The association between cholera in pregnancy and negative fetal outcome has been described since the 19th century. However, there is limited published literature on the subject. We describe pregnancy outcomes from a specialized multidisciplinary hospital unit at the onset of a large cholera outbreak in Haiti in 2010 and 2011.
Pregnant women with cholera were hospitalized in a specialized unit within the MSF hospital compound in Léogâne and treated using standard cholera treatment guidelines but with earlier, more intense fluid replacement. All women had intravenous access established at admission regardless of their hydration status, and all received antibiotic treatment. Data were collected on patient demographics, pregnancy and cholera status, and pregnancy outcome. In this analysis we calculated risk ratios for fetal death and performed logistic regression analysis to control for confounding factors.
263 pregnant women with cholera were hospitalized between December 2010 and July 2011. None died during hospitalization, 226 (86%) were discharged with a preserved pregnancy and 16 (6%) had live fullterm singleton births, of whom 2 died within the first 5 days postpartum. The remaining 21 pregnancies (8%) resulted in intrauterine fetal death. The risk of fetal death was associated with factors reflecting severity of the cholera episode: after adjusting for confounding factors, the strongest risk factor for fetal death was severe maternal dehydration (adjusted risk ratio for severe vs. mild dehydration was 9.4, 95% CI 2.5–35.3, p = 0.005), followed by severe vomiting (adjusted risk ratio 5.1, 95% 1.1–23.8, p = 0.041).
This is the largest cohort of pregnant women with cholera described to date. The main risk factor identified for fetal death was severity of dehydration. Our experience suggests that establishing specialized multidisciplinary units which facilitate close follow-up of both pregnancy and dehydration status due to cholera could be beneficial for patients, especially in large epidemics.
Cholera in pregnancy has been long associated with high rates of stillbirths and abortions, but there is very limited published literature describing this association or possible mechanisms. During the major cholera epidemic that hit Haiti in October 2010, we set-up a specialized cholera treatment unit for pregnant women inside the Médecins sans Frontières hospital in Léogâne, allowing for intensive follow-up of cholera-associated dehydration and of pregnancy, and facilitating access to high-quality obstetric and neonatal services in case of complications. To describe the pregnancy outcomes and risk factors for fetal death, we analyzed routinely collected data from patient files. Of 263 women hospitalized, 21 (8%) lost their pregnancy during hospitalization for cholera; an additional 16 (6%) delivered a live baby at the hospital, and the remaining 226 women (86%) were discharged with preserved pregnancy. The risk factor most strongly associated with fetal demise was severity of dehydration at admission. In large epidemics, multidisciplinary units can help prevent negative maternal, fetal and neonatal outcomes.
The RNA polymerase II (RNAP II)-associated protein (RPAP) 2 has been discovered through its association with various subunits of RNAP II in affinity purification coupled with mass spectrometry experiments. Here, we show that RPAP2 is a mainly cytoplasmic protein that shuttles between the cytoplasm and the nucleus. RPAP2 shuttling is tightly coupled with nuclear import of RNAP II, as RPAP2 silencing provokes abnormal accumulation of RNAP II in the cytoplasmic space. Most notably, RPAP4/GPN1 silencing provokes the retention of RPAP2 in the nucleus. Our results support a model in which RPAP2 enters the nucleus in association with RNAP II and returns to the cytoplasm in association with the GTPase GPN1/RPAP4. Although binding of RNAP II to RPAP2 is mediated by an N-terminal domain (amino acids 1–170) that contains a nuclear retention domain, and binding of RPAP4/GPN1 to RPAP2 occurs through a C-terminal domain (amino acids 156–612) that has a dominant cytoplasmic localization domain. In conjunction with previously published data, our results have important implications, as they indicate that RPAP2 controls gene expression by two distinct mechanisms, one that targets RNAP II activity during transcription and the other that controls availability of RNAP II in the nucleus.
Methylation is a post-translational modification that can affect numerous features of proteins, notably cellular localization, turnover, activity, and molecular interactions. Recent genome-wide analyses have considerably extended the list of human genes encoding putative methyltransferases. Studies on protein methyltransferases have revealed that the regulatory function of methylation is not limited to epigenetics, with many non-histone substrates now being discovered. We present here our findings on a novel family of distantly related putative methyltransferases. Affinity purification coupled to mass spectrometry shows a marked preference for these proteins to associate with various chaperones. Based on the spectral data, we were able to identify methylation sites in substrates, notably trimethylation of K135 of KIN/Kin17, K561 of HSPA8/Hsc70 as well as corresponding lysine residues in other Hsp70 isoforms, and K315 of VCP/p97. All modification sites were subsequently confirmed in vitro. In the case of VCP, methylation by METTL21D was stimulated by the addition of the UBX cofactor ASPSCR1, which we show directly interacts with the methyltransferase. This stimulatory effect was lost when we used VCP mutants (R155H, R159G, and R191Q) known to cause Inclusion Body Myopathy with Paget's disease of bone and Fronto-temporal Dementia (IBMPFD) and/or familial Amyotrophic Lateral Sclerosis (ALS). Lysine 315 falls in proximity to the Walker B motif of VCP's first ATPase/D1 domain. Our results indicate that methylation of this site negatively impacts its ATPase activity. Overall, this report uncovers a new role for protein methylation as a regulatory pathway for molecular chaperones and defines a novel regulatory mechanism for the chaperone VCP, whose deregulation is causative of degenerative neuromuscular diseases.
Methylation, or transfer of a single or multiple methyl groups (CH3), is one of many post-translational modifications that occur on proteins. Such modifications can, in turn, affect numerous aspects of a protein, notably cellular localization, turnover, activity, and molecular interactions. In addition to post-translational modifications, the structural organization of a protein or protein complex can also have a significant impact on its function and stability. A group of factors known as “molecular chaperones” aid newly synthesized proteins in reaching their native conformation or alternating between physiologically relevant states. We present here a new family of factors that promote methylation of chaperones and show that, at least in one case, this modification translates into a modulation in the activity of the substrate chaperone. Our results not only characterize the function of previously unknown gene products, uncover a new role for protein methylation as a regulatory pathway for chaperones, and define a novel regulatory mechanism for the chaperone VCP, whose deregulation is causative of neuromuscular diseases, but also suggest the existence of a post-translational modification code that regulates molecular chaperones. Further decrypting this “chaperone code” will help understanding how the functional organization of the proteome is orchestrated.
Mitral valve thickness is used as a criterion to distinguish the classical from the non-classical form of mitral valve prolapse (MVP). Classical form of MVP has been associated with higher risk of mitral regurgitation (MR) and concomitant complications. We sought to determine the relation of mitral valve morphology and motion to mitral regurgitation severity in patients with MVP.
We prospectively analyzed transthoracic echocardiograms of 38 consecutive patients with MVP and various degrees of MR. In the parasternal long-axis view, leaflets length, diastolic leaflet thickness, prolapsing depth, billowing area and non-coaptation distance between both leaflets were measured.
Twenty patients (53%) and 18 patients (47%) were identified as having moderate to severe and mild MR respectively (ERO = 45 ± 27 mm2 vs. 5 ± 7 mm2, p < 0.001). Diastolic leaflet thickness was similar in both groups (5.5 ± 0.9 mm vs. 5.3 ± 1 mm, p = 0.57). On multivariate analysis, the non-coaptation distance (OR 7.9 per 1 mm increase; 95% CI 1.72-37.2) was associated with significant MR. Thick mitral valve leaflet as traditionally reported (≥ 5 mm) was not associated with significant MR (OR 0.9; 95% CI 0.2-3.4).
In patients with MVP, thick mitral leaflet is not associated with significant MR. Leaflet thickness is probably not as important in risk stratification as previously reported in patients with MVP. Other anatomical and geometrical features of the mitral valve apparatus area appear to be much more closely related to MR severity.
mitral regurgitation; mitral valve; echocardiography; mitral valve prolapse
Long-range interactions between regulatory DNA elements such as enhancers, insulators and promoters play an important role in regulating transcription. As chromatin contacts have been found throughout the human genome and in different cell types, spatial transcriptional control is now viewed as a general mechanism of gene expression regulation. Chromosome Conformation Capture Carbon Copy (5C) and its variant Hi-C are techniques used to measure the interaction frequency (IF) between specific regions of the genome. Our goal is to use the IF data generated by these experiments to computationally model and analyze three-dimensional chromatin organization.
We formulate a probabilistic model linking 5C/Hi-C data to physical distances and describe a Markov chain Monte Carlo (MCMC) approach called MCMC5C to generate a representative sample from the posterior distribution over structures from IF data. Structures produced from parallel MCMC runs on the same dataset demonstrate that our MCMC method mixes quickly and is able to sample from the posterior distribution of structures and find subclasses of structures. Structural properties (base looping, condensation, and local density) were defined and their distribution measured across the ensembles of structures generated. We applied these methods to a biological model of human myelomonocyte cellular differentiation and identified distinct chromatin conformation signatures (CCSs) corresponding to each of the cellular states. We also demonstrate the ability of our method to run on Hi-C data and produce a model of human chromosome 14 at 1Mb resolution that is consistent with previously observed structural properties as measured by 3D-FISH.
We believe that tools like MCMC5C are essential for the reliable analysis of data from the 3C-derived techniques such as 5C and Hi-C. By integrating complex, high-dimensional and noisy datasets into an easy to interpret ensemble of three-dimensional conformations, MCMC5C allows researchers to reliably interpret the result of their assay and contrast conformations under different conditions.
Single nucleotide polymorphisms (SNPs) are the most commonly used polymorphic markers in genetics studies. Among the different platforms for SNP genotyping, Luminex is one of the less exploited mainly due to the lack of a robust (semi-automated and replicable) freely available genotype calling software. Here we describe a clustering algorithm that provides automated SNP calls for Luminex genotyping assays. We genotyped 3 SNPs in a cohort of 330 childhood leukemia patients, 200 parents of patient and 325 healthy individuals and used the Automated Luminex Genotyping (ALG) algorithm for SNP calling. ALG genotypes were called twice to test for reproducibility and were compared to sequencing data to test for accuracy. Globally, this analysis demonstrates the accuracy (99.6%) of the method, its reproducibility (99.8%) and the low level of no genotyping calls (3.4%). The high efficiency of the method proves that ALG is a suitable alternative to the current commercial software. ALG is semi-automated, and provides numerical measures of confidence for each SNP called, as well as an effective graphical plot. Moreover ALG can be used either through a graphical user interface, requiring no specific informatics knowledge, or through command line with access to the open source code. The ALG software has been implemented in R and is freely available for non-commercial use either at http://alg.sourceforge.net or by request to firstname.lastname@example.org
The new recommendations to prevent malaria in pregnant women have recently been implemented in Gabon. There is little information on the pregnancy indicators that are useful for their evaluation. A cross-sectional study for the assessment of the prevalence of peripheral, placental, and cord malaria and anemia among delivering women was performed at the largest public hospital of Gabon. Malaria prevalence was 34.4%, 53.6%, and 18.2% for maternal peripheral, placental, and cord blood respectively, with no difference between primigravidae and multigravidae. Submicroscopic infections were frequent and concerned all the positive cord samples. Maternal peripheral, late placental, and cord infections were all associated with a reduced mean birth weight in primigravidae (P = 0.02). Anemia prevalence was 53%, low birth rate was 13%, and prematurity was 25%. The use of intermittent preventive treatment with sulfadoxine-pyrimethamine (greater than or equal to one dose) combined with bed net was associated with a reduction in infection only in multigravidae and with a reduced risk of maternal anemia.
RNA polymerase II (RNAPII), the 12-subunit enzyme that synthesizes all mRNAs and several non-coding RNAs in eukaryotes, plays a central role in cell function. Although multiple proteins are known to regulate the activity of RNAPII during transcription, little is known about the machinery that controls the fate of the enzyme before or after transcription. We used systematic protein affinity purification coupled to mass spectrometry (AP-MS) to characterize the high resolution network of protein interactions of RNAPII in the soluble fraction of human cell extracts. Our analysis revealed that many components of this network participate in RNAPII biogenesis. We show here that RNAPII-associated protein 4 (RPAP4/GPN1) shuttles between the nucleus and the cytoplasm and regulates nuclear import of POLR2A/RPB1 and POLR2B/RPB2, the two largest subunits of RNAPII. RPAP4/GPN1 is a member of a newly discovered GTPase family that contains a unique and highly conserved GPN loop motif that we show is essential, in conjunction with its GTP-binding motifs, for nuclear localization of POLR2A/RPB1 in a process that also requires microtubule assembly. A model for RNAPII biogenesis is presented.
Spatial chromatin organization is emerging as an important mechanism to regulate the expression of genes. However, very little is known about genome architecture at high-resolution in vivo. Here, we mapped the three-dimensional organization of the human Hox clusters with chromosome conformation capture (3C) technology. We show that computational modeling of 3C data sets can identify candidate regulatory proteins of chromatin architecture and gene expression. Hox genes encode evolutionarily conserved master regulators of development which strict control has fascinated biologists for over 25 years. Proper transcriptional silencing is key to Hox function since premature expression can lead to developmental defects or human disease. We now show that the HoxA cluster is organized into multiple chromatin loops that are dependent on transcription activity. Long-range contacts were found in all four silent clusters but looping patterns were specific to each cluster. In contrast to the Drosophila homeotic bithorax complex (BX-C), we found that Polycomb proteins are only modestly required for human cluster looping and silencing. However, computational three-dimensional Hox cluster modeling identified the insulator-binding protein CTCF as a likely candidate mediating DNA loops in all clusters. Our data suggest that Hox cluster looping may represent an evolutionarily conserved structural mechanism of transcription regulation.
A suite of computer programs to identify genome-wide chromatin conformation signatures with 5C technology is reported.
One of the major genomics challenges is to better understand how correct gene expression is orchestrated. Recent studies have shown how spatial chromatin organization is critical in the regulation of gene expression. Here, we developed a suite of computer programs to identify chromatin conformation signatures with 5C technology . We identified dynamic HoxA cluster chromatin conformation signatures associated with cellular differentiation. Genome-wide chromatin conformation signature identification might uniquely identify disease-associated states and represent an entirely novel class of human disease biomarkers.
Although an extensive body of scientific and patent literature exists describing the development of HIV-1 integrase (IN) inhibitors, Merck’s raltegravir and Gilead’s elvitegravir remain the only IN inhibitors FDA-approved for the treatment of AIDS. The emergence of raltegravir-resistant strains of HIV-1 containing mutated forms of IN underlies the need for continued efforts to enhance the efficacy of IN inhibitors against resistant mutants. We have previously described bicyclic 6,7-dihydroxyoxoisoindolin-1-ones that show good IN inhibitory potency. This report describes the effects of introducing substituents into the 4- and 5- positions of the parent 6,7-dihydroxyoxoisoindolin-1-one platform. We have developed several sulfonamide-containing analogs that enhance potency in cell-based HIV assays by more than two orders-of-magnitude and we describe several compounds that are more potent than raltegravir against the clinically relevant Y143R IN mutant.
HIV-1 integrase; Inhibit; Raltegravir; Sulfonamide
We used next-generation sequencing to characterize the genomes of nine species of Orobanchaceae of known phylogenetic relationships, different life forms, and including a polyploid species. The study species are the autotrophic, nonparasitic Lindenbergia philippensis, the hemiparasitic Schwalbea americana, and seven nonphotosynthetic parasitic species of Orobanche (Orobanche crenata, Orobanche cumana, Orobanche gracilis (tetraploid), and Orobanche pancicii) and Phelipanche (Phelipanche lavandulacea, Phelipanche purpurea, and Phelipanche ramosa). Ty3/Gypsy elements comprise 1.93%–28.34% of the nine genomes and Ty1/Copia elements comprise 8.09%–22.83%. When compared with L. philippensis and S. americana, the nonphotosynthetic species contain higher proportions of repetitive DNA sequences, perhaps reflecting relaxed selection on genome size in parasitic organisms. Among the parasitic species, those in the genus Orobanche have smaller genomes but higher proportions of repetitive DNA than those in Phelipanche, mostly due to a diversification of repeats and an accumulation of Ty3/Gypsy elements. Genome downsizing in the tetraploid O. gracilis probably led to sequence loss across most repeat types.
next-generation sequencing; polyploidy; genome size; genome downsizing; transposable elements; LTR retrotransposons; Ty3/Gypsy; Orobanche; Phelipanche; Orobanchaceae
The contact structure between hosts shapes disease spread. Most network-based models used in epidemiology tend to ignore heterogeneity in the weighting of contacts between two individuals. However, this assumption is known to be at odds with the data for many networks (e.g. sexual contact networks) and to have a critical influence on epidemics' behavior. One of the reasons why models usually ignore heterogeneity in transmission is that we currently lack tools to analyze weighted networks, such that most studies rely on numerical simulations. Here, we present a novel framework to estimate key epidemiological variables, such as the rate of early epidemic expansion () and the basic reproductive ratio (), from joint probability distributions of number of partners (contacts) and number of interaction events through which contacts are weighted. These distributions are much easier to infer than the exact shape of the network, which makes the approach widely applicable. The framework also allows for a derivation of the full time course of epidemic prevalence and contact behaviour, which we validate with numerical simulations on networks. Overall, incorporating more realistic contact networks into epidemiological models can improve our understanding of the emergence and spread of infectious diseases.
Understanding how infectious diseases spread has public health and ecological implications. The contact structure between hosts strongly affects this spread. However, most studies assume that all types of contacts are identical, when in reality some individuals interact more strongly than others. This is particularly striking for sexual-contact networks, where the number of sex acts is not identical for all partnerships. This heterogeneity in activity can either speed up or slow down epidemic spread depending on how strongly the individuals' number of contacts coincides with their activity. There are two limitations to current frameworks that can explain the lack of studies on weighted networks. First, analytical results are difficult to obtain, which requires numerical simulations. Second, inferring weighted networks from survey data is extremely difficult. Here, we present a novel framework that allows to alleviate these two limitations. Building on configuration type network epidemic approaches, we manage to capture disease spread on weighted networks from the distribution of the number of contacts and distribution of the number of interaction events (e.g. sex acts). This allows us to derive analytical estimates for the epidemic threshold and the rate of spread of the disease. It also allows us to readily incorporate survey data, as illustrated in this study with data from the National Survey of Sexual Attitudes and Lifestyles (NATSAL) carried out in the UK.
The trematode flatworms of the genus Schistosoma, the causative agents of schistosomiasis, are among the most prevalent parasites in humans, affecting more than 200 million people worldwide. In this study, we focused on two well-characterized strains of S. mansoni, to explore signatures of selection. Both strains are highly inbred and exhibit differences in life history traits, in particular in their compatibility with the intermediate host Biomphalaria glabrata.
We performed high throughput sequencing of DNA from pools of individuals of each strain using Illumina technology and identified single nucleotide polymorphisms (SNP) and copy number variations (CNV). In total, 708,898 SNPs were identified and roughly 2,000 CNVs. The SNPs revealed low nucleotide diversity (π = 2×10−4) within each strain and a high differentiation level (Fst = 0.73) between them. Based on a recently developed in-silico approach, we further detected 12 and 19 private (i.e. specific non-overlapping) selective sweeps among the 121 and 151 sweeps found in total for each strain.
Functional annotation of transcripts lying in the private selective sweeps revealed specific selection for functions related to parasitic interaction (e.g. cell-cell adhesion or redox reactions). Despite high differentiation between strains, we identified evolutionary convergence of genes related to proteolysis, known as a key virulence factor and a potential target of drug and vaccine development. Our data show that pool-sequencing can be used for the detection of selective sweeps in parasite populations and enables one to identify biological functions under selection.
Adaptation of parasites to their environment is governed by the principle of selection. Favourable mutations are fixed in populations while deleterious mutations are progressively eliminated. Here, we aimed to find signatures of selection in two strains of Schistosoma mansoni, the causative agent of intestinal schistosomiasis. The strains differ in specific characters, in particular in their capacity to infect intermediate host snails. The reason for this is unknown and understanding it could help control the spreading of the disease. Finding footprints of adaptation to different snail hosts would lead to the discovery of genes that are particularly important for the interaction. Since a single parasite does not contain sufficient DNA to be sequenced, we pooled several individuals, sequenced them as a whole analysed them. In the regions under selection we found genes that are indeed linked to the parasitic lifestyle. We also discovered that natural selection led to diversification of genes that are related to proteolysis, the process by which the parasite destroys host tissue. The related proteins are considered good targets for drug development and vaccination. Our results suggest that in natural populations many variants of these genes exist and that they evolve rapidly, which might hamper therapeutic approaches.
Recently there have been significant advances in research on genetic strategies to control populations of disease-vectoring insects. Some of these strategies use the gene drive properties of selfish genetic elements to spread physically linked anti-pathogen genes into local vector populations. Because of the potential of these selfish elements to spread through populations, control approaches based on these strategies must be carefully evaluated to ensure a balance between the desirable spread of the refractoriness-conferring genetic cargo and the avoidance of potentially unwanted outcomes such as spread to non-target populations. There is also a need to develop better estimates of the economics of such releases. We present here an evaluation of two such strategies using a biologically realistic mathematical model that simulates the resident Aedes aegypti mosquito population of Iquitos, Peru. One strategy uses the selfish element Medea, a non-limited element that could permanently spread over a large geographic area; the other strategy relies on Killer-Rescue genetic constructs, and has been predicted to have limited spatial and temporal spread. We simulate various operational approaches for deploying these genetic strategies, and quantify the optimal number of released transgenic mosquitoes needed to achieve definitive spread of Medea-linked genes and/or high frequencies of Killer-Rescue-associated elements. We show that for both strategies the most efficient approach for achieving spread of anti-pathogen genes within three years is generally to release adults of both sexes in multiple releases over time. Even though females in these releases should not transmit disease, there could be public concern over such releases, making the less efficient male-only release more practical. This study provides guidelines for operational approaches to population replacement genetic strategies, as well as illustrates the use of detailed spatial models to assist in safe and efficient implementation of such novel genetic strategies.
Scientific knowledge can help develop interventions that improve public health. The objectives of this review are (1) to describe the status of research on knowledge transfer strategies in the field of complex social interventions in public health and (2) to identify priorities for future research in this field.
A scoping study is an exploratory study. After searching databases of bibliographic references and specialized periodicals, we summarized the relevant studies using a predetermined assessment framework. In-depth analysis focused on the following items: types of knowledge transfer strategies, fields of public health, types of publics, types of utilization, and types of research specifications.
From the 1,374 references identified, we selected 26 studies. The strategies targeted mostly administrators of organizations and practitioners. The articles generally dealt with instrumental utilization and most often used qualitative methods. In general, the bias risk for the studies is high.
Researchers need to consider the methodological challenges in this field of research in order to improve assessment of more complex knowledge transfer strategies (when they exist), not just diffusion/dissemination strategies and conceptual and persuasive utilization.
Systemic inflammation plays an important role in the increased cardiac risk observed in rheumatoid arthritis (RA). Effective control of inflammation and disease activity may be of benefit in reducing cardiovascular risk in RA patients.
Our study was conducted in patients with active RA to investigate the effects of 24-week abatacept treatment on aortic stiffness measured by pulse wave velocity (PWV).
The study included 21 patients, of whom 17 were females, with a mean age of 65.2±13.7 years. Ten patients had positive rheumatoid factors, 16 positive anti-citrullinated protein antibodies, and 19 presented an erosive form of RA. Sixteen patients were nonresponders to anti-tumor necrosis factor-alpha treatments. After 6 months of abatacept treatment, there was a significant increase in PWV levels (9.8±2.9 versus 8.5±3.9 m/second; P=0.02). A nonsignificant increase in total cholesterol and low-density lipoprotein cholesterol was observed. There was also a significant increase in high-density lipoprotein cholesterol levels, which led to a nonsignificant decrease in atherogenic index. The improvement in disease activity was significant, and there was a decrease of systemic inflammatory parameters, but without reaching statistical significancy. Changes in PWV were significantly correlated with changes in Disease Activity Score on 28 joints based on erythrocyte sedimentation rate (r=0.46; P=0.035) and in high-density lipoprotein cholesterol (r=−0.38; P=0.046). No correlation was observed with changes in C-reactive protein and in other parameters of lipid profile or in steroid dose.
The worsening of aortic stiffness found after 6 months of abatacept therapy might be due to an insufficient decrease in systemic inflammation.
arterial stiffness; cardiovascular risk markers; systemic inflammation; atherogenic index
To know whether age has an independent effect on the dawn phenomenon in noninsulin-using type 2 diabetes.
RESEARCH DESIGN AND METHODS
Eighty-one individuals with type 2 diabetes were matched for HbA1c and divided by age into three subgroups of 27 individuals (1: ≥70 years; 2: 60–69 years; and 3: ≤59 years). All underwent ambulatory continuous glucose monitoring for quantifying the dawn phenomenon (i.e., the absolute [∂G, mg/dL] or relative [∂G%] increments from nocturnal nadirs to prebreakfast time points).
HbA1c levels and 24-h glycemic profiles were similar across the three groups. Glucose increments (mean ± SEM) were identical in the three groups: ∂G (mg/dL), 22.0 ± 4.7 (1), 21.3 ± 3.6 (2), and 18.0 ± 3.6 (3) and δG (%), 19.9 ± 4.9 (1), 21.6 ± 4.4 (2), and 17.6 ± 4.2 (3). Using the most common definition (∂G >10 mg/dL), the prevalence of the dawn phenomenon was 52, 70, and 59% in groups 1, 2, and 3, respectively.
The dawn phenomenon is present in the elderly.
To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs).
RESEARCH DESIGN AND METHODS
In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7−10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9−4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis.
In all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI −0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG <3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels <7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar.
Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec.
To explore the perspectives of paediatric residents and faculty regarding how the Collaborator role is taught and assessed.
Using a constructivist grounded theory approach, focus groups at four Canadian universities were conducted. Data were analyzed iteratively for emergent themes.
Residents reported learning about collaboration through faculty role modelling but did not perceive that it was part of the formal curriculum. Faculty reported that they were not trained in how to effectively model this role. Both groups reported a need for training in conflict management, particularly as it applies to intraprofessional (physician-to-physician) relationships. Finally, the participants asserted that current methods to assess residents on their performance as collaborators are suboptimal.
The Collaborator role should be a formal part of the residency curriculum. Residents need to be better educated with regard to managing conflict and handling intraprofessional relationships. Finally, innovative methods of assessing residents on this non-medical expert role need to be created.
Collaboration; CanMEDS roles; Postgraduate training; Pediatrics
Mesenchymal stem cells (MSCs) hold great potential for regenerative medicine and tissue-engineering applications. They have multipotent differentiation capabilities and have been shown to differentiate down various lineages, including osteoblasts, adipocytes, chondrocytes, myocytes, and possibly neurons. The majority of approaches to control the MSC fate have been via the use of chemical factors in the form of growth factors within the culture medium. More recently, it has been understood that mechanical forces play a significant role in regulating MSC fate. We and others have shown that mechanical stimuli can control MSC lineage specification. The cytoskeleton is known to play a large role in mechanotransduction, and a growing number of studies are showing that it can also contribute to MSC differentiation. This review analyzes the significant contribution of actin and integrin distribution, and the smaller role of microtubules, in regulating MSC fate. Osteogenic differentiation is more prevalent in MSCs with a stiff, spread actin cytoskeleton and greater numbers of focal adhesions. Both adipogenic differentiation and chondrogenic differentiation are encouraged when MSCs have a spherical morphology associated with a dispersed actin cytoskeleton with few focal adhesions. Different mechanical stimuli can be implemented to alter these cytoskeletal patterns and encourage MSC differentiation to the desired lineage.
Environmental signals, such heat shock and acidosis, induce a structural and functional remodeling of the nucleolus. This process, which depends on the expression of intergenic long noncoding RNA, reversibly converts the nucleolus from a transcriptionally active ribosome factory into a transcriptionally inert prison for proteins.
The nucleolus is a plurifunctional organelle in which structure and function are intimately linked. Its structural plasticity has long been appreciated, particularly in response to transcriptional inhibition and other cellular stresses, although the mechanism and physiological relevance of these phenomena are unclear. Using MCF-7 and other mammalian cell lines, we describe a structural and functional adaptation of the nucleolus, triggered by heat shock or physiological acidosis, that depends on the expression of ribosomal intergenic spacer long noncoding RNA (IGS lncRNA). At the heart of this process is the de novo formation of a large subnucleolar structure, termed the detention center (DC). The DC is a spatially and dynamically distinct region, characterized by an 8-anilino-1-naphthalenesulfonate–positive hydrophobic signature. Its formation is accompanied by redistribution of nucleolar factors and arrest in ribosomal biogenesis. Silencing of regulatory IGS lncRNA prevents the creation of this structure and allows the nucleolus to retain its tripartite organization and transcriptional activity. Signal termination causes a decrease in IGS transcript levels and a return to the active nucleolar conformation. We propose that the induction of IGS lncRNA by environmental signals operates as a molecular switch that regulates the structure and function of the nucleolus.
The introduction of alien species is one of the major causes of current and global biodiversity loss. The introduction of fish can be a particular threat to native amphibian populations, which are declining worldwide. One way for amphibians to persist in such altered environments is to adopt anti-predator strategies especially at the behavioural level. However, although it has been shown that avoidance behaviour may decrease the probability of being detected by a potential predator, little is known on the consequences on sexual behaviour. In this study, we tested the hypothesis that adult Alpine newts (Ichthyosaura alpestris) use shelters more often and exhibit less sexual activity in the presence of goldfish (Carassius auratus) and that they reduce sexual activity more in risky micro-habitats than in safe environments. To this end, we assessed behavioural patterns of adult newts in a replicated laboratory design. Goldfish were present in direct contact with newts in half of the tanks. Consistently throughout the study period, significantly more newts used shelter in the presence of fish than in their absence. Newts also significantly decreased their sexual activity level overall, but specially outside the shelter when they were in direct contact with fish. These results show that fish presence can affect newts in complex ways, such as through inhibition of their reproduction. Our work highlights that integrating behaviour in conservation studies is essential to understanding the patterns of coexistence and exclusion between introduced fish and amphibians.