Ácido úrico herramienta de tamización para preeclampsia. Una revisión sistemática de la literatura / Uric acid screening tool for preeclampsia a systematic review

Introducción: El ácido úrico se ha descrito como un posible marcador de riesgo para la aparición de preeclampsia; sin embargo, hasta el momento no hay evidencia sólida que lo soporte. El objetivo de este estudio es sintetizar la literatura disponible que permita conocer la utilidad del ácido úrico como una herramienta de tamización para preeclampsia. Metodología: Revisión sistemática de la literatura de estudios primarios que analicen los niveles séricos de ácido úrico en el primer y segundo trimestre de gestación con el desarrollo de preeclampsia. Búsqueda en Pubmed (n: 639). Resultados: Se incluyeron 2 estudios de cohorte con un total de 9.746 gestantes y 398 casos de preeclampsia. En los estudios se encontraron mayores niveles séricos de ácido úrico en las gestantes que desarrollaron preeclampsia (OR 1,8 a 2,0). Conclusiones: El ácido úrico se relaciona con la aparición de preeclampsia y su fisiopatología. Se invita a la comunidad científica a seguir investigando acerca de la utilidad del ácido úrico para su implementación como herramienta de tamización en el primer y el segundo trimestre de embarazo.(AU)

Introduction: Uric acid has been described as a possible risk marker for the appearance of pre-eclampsia. However, so far there is no solid evidence to support it. The objective of this study is to synthesize the available literature to determine the usefulness of uric acid as a screening tool for pre-eclampsia. Methodology: Systematic review of the literature of primary studies that analyse serum uric acid levels in the first and second trimesters of gestation with the development of pre-eclampsia. Search in PubMed (n: 639). Results: Two studies (2 cohort studies) were included with a total of 9,746 pregnant women and 398 cases of pre-eclampsia. In the studies, higher serum uric acid levels were found in pregnant women who developed preeclampsia (OR 1.8 to 2.0). Conclusions: Uric acid is related to the presence of preeclampsia and its pathophysiology. The scientific community is invited to continue investigating the applicability of uric acid for its implementation as a screening tool in the first and second trimester of pregnancy.(AU)

Advances in the treatment of cytomegalovirus.

BACKGROUND: Human cytomegalovirus (HCMV) is a threat to immunologically weak patients. HCMV cannot yet be eliminated with a vaccine, despite recent advances. SOURCES OF DATA: Sources of data are recently published research papers and reviews about HCMV treatments. AREAS OF AGREEMENT: Current antivirals target the UL54 DNA polymerase and are limited by nephrotoxicity and viral resistance. Promisingly, letermovir targets the HCMV terminase complex and has been recently approved by the FDA and EMA. AREAS OF CONTROVERSY: Should we screen newborns for HCMV, and use antivirals to treat sensorineural hearing loss after congenital HCMV infection? GROWING POINTS: Growing points are developing drugs against latently infected cells. In addition to small molecule inhibitors, a chemokine-based fusion toxin protein, F49A-FTP, has shown promise in killing both lytically and latently infected cells. AREAS TIMELY FOR DEVELOPING RESEARCH: We need to understand what immune responses are required to control HCMV, and how best to raise these immune responses with a vaccine.

LPS promotes a monocyte phenotype permissive for human cytomegalovirus immediate-early gene expression upon infection but not reactivation from latency.

Human cytomegalovirus (HCMV) infection of myeloid cells is closely linked with the differentiation status of the cell. Haematopoietic progenitors and CD14+ monocytes are usually non-permissive for lytic gene expression which can lead to the establishment of latent infections. In contrast, differentiation to macrophage or dendritic cell (DC) phenotypes promotes viral reactivation or renders them permissive for lytic infection. The observation that high doses of Lipopolysaccharide (LPS) drove rapid monocyte differentiation in mice led us to investigate the response of human monocytes to HCMV following LPS stimulation in vitro. Here we report that LPS triggers a monocyte phenotype permissiveness for lytic infection directly correlating with LPS concentration. In contrast, addition of LPS directly to latently infected monocytes was not sufficient to trigger viral reactivation which is likely linked with the failure of the monocytes to differentiate to a DC phenotype. Interestingly, we observe that this effect on lytic infection of monocytes is transient, appears to be dependent on COX-2 activation and does not result in a full productive infection. Thus LPS stimulated monocytes are partially permissive lytic gene expression but did not have long term impact on monocyte identity regarding their differentiation and susceptibility for the full lytic cycle of HCMV.

Severe extinction and rapid recovery of mammals across the Cretaceous-Palaeogene boundary, and the effects of rarity on patterns of extinction and recovery.

The end-Cretaceous mass extinction ranks among the most severe extinctions of all time; however, patterns of extinction and recovery remain incompletely understood. In particular, it is unclear how severe the extinction was, how rapid the recovery was and how sampling biases might affect our understanding of these processes. To better understand terrestrial extinction and recovery and how sampling influences these patterns, we collected data on the occurrence and abundance of fossil mammals to examine mammalian diversity across the K-Pg boundary in North America. Our data show that the extinction was more severe and the recovery more rapid than previously thought. Extinction rates are markedly higher than previously estimated: of 59 species, four survived (93% species extinction, 86% of genera). Survival is correlated with geographic range size and abundance, with widespread, common species tending to survive. This creates a sampling artefact in which rare species are both more vulnerable to extinction and less likely to be recovered, such that the fossil record is inherently biased towards the survivors. The recovery was remarkably rapid. Within 300 000 years, local diversity recovered and regional diversity rose to twice Cretaceous levels, driven by increased endemicity; morphological disparity increased above levels observed in the Cretaceous. The speed of the recovery tends to be obscured by sampling effects; faunas show increased endemicity, such that a rapid, regional increase in diversity and disparity is not seen in geographically restricted studies. Sampling biases that operate against rare taxa appear to obscure the severity of extinction and the pace of recovery across the K-Pg boundary, and similar biases may operate during other extinction events.

Transient activation of human cytomegalovirus lytic gene expression during latency allows cytotoxic T cell killing of latently infected cells.

Human cytomegalovirus (HCMV) latency in the myeloid lineage is maintained by repressive histone modifications around the major immediate early promoter (MIEP), which results in inhibition of the lytic viral life cycle. We now show that pharmacological inhibition of histone deacetylases (HDACs) relieves this repression of the MIEP and induces transient expression of the viral lytic immediate early (IE) antigens but, importantly, not full virus reactivation. In turn, these latently infected cells now become targets for IE-specific cytotoxic T cells (CTLs) which are present at high frequency in all normal healthy HCMV positive carriers but would normally be unable to target latent (lytic antigen-negative) cells. This approach of transiently inducing viral lytic gene expression by HDAC inhibition, in otherwise latently infected cells, offers a window of opportunity to target and purge the latent myeloid cell reservoir by making these normally immunologically undetectable cells visible to pre-existing host immune responses to viral lytic antigens.

Diverse specificities, phenotypes, and antiviral activities of cytomegalovirus-specific CD8+ T cells.

UNLABELLED: CD8(+) T cells specific for pp65, IE1, and IE2 are present at high frequencies in human cytomegalovirus (HCMV)-seropositive individuals, and these have been shown to have phenotypes associated with terminal differentiation, as well as both cytokine and proliferative dysfunctions, especially in the elderly. However, more recently, T cell responses to many other HCMV proteins have been described, but little is known about their phenotypes and functions. Consequently, in this study, we chose to determine the diversity of HCMV-specific CD8(+) T cell responses to the products of 11 HCMV open reading frames (ORFs) in a cohort of donors aged 20 to 80 years old as well as the ability of the T cells to secrete gamma interferon (IFN-γ). Finally, we also tested their functional antiviral capacity using a novel viral dissemination assay. We identified substantial CD8(+) T cell responses by IFN-γ enzyme-linked immunospot (ELISPOT) assays to all 11 of these HCMV proteins, and across the cohort, individuals displayed a range of responses, from tightly focused to highly diverse, which were stable over time. CD8(+) T cell responses to the HCMV ORFs were highly differentiated and predominantly CD45RA(+), CD57(+), and CD28(-), across the cohort. These highly differentiated cells had the ability to inhibit viral spread even following direct ex vivo isolation. Taken together, our data argue that HCMV-specific CD8(+) T cells have effective antiviral activity irrespective of the viral protein recognized across the whole cohort and despite viral immune evasion. IMPORTANCE: Human cytomegalovirus (HCMV) is normally carried without clinical symptoms and is widely prevalent in the population; however, it often causes severe clinical disease in individuals with compromised immune responses. HCMV is never cleared after primary infection but persists in the host for life. In HCMV carriers, the immune response to HCMV includes large numbers of virus-specific immune cells, and the virus has evolved many mechanisms to evade the immune response. While this immune response seems to protect healthy people from subsequent disease, the virus is never eliminated. It has been suggested that this continuous surveillance by the immune system may have deleterious effects in later life. The study presented in this paper examined immune responses from a cohort of donors and shows that these immune cells are effective at controlling the virus and can overcome the virus' lytic cycle immune evasion mechanisms.

The effect of hand-arm vibration syndrome on quality of life.

BACKGROUND: It is important to determine how hand-arm vibration syndrome (HAVS), a common occupational condition, affects quality of life (QOL). AIMS: To measure the physical (SF12-P) and mental (SF12-M) components of QOL in workers with HAVS, using the SF12 questionnaire, and to determine the effect of the vascular, sensorineural and musculoskeletal components of HAVS on QOL. METHODS: Subjects were recruited consecutively from workers with HAVS attending an occupational medicine clinic. They were assessed to determine the Stockholm vascular and sensorineural scale stages as well as an upper extremity pain score, measured by the Borg scale, as an indication of musculoskeletal problems associated with the use of vibrating tools. The SF12-P and SF12-M were both compared with Canadian population normal values after adjusting for age and sex. Multiple linear regression was used to determine the effect of the various HAVS components on SF12-P and SF12-M as well as the effects of age and carpal tunnel syndrome. RESULTS: One hundred and forty-one subjects were recruited and 139 (99%) agreed to participate, including 134 men and 5 women. The SF12-P and SF12-M scores were significantly below the Canadian population mean values (P < 0.001), indicating lower QOL. In the multiple regression analysis, the predictor with the largest partial R (2) value for both the SF12-P and SF12-M was the upper extremity pain score. CONCLUSIONS: Both the physical and the mental QOL in workers with HAVS were below Canadian population normal values and subjects' upper extremity pain score had the greatest effect on their QOL.

The disparity of priapulid, archaeopriapulid and palaeoscolecid worms in the light of new data.

Priapulids and their extinct relatives, the archaeopriapulids and palaeoscolecids, are vermiform, carnivorous ecdysozoans with an armoured, extensible proboscis. These worms were an important component of marine communities during the Palaeozoic, but were especially abundant and diverse in the Cambrian. Today, they comprise just seven genera in four families. Priapulids were among the first groups used to test hypotheses concerning the morphological disparity of Cambrian fossils relative to the extant fauna. A previous study sampled at the generic level, concluding that Cambrian genera embodied marginally less morphological diversity than their extant counterparts. Here, we sample predominantly at the species level and include numerous fossils and some extant forms described in the last fifteen years. Empirical morphospaces for priapulids, archaeopriapulids and palaeoscolecids are relatively insensitive to changes in the taxon or character sample: their overall form has altered little, despite the markedly improved sampling. Cambrian and post-Cambrian genera occupy adjacent rather than broadly overlapping regions of these spaces, and Cambrian species still show lower morphological disparity than their post-Cambrian counterparts. Crucially, the significance of this difference has increased with improved taxon sampling over research time. In contrast with empirical morphospaces, the phylogeny of priapulids, archaeopriapulids and palaeoscolecids derived from morphological characters is extremely sensitive to details of taxon sampling and the manner in which characters are weighted. However, the extant Priapulidae and Halicryptidae invariably resolve as sister families, with this entire clade subsequently being sister group to the Maccabeidae. In our most inclusive trees, the extant Tubiluchidae are separated from these other living taxa by a number of small, intervening fossil clades.

DASH work module in workers with hand-arm vibration syndrome.

BACKGROUND: The Disabilities of the Arm, Shoulder and Hand work module (DASH-W) questionnaire has not previously been described in relation to hand-arm vibration syndrome (HAVS). AIMS: To measure work-related disability in workers with HAVS using the DASH-W questionnaire and to determine how the various components of HAVS affect the DASH-W score. METHODS: Workers with HAVS from a variety of industries were assessed over a 2-year period at the occupational health clinic, St Michael's Hospital, Toronto. Subjects completed the DASH-W questionnaire and were assessed by an occupational physician to determine their Stockholm sensorineural and vascular stages and upper extremity pain score measured by the Borg scale, as an indication of musculoskeletal problems associated with HAVS. The average DASH-W score was compared with the average value for the US population. Multiple linear regression was used to determine the contribution of the various components of HAVS to the DASH-W score. RESULTS: There were 139 (134 men and 5 women) participants. The subjects with HAVS had a mean DASH-W score of 54.7 (95% CI: 50.3-59.1), which was considerably higher than the average for the US population (P < 0.001). Statistically significant HAVS variables in the multiple linear regression included the Stockholm sensorineural stage (P < 0.05) and the upper extremity pain score (P < 0.001) with the pain score having the highest partial R (2) value. CONCLUSIONS: Workers with HAVS reported significant upper extremity work-related disability as measured by the DASH-W questionnaire, and the upper extremity pain score made the largest contribution to the DASH-W scores in these subjects.

Wnt/ß-catenin activation promotes prostate tumor progression in a mouse model.

Our previous studies have found that activation of Wnt/ß-catenin signaling resulted in mouse prostatic intraepithelial neoplasia (mPIN). In the large probasin promoter directed SV40-large T-antigen (LPB-Tag) expressing mouse prostate, mPIN forms with rare areas of adenocarcinoma. Combining expression of both Wnt-signaling and Tag expression in the mouse prostate, we have studied the role of Wnt/ß-catenin signaling in the progression from mPIN to adenocarcinoma. Our results show that the prostates of mice expressing Tag alone or nuclear ß-catenin alone developed mPIN, whereas the activation of both Tag and the Wnt/ß-catenin pathway resulted in invasive prostate adenocarcinoma. Furthermore, Foxa2, a forkhead transcription factor, was induced by active Wnt/ß-catenin signaling, and the expression of Foxa2 was associated with the invasive phenotype in the primary prostate cancer. In the LPB-Tag/dominant active (DA) ß-catenin prostates, MMP7, a Wnt/ß-catenin target gene, was upregulated. Furthermore, we also assessed AR and AR signaling pathway in these LPB-Tag/DA ß-catenin mice. Although ß-catenin is a well-known AR co-activator in vitro, our study provides strong in vivo evidences indicating that both AR protein and the AR pathway were downregulated in the prostate of LPB-Tag/DA ß-catenin mice. Histological analysis shows that prostate sections derived from the LPB-Tag/DA ß-catenin mice display neuroendocrine differentiation (NED), but NE cancer does not develop. Together, our findings indicate that Wnt/ß-catenin signaling has an important role in the progression of mPIN to prostate adenocarcinoma.

Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma.

The oncogenic PIM1 kinase has been implicated as a cofactor for c-MYC in prostate carcinogenesis. In this study, we show that in human prostate tumors, coexpression of c-MYC and PIM1 is associated with higher Gleason grades. Using a tissue recombination model coupled with lentiviral-mediated gene transfer we find that Pim1 is weakly oncogenic in naive adult mouse prostatic epithelium. However, it cooperates dramatically with c-MYC to induce prostate cancer within 6-weeks. Importantly, c-MYC/Pim1 synergy is critically dependent on Pim1 kinase activity. c-MYC/Pim1 tumors showed increased levels of the active serine-62 (S62) phosphorylated form of c-MYC. Grafts expressing a phosphomimetic c-MYCS62D mutant had higher rates of proliferation than grafts expressing wild type c-MYC but did not form tumors like c-MYC/Pim1 grafts, indicating that Pim1 cooperativity with c-MYC in vivo involves additional mechanisms other than enhancement of c-MYC activity by S62 phosphorylation. c-MYC/Pim1-induced prostate carcinomas show evidence of neuroendocrine (NE) differentiation. Additional studies, including the identification of tumor cells coexpressing androgen receptor and NE cell markers synaptophysin and Ascl1 suggested that NE tumors arose from adenocarcinoma cells through transdifferentiation. These results directly show functional cooperativity between c-MYC and PIM1 in prostate tumorigenesis in vivo and support efforts for targeting PIM1 in prostate cancer.

Immune evasion proteins gpUS2 and gpUS11 of human cytomegalovirus incompletely protect infected cells from CD8 T cell recognition.

Human cytomegalovirus (HCMV) encodes four glycoproteins, termed gpUS2, gpUS3, gpUS6 and gpUS11 that interfere with MHC class I biosynthesis and antigen presentation. Despite gpUS2-11 expression, however, HCMV infection is efficiently controlled by cytolytic CD8 T lymphocytes (CTL). To address the role of gpUS2 and gpUS11 in antigen presentation during viral infection, HCMV mutants were generated that expressed either gpUS2 or gpUS11 alone without coexpression of the three other proteins. Fibroblasts infected with these viruses showed reduced HLA-A2 and HLA-B7 surface expression. Surprisingly, however, CTL directed against the tegument protein pp65 and the regulatory IE1 protein still recognized and lysed mutant virus infected fibroblasts. Yet, suppression of IE1 derived peptide presentation by gpUS2 or gpUS11 was far more pronounced. The results show that gpUS2 and gpUS11 alone only incompletely protect HCMV infected fibroblasts from CTL recognition and underline the importance of studying infected cells to elucidate HCMV immune evasion.

Fossil ghost ranges are most common in some of the oldest and some of the youngest strata.

Biologists routinely compare inferences about the order of evolutionary branching (phylogeny) with the order in which groups appear in the fossil record (stratigraphy). Where they conflict, ghost ranges are inferred: intervals of geological time where a fossil lineage should exist, but for which there is no direct evidence. The presence of very numerous and/or extensive ghost ranges is often believed to imply spurious phylogenies or a misleadingly patchy fossil record, or both. It has usually been assumed that the frequency of ghost ranges should increase with the age of rocks. Previous studies measuring ghost ranges for whole trees in just a small number of temporal bins have found no significant increase with antiquity. This study uses a much higher resolution approach to investigate the gappiness implied by 1,000 animal and plant cladograms over 77 series and stages of the Phanerozoic. It demonstrates that ghost ranges are indeed relatively common in some of the oldest strata. Surprisingly, however, ghost ranges are also relatively common in some of the youngest, fossil-rich rocks. This pattern results from the interplay between several complex factors and is not a simple function of the completeness of the fossil record. The Early Palaeozoic record is likely to be less organismically and stratigraphically complete, and its fossils -- many of which are invertebrates-may be more difficult to analyse cladistically. The Late Cenozoic is subject to the pull of the Recent, but this accounts only partially for the increased gappiness in the younger strata.

The association between body size, prostate volume and prostate-specific antigen.

Increasing prostate volume contributes to urinary tract symptoms and may obscure prostate cancer detection. We investigated the association between obesity and prostate volume, prostate-specific antigen (PSA) and PSA density among 753 men referred for prostate biopsy. Among men with a negative biopsy, prostate volume significantly increased approximately 25% from the lowest to highest body mass index (BMI), waist or hip circumference or height categories. PSA was 0.7 ng/ml lower with a high waist-to-hip ratio. These associations were less consistent among subjects diagnosed with high-grade prostatic intraepithelial neoplasia or cancer. Our data suggest that obesity and height are independently associated with prostate volume..

Do u smoke after txt? Results of a randomised trial of smoking cessation using mobile phone text messaging.

OBJECTIVES: To determine the effectiveness of a mobile phone text messaging smoking cessation programme. DESIGN: Randomised controlled trial SETTING: New Zealand PARTICIPANTS: 1705 smokers from throughout New Zealand who wanted to quit, were aged over 15 years, and owned a mobile phone were randomised to an intervention group that received regular, personalised text messages providing smoking cessation advice, support, and distraction, or to a control group. All participants received a free month of text messaging; starting for the intervention group on their quit day to assist with quitting, and starting for the control group at six months to encourage follow up. Follow up data were available for 1624 (95%) at six weeks and 1265 (74%) at six months. MAIN OUTCOME MEASURES: The main trial outcome was current non-smoking (that is, not smoking in the past week) six weeks after randomisation. Secondary outcomes included current non-smoking at 12 and 26 weeks. RESULTS: More participants had quit at six weeks in the intervention compared to the control group: 239 (28%) v 109 (13%), relative risk 2.20 (95% confidence interval 1.79 to 2.70), p < 0.0001. This treatment effect was consistent across subgroups defined by age, sex, income level, or geographic location (p homogeneity > 0.2). The relative risk estimates were similar in sensitivity analyses adjusting for missing data and salivary cotinine verification tests. Reported quit rates remained high at six months, but there was some uncertainty about between group differences because of incomplete follow up. CONCLUSIONS: This programme offers potential for a new way to help young smokers to quit, being affordable, personalised, age appropriate, and not location dependent. Future research should test these findings in different settings, and provide further assessment of long term quit rates.

Rounded atelectasis in an asbestos exposed worker.

The case history is presented of a 51-year-old electrical power worker with a history of asbestos exposure presenting with rounded atelectasis. No other radiological markers of asbestos exposure were present. A documented history of asbestos exposure and exclusion of other causes of rounded atelectasis led to the diagnosis of asbestos related rounded atelectasis. It is important to understand that rounded atelectasis can be an isolated finding due to asbestos exposure. This facilitates investigation of lung masses of unknown etiology and initiation of appropriate follow up of patients at risk for future development of more debilitating asbestos related pathology.

Effects of Chlamydia trachomatis infection on the expression of natural killer (NK) cell ligands and susceptibility to NK cell lysis.

Natural killer (NK) cells are an important component of the immediate immune response to infections, including infection by intracellular bacteria. We have investigated recognition of Chlamydia trachomatis (CT) by NK cells and show that these cells are activated to produce interferon (IFN)-gamma when peripheral blood mononuclear cells (PBMC) are stimulated with CT organisms. Furthermore, infection of epithelial cell lines with CT renders them susceptible to lysis by human NK cells. Susceptibility was observed 18-24 h following infection and required protein synthesis by the infecting chlamydiae, but not by the host cell; heat or UV inactivated chlamydiae did not induce susceptibility to NK cell lysis. CT infection was also shown to decrease the expression of classical and non-classical major histocompatibility complex (MHC) molecules on infected cells, thus allowing recognition by NK cells when combined with an activating signal. A candidate activating signal is MICA/B, which was shown to be expressed constitutively on epithelial cells.

Vaccines against persistent DNA virus infections.

Persistent viruses present some particular problems for vaccine design. As for acute non-persistent viruses, the prime goal of a vaccine should be to prevent primary infection. Vaccines might also be used to modify the course of established persistent virus infections - so-called postinfective immunisation. This chapter deals with selected persistent DNA viruses, in particular the human herpes viruses.