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This pilot study examined the use of early HbA1c in screening for gestational diabetes mellitus and adverse pregnancy outcomes in Singapore. One hundred and fifty-one pregnant women with a gestational age of under 14 weeks had an HbA1c test measured with their antenatal bloods prior to a second trimester oral glucose tolerance test. Patient characteristics and pregnancy outcome data were collected. Gestational diabetes mellitus prevalence was 11%. A receiver operating characteristic curve showed an HbA1c level of 5.2% (33 mmol/mol), had an 82% sensitivity, 72% specificity, 97% negative predictive value and 27% positive predictive value to predict gestational diabetes mellitus. Women with HbA1c of 5.2% (33 mmol/mol) or over 5.2% (33 mmol/mol) were older, had higher BMI and were less likely to be Chinese than those with HbA1c less than 5.2% (33 mmol/mol). There was no difference in pregnancy outcomes. Early HbA1c less than 5.2% (33 mmol/mol) may be useful to exclude low-risk Singaporean women from further testing, while those with HbA1c of 5.2% (33 mmol/mol) or greater would still need a oral glucose tolerance test between 24 and 28 weeks' gestation. [ABSTRACT FROM AUTHOR]

Objective: We previously described a technique for repair of the myometrial defect at repeat Caesarean section which increases residual myometrial thickness thereby potentially reducing future niche-related complications. Here we describe how this technique can be modified for use for placenta accreta spectrum disorders, in line with emerging evidence that this is more a disorder of myometrial deficiency than morbid adherence. Design: The surgical performance of peripartum hysterectomy was compared with that of the modified technique in all women having repeat Caesarean delivery for placenta accreta spectrum disorder in a tertiary unit in Singapore between December 2019 and October 2021. Methods: Modification of the original technique involved the systematic delivery of the placenta starting from its most posterior attachment after uterine exteriorization. This is followed by the identification, mobilization, and apposition of the boundaries of myometrial defects as described previously. Results: Ten women had Caesarean hysterectomy and ten had Caesarean section using the modified approach. Age and gestational age at delivery were similar for the two groups. Women in the modified technique group had had fewer prior Caesarean sections and had a lower body mass index. Operating time, estimated blood loss and need for transfusion were all lower in the myometrial repair group but without statistical significance. There were no visceral injuries in the repair group but there was one bladder injury in the hysterectomy group. Conclusion: The modified approach provides an effective alternative to peripartum hysterectomy with favourable surgical profile and allows uterine conservation with restoration of myometrial thickness. [ABSTRACT FROM AUTHOR]

Time for reflective thought is constricted in busy academic lives, with available thinking time focused on urgent, analytical inquiry. Paradoxically, time spent in contemplative mindfulness, stepping back from insistent probing into a still, calm space, may allow increased clarity and focus on problems worthy of inquiry, once re-engaged. This paper highlights the dual dimension of reflection captured in the concept of ‘mindful inquiry’ as a dialectic interchange between active critical inquiry and receptive open mindfulness. In the focus on robust critique in contemporary higher education, the value of contemplation is lost. Insights from Western and Eastern philosophy, as well as evidence from empirical research, suggest an integrated approach may allow alternative, creative and intuitive ways of approaching problems to supplement rational, problem solving strategies. The practice of ‘mindful inquiry’ also offers a practical tool, to enhance academic wellbeing as well as help prepare students for participation in life beyond university. [ABSTRACT FROM AUTHOR]

Background: Disruption of synaptic connectivity is a significant early event in many neurodegenerative conditions affecting the aging CNS, including Alzheimer's disease and Parkinson's disease. Therapeutic approaches that protect synapses from degeneration in the aging brain offer the potential to slow or halt the progression of such conditions. A range of animal models expressing the slow Wallerian Degeneration (WldS) gene show robust neuroprotection of synapses and axons from a wide variety of traumatic and genetic neurodegenerative stimuli in both the central and peripheral nervous systems, raising that possibility that WldS may be useful as a neuroprotective agent in diseases with synaptic pathology. However, previous studies of neuromuscular junctions revealed significant negative effects of increasing age and positive effects of gene-dose on WldS-mediated synaptic protection in the peripheral nervous system, raising doubts as to whether WldS is capable of directly conferring synapse protection in the aging brain. Methodology/Principal Findings: We examined the influence of age and gene-dose on synaptic protection in the brain of mice expressing the WldS gene using an established cortical lesion model to induce synaptic degeneration in the striatum. Synaptic protection was found to be sensitive to WldS gene-dose, with heterozygous WldS mice showing approximately half the level of protection observed in homozygous WldS mice. Increasing age had no influence on levels of synaptic protection. In contrast to previous findings in the periphery, synapses in the brain of old WldS mice were just as strongly protected as those in young mice. Conclusions/Significance: Our study demonstrates that WldS-mediated synaptic protection in the CNS occurs independently of age, but is sensitive to gene dose. This suggests that the WldS gene, and in particular its downstream endogenous effector pathways, may be potentially useful therapeutic agents for conferring synaptic protection in the aging brain. [ABSTRACT FROM AUTHOR]

Continuing to learn is universally accepted and expected by professionals and other stakeholders across all professions. However despite changes in response to research findings about how professionals learn, many professional development practices still focus on delivering content rather than enhancing learning. In exploring reasons for the continuation of didactic practices in professional development, this article critiques the usual conceptualization of professional development through a review of recent literature across professions. An alternative conceptualization is proposed, based on philosophical assumptions congruent with evidence about professional learning from seminal educational research of the past two decades. An argument is presented for a shift in discourse and focus from delivering and evaluating professional development programs to understanding and supporting authentic professional learning. [ABSTRACT FROM AUTHOR]

Abstract: A progressive model of Parkinson''s disease has been recently developed in the rat where a unilateral excitotoxic injection into the globus pallidus leads to a gradual loss of dopaminergic neurons in the ipsilateral substantia nigra over a period of at least 6 weeks. In this model microglial activation is observed in the ipsilateral substantia nigra 3 weeks after the lesion and could contribute to neuronal death at this time. The immunosuppressant drug tacrolimus (FK506) reduces dopamine cell death at 3 weeks following a globus pallidus lesion, but not thereafter. Tacrolimus-mediated neuroprotection could result from suppression of microglial activation but the microglial activation at three weeks post-lesion was not much reduced. Microglial activation was observed even in the apparent absence of neuronal death, prompting the suggestion that tacrolimus may prevent, or at least delay, the release of toxic cytokines from activated microglia. By 6 weeks after the GP lesion, even this mechanism fails to protect the dopamine cells from damage. [Copyright &y& Elsevier]

The article discusses strategies to assess students' understanding prior and during the use of instructional tools for probing biology. Determination of prior knowledge of students will help the teacher customize lessons to improve student learning. One strategy is to engage students in dialogue. The goal of teaching science should be to help all students establish a more correct basic understanding of scientific issues they will encounter. Meeting the needs of students prior to adoption of instructional innovation are expected of teachers.

Discusses the contradiction between teachers instructional goals and their assessment strategies. Methods in using effectively any assessment methods; Importance of assessments; Type of assessments.

Presents a directed case study method for teaching human anatomy and physiology. Case analysis; Student performance and response; Study exam scores; Multiple choice questions.

Describes a directed case study method for teaching human anatomy and physiology in the United States. Learning objectives; Case scenario; Didactic questions; Availability of information to answer case questions.

This article discusses the complications that can arise from a previous caesarean section, specifically focusing on the caesarean scar defect. It emphasizes the importance of recognizing and managing these complications, as they can occur even after a successful vaginal birth after caesarean section. The article describes the anatomical changes of the caesarean scar defect and its relationship with placenta accrete spectrum disorder. It also addresses the management of these complications during pregnancy, including a technique for myometrial uterine repair. The article provides case studies to demonstrate how knowledge of scar anatomy can be used to manage complications related to the caesarean scar defect. The authors suggest the potential benefit of dedicated teams in Obstetrics and Gynecology departments to manage scar complications and improve outcomes. [Extracted from the article]

The dynamics of oxygen transport by the blood can be a particularly difficult topic for students to grasp. A directed case study about carbon monoxide poisoning was designed to help deepen student understanding of the solution chemistry of the oxygen-hemoglobin reaction and the role that hemoglobin plays in external respiration. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness of tranexamic acid (TXA) in reducing blood loss during elective caesarean sections in women with and without risk factors for postpartum haemorrhage (PPH). Design: A double‐blind, randomised placebo‐controlled trial. Setting: An academic tertiary referral centre in Singapore. Population: Multiethnic women aged 21 years or older undergoing elective caesarean section. Methods: Randomisation to intravenous TXA or normal saline (placebo) 10 minutes before skin incision. Main outcome measures: Calculated estimated blood loss (cEBL), derived from blood volume and haematocrit levels. Results: Between June 2020 and October 2021, 200 women were randomised to the placebo or TXA groups. Women who received prophylactic TXA had a significantly lower mean cEBL compared with those receiving placebo (adjusted mean difference −126.4 mL, 95% CI −243.7 to −9.1, p = 0.035). The effect was greatest in those at high risk for PPH, with a reduction in cEBL (mean difference −279.6 mL, 95% CI −454.8 to −104.3, p = 0.002) and a lower risk of cEBL ≥500 mL (risk ratio [RR] 0.54, 95% CI 0.36–0.83, p = 0.007) and cEBL ≥1000 mL (RR 0.44, 95% CI 0.20–0.98, p = 0.016). Subgroup analysis showed benefit for women with preoperative haemoglobin <10.5 g/dL (mean difference −281.9 mL, 95% CI −515.0 to −48.8, p = 0.019). There was no significant difference in need for additional medical or surgical interventions. There were no maternal or neonatal adverse outcomes. Conclusion: Prophylactic TXA should be considered in women with risk factors for PPH, and those most likely to benefit are those with preoperative haemoglobin <10.5 g/dL. [ABSTRACT FROM AUTHOR]

Details a student poetry contest as a learning tool in the teaching of undergraduate course in human anatomy and physiology. Mechanics of the contest; Topics used in the poetry contest; Reasons why the concept of writing poetry about physiology appeals to students. INSETS: The Spleen.;poem by Elaina Hayes.

A second National Science Foundation-sponsored workshop on Conceptual Assessment in Biology was held in January 2008. Reports prepared for the workshop revealed that research groups working in a variety of biological sciences are continuing to develop conceptual assessment instruments for use in the classroom. Discussions at this meeting largely focused on two issues: 1) the utility of the backwards design approach of Wiggins and McTighe (11), in which identification of learning outcomes (determining what to assess) lies at the beginning of course design; and 2) the utility of defining expected learning outcomes as the building of runable mental models (and designing conceptual assessments that would test the correctness of these mental models). A third meeting is being planned that will focus on the processes involved in writing and validating conceptual assessment instruments. [ABSTRACT FROM AUTHOR]

Background: To investigate whether the existing surgical technique for uterine closure at repeat lower segment Caesarean section (LSCS) can be modified to achieve adequate residual myometrial thickness (RMT) to ensure scar integrity and reduce complications in future pregnancy.Methods: Women with a significant scar defect at repeat LSCS had the anterior uterine wall closed by a single experienced obstetrician with a technique focused on recognition, mobilisation and apposition of the retracted myometrial edges at the boundary of the defect. This was aimed at anatomical restoration of the lower segment. The RMT at the scar area was assessed by postnatal pelvic ultrasound scan at three months.Results: Thirty women with a history of at least one previous CS, incidentally found to have a large defect at operation underwent the technique with prior consent. A postnatal scan showed a mean residual myometrial thickness of 8.4 mm (SD ±1.3 mm; range 5.6-11.0 mm). The average operating time was 91 mins and the average blood loss 728 ml. Two women who underwent the repair have gone on to have a further uneventful CS.Conclusion: This modified technique resulted in scan evidence of an RMT indicative of uterine wall stability postnatally and offers the potential for reducing the risk of rupture and placenta accreta spectrum (PAS) in future pregnancy. [ABSTRACT FROM AUTHOR]

Aims: We investigated which patients with heart failure (HF) should receive specialist palliative care (SPC) by first creating a definition of need for SPC in patients hospitalised with HF using patient-reported outcome measures (PROMs) and then testing this definition using the outcome of days alive and out of hospital (DAOH). We also evaluated which baseline variables predicted need for SPC and whether those with this need received SPC.Methods and Results: PROMs assessing quality of life (QoL), symptoms, and mood were administered at baseline and every 4 months. SPC need was defined as persistently severe impairment of any PROM without improvement (or severe impairment immediately preceding death). We then tested whether need for SPC, so defined, was reflected in DAOH, a measure which combines length of stay, days of hospital re-admission, and days lost due to death. Of 272 patients recruited, 74 (27%) met the definition of SPC needs. These patients lived one third fewer DAOH than those without SPC need (and less than a quarter of QoL-adjusted DAOH). A Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score of <29 identified patients who subsequently had SPC needs (area under receiver operating characteristic curve 0.78). Twenty-four per cent of patients with SPC needs actually received SPC (n = 18).Conclusions: A quarter of patients hospitalised with HF had a need for SPC and were identified by a low KCCQ score on admission. Those with SPC need spent many fewer DAOH and their DAOH were of significantly worse quality. Very few patients with SPC needs accessed SPC services. [ABSTRACT FROM AUTHOR]

Abstract Medical device biocompatibility testing is used to evaluate the risk of adverse effects on tissues from exposure to leachates/extracts. A battery of tests is typically recommended in accordance with regulatory standards to determine if the device is biocompatible. In vitro cytotoxicity, a key element of the standards, is a required endpoint for all types of medical devices. Each validated cytotoxicity method has different methodology and acceptance criteria that could influence the selection of a specific test. In addition, some guidances are more specific than others as to the recommended test methods. For example, the International Organization for Standardization (ISO1) cites preference for quantitative methods (e.g., tetrazolium (MTT/XTT), neutral red (NR), or colony formation assays (CFA)) over qualitative methods (e.g., elution, agar overlay/diffusion, or direct), while a recent ISO standard for contact lens/lens care solutions specifically requires a qualitative direct test. Qualitative methods are described in United States Pharmacopeia (USP) while quantitative CFAs are listed in Japan guidance. The aim of this review is to compare the methodologies such as test article preparation, test conditions, and criteria for six cytotoxicity methods recommended in regulatory standards in order to inform decisions on which method(s) to select during the medical device safety evaluation. Highlights • Paper provides a comparison of cytotoxicity assays for medical devices to inform test selection decisions. • Quantitative cytotoxicity tests are preferred over qualitative methods. • Results are impacted by test article preparation, exposure times, test conditions, and criteria. • The choice of the methods is critical for results and success or failure of a product. • Results should be viewed in a full battery of biocompatibility tests to avoid false positive/negative classification. [ABSTRACT FROM AUTHOR]

We describe a new, quantitative, cytotoxicity method using mouse lymphoma L5178Y thymidine kinase +/− (TK) suspension cells for medical device safety assessment that has equivalent sensitivity, and greater efficiency compared to the colony formation assay (CFA) using adherent V79-4 cells. Assays were carried out in 24-well plates. TK cells were seeded on concave side of six types of contact lenses and cell growth rate after 72 h determined using the Vi-Cell XR. Five of six contact lenses studied demonstrated the same results between the TK and the CFA methods. One lens showed a difference between the CFA and TK suspension cell methods (79% colony formation rate vs. 17% cell growth rate). Although colony size is not a CFA test criterion, colonies were smaller than control indicating a cytotoxic effect that is reflected in the TK suspension cell assay which measures cell number. The mouse lymphoma TK suspension cell assay performs as well as the CFA direct contact method with distinct advantages. This quantitative, automated method is not susceptible to mechanical damage from test materials, does not depend on cell adherence to test materials and represents a valuable tool to evaluate medical device cytotoxicity. [ABSTRACT FROM AUTHOR]

We have created and validated a conceptual framework for the core physiology concept of “cell-cell communication.” The conceptual framework is composed of 51 items arranged in a hierarchy that is, in some instances, four levels deep. We have validated it with input from faculty who teach at a wide variety of institutional types. All items making up the framework were deemed essential to moderately important. However, some of the main ideas were clearly judged to be more important than others. Furthermore, the lower in the hierarchy an item is, the less important it is thought to be. Finally, there was no significant difference in the ratings given by faculty at different types of institutions. [ABSTRACT FROM AUTHOR]

A practical synthesis of capromorelin ( 1 ), a growth hormone secretagogue, is described that utilizes as a key step a crystallization-induced dynamic resolution (CIDR) of (±)-3a-benzyl-2-methyl-4,5,6,7-tetrahydro-2 H -pyrazolo[4,3- c ]pyridin-3(3aH)-one [(±)- 2 ] by L -tartaric acid salt formation, yielding ( R )- 2. L -tartaric acid in high chemical yield (>85%) and with diastereomeric excess (de) of ∼98%. Treatment of ( R )- 2. L -tartaric acid with ammonium hydroxide provided ( R )- 2 without loss of chiral purity. In situ generated ( R )- 2 was coupled with ( R )-3-(benzyloxy)-2-(2-( tert -butoxycarbonyl)-2-methylpropanamido)propanoic acid [( R )- 3 ] to give predominantly a single diastereomer of N -Boc-protected capromorelin [(1 R ,3a R )- 4 ]. This process was used to prepare bulk quantities of capromorelin from (±)- 2 to support preclinical toxicology studies. [ABSTRACT FROM AUTHOR]

We have developed and validated a conceptual framework for understanding and teaching organismal homeostasis at the undergraduate level. The resulting homeostasis conceptual framework details critical components and constituent ideas underlying the concept of homeostasis. It has been validated by a broad range of physiology faculty members from community colleges, primarily undergraduate institutions, research universities, and medical schools. In online surveys, faculty members confirmed the relevance of each item in the framework for undergraduate physiology and rated the importance and difficulty of each. The homeostasis conceptual framework was constructed as a guide for teaching and learning of this critical core concept in physiology, and it also paves the way for the development of a concept inventory for homeostasis. [ABSTRACT FROM AUTHOR]

Homeostasis is a core concept necessary for understanding the many regulatory mechanisms in physiology. Claude Bernard originally proposed the concept of the constancy of the “milieu interieur,” but his discussion was rather abstract. Walter Cannon introduced the term “homeostasis” and expanded Bernard’s notion of “constancy” of the internal environment in an explicit and concrete way. In the 1960s, homeostatic regulatory mechanisms in physiology began to be described as discrete processes following the application of engineering control system analysis to physiological systems. Unfortunately, many undergraduate texts continue to highlight abstract aspects of the concept rather than emphasizing a general model that can be specifically and comprehensively applied to all homeostatic mechanisms. As a result, students and instructors alike often fail to develop a clear, concise model with which to think about such systems. In this article, we present a standard model for homeostatic mechanisms to be used at the undergraduate level. We discuss common sources of confusion (“sticky points”) that arise from inconsistencies in vocabulary and illustrations found in popular undergraduate texts. Finally, we propose a simplified model and vocabulary set for helping undergraduate students build effective mental models of homeostatic regulation in physiological systems. [ABSTRACT FROM AUTHOR]

Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure–activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2–7.5 channel openers was explored. PF-05020182 ( 2 ) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 ( 2 ) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 ( 2 ) support further development as an adjunctive treatment of refractory epilepsy. [ABSTRACT FROM AUTHOR]

Introduction: Non-pathological, age-related cognitive decline varies markedly between individuals andplaces significant financial and emotional strain on people, their families and society as a whole. Understanding the differential age-related decline in brain function is critical not only for the development of therapeutics to prolong cognitive health into old age, but also to gain insight into pathological ageing suchas Alzheimer's disease. The Lothian Birth Cohort of 1936 (LBC1936) comprises a rare group of people forwhom there are childhood cognitive test scores and longitudinal cognitive data during older age, detailedstructural brain MRI, genome-wide genotyping, and a multitude of other biological, psycho-social, andepidemiological data. Synaptic integrity is a strong indicator of cognitive health in the human brain;however, until recently, it was prohibitively difficult to perform detailed analyses of synaptic and axonalstructure in human tissue sections. We have adapted a novel method of tissue preparation at autopsy toallow the study of human synapses from the LBC1936 cohort in unprecedented morphological andmolecular detail, using the high-resolution imaging techniques of array tomography and electronmicroscopy. This allows us to analyze the brain at sub-micron resolution to assess density, proteincomposition and health of synapses. Here we present data from the first donated LBC1936 brain andcompare our findings to Alzheimer's diseased tissue to highlight the differences between healthy andpathological brain ageing. Results: Our data indicates that compared to an Alzheimer's disease patient, the cognitively normalLBC1936 participant had a remarkable degree of preservation of synaptic structures. However, morphological and molecular markers of degeneration in areas of the brain associated with cognition(prefrontal cortex, anterior cingulate cortex, and superior temporal gyrus) were observed. Conclusions: Our novel post-mortem protocol facilitates high-resolution neuropathological analysis of the wellcharacterized LBC1936 cohort, extending phenotyping beyond cognition and in vivo imaging to nowinclude neuropathological changes, at the level of single synapses. This approach offers an unprecedentedopportunity to study synaptic and axonal integrity during ageing and how it contributes to differences in agerelatedcognitive change. [ABSTRACT FROM AUTHOR]

Purpose: To further improve in vitro models of the cornea, this study focused on the creation of a three-dimensional, stratified, curved epithelium; and the subsequent characterization and evaluation of its suitability as a model for biocompatibility testing. Methods: Immortalized human corneal epithelial cells were grown to confluency on curved cellulose filters for seven days, and were then differentiated and stratified using an air-liquid interface for seven days before testing. Varying concentrations of a commercial ophthalmic solution containing benzalkonium chloride (BAK), a known cytotoxic agent, and two relevant ocular surfactants were tested on the model. A whole balafilcon A lens soaked in phosphate buffered saline (BA PBS) was also used to assess biocompatibility and verify the validity of the model. Viability assays as well as flow cytometry were performed on the cells to investigate changes in cell death and integrin expression. Results: The reconstructed curved corneal epithelium was composed of 3–5 layers of cells. Increasing concentrations of BAK showed dose-dependent decreased cell viability and increased integrin expression and cell death. No significant change in viability was observed in the presence of the surfactants. As expected, the BA PBS combination appeared to be very biocompatible with no adverse change in cell viability or integrin expression. Conclusions: The stratified, curved, epithelial model proved to be sensitive to distinct changes in cytotoxicity and is suitable for continued assessment for biocompatibility testing of contact lenses. Our results showed that flow cytometry can provide a quantitative measure of the cell response to biomaterials or cytotoxic compounds for both the supernatant and adherent cell populations. As a specifically designed in vitro model of the corneal epithelium, this quantitative model for biocompatibility at the ocular surface may help improve our understanding of cell-material interactions and reduce the use of animal testing. [ABSTRACT FROM AUTHOR]

Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegen- eration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in the current study represent attractive targets for developing therapeutics aimed at modulating synaptic and axonal stability and neurodegeneration in vivo. [ABSTRACT FROM AUTHOR]

Cathepsin D (CTSD) deficiencies are fatal neurological diseases that in human infants and in sheep are characterized by extreme loss of neurons and myelin. To date, similar morphological evidence for myelin disruption in CTSD knockout mice has not been reported. Here, we show that CTSD deficiency leads to pronounced myelin changes in the murine brain: myelin-related proteolipid protein and myelin basic protein were both markedly reduced at postnatal day 24, and the amount of lipids characteristically high in myelin (e.g. plasmalogen-derived alkenyl chains and glycosphingolipid-derived 20- and 24-carbon acyl chains) were significantly lowered compared with controls. These changes were accompanied by ultrastructural alterations of myelin, including significant thinning of myelin sheaths. Furthermore, in CTSD knockout brains there was a pronounced accumulation of cholesteryl esters and abnormal levels of proteins related to cholesterol transport, with an increased content of apolipoprotein E and a reduced content of ATP-binding cassette transporter A1. These results provide evidence for dysmyelination and altered trafficking of cholesterol in brains of CTSD knockout mice, and warrant further studies on the role of lipid metabolism in the pathogenesis of CTSD deficiencies. [ABSTRACT FROM AUTHOR]

Abstract: Sulfonamides, exemplified by 3a, were identified as highly selective EP2 agonists. Lead optimization led to the identification of CP-533536, 7f, a potent and selective EP2 agonist. CP-533536 demonstrated the ability to heal fractures when administered locally as a single dose in rat models of fracture healing. [Copyright &y& Elsevier]