We report a case of mixed adenoendocrine carcinoma of the upper thoracic esophagus arising from ectopic gastric mucosa. A 64-year-old man who had been diagnosed with an esophageal tumor on the basis of esophagoscopy was referred to our hospital. Upper gastrointestinal endoscopy revealed the presence of ectopic gastric mucosa and an adjacent pedunculated lesion located on the posterior wall of the upper thoracic esophagus. Subtotal esophagectomy with three-field lymph node dissection was performed. A microscopic examination revealed that there was a partially intermingling component of neuroendocrine carcinoma adjacent to a tubular adenocarcinoma which was conterminous with the area of the ectopic gastric mucosa. Although the tubular adenocarcinoma was confined to the mucosa and submucosa, the neuroendocrine carcinoma had invaded the submucosaand there was vascular permeation. Each component accounted for 30% or more of the tumor, so the final histopathological diagnosis was mixed adenoendocrine carcinoma of the upper thoracic esophagus arising from ectopic gastric mucosa. Adjuvant chemotherapy was not performed, because the postoperative tumor stage was IA. The patient was well and had no evidence of recurrence 16 months after surgery.
Adenocarcinoma; Ectopic gastric mucosa; Esophagus; Mixed adenoendocrine carcinoma
Many people living with HIV in sub-Saharan Africa desire biological children. Implementation of HIV prevention strategies that support the reproductive goals of people living with HIV while minimizing HIV transmission risk to sexual partners and future children requires a comprehensive understanding of pregnancy in this population. We analyzed prospective cohort data to determine pregnancy incidence and predictors among HIV-positive women initiating antiretroviral therapy (ART) in a setting with high HIV prevalence and fertility.
Participants were enrolled in the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort of HIV-positive individuals initiating ART in Mbarara. Bloodwork (including CD4 cells/mm3, HIV viral load) and questionnaires (including socio-demographics, health status, sexual behavior, partner dynamics, HIV history, and self-reported pregnancy) were completed at baseline and quarterly. Our analysis includes 351 HIV-positive women (18–49 years) who enrolled between 2005–2011. We measured pregnancy incidence by proximal and distal time relative to ART initiation and used multivariable Cox proportional hazards regression analysis (with repeated events) to identify baseline and time-dependent predictors of pregnancy post-ART initiation.
At baseline (pre-ART initiation), median age was 33 years [IQR: 27–37] and median prior livebirths was four [IQR: 2–6]. 38% were married with 61% reporting HIV-positive spouses. 73% of women had disclosed HIV status to a primary sexual partner. Median baseline CD4 was 137 cells/mm3 [IQR: 81–207]. At enrolment, 9.1% (31/342) reported current pregnancy. After ART initiation, 84 women experienced 105 pregnancies over 3.8 median years of follow-up, yielding a pregnancy incidence of 9.40 per 100 WYs. Three years post-ART initiation, cumulative probability of at least one pregnancy was 28% and independently associated with younger age (Adjusted Hazard Ratio (AHR): 0.89/year increase; 95%CI: 0.86–0.92) and HIV serostatus disclosure to primary sexual partner (AHR: 2.45; 95%CI: 1.29–4.63).
Nearly one-third of women became pregnant within three years of initiating ART, highlighting the need for integrated services to prevent unintended pregnancies and reduce periconception-related risks for HIV-infected women choosing to conceive. Association with younger age and disclosure suggests a role for early and couples-based safer conception counselling.
Crohn’s disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry with rising prevalence in other populations1. Genome-wide association studies (GWAS) and subsequent meta-analyses of CD and UC2,3 as separate phenotypes implicated previously unsuspected mechanisms, such as autophagy4, in pathogenesis and showed that some IBD loci are shared with other inflammatory diseases5. Here we expand knowledge of relevant pathways by undertaking a meta-analysis of CD and UC genome-wide association scans, with validation of significant findings in more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional and balancing selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe striking overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
Integrated reproductive health services for people living with HIV must address their fertility intentions. For HIV-serodiscordant couples who want to conceive, attempted conception confers a substantial risk of HIV transmission to the uninfected partner. Behavioral and pharmacologic strategies may reduce HIV transmission risk among HIV-serodiscordant couples who seek to conceive. In order to develop effective pharmaco-behavioral programs, it is important to understand and address the contexts surrounding reproductive decision-making; perceived periconception HIV transmission risk; and periconception risk behaviors. We present a conceptual framework to describe the dynamics involved in periconception HIV risk behaviors in a South African setting. We adapt the Information-Motivation-Behavioral Skill Model of HIV Preventative Behavior to address the structural, individual and couple-level determinants of safer conception behavior. The framework is intended to identify factors that influence periconception HIV risk behavior among serodiscordant couples, and therefore to guide design and implementation of integrated and effective HIV, reproductive health and family planning services that support reproductive decision-making.
conceptual framework; HIV; serodiscordant couples; pregnancy; safer conception
The objective of this study was to develop a reliable HAART optimism scale among HIV-positive women in Uganda and to test the scale’s validity against measures of fertility intentions, sexual activity, and unprotected sexual intercourse. We used cross-sectional survey data of 540 women (18–50 years) attending Mbarara University’s HIV clinic in Uganda. Women were asked how much they agreed or disagreed with 23 statements about HAART. Data were subjected to a principal components and factor analyses. Subsequently, we tested the association between the scale and fertility intentions and sexual behaviour using Wilcoxon rank sum test. Factor analysis yielded three factors, one of which was an eight-item HAART optimism scale with moderately high internal consistency (α = 0.70). Women who reported that they intended to have (more) children had significantly higher HAART optimism scores (median = 13.5 [IQR: 12–16]) than women who did not intend to have (more) children (median = 10.5 [IQR: 8–12]; P <0.0001). Similarly, women who were sexually active and who reported practicing unprotected sexual intercourse had significantly higher HAART optimism scores than women who were sexually abstinent or who practiced protected sexual intercourse. Our reliable and valid scale, termed the Women’s HAART Optimism Monitoring and EvaluatioN scale (WHOMEN’s scale), may be valuable to broader studies investigating the role of HAART optimism on reproductive intentions and sexual behaviours of HIV-positive women in high HIV prevalence settings.
HIV; HAART; Uganda; Scale; HAART optimism; Women; Fertility intentions; Sexual behaviour; HAART optimism scale
To assess the association between antiretroviral therapy (ART) and fertility history and desire among HIV-positive Ugandan women, we conducted a cross-sectional study among HIV-positive Ugandan women aged 18–50 years who attended an HIV clinic at Mbarara University in western Uganda between November 1, 2005 and June 6, 2006. Of 538 women approached, 501 were enrolled. ART use was associated with increased odds of fertility desire (AOR 2.99, 95% CI 1.38–6.28), and decreased odds of pregnancy (AOR 0.56, 95% CI 0.33–0.95) and live birth (AOR 0.30, 95% CI 0.13–0.66). ART was associated with an increase in fertility desire, but was not associated with an increase in fertility. Additional studies will be needed to determine if this greater fertility desire among ART-treated women leads to an increase in fertility as ART use expands.
Uganda; Fertility; HIV/AIDS; Fertility desires; Antiretroviral therapy
The increasing proportion of women living with HIV has evoked calls for tailored services that respond to women's specific needs. The objective of this investigation was to explore the concept of women-specific HIV/AIDS services to identify and define what key elements underlie this approach to care.
A comprehensive review was conducted using online databases (CSA Social Service Abstracts, OvidSP, Proquest, Psycinfo, PubMed, CINAHL), augmented with a search for grey literature. In total, 84 articles were retrieved and 30 were included for a full review. Of these 30, 15 were specific to HIV/AIDS, 11 for mental health and addictions and four stemmed from other disciplines.
Results and discussion
The review demonstrated the absence of a consensual definition of women-specific HIV/AIDS services in the literature. We distilled this concept into its defining features and 12 additional dimensions (1) creating an atmosphere of safety, respect and acceptance; (2) facilitating communication and interaction among peers; (3) involving women in the planning, delivery and evaluation of services; (4) providing self-determination opportunities; (5) providing tailored programming for women; (6) facilitating meaningful access to care through the provision of social and supportive services; (7) facilitating access to women-specific and culturally sensitive information; (8) considering family as the unit of intervention; (9) providing multidisciplinary integration and coordination of a comprehensive array of services; (10) meeting women “where they are”; (11) providing gender-, culture- and HIV-sensitive training to health and social care providers; and (12) conducting gendered HIV/AIDS research.
This review highlights that the concept of women-specific HIV/AIDS services is a complex and multidimensional one that has been shaped by diverse theoretical perspectives. Further research is needed to better understand this emerging concept and ultimately assess the effectiveness of women-specific services on HIV-positive women's health outcomes.
HIV; women; gender; women-specific services; women-centred care; HIV/AIDS programming; health services; CHIWOS
U1 snRNP (U1), in addition to its splicing role, protects pre-mRNAs from drastic premature termination by cleavage and polyadenylation (PCPA) at cryptic polyadenylation signals (PASs) in introns. Here, a high throughput sequencing strategy of differentially expressed transcripts (HIDE-seq), mapped PCPA sites genome-wide in divergent organisms. Surprisingly, while U1 depletion terminated most nascent gene transcripts within ~1 kb, moderate functional U1 level decreases, insufficient to inhibit splicing, dose-dependently shifted PCPA downstream, eliciting mRNA 3′ UTR shortening and proximal 3′ exon switching characteristic of activated immune and neuronal cells, stem cells and cancer. Activated neurons’ signature mRNA shortening could be recapitulated by U1 decrease and antagonized by U1 over-expression. Importantly, we show that rapid and transient transcriptional up-regulation inherent to neuronal activation physiology creates U1 shortage relative to pre-mRNAs. Additional experiments suggest co-transcriptional PCPA counteracted by U1 association with nascent-transcripts, a process we term telescripting, ensuring transcriptome integrity and regulating mRNA length.
Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a recently reported group of disorders characterized by fibrotic thickening of the pleural and subpleural parenchyma predominantly in the upper lobes. We report five Japanese cases fulfilling the criteria of IPPFE and address whether it should be considered a separate clinicopathologic entity. And this study was an attempt to identify features in common between IPPFE and previously described idiopathic upper lobe fibrosis (IPUF), allowing IPPFE to be considered as a distinct entity in our Japanese series.
Five consecutive cases of idiopathic interstitial lung disease confirmed as IPPFE by surgical lung biopsy were studied.
There were four males and one female, aged 70±2.76 yr. No associated disorder or presumed cause was found in any case. Lung function tests found a restrictive ventilatory defect (4/5) and/or impairment of DLco (4/5). Chest X-ray showed marked apical pleural thickening in all cases. Computed tomography of the chest in all cases mainly showed intense pleural thickening and volume loss associated with evidence of fibrosis, predominantly in the upper lobes. In all cases in this study, markedly thickened visceral pleura and prominent subpleural fibrosis characterized by both elastic tissue and dense collagen were clearly shown. All cases were alive at the last follow-up, 17.6±13.59 months after diagnosis; however, all had deteriorated both clinically and radiologically.
IPPFE deserves to be defined as a separate, original clinicopathologic entity owing to its uniformity and IPPFE has some features in common with previously described idiopathic upper lobe fibrosis (IPUF). Our limited experience with a cohort of 5 subjects suggests that IPPFE can be rapidly progressive.
Idiopathic interstitial lung disease; Pleural fibrosis; Fibroelastosis; Pleuroparenchymal fibroelastosis
Background. HIV-infected women are disproportionately burdened by gynaecological complications, psychological disorders, and certain sexually transmitted infections that may not be adequately addressed by HIV-specific care. We estimate the prevalence and covariates of women's health care (WHC) utilization among harder-to-reach, treatment-experienced HIV-infected women in British Columbia (BC), Canada. Methods. We used survey data from 231 HIV-infected, treatment-experienced women enrolled in the Longitudinal Investigations into Supportive and Ancillary Health Services (LISA) study, which recruited harder-to-reach populations, including aboriginal people and individuals using injection drugs. Independent covariates of interest included sociodemographic, psychosocial, behavioural, individual health status, structural factors, and HIV clinical variables. Logistic regression was used to generate adjusted estimates of associations between use of WHC and covariates of interest.
Results. Overall, 77% of women reported regularly utilizing WHC. WHC utilization varied significantly by region of residence (P value <0.01). In addition, women with lower annual income (AOR (95% CI) = 0.14 (0.04–0.54)), who used illicit drugs (AOR (95% CI) = 0.42 (0.19–0.92)) and who had lower provider trust (AOR (95% CI) = 0.97 (0.95–0.99)), were significantly less likely to report using WHC. Conclusion. A health service gap exists along geographical and social axes for harder-to-reach HIV-infected women in BC. Women-centered WHC and HIV-specific care should be streamlined and integrated to better address women's holistic health.
It is becoming increasingly evident that people with chronic, recurrent low back pain (LBP) exhibit changes in cerebrocortical activity that associate with altered postural coordination, suggesting a need for a better understanding of how the experience of LBP alters postural coordination and cerebrocortical activity. To characterize changes in postural coordination and pre-movement cerebrocortical activity related to the experience of acutely induced LBP, 14 healthy participants with no history of LBP performed sit-to-stand movements in 3 sequential conditions: (1) without experimentally induced LBP; NoPain1, (2) with movement-associated LBP induced by electrocutaneous stimulation; Pain, and (3) again without induced LBP; NoPain2. The Pain condition elicited altered muscle activation and redistributed forces under the seat and feet prior to movement, decreased peak vertical force exerted under the feet during weight transfer, longer movement times, as well as decreased and earlier peak hip extension. Stepwise regression models demonstrated that electroencephalographic amplitudes of contingent negative variation during the Pain condition significantly correlated with the participants’ change in sit-to-stand measures between the NoPain1 and Pain conditions, as well as with the subsequent difference in sit-to-stand measures between the NoPain1 and NoPain2 conditions. The results, therefore, identify the contingent negative variation as a correlate for the extent of an individual’s LBP-related movement modifications and to the subsequent change in movement patterns from before to after the experience of acutely induced LBP, thereby providing a direction for future studies aimed to understand the neural mechanisms underlying the development of altered movement patterns with LBP.
contingent negative variation; low back pain; posture; sit-to-stand; electroencephalography
A randomized controlled trial of the plastic BioSand filter (BSF) was performed in rural communities in Tamale (Ghana) to assess reductions in diarrheal disease and improvements in household drinking water quality. Few studies of household water filters have been performed in this region, where high drinking water turbidity can be a challenge for other household water treatment technologies. During the study, the longitudinal prevalence ratio for diarrhea comparing households that received the plastic BSF to households that did not receive it was 0.40 (95% confidence interval: 0.05, 0.80), suggesting an overall diarrheal disease reduction of 60%. The plastic BSF achieved a geometric mean reduction of 97% and 67% for E. coli and turbidity, respectively. These results suggest the plastic BSF significantly improved drinking water quality and reduced diarrheal disease during the short trial in rural Tamale, Ghana. The results are similar to other trials of household drinking water treatment technologies.
water quality; E. coli; diarrheal disease; water treatment; water filtration
Background. Understanding HIV-infected patient experiences and perceptions of reproductive counseling in the health care context is critical to inform design of effective pharmaco-behavioral interventions that minimize periconception HIV risk and support HIV-affected couples to realize their fertility goals. Methods. We conducted semistructured, in-depth interviews with 30 HIV-infected women (with pregnancy in prior year) and 20 HIV-infected men, all reporting serodiscordant partners and accessing care in Durban, South Africa. We investigated patient-reported experiences with safer conception counseling from health care workers (HCWs). Interview transcripts were reviewed and coded using content analysis for conceptual categories and emergent themes. Results. The study findings indicate that HIV-infected patients recognize HCWs as a resource for periconception-related information and are receptive to speaking to a HCW prior to becoming pregnant, but seldom seek or receive conception advice in the clinic setting. HIV nondisclosure and unplanned pregnancy are important intervening factors. When advice is shared, patients reported receiving a range of information. Male participants showed particular interest in accessing safer conception information. Conclusions. HIV-infected men and women with serodiscordant partners are receptive to the idea of safer conception counseling. HCWs need to be supported to routinely initiate accurate safer conception counseling with HIV-infected patients of reproductive age.
Enterovirus 104; viruses; acute respiratory tract infection; adult; Japan
Understanding reproductive decisions and periconception behavior among HIV-discordant couples is important for designing risk reduction interventions for couples who choose to conceive. In-depth interviews were conducted to explore reproductive decision-making and periconception practices among HIV-positive women with recent pregnancy (n = 30), and HIV-positive men (n = 20), all reporting partners of negative or unknown HIV-status, and attending HIV services in Durban, South Africa. Transcripts were coded for categories and emergent themes. Participants expressed strong reasons for having children, but rarely knew how to reduce periconception HIV transmission. Pregnancy planning occurred on a spectrum ranging from explicitly intended to explicitly unintended, with many falling in between the two extremes. Male fertility desire and misunderstanding serodiscordance contributed to HIV risk behavior. Participants expressed openness to healthcare worker advice for safer conception and modified risk behavior post-conception, suggesting the feasibility of safer conception interventions which may target both men and women and include serodiscordance counseling and promotion of contraception.
HIV-serodiscordant couples; HIV prevention; Safer conception; Family planning; South Africa
Enterovirus 68 strains were detected in 14 specimens from children with respiratory tract infections and 1 specimen from a child with febrile convulsions during 2010 in Osaka, Japan. These strains had deletions in the 5′ untranslated region and were genetically different from reported strains. This virus is associated with respiratory tract infections in Japan.
Enterovirus 68; enterovirus; viruses; acute respiratory tract infections; febrile convulsions; respiratory infections; Japan; children; infants; dispatch
In higher eukaryotes, U1 snRNP forms spliceosomes in equal stoichiometry with U2, U4, U5 and U6, however its abundance far exceeds that of the other snRNPs. Here, we used antisense morpholino oligonucleotide (AMO) to U1 snRNA for functional U1 snRNP knockdown in HeLa cells and identified accumulated unspliced pre-mRNAs by genomic tiling microarrays. Remarkably, in addition to inhibiting splicing, U1 snRNP knockdown caused premature cleavage and polyadenylation (PCPA) in numerous pre-mRNAs at cryptic polyadenylation signals (PASs), frequently in introns near (< 5 kb) the start of the transcript. This did not occur when splicing was inhibited with U2 snRNA AMO or the U2 snRNP inactivating drug, spliceostatin A, unless U1 AMO was also included. We further show that U1 snRNA-pre-mRNA base pairing was required to suppress PCPA from nearby cryptic PASs located in introns. These findings reveal a critical splicing-independent function for U1 snRNP in protecting the transcriptome, which we propose explains its overabundance.
HIV/AIDS has orphaned 11.6 million children in sub-Saharan Africa. Expanded antiretroviral therapy (ART) use may reduce AIDS orphanhood by decreasing adult mortality and population-level HIV transmission.
We modeled two scenarios to measure the impact of adult ART use on the incidence of orphanhood in 10 sub-Saharan African countries, from 2009 to 2020. Demographic model data inputs were obtained from cohort studies, UNAIDS, UN Population Division, WHO and the US Census Bureau.
Compared to current rates of ART uptake, universal ART access averted 4.37 million more AIDS orphans by year 2020, including 3.15 million maternal, 1.89 million paternal and 0.75 million double orphans. The number of AIDS orphans averted was highest in South Africa (901.71 thousand) and Nigeria (839.01 thousand), and lowest in Zimbabwe (86.96 thousand) and Côte d'Ivoire (109.12 thousand).
Universal ART use may significantly reduce orphanhood in sub-Saharan Africa.
Preventing unintended pregnancy among HIV-positive women constitutes a critical and cost-effective approach to primary prevention of mother-to-child transmission of HIV and is a global public health priority for addressing the desperate state of maternal and child health in HIV hyper-endemic settings. We sought to investigate whether the prevalence of contraceptive use and method preferences varied by HIV status and receipt of highly active antiretroviral therapy (HAART) among women in Soweto, South Africa.
We used survey data from 563 sexually active, non-pregnant women (18–44 years) recruited from the Perinatal HIV Research Unit in Soweto (May–December, 2007); 171 women were HIV-positive and receiving HAART (median duration of use = 31 months; IQR = 28, 33), 178 were HIV-positive and HAART-naïve, and 214 were HIV-negative. Medical record review was conducted to confirm HIV status and clinical variables. Logistic regression models estimated adjusted associations between HIV status, receipt of HAART, and contraceptive use.
Overall, 78% of women reported using contraception, with significant variation by HIV status: 86% of HAART users, 82% of HAART-naïve women, and 69% of HIV-negative women (p<0.0001). In adjusted models, compared with HIV-negative women, women receiving HAART were significantly more likely to use contraception while HAART-naïve women were non-significantly more likely (AOR: 2.40; 95% CI: 1.25, 4.62 and AOR: 1.59; 95% CI: 0.88, 2.85; respectively). Among HIV-positive women, HAART users were non-significantly more likely to use contraception compared with HAART-naïve women (AOR: 1.55; 95% CI: 0.84, 2.88). Similar patterns held for specific use of barrier (primarily male condoms), permanent, and dual protection contraceptive methods.
Among HIV-positive women receiving HAART, the observed higher prevalence of contraceptive use overall and condoms in particular promises to yield fewer unintended pregnancies and reduced risks of vertical and sexual HIV transmission. These findings highlight the potential of integrated HIV and reproductive health services to positively impact maternal, partner, and child health.
Guillain–Barré syndrome (GBS) is an acute immune-mediated polyradiculoneuropathy which can cause acute quadriplegia. Infection with micro-organisms, including Campylobacter jejuni (C. jejuni), Haemophilus influenzae, and Cytomegalovirus (CMV), is recognized as a main triggering event for the disease. Lipooligosaccharide (LOS) genes are responsible for the formation of human ganglioside-like LOS structures in infectious micro-organisms that can induce GBS. Molecular mimicry of LOSs on the surface of infectious agents and of ganglioside antigens on neural cells is thought to induce cross-reactive humoral and cellular immune responses. Patients with GBS develop antibodies against those gangliosides, resulting in autoimmune targeting of peripheral nerve sites, leading to neural damage. Heterogeneity of ganglioside expression in the peripheral nervous system (PNS) may underlie the differential clinical manifestation of the GBS variants. Recent studies demonstrate that some GBS sera react with ganglioside complexes consisting of two different gangliosides, such as GD1a and GD1b, or GM1 and GD1a, but not with each constituent ganglioside alone. The discovery of antiganglioside complex antibodies not only improves the detection rate of autoantibodies in GBS, but also provides a new concept in the antibody–antigen interaction through clustered carbohydrate epitopes. Although ganglioside mimicry is one of the possible etiological causes of GBS, unidentified factors may also contribute to the pathogenesis of GBS. While GBS is not considered a genetic disease, host factors, particularly human lymphocyte antigen type, appear to have a role in the pathogenesis of GBS following C. jejuni infection.
Guillain-Barré syndrome; peripheral neuropathy; molecular mimicry; llipopolysaccharides; bacterial infection; inflammation
A triploid (2n = 3x = 36) rice plant was obtained by screening a twin seedling population in which each seed germinated to two or three sprouts that were then crossed with diploid plants. One diploid plant was chosen among the various F1 progenies and developed into an F 2 population via self-pollination. Compared with the control variety Shanyou 63, this F 2 population had a stable agronomical performance in field trials, as confirmed by the F-test. The stability of the F 2 population was further substantiated by molecular analysis with simple sequence repeat markers. Specifically, of 160 markers assayed, 37 (covering all 12 chromosomes) were polymorphic between the parental lines. Testing the F 1 hybrid individually with these markers showed that each PCR product had only a single band instead of two bands from each parent. The bands were identical to either maternal (23 markers) or paternal (eight markers) bands or distinct from both parents (six markers). The amplified bands of all 60 randomly selected F 2 plants were uniform and identical to those of the F 1 hybrid. These results suggest that the F 1 plant is a non-segregating hybrid and that a stable F 2 population was obtained. This novel system provides an efficient means for shortening the cycle of hybrid rice seed production.
F-test; polyploidy; rice; SSR marker; stability
Bioactive compounds have been invaluable for dissecting the mechanisms, regulation, and functions of cellular processes. However, very few such reagents have been described for pre-mRNA splicing. To facilitate their systematic discovery, we developed a high-throughput cell-based assay that measures pre-mRNA splicing by utilizing a quantitative reporter system with advantageous features. The reporter, consisting of a destabilized, intron-containing luciferase expressed from a short-lived mRNA, allows rapid screens (<4 h), thereby obviating the potential toxicity of splicing inhibitors. We describe three inhibitors (out of >23,000 screened), all pharmacologically active: clotrimazole, flunarizine, and chlorhexidine. Interestingly, none was a general splicing inhibitor. Rather, each caused distinct splicing changes of numerous genes. We further discovered the target of action of chlorhexidine and show that it is a selective inhibitor of specific Cdc2-like kinases (Clks) that phosphorylate serine-arginine-rich (SR) protein splicing factors. Our findings reveal unexpected activities of clinically used drugs in splicing and uncover differential regulation of constitutively spliced introns.
The plasma or serum levels of various enzymes and components are known to increase in rats with water-immersion restraint stress (WIRS). We examined whether oxidative stress is involved in increases in the serum levels of various enzymes and components in rats with WIRS. Rats were exposed to WIRS for 6 h after oral administration of vitamin E (VE) (50 or 250 mg/kg). Rats with WIRS had increased serum alanine aminotransferase, aspartate aminotranseferase, lactate dehydrogenase, creatine kinase, urea nitrogen, creatinine, glucose, corticosterone, adrenocorticotropic hormone and lipid peroxide (LPO) levels, increased kidney and heart VE levels, decreased skeletal muscle VE level, and increased LPO levels in all tissues studied. Pre-administered VE (50 or 250 mg/kg) attenuated the increased serum alanine aminotransferase, aspartate aminotranseferase, lactate dehydrogenase, creatine kinase, urea nitrogen, creatinine, and LPO levels, the decreased skeletal muscle VE level, and the increased LPO levels in all tissues studied more effectively at its higher dose than at its lower dose. However, either dose of the pre-administered VE did not affect the increased serum glucose, corticosterone, and adrenocorticotropic hormone levels. These results suggest that oxidative stress is involved in increases in the serum levels of various enzymes and components in rats with WIRS.
water-immersion restraint stress (rat); serum enzymes and components; vitamin E; lipid peroxide; oxidative stress
Deficiencies in emergency department (ED) charting is a common international problem. While unintentional falls account for the largest proportion of injury related ED visits by youth, insufficient charting details result in more than one third of these falls being coded as “unspecified”. Non‐specific coding compromises the utility of injury surveillance data.
To re‐examine the ED charts of unspecified youth falls to determine the possibility of assigning more specific codes.
400 ED charts for youth (aged 0–19 years) treated at four EDs in an urban Canadian health region between 1997 and 1999 and coded as “Other or unspecified fall” (ICD‐9 E888) were randomly selected. A structured chart review was completed and a blinded nosologist recoded the cause of injury using the extracted data. Differences in coding specificity were compared with the original data, and logistic regression was undertaken to examine variables that predicted assignment of a specific E‐code.
A more specific code was assigned to 46% of cases initially coded as unspecified. Of these, 73% were recoded as “Slips, trips, and stumbles” (E885), which still lacks the specificity required for injury prevention planning; 2% of charts had no fall documented. Multivariate analysis revealed that dichotomized injury severity (adjusted odds ratio (OR) = 1.75 (95% confidence interval, 1.11 to 2.78)), arrival at the ED by ambulance (adjusted OR = 5.41 (1.07 to 27.0)), and the availability of nurse's notes or triage forms, or both, in the chart (adjusted OR = 3.75 (2.17 to 6.45)) were the strongest predictors of a more specific E‐code assignment.
Deficiencies in both chart documentation and coding specificity contribute to the use of non‐specific E‐codes. More comprehensive triage coding, improved chart documentation, and alternative methods of data collection in the acute care setting are required to improve ED injury surveillance initiatives.
accidental falls; emergency department; pediatrics; chart review; coding specificity