarrays, RNA interference, and in silico promoter analysis to promote the dissection of the transcriptional networks responsible for regulating cellular senescence. We first identified changes in the transcriptome when HMF3A cells undergo senescence and then compared them with those observed upon replicative senescence in primary human mammary fibroblasts. In addition to DUSP1 and known p53 and E2F targets, a number of genes such as PHLDA1, NR4A3, and a novel splice variant of STAC were implicated in senescence. Their role in senescence was then analyzed by RNA silencing followed by microarray analysis. In silico promoter analysis of all differential genes predicted that nuclear factor-kappaB and C/EBP transcription factors are activated upon senescence, and we confirmed this by electrophoretic mobility shift assay. The results suggest a putative signaling network for cellular senescence.


Hematopoietic stem cells debut in embryonic lymphomyeloid tissues of elasmobranchs.
The evolutionary initiation of the appearance in lymphomyeloid tissue of the hemopoietic stem cell in the earliest (most primitive) vertebrate model, i.e. the elasmobranch (chondroichthyan) Torpedo marmorata Risso, has been studied. The three consecutive developmental stages of torpedo embryos were obtained by cesarean section from a total of six pregnant torpedoes. Lymphomyeloid tissue was identified in the Leydig organ and epigonal tissue. The sections were treated with monoclonal anti-CD34 and anti-CD38 antibodies to detect hematopoietic stem cells. At stage I (2-cm-long embryos with external gills) and at stage II (3-4 cm-long embryos with a discoidal shape and internal gills), some lymphoid-like cells that do not demonstrate any immunolabeling for these antibodies are present. Neither CD34+ nor CD38+ cells are identifiable in lymphomyeloid tissue of stage I and stage II embryos, while a CD34+CD38- cell was identified in the external yolk sac of stage II embryo. The stage III (10-11-cm-long embryos), the lymphomyeloid tissue contained four cell populations, respectively CD34+CD38-, CD34+CD38+, CD34-CD38+, and CD34-CD38- cells. The spleen and lymphomyeloid tissue are the principal sites for the development of hematopoietic progenitors in embryonic Torpedo marmorata Risso. The results demonstrated that the CD34 expression on hematopoietic progenitor cells and its extraembryonic origin is conserved throughout the vertebrate evolutionary scale.


Transdermal buprenorphine in chronic pain: indications and clinical experience.
Transdermal buprenorphine has been shown to be effective in managing moderate-to-severe cancer pain and severe pain that is unresponsive to nonopioid analgesics. In clinical trials, it provided better pain relief than placebo, despite a higher consumption of rescue analgesia by placebo patients. Analgesia was rated as satisfactory or better by 90% of patients in a long-term follow-up study and 94.6% considered the buprenorphine matrix patch to be user friendly. Transdermal buprenorphine is well tolerated; most adverse events are transient local reactions to the patch or systemic effects typical of treatment with opioids. Even in opioid-experienced volunteers, buprenorphine does not cause respiratory depression at doses up to 70-times higher than those used for analgesia. No problems have been encountered when switching from another opioid to transdermal buprenorphine, or in combining the buprenorphine patch with intravenous morphine or tramadol for breakthrough pain. There is a growing body of evidence that transdermal buprenorphine may be particularly useful for managing neuropathic pain. Most notably, it appears to be effective in treating hyperalgesic states and syndromes characterized by pronounced central sensitization.


Chk1 Promotes DNA Damage Response Bypass following Oxidative Stress in a Model of Hydrogen Peroxide-Associated Ulcerative Colitis through JNK Inactivation and Chromatin Binding.
Dysregulation of c-Jun N-terminal kinase (JNK) activation promoted DNA damage response bypass and tumorigenesis in our model of hydrogen peroxide-associated ulcerative colitis (UC) and in patients with quiescent UC (QUC), UC-related dysplasia, and UC-related carcinoma (UC-CRC), thereby adapting to oxidative stress. In the UC model, we have observed features of oncogenic transformation: increased proliferation, undetected DNA damage, and apoptosis resistance. Here, we show that Chk1 was downregulated but activated in the acute and quiescent chronic phases. In both phases, Chk1 was linked to DNA damage response bypass by suppressing JNK activation following oxidative stress, promoting cell cycle progression despite DNA damage. Simultaneously, activated Chk1 was bound to chromatin. This triggered histone acetylation and the binding of histone acetyltransferases and transcription factors to chromatin. Thus, chromatin-immobilized activated Chk1 executed a dual function by suppressing DNA damage response and simultaneously inducing chromatin modulation. This caused undetected DNA damage and increased cellular proliferation through failure to transmit the appropriate DNA damage signal. Findings in vitro were corroborated by chromatin accumulation of activated Chk1, Ac-H3, Ac-H4, and c-Jun in active UC (AUC) in vivo. Targeting chromatin-bound Chk1, GCN5, PCAF, and p300/CBP could be a novel therapeutic strategy to prevent UC-related tumor progression.


Building Bridges: Integrating Disability Ethics Into Occupational Therapy Practice.
Throughout the course of their careers, occupational therapy practitioners will encounter many ethical dilemmas as a part of service provision to disabled people. This article illustrates how disability ethics can strengthen the application of the Occupational Therapy Code of Ethics in practice. To maintain the integrity of the occupational therapy profession, it is critical that practitioners integrate concepts of disability ethics into the profession so their practice will promote environments in which disabled people will flourish.


Quantitative evaluation of micronuclei in oral squamous cell carcinoma and oral submucous fibrosis patients: a comparative study.
The forte of research today aims at determining genotoxic changes in human cells as rapidly as possible. Micronuclei estimation in exfoliated cells is an easy, noninvasive and a reliable method to monitor genotoxic changes due to various reasons in oral mucosal cells. To identify, quantify and compare micronuclei in exfoliated buccal mucosal cells of healthy, oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC) participants. In the present study, buccal smears from the 60 participants (30 each of OSMF and OSCC) and 30 age and sex matched controls were obtained and stained using Papanicolaou (PAP) staining method and observed under 100X magnification to identify and quantify micronuclei in the exfoliated cells of oral mucosa. There was a significant increase in micronuclei count from control to OSMF to OSCC. Also, a significant increase in the micronuclei frequency is observed with the different clinical stages and histological grades of OSMF and different histological grades of OSCC. Micronucleus assay can be used as an easy and consistent marker for genotoxic evaluation in higher risk groups and can be used for better treatment evaluation and prognosis in cases of OSMF and OSCC. Some relevant patents are also outlined in this article.


Radioprotection of normal and malignant tissue in the mouse by diethylaminoreserpine.
The protective effect of pre-irradiation injections of diethylaminoreserpine (DL-152) for normal and malignant tissues in the mouse has been investigated. Dose modifying factors (DMFs) obtained for normal tissue ranged from 1.0 for bone marrow CFUs to more than 1.8 for skin. The DMFs for two transplantable tumours investigated were 1.0 for the EMT6 adenocarcinoma and 1.70 for the KHT fibrosarcoma (at a surviving fraction of 0.1. Acutely hypoxic KHT tumours were protected to a slightly lesser extent than were aerated tumours. For the KHT tumour, the number of clonogenic cells recovered from non-irradiated tumours one hour after DL-152 injection was reduced to 60 per cent of the number covered fro saline-injected controls, while, if DL-152 injected mice were acutely hypoxic at the time of sacrifice, the number of clonogenic cells was further reduced. The survival of non-irradiated EMT6 tumour cells was unaffected by DL-152 injection prior to sacrifice.


Use of an educational support program to assist patients receiving injectable osteoporosis treatment: experience with teriparatide.
Low treatment adherence and persistence are important considerations in the management of chronic disorders such as osteoporosis, as they are linked to the reduced effectiveness of drug therapy. As teriparatide (Forsteo, Eli Lilly and Company, Alcobendas, Spain) is administered by subcutaneous injection using a customized delivery device for 24 months to reduce fracture risk in patients with osteoporosis, an educational support program was developed to assist patients with correctly administering the treatment. All patients in Spain can voluntarily participate in this ongoing program, which consists of up to 22 phone calls, by a qualified and licensed nurse trained in use of the delivery device, that are designed to improve patients' knowledge of, and to provide a reminder as to how to use, the device. Patients are also sent educational material regarding the delivery device and osteoporosis, and regularly receive needles suitable for the device. This study presents persistence data for all 23,069 patients registered in the program and prescribed teriparatide between September 2007 and June 2010. Persistence in the program was 90.8% at 3 months, 83.5% at 6 months, 74.8% at 12 months, 68.5% at 18 months, and 64.1% at 24 months. Patient satisfaction with the educational support program was high at all assessment times, and patients generally found the delivery device easy to use. These results show that patients from all provinces in Spain with severe osteoporosis receiving teriparatide and enrolled in an educational support program had high persistence and satisfaction with the program. However, no control group was included in these analyses and it is possible that selection bias occurred. It is suggested that patient-based strategies similar to this could be beneficial for all long-term treatments.


[Eosinophilic cystitis in children].
Eosinophilic cystitis is an inflammatory disorder of the urinary bladder, characterised by irritative voiding symptoms, negative urine cultures, and eosinophilic infiltration of the bladder wall. Since 1960 only about 20 cases have been described in the English scientific reports, making it a rather rare entity. In children the disease appears to be shortlived and self-limited, requiring no specific treatment. We present a case with a 7.5-year-old boy, who experienced spontaneous remission of all symptoms, following an acute attack of eosinophilic cystitis.


Preoperative valproate administration does not increase blood loss during temporal lobectomy.
Surgical treatment is increasingly used for patients with medically re fractory seizures. Valproate (VPA) is an effective, widely used anticonvulsant in this patient population, but believed by some researchers to increase surgical bleeding because of quantitative thrombocytopenia and functional defects in platelet aggregation. Because we have observed no clinical evidence that perioperative administration of VPA increases blood loss or complications related to postoperative bleeding in patients undergoing temporal lobectomy at our institution, we sought to test this hypothesis. We made a retrospective review of the medical records of all patients who underwent epilepsy surgery at the University of California, San Francisco Medical Center, from September 1986 through January 1993. Patients who had a temporal lobectomy and whose medical records documented preoperative platelet counts and pre- and postoperative hematocrit and hemoglobin values were included. We excluded patients who had cranial surgery before temporal lobectomy and those with intracranial neoplasms or vascular malformations. Patients were divided into two groups: those who received VPA in the immediate preoperative period and those who had not received VPA recently. We compared the estimated surgical blood loss and the estimated change in red blood cell (RBC) volume between groups by unpaired t tests. The charts of 87 consecutive patients qualified for inclusion in the study. Patients in the VPA group had relative (but not absolute) thrombocytopenia preoperatively (235 +/- 64 vs. 277 +/- 69 k in the No-VPA group). There were no differences in the estimated blood loss, RBC volume, or in the incidence of postoperative transfusion. VPA apparently does not increase complications of hemostasis during therapeutic surgical resections for epilepsy. Therefore, we do not recommend routinely discontinuing VPA before craniotomy.


Medical repatriation of British diplomats resident overseas.
The aim of this study was to analyse medical evacuations and short tours (collectively known as medevacs) in British Foreign and Commonwealth Office (FCO) staff and dependents residing overseas. Further aims were to look for groups with a disproportionate number of medical evacuations/short tours, and to identify events which may have been predictable in retrospect. For the purposes of this study, a medical evacuation was defined as a journey to the UK or an appropriate regional referral center for medical treatment or review, and a medical short tour was an early termination of posting for medical reasons. The medical records of all staff and dependents who had been medically evacuated/short toured in 1995 were retrospectively analysed. Information collected included demographic details, whether the medevac was an emergency or a predicted necessity, why the medevac was required, the diagnosis, and the time from medical clearance to medevac. In 1995, 160 medevacs involving 137 individuals were authorized. This represented 3.08% of individuals overseas, with only 0.4% of individuals posted overseas being evacuated with new medical events within 1 year of medical clearance. The proportion of medevacs for staff was significantly higher than for dependents (spouses and children), and staff in their 20s and fast-stream diplomats (young "high-flyers" with a university education) were over-represented in the evacuee group. Non-physical problems were predominant in the latter groups. The main reason for evacuation (70%) was that medical facilities were considered unsuitable, and just over half of the medevacs (51%) were considered by the investigating team to have been unpredictable. Only a small percent of individuals posted overseas required medevac. The likelihood of evacuation was significantly higher in staff when compared to dependents, and certain grades/age groups appeared to be over-represented in the evacuee group. These groups are possibly more vulnerable, particularly to non-physical problems, and this is a potential area for future research. A prospective study of medical events overseas is proposed to see if these results are reproduced. If these findings are confirmed, medical clearance and FCO posting procedures may need to be altered for groups which are identified as being vulnerable.


Artwork in anatomy education: A way to improve undergraduate students' self-efficacy and attitude.
Anatomy is one of the leading subjects in health science, and students need a strong anatomy background in these fields. Traditional lecturer-oriented anatomy education is based predominantly on passive learning methods. In recent years, alternative educational methods like hands-on art and 3D atlas-based education methods have become more popular as competitive alternatives to traditional approaches. This is a prospective, randomized, longitudinal, interventional study, and a total of 181 undergraduate students participated in this study. A comparative design was used with two groups: Artwork and Atlas. This study aims to evaluate the effectiveness of creative and artistic approaches in improving undergraduate students' attitudes and self-efficacy toward anatomy courses. A Pearson correlation, an independent t-test, and a paired t-test were used to analyze the results. Both groups experienced a negative mean score on the anatomy self-efficacy scale, suggesting an increase in anatomy self-efficacy, and showed significant self-efficacy improvements (p < 0.005). An independent t-test analysis found no statistically significant difference between the Atlas group and the Artwork group on the anatomy self-efficacy scales (pretest and posttest) and the anatomy attitudes scale (p > 0.005). Artwork-based education and learning methods can be used as active learning methods to improve students' self-efficacy toward anatomy. This method allows learners to employ their creative abilities in order to express their ideas visually, making complex concepts easier to comprehend. It can also help students develop practical, problem-solving, critical thinking, and teamwork skills. It is cost-effective and engaging since it does not need any expensive equipment.


The Trials (and Tribulations) of Complementary and Alternative Medicine in Oncology.
Two decades following the creation of the Office of Cancer Complementary and Alternative Medicine at the National Cancer Institute, the status of complementary and alternative medicine (CAM) research within oncology remains opaque. To better understand the landscape of CAM studies in oncology, we identified CAM-related phase III randomized controlled trials (RCTs) through ClinicalTrials.gov and compared these CAM trials to all non-CAM oncologic RCTs. Pearson χ2 testing was used to compare proportions across groups; all tests were two-sided. Comparing the 25 identified CAM RCTs with 739 non-CAM RCTs, CAM studies were more likely to be sponsored by a cooperative group (64.0% vs 28.6%, P < .001) and less likely to be industry funded (8.0% vs 76.5%, P < .001). CAM trials disproportionately excluded disease-related outcomes as endpoints (8.0% vs 84.6%, P < .001), were unsupported by prior early-phase data (55.0% vs 96.1%, P < .001), and did not meet the primary endpoint (8.7% vs 53.0%, P < .001). Given the observed relationship between encouraging pilot data and subsequent phase III trial success, we contend that future CAM RCTs may yield more promising findings if better supported by appropriately designed and well-characterized early-phase signals.


Loneliness, social isolation, and pain following the COVID-19 outbreak: data from a nationwide internet survey in Japan.
The aim of cross-sectional study was to investigate the association between loneliness, increased social isolation, and pain following the COVID-19 outbreak. A total of 25,482 participants, aged 15-79 years, were assessed using an internet survey; the University of California, Los Angeles Loneliness Scale (Version 3), Short Form 3-item (UCLA-LS3-SF3) was used to assess loneliness, and a modified item of the UCLA-LS3-SF3 was used to measure the perception of increased social isolation during the pandemic. The outcome measures included the prevalence/incidence of pain (i.e., headache, neck or shoulder pain, upper limb pain, low back pain, and leg pain), pain intensity, and the prevalence of past/present chronic pain. Pain intensity was measured by the pain/discomfort item of the 5-level version of the EuroQol 5 Dimension scale. Odds ratios of pain prevalence/incidence and past/present chronic pain prevalence according to the UCLA-LS3-SF3 scoring groups (tertiles) and the frequency of the perceived increase in social isolation (categories 1-5) were calculated using multinomial logistic regression analysis. The mean pain intensity values among different loneliness and social isolation levels were tested using an analysis of covariance. Increased loneliness and the severity of the perceived social isolation were positively associated with the prevalence/incidence of pain, pain intensity, and the prevalence of past/present chronic pain.


Associations of Cumulative Family Risk With Academic Performance and Substance Involvement: Tests of Moderation by Child Reading Engagement.
Background: Exposure to cumulative contextual risk within the family early in life increases children's risk for substance involvement and related difficulties, including school failure, in adolescence and young adulthood. However, potential protective factors that buffer these risk associations are relatively untested, yet such tests are needed to improve existing preventive interventions for enhancing resilience among vulnerable children. Objectives: This study tested child reading engagement with parents at home as a moderator of cumulative family risk associations with adolescent substance use and academic performance as well as young adult substance abuse. Methods: Population register data as well as parent-report and adolescent-report data from 6,963 participants of the 1986 Northern Finland Birth Cohort study were analyzed via structural equation modeling with latent variable interactions. Results: Results showed that child reading engagement moderated the associations of cumulative family risk with both adolescent academic performance and young adult substance abuse, but not with adolescent substance use. The highest levels of academic performance were observed under conditions of low risk and high reading engagement. Interestingly, cumulative family risk had a small positive association with substance abuse when reading engagement was low and a negative association with the young adult outcome when reading engagement was high. Conclusions/Importance: Moderation tests revealed complex interaction forms that may have implications for both theory and family-based preventive interventions.


Assessment of harms, benefits, and cost-effectiveness of prostate cancer screening: A micro-simulation study of 230 scenarios.
Prostate cancer screening incurs a high risk of overdiagnosis and overtreatment. An organized and age-targeted screening strategy may reduce the associated harms while retaining or enhancing the benefits. Using a micro-simulation analysis (MISCAN) model, we assessed the harms, benefits, and cost-effectiveness of 230 prostate-specific antigen (PSA) screening strategies in a Dutch population. Screening strategies were varied by screening start age (50, 51, 52, 53, 54, and 55), stop age (51-69), and intervals (1, 2, 3, 4, 8, and single test). Costs and effects of each screening strategy were compared with a no-screening scenario. The most optimum strategy would be screening with 3-year intervals at ages 55-64 resulting in an incremental cost-effectiveness ratio (ICER) of €19 733 per QALY. This strategy predicted a 27% prostate cancer mortality reduction and 28 life years gained (LYG) per 1000 men; 36% of screen-detected men were overdiagnosed. Sensitivity analyses did not substantially alter the optimal screening strategy. PSA screening beyond age 64 is not cost-effective and associated with a higher risk of overdiagnosis. Similarly, starting screening before age 55 is not a favored strategy based on our cost-effectiveness analysis.


Dissociation between sickness behavior and emotionality during lipopolysaccharide challenge in lymphocyte deficient Rag2(-/-) mice.
Inflammatory diseases are highly associated with affective disorders including depression and anxiety. While the role of the innate immune system on emotionality has been extensively studied, the role of adaptive immunity is less understood. Considering that chronic inflammatory conditions are mediated largely by maladaptive lymphocyte function, the role of these cells on brain function and behavior during inflammation warrants investigation. In the present study we employed mice deficient in lymphocyte function and studied behavioral and inflammatory responses during challenge with bacterial lipopolysaccharides (LPS). Rag2(-/-) mice lacking mature lymphocytes were susceptible to death under sub-septic (5 mg/kg) doses of LPS and survived only to moderate (1 mg/kg) doses of LPS. Under these conditions, they displayed attenuated TNF-alpha responses and behavioral symptoms of sickness when compared with immunocompetent mice. Nevertheless, Rag2(-/-) mice had protracted motivational impairments after recovery from sickness suggesting a specific function for lymphocytes on the re-establishment of motivational states after activation of the innate immune system. The behavioral impairments in Rag2(-/-) mice were paralleled by an elevation in plasma corticosterone after behavioral tests. These results provide evidence that the absence of adaptive immunity may be associated with emotional deficits during inflammation and suggest that depressive states associated with medical illness may be mediated in part by impaired lymphocyte responses.


Validation of participant eligibility for pre-exposure prophylaxis: Baseline data from the PRELUDE demonstration project.
In Australia, pre-exposure prophylaxis (PrEP) is targeted to individuals at high risk for HIV infection. We describe the HIV risk profile and characteristics of PRELUDE participants, and evaluate the population validity of the sample in representing high-risk gay and bisexual men (GBM) eligible for PrEP. PRELUDE is an on-going, open-label, single-arm observational study. Participants were identified in clinics and screened for eligibility using a paper-based risk assessment tool which followed the New South Wales (NSW) PrEP guidelines. Selection was validated using an independent online behavioural survey, completed by study participants upon enrolment. Demographic information was analysed using descriptive statistics, and kappa tests were used to determine agreement between reporting of high-risk practices in the risk assessment and behavioural survey. During 2014-15, 471 individuals were targeted for enrolment; 341 were assessed for PrEP eligibility and 313 were enrolled. Of these, 303 (97%) identified as GBM. Overall, 85% of GBM met at least one high-risk criterion; 68% reported receptive intercourse with an HIV-positive or unknown status casual male partner, and 37% reported methamphetamine use in the three months preceding enrolment. The remaining 15% were enrolled based on medium-risk behaviours, or at the clinicians' discretion. We found an 82% total agreement between self-reported high-risk behaviour and clinicians' categorisation of GBM as being at high risk for HIV based on PrEP eligibility criteria. Behavioural eligibility criteria used by clinicians successfully identified individuals at high risk for HIV infection. This targeted approach ensures that the greatest public health and HIV prevention benefits can be derived in a setting without universal access to PrEP.


Expression of tissue-type plasminogen activator in smooth muscle cells of injured iliac arteries in rabbits.
In this experiment, expression of tissue-type plasminogen activator (t-PA) in smooth muscle cells (SMCs) was measured at different intervals after the arterial injury. In the normal iliac arteries, only low levels of t-PA activity were estimated. t-PA activity in extracts of the iliac arteries increased significantly at the 4th day after the injury, equivalent to the process that SMCs migrated from the media to the intima, and the t-PA activity was then decreased approximately to the normal level at the 7th day. Coexistent to the above data, results from in situ hybridization showed that the expression of t-PA mRNA in the intima as well as media increased also significantly at the 4th day after the arterial injury, and at the 7th day, t-PA mRNA was detected only in those SMCs locating closely adjacent to the internal elastic lamina. These results suggest that t-PA might play an important role in SMC migration following endothelial injury, and antagonism of t-PA expression and/or activity within the vessel wall might be helpful in intervening the development of restenosis following angioplasty.


Relationships between housing and management factors and clinical health events in elephants in North American zoos.
Elephants experience a number of health issues that can contribute to their well-being and survival. In managed populations, housing conditions and management practices can influence individual health, so potential risk factors associated with morbidity or mortality should be identified to ensure the best possible standards of care. The goal of this study was to determine if the number of clinical events experienced could be a useful welfare indicator in zoo elephants, and to determine factors associated with key pathologies. We used an epidemiological approach to investigate how intrinsic (species, sex, age) and extrinsic (housing, management) factors were associated with both the total number of clinical events, and each of the four most prevalent pathology types (gastrointestinal issues, skin lesions, lameness, foot lesions), over a 12-month period. The study included 220 (127 African; 93 Asian) elephants housed at 61 facilities across North America. More than 1100 clinical events were identified. Species and sex differences were apparent in the types of pathology encountered, and unsurprisingly, the number of clinical events was positively correlated with age. Factors relating to housing (percent time with indoor/outdoor choice, space experience inside, number of unique environments an elephant was housed in, percent time on soft substrate) and management (enrichment diversity, spread of feeding opportunities) were also related to the number of clinical events. However, relationships were often counter to our initial hypotheses, highlighting caution in assuming cause and effect from correlational analyses such as these. Other welfare indicators such as serum and fecal glucocorticoids and serum prolactin were also associated with health status, being higher or more variable in individuals with a greater number of events. This approach provides insight into housing and management factors related to the health of these species in zoos, and in some cases, may reflect management changes that have already been made to mitigate existing or anticipated health concerns.


Unproven diagnostic procedures in IgE-mediated allergic diseases.
A considerable body of literature on therapeutic aspects of complementary and alternative medicine has been published in recent years, but little is known on diagnostic procedures. This short review lists complementary and alternative diagnostic procedures for the diagnosis of allergic diseases and presents an assessment of their usefulness for the daily practice. The review of the literature revealed that neither the determination of specific immunoglobulin G-antibodies in serum, the hair-analysis, the cytotoxic test, kinesiology, iridology, or electrodermal testing represent useful tests for the daily practice. To date, no complementary or alternative diagnostic procedure can be recommended as a meaningful element in the diagnostic work-up of allergic diseases. This is especially true for food allergy: properly performed oral food challenges still represent the gold standard for implementing specific diets in food allergic individuals. Ineffective diagnostic approaches may be costly for the consumer and delay appropriate therapy.


Mononuclear Non-Heme Manganese-Catalyzed Enantioselective cis-Dihydroxylation of Alkenes Modeling Rieske Dioxygenases.
The practical catalytic enantioselective cis-dihydroxylation of olefins that utilize earth-abundant first-row transition metal catalysts under environmentally friendly conditions is an important yet challenging task. Inspired by the cis-dihydroxylation reactions catalyzed by Rieske dioxygenases and non-heme iron models, we report the biologically inspired cis-dihydroxylation catalysis that employs an inexpensive and readily available mononuclear non-heme manganese complex bearing a tetradentate nitrogen-donor ligand and aqueous hydrogen peroxide (H2O2) and potassium peroxymonosulfate (KHSO5) as terminal oxidants. A wide range of olefins are efficiently oxidized to enantioenriched cis-diols in practically useful yields with excellent cis-dihydroxylation selectivity and enantioselectivity (up to 99% ee). Mechanistic studies, such as isotopically 18O-labeled water experiments, and density functional theory (DFT) calculations support that a manganese(V)-oxo-hydroxo (HO-MnV═O) species, which is formed via the water-assisted heterolytic O-O bond cleavage of putative manganese(III)-hydroperoxide and manganese(III)-peroxysulfate precursors, is the active oxidant that effects the cis-dihydroxylation of olefins; this is reminiscent of the frequently postulated iron(V)-oxo-hydroxo (HO-FeV═O) species in the catalytic arene and alkene cis-dihydroxylation reactions by Rieske dioxygenases and synthetic non-heme iron models. Further, DFT calculations for the mechanism of the HO-MnV═O-mediated enantioselective cis-dihydroxylation of olefins reveal that the first oxo attack step controls the enantioselectivity, which exhibits a high preference for cis-dihydroxylation over epoxidation. In this study, we are able to replicate both the catalytic function and the key chemical principles of Rieske dioxygenases in mononuclear non-heme manganese-catalyzed enantioselective cis-dihydroxylation of olefins.


Etoposide hypersensitivity reactions associated with in-line filter use: A retrospective cohort study at CHU de Québec-Université Laval.
A case series of hypersensitivity reactions (HSRs) during intravenous administration of etoposide was observed following the introduction of in-line filters (ILFs) at a specialized university-affiliated center. This raised questions about the possible involvement of filters in these reactions. Despite there being very little published evidence to inform clinical decision making in this potentially clinically significant situation, the use of ILFs was discontinued at this center pending further investigation. The aims of this study were to evaluate the cumulative incidence of etoposide-related HSR with and without the use of ILF and to describe the reactions in adult and pediatric patients with cancer. A retrospective cohort study was performed among all pediatric and adult patients treated with intravenous etoposide at a maximal concentration of 0.4 mg/mL at our center between 30 September 2015 and 16 August 2018. This covered periods of time during which ILFs were used, as well as 6 months before their implementation and after their withdrawal. Data were extracted from medical records and cumulative incidence was calculated for each of the time periods (pre-ILF, ILF, and post-ILF) as the proportion of patients who recorded an HSR (one or more). Confidence intervals were calculated for each proportion using Fisher's Exact 95%. Comparisons of proportions between time periods were performed using Exact Pearson Chi-squared tests. Data were stratified by a number of perfusion cycles (single cycle or multiple cycles) and by patient population (adult and pediatric). A total of 284 patients were included in the study. The overall cumulative incidence of etoposide HSR was 9.9%. The cumulative incidence of HSR tended to be higher during ILF use when compared with combined pre- and post-ILF periods (12.2% [95% CI: 7.9-17.8] vs. 5.2% [95% CI: 1.7-11.7], p = 0.09). In patients who received multiple cycles of etoposide, the cumulative incidence of HSRs was higher during ILF use when compared with combined pre- and post-ILF periods (15.0% [95% CI: 9.6-21.8] vs. 3.9% [95% CI: 0.8-11.0], p = 0.01). The majority of HSRs' maximal severity were grade 1 or 2 (85.7%) according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. This study suggests a link between the use of ILFs and increased incidence of HSR during etoposide perfusion.


[Use of myocardial scintigraphy with 201T1 in combination with the dipyridamole test in patients with ischemic heart disease].
Possible diagnostic use of myocardial 201T1-scintigraphy combined with the dipyridamole test in coronary patients is described. Twenty-six patients were investigated. Coronarography showed atherosclerotic lesions of coronary arteries in 12. The dipyridamole test was positive in all patients with affected coronary arteries, as evidenced by myocardial 201T1-scintigraphy. In the patients with intact coronary arteries, myocardial 201T1-scintigraphy combined with the dipyridamole test was negative in 9 cases and positive in 3. The study demonstrates high sensitivity of the method described.


AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice.
Fatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class of signaling lipids with anti-inflammatory and anti-diabetic properties. However, the endogenous regulation of FAHFAs remains a pressing but unanswered question. Here, using MS-based FAHFA hydrolysis assays, LC-MS-based lipidomics analyses, and activity-based protein profiling, we found that androgen-induced gene 1 (AIG1) and androgen-dependent TFPI-regulating protein (ADTRP), two threonine hydrolases, control FAHFA levels in vivo in both genetic and pharmacologic mouse models. Tissues from mice lacking ADTRP (Adtrp-KO), or both AIG1 and ADTRP (DKO) had higher concentrations of FAHFAs particularly isomers with the ester bond at the 9th carbon due to decreased FAHFA hydrolysis activity. The levels of other lipid classes were unaltered indicating that AIG1 and ADTRP specifically hydrolyze FAHFAs. Complementing these genetic studies, we also identified a dual AIG1/ADTRP inhibitor, ABD-110207, which is active in vivo Acute treatment of WT mice with ABD-110207 resulted in elevated FAHFA levels, further supporting the notion that AIG1 and ADTRP activity control endogenous FAHFA levels. However, loss of AIG1/ADTRP did not mimic the changes associated with pharmacologically administered FAHFAs on extent of upregulation of FAHFA levels, glucose tolerance, or insulin sensitivity in mice, indicating that therapeutic strategies should weigh more on FAHFA administration. Together, these findings identify AIG1 and ADTRP as the first endogenous FAHFA hydrolases identified and provide critical genetic and chemical tools for further characterization of these enzymes and endogenous FAHFAs to unravel their physiological functions and roles in health and disease.


Childbirth Satisfaction during the COVID-19 Pandemic in a Hospital in Southwestern Spain.
Satisfaction, in relation to care received, is a good indicator of quality of care. The objective of this study was to analyze the degree of satisfaction with childbirth and postpartum care as reported by women from one hospital in southwestern Spain during the COVID-19 pandemic. Factors that influenced care were also examined. A cross-sectional study was carried out between the months of October 2020 and February 2021. Satisfaction was measured through the COMFORTS scale, validated in Spanish. A final sample of 116 women was included in the study. The mean age was 32.08 (±4.68) years. A total of 111 (95.69%) women were satisfied or very satisfied with the care received. The median satisfaction score was higher among multiparous women (187 (199-173)) than among primiparous women (174 (193-155.50)) (p = 0.003). Differences in satisfaction were found as a function of the use of epidural analgesia, being higher among women who had planned its use but ultimately did not use it (188 (172.50-199.75)) or who planned its use and did (186 (169.50-198)) than among those who had not planned to use epidural analgesia but ultimately received it (173.50 (187.50-146.25)) or those who did not use it, as planned, before childbirth (172 (157-185)) (p = 0.020). Overall satisfaction rate between SARS-CoV-2-negative women assisted was high. Parity and use of epidural analgesia were two factors influencing satisfaction scores in our sample.


Ventricular assist device implantation using a right thoracotomy.
Most patients needing implantation of a ventricular assist device (VAD) require repeated sternotomy; some after cardiac surgery, and others later for heart transplantation. The purpose of this study was to establish the right thoracotomy technique as an alternative for VAD implantation to reduce repeated sternotomy-related morbidity and mortality. We performed a right thoracotomy in animals, preclinical cadaver fitting tests, and a clinical case. A total of 20 various animals underwent right thoracotomy for implantation of bi-VAD (BVAD, n = 17) and left VAD (LVAD, n = 3). The right chest cavity was entered through the fourth intercostal space with partial resection of the fifth rib. There was no procedure-related morbidity or mortality, except for one calf with right anterior leg paralysis. Preclinical fitting tests were performed on 7 human cadavers to observe the anatomical feasibility of BVAD cannulation from the right side of the heart. In humans, the ascending aorta, interatrial groove, right atrium, and main pulmonary artery were identified as optimal cannula insertion sites for BVAD implantation. A patient with cardiogenic shock underwent a right thoracotomy for implantation of an external LVAD. Cardiac function recovered after 3 weeks, and the device was successfully explanted through a repeat right thoracotomy. In conclusion, a right thoracotomy can be an alternative method to the standard median sternotomy for patients who need repeated sternotomy because of previous cardiac surgery, transplantation at a later date, or those with mediastinal infections.


Commercial watercress as an emerging source of fascioliasis in Northern France in 2002: results from an outbreak investigation.
In April 2002, five cases of fascioliasis were diagnosed in Tourcoing. A case-finding and a case-control study were carried out to identify the source of the outbreak and take appropriate control measures. Eighteen cases were identified through the medical laboratories carrying out serology for fascioliasis. Fourteen cases and 23 controls, identified by the physicians of the cases, were interviewed on symptoms of the disease and their consumption of uncooked plants. Cases were more likely than controls to have eaten commercialized raw watercress (OR 86.7, P < 0.001) and 13 (93%) of the cases reported its consumption. A single producer common to all cases was identified. The inspection of his watercress beds showed a lack of protection against Lymnaea truncatula. This outbreak of fascioliasis due to commercialized watercress indicates that actual sanitary regulations do not allow for the efficient prevention of infestation of watercress production in France.


Hysteresis in DNA compaction by Dps is described by an Ising model.
In all organisms, DNA molecules are tightly compacted into a dynamic 3D nucleoprotein complex. In bacteria, this compaction is governed by the family of nucleoid-associated proteins (NAPs). Under conditions of stress and starvation, an NAP called Dps (DNA-binding protein from starved cells) becomes highly up-regulated and can massively reorganize the bacterial chromosome. Although static structures of Dps-DNA complexes have been documented, little is known about the dynamics of their assembly. Here, we use fluorescence microscopy and magnetic-tweezers measurements to resolve the process of DNA compaction by Dps. Real-time in vitro studies demonstrated a highly cooperative process of Dps binding characterized by an abrupt collapse of the DNA extension, even under applied tension. Surprisingly, we also discovered a reproducible hysteresis in the process of compaction and decompaction of the Dps-DNA complex. This hysteresis is extremely stable over hour-long timescales despite the rapid binding and dissociation rates of Dps. A modified Ising model is successfully applied to fit these kinetic features. We find that long-lived hysteresis arises naturally as a consequence of protein cooperativity in large complexes and provides a useful mechanism for cells to adopt unique epigenetic states.


Prophylactic efficacy on periprosthetic bone loss in calcar region after total hip arthroplasty of antiosteoporotic drugs: a network meta-analysis of randomised controlled studies.
The aim of this study was to evaluate the effect of antiosteoporotic drugs on preventing periprosthetic bone loss in calcar 6 and 12 months after total hip arthroplasty. The network meta-analysis was conducted guided by the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline. A systematic literature search was conducted and 21 studies that enrolled a total of 955 patients with 9 antiosteoporotic drugs met the inclusion criteria. Network meta-analysis and conventional meta-analysis were carried out for calculating standard mean difference (SMD) and the surface under cumulative ranking curve (SUCRA) of the bone mineral density (BMD) in calcar (Gruen zone 7) as well as bone turnover markers (BTMs) including bone-specific alkaline phosphatase (BSAP) and collagen type I cross-linked N telopeptide (NTX) at 6 and 12 months between different antiosteoporotic drugs. At 6 months after total hip arthroplasty, zoledronate (SUCRA=86.4%), risedronate (SUCRA=51.3%) and etidronate (SUCRA=44.5%) were effective in retaining BMD in calcar; zoledronate was significantly more effective than etidronate (SMD=0.65, 95% CI 0.03 to 1.27). Teriparatide (SUCRA=84.5%), denosumab (SUCRA=82.5%), zoledronate (SUCRA=69.2%), alendronate+alfacalcidol (SUCRA=66.2%) and etidronate (SUCRA=51.5%) were the top five drugs in retaining BMD in calcar at 12 months after total hip arthroplasty and the efficacy were comparable. After simultaneously excluding studies in which the prosthesis were cement and the drug dosages as well as treatment durations were inconsistent with those in treating osteoporosis, the above results were robust with the exception that alendronate showed significant efficacy compared with placebo (SMD=1.22, 95% CI 0.46 to 1.99) and was comparable with those effective drugs at 12 months. Long-term residual effect was corroborated only in etidronate, alendronate and zoledronate from previous studies. BTMs were significantly decreased as early as 6 months (SMD of BSAP -0.49, 95% CI -0.84 to -0.13; SMD of NTX -0.93, 95% CI -1.21 to -0.64) and sustained until 12 months (SMD of BSAP -0.27, 95% CI -0.50 to -0.03; SMD of NTX -0.84, 95% CI -1.11 to -0.56) during the prophylaxis. Antiosteoporotic drugs showed prophylactic efficacy on periprosthetic bone loss after total hip arthroplasty in calcar, the effectiveness varied. Zoledronate was the best recommendation due to its optimal efficacy both within 6 and 12 months as well as its residual effect in the long term. BTMs could be used as indicators for monitoring through the treatment. More head-to-head clinical trials are needed to confirm those findings.


Urinary incontinence in community-dwelling older Mexican American and European American women.
The aim was to measure prevalence and correlates of urinary incontinence in community-dwelling Mexican American (MA) and European American (EA) women from a cross-sectional analysis of baseline data from a longitudinal cohort. Participants were MA and EA women, aged 65 years and older, in the San Antonio Longitudinal Study of Aging (SALSA), of whom 421 (97.4%) responded to the question "How often do you have difficulty holding your urine until you can get to a toilet." Measurements included sociodemographic, functional, cognitive, psychosocial, and clinical status variables derived from bilingual interviews and performance-based tests. Urinary incontinence prevalence was 36.6% (n=154). MA women reported less incontinence than did EAs (29% versus 45%, p=0.001). In multivariable analyses in MA women, urinary incontinence correlated with the presence of fecal incontinence (OR 4.0, 95% CI 1.1-14.0) and more dependency in activities of daily living (1.4, 1.1-1.8) after controlling for significant sociodemographic factors. In EA women, only age >75 (4.2, 1.4-12.4) was associated with urinary incontinence. MA women were less likely to report incontinence compared to EAs, despite MAs having increased number of children, less education, higher BMI, and more diabetes. Further research is needed to evaluate risk factors for urinary incontinence among MA women.


Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein.
Members of the Smad family of proteins are thought to play important roles in transforming growth factor beta (TGF-beta)-mediated signal transduction. In response to TGF-beta, specific Smads become inducibly phosphorylated, form heteromers with Smad4, and undergo nuclear accumulation. In addition, overexpression of specific Smad combinations can mimic the transcriptional effect of TGF-beta on both the plasminogen activator inhibitor 1 (PAI-1) promoter and the reporter construct p3TP-Lux. Although these data suggest a role for Smads in regulating transcription, the precise nuclear function of these heteromeric Smad complexes remains largely unknown. Here we show that in Mv1Lu cells Smad3 and Smad4 form a TGF-beta-induced, phosphorylation-dependent, DNA binding complex that specifically recognizes a bipartite binding site within p3TP-Lux. Furthermore, we demonstrate that Smad4 itself is a DNA binding protein which recognizes the same sequence. Interestingly, mutations which eliminate the Smad DNA binding site do not interfere with either TGF-beta-dependent transcriptional activation or activation by Smad3/Smad4 cooverexpression. In contrast, mutation of adjacent AP1 sites within this context eliminates both TGF-beta-dependent transcriptional activation and activation in response to Smad3/Smad4 cooverexpression. Furthermore, concatemerized AP1 sites, in isolation, are activated by Smad3/Smad4 cooverexpression and, to a certain extent, by TGF-beta. Taken together, these data suggest that the Smad3/Smad4 complex has at least two separable nuclear functions: it forms a rapid, yet transient sequence-specific DNA binding complex, and it potentiates AP1-dependent transcriptional activation.


Radiation therapy in the management of limited small cell lung cancer: when, where, and how much?
Progress in the treatment of patients with small cell lung cancer (SCLC) has come in two phases. In the first phase, SCLC was recognized, even when seemingly localized to the lung and intrathoracic lymph nodes, to be widely metastatic and to require effective systemic therapy from the outset. The development of active chemotherapeutic agents and combinations in the 1970s improved median survival from the 6 months seen with radiotherapy alone to about 1 year. In the second phase has come the recognition that local control of a disease, even one with systemic spread, is necessary for its cure. This has resulted both in a better appreciation of the role of radiation therapy in SCLC treatment and in efforts to optimize combined-modality regimens using radiotherapy and chemotherapy. With current treatment regimens involving concurrent or closely interdigitated administration of cisplatin and etoposide chemotherapy and radiation doses of 45 Gy given over 3 to 5 weeks, median survivals of 20 to 24 months have been reported by many single institutions and confirmed in large cooperative group trials. Issues remaining to be resolved include optimization of radiation dose, volume, and timing; the role of prophylactic cranial irradiation; and how to reduce acute and late toxic reactions of treatment. As we develop more specific therapies based on specific molecular and biological characteristics of SCLC, including its autocrine growth regulation, we will be challenged to integrate these successfully with current radiation and chemotherapeutic approaches.


Can insignificant prostate cancer be predicted preoperatively in men with stage T1 disease?
This study reviews the pathological findings in nonpalpable prostate cancer detected on transurethral resection (TUR) (stages T1a and T1b) and on needle biopsy (stage T1c) to determine whether insignificant cancers can be predicted preoperatively. The majority of stage T1a cancers are insignificant and all stage T1b cancers are significant. Preoperative pathological parameters cannot identify the minority of T1a cancers that are more significant and the minority of T1b cancers with relatively little residual cancer. Although most nonpalpable tumors diagnosed by screening techniques are usually significant tumors, which would be treated aggressively if they were palpable, 12% to 26% of cancers removed from nonpalpable disease are relatively insignificant. There is conflicting data as to whether a combination of needle biopsy findings and PSA density measurements can aid in the prediction of insignificant cancers. If conservative management is considered, a patient should undergo repeat biopsies (including transition zone biopsies) to detect those more significant cancers that may have been undersampled. In addition, serial serum PSA measurements should be performed to detect whether serum PSA levels increase to a point where these tumors would be reclassified as significant. When planning therapy for T1 patients, the age, comorbidity, and treatment preferences of the patient are key factors that must also be taken into account.


Plasma Membrane Cholesterol Regulates the Allosteric Binding of 1-Methyl-4-Phenylpyridinium to Organic Cation Transporter 2 (SLC22A2).
The human organic cation transporter 2 (OCT2) mediates the first step of tubular secretion of most positively charged substances. We describe the role of plasma membrane cholesterol in OCT2 activity. Human embryonic kidney 293 cells overexpressing OCT2 (OCT2-HEK293) and wild-type HEK293 cells (WT-HEK293) were employed. Cellular cholesterol content, assessed by thin layer chromatography, was manipulated using empty methyl-β-cyclodextrin (mβcd) and cholesterol-presaturated mβcd (RAMEB). The effect of mβcd on OCT2 protein stability and oligomerization state was evaluated by immunofluorescence and Western blotting. Transport activity of OCT2 was measured using [3H]1-methyl-4-phenylpyridinium (MPP+). A 20-minute incubation with mβcd reduced the total cellular cholesterol content by 40% to 60% as compared with that in untreated cells, without altering the content of the other main lipid species. In this condition, OCT2-mediated uptake of MPP+ was reduced by ∼50%. When cells were coincubated with empty mβcd and RAMEB, the cholesterol content and OCT2-mediated uptake of MPP+ were comparable to those in untreated cells, suggesting that the mβcd effect on OCT2 activity was cholesterol dependent. In untreated cells, the MPP+ influx kinetics was allosteric, whereas in cells treated with mβcd, one binding site was observed. Our findings suggest that changes in cellular cholesterol content can dramatically alter OCT2-mediated transport, potentially resulting in abnormal tubular secretion and unexpected drug toxicity and drug-drug interactions. SIGNIFICANCE STATEMENT: Plasma membrane cholesterol is important for the allosteric properties of OCT2. From a pharmacologic standpoint, the variability in cholesterol content stemming from certain pathophysiologic conditions such as aging and acute kidney injury should be taken into account as additional source of interpatient pharmacokinetic/pharmacodynamic variability and unexpected toxicity profile of OCT2 substrates, which can escape preclinical and clinical development.


Emergence, Transmission, and Potential Therapeutic Targets for the COVID-19 Pandemic Associated with the SARS-CoV-2.
The pandemic of the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 at the end of 2019 marked the third outbreak of a highly pathogenic coronavirus affecting the human population in the past twenty years. Cross-species zoonotic transmission of SARS-CoV-2 has caused severe pathogenicity and led to more than 655,000 fatalities worldwide until July 28, 2020. Outbursts of this virus underlined the importance of controlling infectious pathogens across international frontiers. Unfortunately, there is currently no clinically approved antiviral drug or vaccine against SARS-CoV-2, although several broad-spectrum antiviral drugs targeting multiple RNA viruses have shown a positive response and improved recovery in patients. In this review, we compile our current knowledge of the emergence, transmission, and pathogenesis of SARS-CoV-2 and explore several features of SARS-CoV-2. We emphasize the current therapeutic approaches used to treat infected patients. We also highlight the results of in vitro and in vivo data from several studies, which have broadened our knowledge of potential drug candidates for the successful treatment of patients infected with and discuss possible virus and host-based treatment options against SARS-CoV-2.


Continuous versus intermittent treatment strategies during primary HIV-1 infection: the randomized ANRS INTERPRIM Trial.
The ANRS-112 INTERPRIM trial assessed whether fixed-cycles of antiretroviral treatment interruption (ART-STI) combined or not with pegylated interferon alpha-2b (peg-IFN) could lower viral load and achieve a healthier immune system in patients diagnosed during primary HIV-1-infection (PHI). Patients were randomized to receive either continuous ART (cART) during 72 weeks, or cART during 36 weeks followed by three ART-STIs, or the same ART-STIs associated with peg-IFN during the first 14 weeks and each interruption (ART-STI-IFN). Treatment was stopped at week 72. Final evaluation was based on plasma HIV-RNA level 6 months after the last treatment interruption. Eighty-seven percent of patients achieved undetectable HIV-RNA at week 32, with no deleterious impact of sequential treatment interruptions (STIs). Viral rebounds during interruptions were lower in the ART-STI-IFN than in the ART-STI group and during the second and third interruptions compared with the first one. However, HIV-RNA levels, CD4 T-cell counts and CD4 T/CD8 T ratios were similar between groups after the 6-month interruption, with a persistent effect on CD4 T cells and total cell-associated HIV-DNA levels. Predictive factors of virological outcome were HIV-RNA and HIV-DNA levels at PHI and HIV-DNA levels at treatment interruption. HIV-specific responses did not differ between strategies and were not associated with outcome. Forty-eight percent of patients experienced treatment resumption during long-term follow-up without difference between groups. When initiated during PHI, STIs associated or not with IFN did not result in a different outcome as compared to cART. All regimens showed a high response rate and a sustained immunological benefit after cessation.


Ultrasound characteristics of connective tissue around porous hydroxyapatite hypodermic implants in rats.
Adults Sprague-Dawley rats were implanted with porous hydroxyapatite (Interpore 200), following a procedure different from that of Kawaguchi et al (1992). Instead of implanting hydroxyapatite (Ha) in periodontal osseus defects, we introduced Ha-implants in the hypodermis of rats. Animals were sacrificed on days 30, 90 and 150 (six in each stage). The interface between the Ha and connective tissue was studied by transmission electron microscopy, with the aim of understanding the biocompatibility and mechanisms of union of both parts. The connective tissue reaction to the Ha implant was characterized by fibrovascular proliferation, with abundant fibroblasts, macrophages, multinucleated giant cells, and by the formation of a capsule surrounding the implant. The multinucleated giant cells were observed in the interface along all stages and exhibited: (a) a progressive increase in mitochondria, ribosomes, rough endoplasmic reticulum and vesicles containing particles of Ha; and b) an electronlucent material of variable aspect in vesicles contained in their cytoplasmic expansions. The prominent cytologic aspects of the multinucleated giant cells in the juxta-Ha zone may indicate that both, the biocompatibility and the intimate union between connective tissue and Ha, are strongly dependent on the presence of these cells.


IL28B rs12980275 polymorphism shows association with response to treatment in Pakistani patients with chronic hepatitis C.
The aim of this study was to describe the genetic characteristics of Pakistani patients infected with hepatitis C virus (HCV) in relation to IL28B polymorphisms and its association to interferon and ribavirin treatment response. A total of 220 patients, infected with HCV were enrolled, out of which 100 were responders and 120 were nonresponders. The whole blood samples were collected to extract viral RNA and genomic DNA. PCR following the restriction fragment length polymorphism method was used to genotype IL28B rs12979860, rs8099917, and rs12980275 polymorphisms. Liver biopsies and HCV genotyping were performed in nonresponder patients. The rs12980275 AA genotype exhibited significant correlation to treatment response and was found in 62% of the responders and 37.5% of nonresponder patients, whereas AG genotype was noticed frequently in the nonresponder group (P < 0.0001). The rs12979860 CT and rs8099917 TT genotypes were found in 74% and 66% of the responders as compared to 58.3% and 50.8% in nonresponder patients (P = 0.001 and P = 0.032) respectively. HCV 3a genotypes were detected in 50.8% of the nonresponder patients. No significant association was detected between liver biopsy findings and IL28B SNPs (P > 0.05). The results showed the significant association of rs12980275 polymorphism with treatment response in HCV patients followed by rs12979860 and rs8099917. This is the first report describing the association of rs12980275 with response to HCV treatment from Pakistan. These findings may help in predicting the outcome of pegylated interferon and ribavirin treatment in HCV patients, and may reduce the side effects and cost of treatment in predicting non-responder patients.


MicroRNAs in Experimental Models of Movement Disorders.
MicroRNAs (miRNAs) are small RNAs comprised of 20-25 nucleotides that regulates gene expression by inducing translational repression or degradation of target mRNA. The importance of miRNAs as a mediator of disease pathogenesis and therapeutic targets is rapidly emerging in neuroscience, as well as oncology, immunology, and cardiovascular diseases. In Parkinson's disease and related disorders, multiple studies have identified the implications of specific miRNAs and the polymorphisms of miRNA target genes during the disease pathogenesis. With a focus on Parkinson's disease, spinocerebellar ataxia, hereditary spastic paraplegia, and Huntington's disease, this review summarizes and interprets the observations, and proposes future research topics in this field.