Synaptic vesicle clustering requires a distinct MIG-10/Lamellipodin isoform and ABI-1 downstream from Netrin

The chemotrophic factor Netrin can simultaneously instruct different neurodevelopmental programs in individual neurons in vivo. How neurons correctly interpret the Netrin signal and undergo the appropriate neurodevelopmental response is not understood. Here we identify MIG-10 isoforms as critical determinants of individual cellular responses to Netrin. We determined that distinct MIG-10 isoforms, varying only in their N-terminal motifs, can localize to specific subcellular domains and are differentially required for discrete neurodevelopmental processes in vivo. We identified MIG-10B as an isoform uniquely capable of localizing to presynaptic regions and instructing synaptic vesicle clustering in response to Netrin. MIG-10B interacts with Abl-interacting protein-1 (ABI-1)/Abi1, a component of the WAVE complex, to organize the actin cytoskeleton at presynaptic sites and instruct vesicle clustering through SNN-1/Synapsin. We identified a motif in the MIG-10B N-terminal domain that is required for its function and localization to presynaptic sites. With this motif, we engineered a dominant-negative MIG-10B construct that disrupts vesicle clustering and animal thermotaxis behavior when expressed in a single neuron in vivo. Our findings indicate that the unique N-terminal domains confer distinct MIG-10 isoforms with unique capabilities to localize to distinct subcellular compartments, organize the actin cytoskeleton at these sites, and instruct distinct Netrin-dependent neurodevelopmental programs.     

Systemic inflammation and blood–brain barrier abnormality in relapsing–remitting multiple sclerosis

Background

Systemic inflammation can affect disease expression in multiple sclerosis. The mechanism might involve blood–brain barrier disruption. We aimed to assess the effects of systemic inflammation on disease progression in multiple sclerosis and the role of blood–brain barrier disruption.

Investigating postmenopausal bleeding for endometrial cancer: cost-effectiveness of initial diagnostic strategies

OBJECTIVE: To determine the most cost-effective outpatient testing strategy for diagnosing endometrial cancer in women with postmenopausal bleeding (PMB). DESIGN: Decision analysis modelling. POPULATION: Women with postmenopausal bleeding. METHODS: A decision analytic model was constructed to reflect current service provision, which evaluated 12 diagnostic strategies using endometrial biopsy (EB), ultrasonography (USS) (4- and 5-mm endometrial thickness cutoff) and hysteroscopy. Diagnostic probability estimates were derived from systematic quantitative reviews, clinical outcomes from published literature and cost estimates from local and NHS sources. MAIN OUTCOME MEASURES: The cost per additional life year gained (pound/LYG) was determined and compared for each diagnostic strategy, and sensitivity analyses were performed. RESULTS: Compared with carrying out no initial investigation, a strategy based on initial diagnosis with USS using a 5-mm cutoff was the least expensive (11,470 pound/LYG). Initial investigation with EB or USS using a 4-mm cutoff was comparably cost-effective (less than 30,000 pound/LYG versus USS with a 5-mm cutoff) at their most favourable diagnostic performance and at disease prevalence of 10% or more. The strategies involving initial evaluation with test combinations or hysteroscopy alone were not cost-effective. CONCLUSIONS: Women presenting for the first time with PMB should undergo initial evaluation with USS or EB.     

Ovarian reserve tests for predicting fertility outcomes for assisted reproductive technology: the International Systematic Collaboration of Ovarian Reserve Evaluation protocol for a systematic review of ovarian reserve test accuracy

BACKGROUND: The presence of a wide range of tests of ovarian reserve suggests that no single test provides a sufficiently accurate result. Many tests are used without reference to an evidence base. So far, individual studies conducted on these tests are too small to give precise estimates of prognostic accuracy. OBJECTIVES: To systematically assess the accuracy of the available tests of ovarian reserve in terms of prediction of fertility outcomes. SEARCH STRATEGY: The search will be conducted using the name of the respective index test being studied (as listed on the MESH database), if more than 2000 citations are listed, 'ovary' and or 'ovarian', 'fertility' and or 'reserve' will be combined with the original search term as required. Studies of the accuracy of tests of ovarian reserve will be obtained without language restrictions from 1980 to 2005 using the following electronic databases and Ovid software: MEDLINE, EMBASE, PUBmed, Biological extracts, Pascal, Cochrane Library (CDSR, DARE, CCTR, HTA), Best Evidence databases, SCISEARCH, Conference Proceedings (ISI Proceedings, Healthstar, Current Contents, Science Citation Index, Cancerlit and Econlit and NHS Economic Evaluation database. The National Research Register, the Medical Research Council's Clinical Trials Register, MEDION, DARE, and the US Clinical Trials register. SELECTION CRITERIA: Studies will be selected if accuracy of tests are compared with a reference standard and include data that can be abstracted into a two-by-two table to calculate sensitivity and specificity. The studies to be included in this review will examine one of the following index 'tests' within a study population of women undergoing assisted reproductive technology: * Clinical variables--age, history of cancelled cycles. * Basal blood tests--follicle-stimulating hormone (FSH), lutenising hormone (LH), FSH:LH ratios, estradiol (E(2)), inhibin A and B, progesterone (P(4)), P(4):E(2) ratios, antimullerian hormone, testosterone, vascular endothelial growth factor, insulin-like growth factor-1:insulin-like growth factor binding protein-1 ratios. * Dynamic tests--clomiphene citrate challenge test, gonadotropin analogue stimulating test, exogenous FSH ovarian reserve test. * Ultrasound tests-antral follicle count, ovarian volume, ovarian stromal peak systolic velocity, including waveform and pulsatility index, ovarian follicular vascularity. * Histology--ovarian biopsy. Data collection and analysis Two independent reviewers will perform quality assessment and data extraction. Prognostic accuracy will be determined by calculating positive and negative likelihood ratios for the following outcomes or reference standards: live birth, ongoing pregnancy, clinical pregnancy, biochemical pregnancy, embryos available for transfer, eggs obtained at oocyte retrieval, cycles cancelled prior to oocyte retrieval. Main results and conclusions N/A.     

Running hot and cold: behavioral strategies, neural circuits, and the molecular machinery for thermotaxis in C. elegans and Drosophila

Like other ectotherms, the roundworm Caenorhabditis elegans and the fruit fly Drosophila melanogaster rely on behavioral strategies to stabilize their body temperature. Both animals use specialized sensory neurons to detect small changes in temperature, and the activity of these thermosensors governs the neural circuits that control migration and accumulation at preferred temperatures. Despite these similarities, the underlying molecular, neuronal, and computational mechanisms responsible for thermotaxis are distinct in these organisms. Here, we discuss the role of thermosensation in the development and survival of C. elegans and Drosophila, and review the behavioral strategies, neuronal circuits, and molecular networks responsible for thermotaxis behavior.     

Olfactory behavior of swimming C. elegans analyzed by measuring motile responses to temporal variations of odorants

Caenorhabditis elegans responds to chemical cues using a small number of chemosensory neurons that detect a large variety of molecules in its environment. During chemotaxis, C. elegans biases its migration in spatial chemical gradients by lengthening (/shortening) periods of forward movement when it happens to be moving toward (/away) from preferred locations. In classical assays of chemotactic behavior, a group of crawling worms is placed on an agar plate containing a point source of chemical, the group is allowed to navigate for a period of time, and aggregation of worms near the source is quantified. Here we show that swimming worms exhibit acute motile responses to temporal variations of odor in their surrounding environment, allowing our development of an automated assay of chemotactic behavior with single-animal resolution. By placing individual worms in small microdroplets and quantifying their movements as they respond to the addition and removal of odorized airstreams, we show that the sensorimotor phenotypes of swimming worms (wild-type behavior, the effects of certain mutations, and the effects of laser ablation of specific olfactory neurons) are consistent with aggregation phenotypes previously obtained in crawling assays. The microdroplet swimming assay has certain advantages over crawling assays, including flexibility and precision in defining the stimulus waveform and automated quantification of motor response during stimulus presentation. In this study, we use the microdroplet assay to quantify the temporal dynamics of the olfactory response, the sensitivity to odorant concentration, combinations, and gradients, and the contribution of specific olfactory neurons to overall behavior.     

Hydrosalpinx and pregnancy loss: a systematic review and meta-analysis

Research question

What is the association between hydrosalpinx and pregnancy loss and the effects of treatment for hydrosalpinx?

Bias associated with delayed verification in test accuracy studies: accuracy of tests for endometrial hyperplasia may be much higher than we think!

Background

To empirically evaluate bias in estimation of accuracy associated with delay in verification of diagnosis among studies evaluating tests for predicting endometrial hyperplasia.

Methods

Systematic reviews of all published research on accuracy of miniature endometrial biopsy and endometr ial ultrasonography for diagnosing endometrial hyperplasia identified 27 test accuracy studies (2,982 subjects). Of these, 16 had immediate histological verification of diagnosis while 11 had verification delayed > 24 hrs after testing. The effect of delay in verification of diagnosis on estimates of accuracy was evaluated using meta-regression with diagnostic odds ratio (dOR) as the accuracy measure. This analysis was adjusted for study quality and type of test (miniature endometrial biopsy or endometrial ultrasound).

Results

Compared to studies with immediate verification of diagnosis (dOR 67.2, 95% CI 21.7–208.8), those with delayed verification (dOR 16.2, 95% CI 8.6–30.5) underestimated the diagnostic accuracy by 74% (95% CI 7%–99%; P value = 0.048).

Conclusion

Among studies of miniature endometrial biopsy and endometrial ultrasound, diagnostic accuracy is considerably underestimated if there is a delay in histological verification of diagnosis.