Bayesian P-Splines to investigate the impact of covariates on Multiple Sclerosis clinical course

This paper aims at proposing suitable statistical tools to address heterogeneity in repeated measures, within a Multiple Sclerosis (MS) longitudinal study. Indeed, due to unobservable sources of heterogeneity, modelling the effect of covariates on MS severity evolves as a very difficult feature. Bayesian P-Splines are suggested for modelling non linear smooth effects of covariates within generalized additive models. Thus, based on a pooled MS data set, we show how extending Bayesian P-splines to mixed effects models (Lang and Brezger, 2001), represents an attractive statistical approach to investigate the role of prognostic factors in affecting individual change in disability

Induced Abortion in Nigeria

Objective: To obtain information on societal attitude to the issues of family planning, unwanted pregnancy, abortion, adoption of children and laws relating to them.Design: Focused group discussions.Setting: Twelve subgroups in the urban and rural areas of Ogun State, Nigeria were identified, and focus group sessions held for each subgroup.Subjects: Males and females, with their ages ranging from 15 years to above 50 years drawn from different segments of the community.Intervention: A set of guidelines/questions for the FGD were developed, field-tested and used.Main outcome measures: Rich information on such relevant issues as family planning, unwanted pregnancy, abortion and adoption of children, and the laws relating to them..Results: Participants felt that there was high prevalence of unwanted pregnancy and abortion particularly among youths. They had high level of awareness of contraceptives and attributed its low use to negative side-effects, high cost and provider bias. More Christians than Muslims favoured planning of pregnancies. Majority of the respondents had negative perception of induced abortion. Some of them supported abortion if the education of the young girl would be disrupted, if paternity of pregnancy is in dispute, or if it would save the family from shame as in rape or incest. Participants supported the enactment of laws that would make adoption of unwanted children easier.Conclusion: There is a need for policymakers to address the issue of abortion and unwanted children, and enact acceptable abortion and adoption laws to protect the rights of women and children in Nigeria

A putative relay circuit providing low-threshold mechanoreceptive input to lamina I projection neurons via vertical cells in lamina II of the rat dorsal horn

Background: Lamina I projection neurons respond to painful stimuli, and some are also activated by touch or hair movement. Neuropathic pain resulting from peripheral nerve damage is often associated with tactile allodynia (touch-evoked pain), and this may result from increased responsiveness of lamina I projection neurons to non-noxious mechanical stimuli. It is thought that polysynaptic pathways involving excitatory interneurons can transmit tactile inputs to lamina I projection neurons, but that these are normally suppressed by inhibitory interneurons. Vertical cells in lamina II provide a potential route through which tactile stimuli can activate lamina I projection neurons, since their dendrites extend into the region where tactile afferents terminate, while their axons can innervate the projection cells. The aim of this study was to determine whether vertical cell dendrites were contacted by the central terminals of low-threshold mechanoreceptive primary afferents. Results: We initially demonstrated contacts between dendritic spines of vertical cells that had been recorded in spinal cord slices and axonal boutons containing the vesicular glutamate transporter 1 (VGLUT1), which is expressed by myelinated low-threshold mechanoreceptive afferents. To confirm that the VGLUT1 boutons included primary afferents, we then examined vertical cells recorded in rats that had received injections of cholera toxin B subunit (CTb) into the sciatic nerve. We found that over half of the VGLUT1 boutons contacting the vertical cells were CTb-immunoreactive, indicating that they were of primary afferent origin. Conclusions: These results show that vertical cell dendritic spines are frequently contacted by the central terminals of myelinated low-threshold mechanoreceptive afferents. Since dendritic spines are associated with excitatory synapses, it is likely that most of these contacts were synaptic. Vertical cells in lamina II are therefore a potential route through which tactile afferents can activate lamina I projection neurons, and this pathway could play a role in tactile allodynia

Axon diversity of lamina I local-circuit neurons in the lumbar spinal cord

Spinal lamina I is a key area for relaying and integrating information from nociceptive primary afferents with various other sources of inputs. Although lamina I projection neurons have been intensively studied, much less attention has been given to local-circuit neurons (LCNs), which form the majority of the lamina I neuronal population. In this work the infrared light-emitting diode oblique illumination technique was used to visualize and label LCNs, allowing reconstruction and analysis of their dendritic and extensive axonal trees. We show that the majority of lamina I neurons with locally branching axons fall into the multipolar (with ventrally protruding dendrites) and flattened (dendrites limited to lamina I) somatodendritic categories. Analysis of their axons revealed that the initial myelinated part gives rise to several unmyelinated small-diameter branches that have a high number of densely packed, large varicosities and an extensive rostrocaudal (two or three segments), mediolateral, and dorsoventral (reaching laminae III–IV) distribution. The extent of the axon and the occasional presence of long, solitary branches suggest that LCNs may also form short and long propriospinal connections. We also found that the distribution of axon varicosities and terminal field locations show substantial heterogeneity and that a substantial portion of LCNs is inhibitory. Our observations indicate that LCNs of lamina I form intersegmental as well as interlaminar connections and may govern large numbers of neurons, providing anatomical substrate for rostrocaudal “processing units” in the dorsal horn

A synaptic nidogen: developmental regulation and role of nidogen-2 at the neuromuscular junction

Background: The skeletal neuromuscular junction is a useful model for elucidating mechanisms that regulate synaptogenesis. Developmentally important intercellular interactions at the neuromuscular junction are mediated by the synaptic portion of a basal lamina that completely ensheaths each muscle fiber. Basal laminas in general are composed of four main types of glycosylated proteins: laminins, collagens IV, heparan sulfate proteoglycans and nidogens (entactins). The portion of the muscle fiber basal lamina that passes between the motor nerve terminal and postsynaptic membrane has been shown to bear distinct isoforms of the first three of these. For laminins and collagens IV, the proteins are deposited by the muscle; a synaptic proteoglycan, z-agrin, is deposited by the nerve. In each case, the synaptic isoform plays key roles in organizing the neuromuscular junction. Here, we analyze the fourth family, composed of nidogen-1 and -2.Results: In adult muscle, nidogen-1 is present throughout muscle fiber basal lamina, while nidogen- 2 is concentrated at synapses. Nidogen-2 is initially present throughout muscle basal lamina, but is lost from extrasynaptic regions during the first three postnatal weeks. Neuromuscular junctions in mutant mice lacking nidogen-2 appear normal at birth, but become topologically abnormal as they mature. Synaptic laminins, collagens IV and heparan sulfate proteoglycans persist in the absence of nidogen-2, suggesting the phenotype is not secondary to a general defect in the integrity of synaptic basal lamina. Further genetic studies suggest that synaptic localization of each of the four families of synaptic basal lamina components is independent of the other three.Conclusion: All four core components of the basal lamina have synaptically enriched isoforms. Together, they form a highly specialized synaptic cleft material. Individually, they play distinct roles in the formation, maturation and maintenance of the neuromuscular junction

AGE-modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival

Biomechanical strain imposed by age-related thickening of the basal lamina and augmented tissue stiffness in the prostate gland coincides with increased cancer risk. Here we hypothesized that the structural alterations in the basal lamina associated with age can induce mechanotransduction pathways in prostate epithelial cells (PECs) to promote invasiveness and cancer progression. To demonstrate this, we developed a 3D model of PEC acini in which thickening and stiffening of basal lamina matrix was induced by advanced glycation end-product (AGE)-dependent non-enzymatic crosslinking of its major components, collagen IV and laminin. We used this model to demonstrate that antibody targeted blockade of CTLD2, the second of eight C-type lectin-like domains in Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) that can recognize glycosylated collagens, reversed actinomyosin-based contractility [myosin-light chain-2 (MLC2) phosphorylation], loss of cell polarity, loss of cell–cell junctions, luminal infiltration and basal invasion induced by AGE-modified basal lamina matrix in PEC acini. Our in vitro results were concordant with luminal occlusion of acini in the prostate glands of adult Endo180ΔEx2–6/ΔEx2–6 mice, with constitutively exposed CTLD2 and decreased survival of men with early (non-invasive) prostate cancer with high epithelial Endo180 expression and levels of AGE. These findings indicate that AGE-dependent modification of the basal lamina induces invasive behaviour in non-transformed PECs via a molecular mechanism linked to cancer progression. This study provides a rationale for targeting CTLD2 in Endo180 in prostate cancer and other pathologies in which increased basal lamina thickness and tissue stiffness are driving factors

IMPLEMENTASI PEMBELAJARAN MODEL ASSURE BERBASIS PROBLEM BASED LEARNING UNTUK MENINGKATKAN HASIL BELAJAR MATEMATIKA KURIKULUM MERDEKA PESERTA DIDIK KELAS I SDN NGAGLIK 01 BATU

This study aims to produce a valid, practical, and effective ASSURE model learning design to improve learning outcomes in the independent curriculum mathematics learning on the topic "Build Space" class I Elementary School. The learning design developed is in the form of a Teaching Module. The subjects of this study were first grade students at SDN Ngaglik 01 Batu. The ASSURE steps are: Analyze learners (analyze students), State standards and objectives (formulate standards and learning objectives), Select Strategies and resources (choose strategies and learning resources), Utilize resources (utilize learning resources), Require learner participation (participation students in learning), as well as Evaluate and revise (assess and revise learning). Based on the trial results, the average number of pre-cycle stages was 42.8%. The results of the research show that the learning design through Problem-Based Learning can improve student learning outcomes. The average value of learning outcomes has increased in the first cycle of mastery learning outcomes reaching 71.6% while in the second cycle, the learning outcomes of students reach 85.2%. This increase proves that the Problem-Based Learning model can improve student learning outcomes in Construct Space material

Weaving a pattern from disparate threads: lamin function in nuclear assembly and DNA replication

The major residual structure that remains associated with the nuclear envelope following extraction of isolated nuclei or oocyte germinal vesicles with non-ionic detergents, nucleases and high salt is the lamina (Fawcett, 1966; Aaronson and Blobel, 1975; Dwyer and Blobel, 1976). The nuclear lamina is composed of intermediate filament proteins, termed lamins (Gerace and Blobel, 1980; Shelton et al., 1980), which polymerise to form a basket-weave lattice of fibrils, which covers the entire inner surface of the nuclear envelope and interlinks nuclear pores (Aebi et al., 1986; Stewart and Whytock, 1988; Goldberg and Allen, 1992). At mitosis, the nuclear envelope and the lamina both break down to allow chromosome segregation. As a consequence, each structure has to be rebuilt during anaphase and telophase, allowing cells an opportunity to reposition chromosomes (Heslop-Harrison and Bennett, 1990) and to reorganise looped chromatin domains (Franke, 1974; Franke et al., 1981; Hochstrasser et al., 1986), which may in turn control the use of subsets of genes. Because of the position that it occupies, its dynamics during mitosis and the fact that it is an essential component of proliferating cells, the lamina has been assigned a number of putative roles both in nuclear metabolism and in nuclear envelope assembly (Burke and Gerace, 1986; Nigg, 1989). However, to date there is little clear cut evidence that satisfactorily explains the function of the lamina in relation to its structure. In this Commentary we will describe some of the recent work that addresses this problem and attempt to provide a unified model for the role of lamins in nuclear envelope assembly and for the lamina in the initiation of DNA replication

Prevalence and determinants of unintended pregnancy among women in south-western Nigeria

Objective: To study the prevalence of unwanted pregnancy in urban and rural settlements in Southwestern Nigeria.Design: A prospective cross-sectional study of women within reproductive age.Setting: Community-based study of unwanted pregnancy was conducted in 2012.Participants: They were women of reproductive age who had experienced unintended and/or unwanted pregnancies and they were randomly selected from rural and urban areas of Ogun state in Nigeria.Intervention: A semi-structured questionnaire was used for data collection.Main outcome measure: The prevalence of unintended/ unwanted pregnancy, associated factors including the views, perception and attitudes of community members in both urban and rural settlements and the pattern of help-seeking behavior on the problem.Results: The age range of respondents was 15-48 years (mean age 31.2± 6.7 years). One thousand, two hundred and twenty-one (51.6%) of the respondents were married. The percentage of illiterate respondents was 3.5% in urban area and 4.1% in rural area. There was a statistically significant association between level of education and use of a method to avoid or delay pregnancy (p <0.001). The prevalence of unintended pregnancy was 35.9% while that of induced abortion was 33.5%. Quality of service was the most important factor in the choice of a place for pregnancy termination in urban and rural areas. Economic reasons were often cited as reasons women make use of abortion services.Conclusion: Unwanted pregnancy constitutes a problem, even at the community level. The high contraceptive awareness should be translated to an increased use so as to bridge the large gap of unmet need.Keywords: Unintended pregnancy; induced abortion; determinants; contraception; urban area; rural area; Nigeri