When to Monitor CD4 Cell Count and HIV RNA to Reduce Mortality and AIDS-Defining Illness in Virologically Suppressed HIV-Positive Persons on Antiretroviral Therapy in High-Income Countries: A Prospective Observational Study.

OBJECTIVE To illustrate an approach to compare CD4 cell count and HIV-RNA monitoring strategies in HIV-positive individuals on antiretroviral therapy (ART). DESIGN Prospective studies of HIV-positive individuals in Europe and the USA in the HIV-CAUSAL Collaboration and The Center for AIDS Research Network of Integrated Clinical Systems. METHODS Antiretroviral-naive individuals who initiated ART and became virologically suppressed within 12 months were followed from the date of suppression. We compared 3 CD4 cell count and HIV-RNA monitoring strategies: once every (1) 3 ± 1 months, (2) 6 ± 1 months, and (3) 9-12 ± 1 months. We used inverse-probability weighted models to compare these strategies with respect to clinical, immunologic, and virologic outcomes. RESULTS In 39,029 eligible individuals, there were 265 deaths and 690 AIDS-defining illnesses or deaths. Compared with the 3-month strategy, the mortality hazard ratios (95% CIs) were 0.86 (0.42 to 1.78) for the 6 months and 0.82 (0.46 to 1.47) for the 9-12 month strategy. The respective 18-month risk ratios (95% CIs) of virologic failure (RNA >200) were 0.74 (0.46 to 1.19) and 2.35 (1.56 to 3.54) and 18-month mean CD4 differences (95% CIs) were -5.3 (-18.6 to 7.9) and -31.7 (-52.0 to -11.3). The estimates for the 2-year risk of AIDS-defining illness or death were similar across strategies. CONCLUSIONS Our findings suggest that monitoring frequency of virologically suppressed individuals can be decreased from every 3 months to every 6, 9, or 12 months with respect to clinical outcomes. Because effects of different monitoring strategies could take years to materialize, longer follow-up is needed to fully evaluate this question.

Analysis of BMP signalling through the receptor type IA in embryogenesis using conditional gene inactivation in mice

Although bone morphogenetic proteins (BMPs) were initially identified for their potent bone-inducing activity, their precise roles in processes of endochondral and intramembranous bone formation are far from being clear. Tissue-specific loss-of-function experiments using the BMP receptor type IA (BMPR-IA) are particularly attractive since this receptor is thought to be essential for signaling by the closely related BMPs -2, 4, and 7. To ablate signaling through this receptor during chondrogenesis, we have generated transgenic mice expressing Cre recombinase under the control of the collagen type II (Col2a1) gene regulatory sequences. Mice lacking BMPR-IA function in chondrocytes display a number of skeletal abnormalities, including defects in bones of the chondrocranium, abnormal dorsal vertebral processes, scapulae with severe hypoplasia of dorsal elements, and shortening of the long bones. Alterations in the growth plate of long bones in mutants suggest that BMPR-IA is not required for early steps of the chondrocyte specification, but is rather important in regulation of terminal differentiation. Molecular analysis revealed noticeable downregulation of the Ihh/Ptch signalling pathway, decreased chondrocyte proliferation rate and deregulation of hypertrophy. ^ In order to elucidate the role of BMP signalling in development of the limb and intramembranous ossification, we have used mice expressing Cre recombinase under control of the Prx1 (MHox) regulatory elements (M. Logan, pers comm.). Cre activity was found in those mice in the developing limb bud mesenchyme, as well as in a subset of cranial neural crest cells. Prx1-Cre-induced conditional mutants display prominent defects in distal limb outgrowth, as well as ossification defects in a number of neural crest-derived calvarial bones. Intriguingly, mutant limbs displayed alterations in patterning along all three axes. Molecular analysis revealed ectopic anterior Shh/Ptch signalling pathway activation and expression of some Hox genes. Observed loss of Msx1 and Msx2 expression in the progress zone correlates with downregulation of Cyclin D1 and decreased distal outgrowth. Abnormal ventral localization of Lmx1b-expressing cells along with observed later morphological abnormalities suggest a novel role for BMP signalling in establishment or maintaining of the dorso-ventral polarity in the limb mesoderm. ^

MEASURING THE EFFECT OF ILLNESS ON THE EXPECTED REMAINING SERVICE TIME FOR THE ACTIVE DUTY ARMY: A LIFE TABLE APPROACH

A life table methodology was developed which estimates the expected remaining Army service time and the expected remaining Army sick time by years of service for the United States Army population. A measure of illness impact was defined as the ratio of expected remaining Army sick time to the expected remaining Army service time. The variances of the resulting estimators were developed on the basis of current data. The theory of partial and complete competing risks was considered for each type of decrement (death, administrative separation, and medical separation) and for the causes of sick time.^ The methodology was applied to world-wide U.S. Army data for calendar year 1978. A total of 669,493 enlisted personnel and 97,704 officers were reported on active duty as of 30 September 1978. During calendar year 1978, the Army Medical Department reported 114,647 inpatient discharges and 1,767,146 sick days. Although the methodology is completely general with respect to the definition of sick time, only sick time associated with an inpatient episode was considered in this study.^ Since the temporal measure was years of Army service, an age-adjusting process was applied to the life tables for comparative purposes. Analyses were conducted by rank (enlisted and officer), race and sex, and were based on the ratio of expected remaining Army sick time to expected remaining Army service time. Seventeen major diagnostic groups, classified by the Eighth Revision, International Classification of Diseases, Adapted for Use In The United States, were ranked according to their cumulative (across years of service) contribution to expected remaining sick time.^ The study results indicated that enlisted personnel tend to have more expected hospital-associated sick time relative to their expected Army service time than officers. Non-white officers generally have more expected sick time relative to their expected Army service time than white officers. This racial differential was not supported within the enlisted population. Females tend to have more expected sick time relative to their expected Army service time than males. This tendency remained after diagnostic groups 580-629 (Genitourinary System) and 630-678 (Pregnancy and Childbirth) were removed. Problems associated with the circulatory system, digestive system and musculoskeletal system were among the three leading causes of cumulative sick time across years of service. ^

Relationships, Income Support and Decision Making: A Qualitative Synopsis

This qualitative study of one midwestern state’s child protective services addresses whether an income support measure for poor biological caregivers reduces the length of time that their children spend in foster care. The overall findings suggest that workers do value the worker-family relationship. However, some view the immediate worker-client relationship as secondary to the inclusion of extended familial supports particularly as related to sustained more long-term outcome achievement. Most workers additionally agree that client involvement during all phases of the reunification process is critical.

Glaciological characteristics and carbon dioxide record of ice cores from Antarctica

We report a decadally resolved record of atmospheric CO2 concentration for the last 1000 years, obtained from the West Antarctic Ice Sheet (WAIS) Divide shallow ice core. The most prominent feature of the pre-industrial period is a rapid ~7 ppm decrease of CO2 in a span of ~20-50 years at ~1600 A.D. This observation confirms the timing of an abrupt atmospheric CO2 decrease of ~10 ppm observed for that time period in the Law Dome ice core CO2 records, but the true magnitude of the decrease remains unclear. Atmospheric CO2 variations over the time period 1000-1800 A.D. are statistically correlated with northern hemispheric climate and tropical Indo-Pacific sea surface temperature. However, the exact relationship between CO2 and climate remains elusive due to regional climate variations and/or uneven geographical data density of paleoclimate records. We observe small differences of 0 ~2% (0 ~ 6 ppm) among the high-precision CO2 records from the Law Dome, EPICA Dronning Maud Land and WAIS Divide Antarctic ice cores. However, those records share common trends of CO2 change on centennial to multicentennial time scales, and clearly show that atmospheric CO2 has been increasing above preindustrial levels since ~1850 A.D.

¿Ya nos conocemos? Apuntes sobre la intertextualidad en la serie Penny Dreadful

En este artículo se realiza un análisis de la serie televisiva "Penny Dreadull", creada por John Logan. Esta ficción articula elementos de la literatura gótica, el cine de terror y las publicaciones periódicas que dan su título a la serie. En esa amalgama, las referencias a diferentes ficciones clásicas del terror (las de Stoker, Shelley, Wilde y otros) son constantes, como así también las refundiciones de sus tramas y personajes. Esta investigación se adentra específicamente en la intertextualidad y las producciones de sentido que se dan en esta serie a partir del trabajo sobre la base de historias ya conocidas

¿Ya nos conocemos? Apuntes sobre la intertextualidad en la serie Penny Dreadful

En este artículo se realiza un análisis de la serie televisiva "Penny Dreadull", creada por John Logan. Esta ficción articula elementos de la literatura gótica, el cine de terror y las publicaciones periódicas que dan su título a la serie. En esa amalgama, las referencias a diferentes ficciones clásicas del terror (las de Stoker, Shelley, Wilde y otros) son constantes, como así también las refundiciones de sus tramas y personajes. Esta investigación se adentra específicamente en la intertextualidad y las producciones de sentido que se dan en esta serie a partir del trabajo sobre la base de historias ya conocidas

¿Ya nos conocemos? Apuntes sobre la intertextualidad en la serie Penny Dreadful

En este artículo se realiza un análisis de la serie televisiva "Penny Dreadull", creada por John Logan. Esta ficción articula elementos de la literatura gótica, el cine de terror y las publicaciones periódicas que dan su título a la serie. En esa amalgama, las referencias a diferentes ficciones clásicas del terror (las de Stoker, Shelley, Wilde y otros) son constantes, como así también las refundiciones de sus tramas y personajes. Esta investigación se adentra específicamente en la intertextualidad y las producciones de sentido que se dan en esta serie a partir del trabajo sobre la base de historias ya conocidas

(Table, page 500) Geochemistry of a pancake-shaped concretion from lake Charlotte, Canada

A pancake-shaped concretion from Ship Harbour Lake, a small freshwater lake in eastern Nova Scotia (now named Lake Charlotte) is part of collection sent to the National Museum of Canada by Mr. R. A. Logan, of the Pan American Airvays. These concretions are of similar to the well-known marine concretions with a composition similar to wad. These are known only from abyssmal depths of the sea in the red clay deposits, while the present concretions occur in very shallow lake waters. They should be of interest to geologists, who may be concerned with the rather difficult problem which some concretions raise of distinguishing between concretions of syngenitic and epigenetic origin.

Structure of the Ets-1 pointed domain and mitogen-activated protein kinase phosphorylation site

The Pointed (PNT) domain and an adjacent mitogen-activated protein (MAP) kinase phosphorylation site are defined by sequence conservation among a subset of ets transcription factors and are implicated in two regulatory strategies, protein interactions and posttranslational modifications, respectively. By using NMR, we have determined the structure of a 110-residue fragment of murine Ets-1 that includes the PNT domain and MAP kinase site. The Ets-1 PNT domain forms a monomeric five-helix bundle. The architecture is distinct from that of any known DNA- or protein-binding module, including the helix-loop-helix fold proposed for the PNT domain of the ets protein TEL. The MAP kinase site is in a highly flexible region of both the unphosphorylated and phosphorylated forms of the Ets-1 fragment. Phosphorylation alters neither the structure nor monomeric state of the PNT domain. These results suggest that the Ets-1 PNT domain functions in heterotypic protein interactions and support the possibility that target recognition is coupled to structuring of the MAP kinase site.

Solution structure and peptide binding studies of the C-terminal Src homology 3-like domain of the diphtheria toxin repressor protein

The diphtheria toxin repressor (DtxR) is the best-characterized member of a family of homologous proteins that regulate iron uptake and virulence gene expression in the Gram-positive bacteria. DtxR contains two domains that are separated by a short, unstructured linker. The N-terminal domain is structurally well-defined and is responsible for Fe2+ binding, dimerization, and DNA binding. The C-terminal domain adopts a fold similar to eukaryotic Src homology 3 domains, but the functional role of the C-terminal domain in repressor activity is unknown. The solution structure of the C-terminal domain, consisting of residues N130-L226 plus a 13-residue N-terminal extension, has been determined by using NMR spectroscopy. Residues before A147 are highly mobile and adopt a random coil conformation, but residues A147-L226 form a single structured domain consisting of five β-strands and three helices arranged into a partially orthogonal, two-sheet β-barrel, similar to the structure observed in the crystalline Co2+ complex of full-length DtxR. Chemical shift perturbation studies demonstrate that a proline-rich peptide corresponding to residues R125-G139 of intact DtxR binds to the C-terminal domain in a pocket formed by residues in β-strands 2, 3, and 5, and helix 3. Binding of the proline-rich peptide by the C-terminal domain of DtxR presents an example of peptide binding by a prokaryotic Src homology 3-like protein. The results of this study, combined with previous x-ray studies of intact DtxR, provide insights into a possible biological function of the C-terminal domain in regulating repressor activity.