Topographical and cell type-specific connectivity of rostral and caudal forelimb corticospinal neuron populations.

Corticospinal neurons (CSNs) synapse directly on spinal neurons, a diverse assortment of cells with unique structural and functional properties necessary for body movements. CSNs modulating forelimb behavior fractionate into caudal forelimb area (CFA) and rostral forelimb area (RFA) motor cortical populations. Despite their prominence, the full diversity of spinal neurons targeted by CFA and RFA CSNs is uncharted. Here, we use anatomical and RNA sequencing methods to show that CSNs synapse onto a remarkably selective group of spinal cell types, favoring inhibitory populations that regulate motoneuron activity and gate sensory feedback. CFA and RFA CSNs target similar spinal neuron types, with notable exceptions that suggest that these populations differ in how they influence behavior. Finally, axon collaterals of CFA and RFA CSNs target similar brain regions yet receive highly divergent inputs. These results detail the rules of CSN connectivity throughout the brain and spinal cord for two regions critical for forelimb behavior.

Topographical and cell type-specific connectivity of rostral and caudal forelimb corticospinal neuron populations.

Corticospinal neurons (CSNs) synapse directly on spinal neurons, a diverse group of neurons with unique structural and functional properties necessary for body movements. CSNs modulating forelimb behavior fractionate into caudal forelimb area (CFA) and rostral forelimb area (RFA) motor cortical populations. Despite their prominence, no studies have mapped the diversity of spinal cell types targeted by CSNs, let alone compare CFA and RFA populations. Here we use anatomical and RNA-sequencing methods to show that CSNs synapse onto a remarkably selective group of spinal cell types, favoring inhibitory populations that regulate motoneuron activity and gate sensory feedback. CFA and RFA CSNs target similar spinal cell types, with notable exceptions that suggest these populations differ in how they influence behavior. Finally, axon collaterals of CFA and RFA CSNs target similar brain regions yet receive surprisingly divergent inputs. These results detail the rules of CSN connectivity throughout the brain and spinal cord for two regions critical for forelimb behavior.

Towards Cell and Subtype Resolved Functional Organization: Mouse as a Model for the Cortical Control of Movement.

Despite a long history of interrogation, the functional organization of motor cortex remains obscure. A major barrier has been the inability to measure and perturb activity with sufficient resolution to reveal clear functional elements within motor cortex and its associated circuits. Increasingly, the mouse has been employed as a model to facilitate application of contemporary approaches with the potential to surmount this barrier. In this brief essay, we consider these approaches and their use in the context of studies aimed at resolving the logic of motor cortical operation.

New insights into the evolutionary origins of the recombination-activating gene proteins and V(D)J recombination.

The adaptive immune system of jawed vertebrates relies on V(D)J recombination as one of the main processes to generate the diverse array of receptors necessary for the recognition of a wide range of pathogens. The DNA cleavage reaction necessary for the assembly of the antigen receptor genes from an array of potential gene segments is mediated by the recombination-activating gene proteins RAG1 and RAG2. The RAG proteins have been proposed to originate from a transposable element (TE) as they share mechanistic and structural similarities with several families of transposases and are themselves capable of mediating transposition. A number of RAG-like proteins and TEs with sequence similarity to RAG1 and RAG2 have been identified, but only recently has their function begun to be characterized, revealing mechanistic links to the vertebrate RAGs. Of particular significance is the discovery of ProtoRAG, a transposon superfamily found in the genome of the basal chordate amphioxus. ProtoRAG has many of the sequence and mechanistic features predicted for the ancestral RAG transposon and is likely to be an evolutionary relative of RAG1 and RAG2. In addition, early observations suggesting that RAG1 is able to mediate V(D)J recombination in the absence of RAG2 have been confirmed, implying independent evolutionary origins for the two RAG genes. Here, recent progress in identifying and characterizing RAG-like proteins and the TEs that encode them is summarized and a refined model for the evolution of V(D)J recombination and the RAG proteins is presented.

INNOVATE: A prospective cohort study combining serum and urinary biomarkers with novel diffusion-weighted magnetic resonance imaging for the prediction and characterization of prostate cancer.

BACKGROUND: Whilst multi-parametric magnetic resonance imaging (mp-MRI) has been a significant advance in the diagnosis of prostate cancer, scanning all patients with elevated prostate specific antigen (PSA) levels is considered too costly for widespread National Health Service (NHS) use, as the predictive value of PSA levels for significant disease is poor. Despite the fact that novel blood and urine tests are available which may predict aggressive disease better than PSA, they are not routinely employed due to a lack of clinical validity studies. Furthermore approximately 40 % of mp-MRI studies are reported as indeterminate, which can lead to repeat examinations or unnecessary biopsy with associated patient anxiety, discomfort, risk and additional costs. METHODS/DESIGN: We aim to clinically validate a panel of minimally invasive promising blood and urine biomarkers, to better select patients that will benefit from a multiparametric prostate MRI. We will then test whether the performance of the mp-MRI can be improved by the addition of an advanced diffusion-weighted MRI technique, which uses a biophysical model to characterise tissue microstructure called VERDICT; Vascular and Extracellular Restricted Diffusion for Cytometry in Tumours. INNOVATE is a prospective single centre cohort study in 365 patients. mp-MRI will act as the reference standard for the biomarker panel. A clinical outcome based reference standard based on biopsy, mp-MRI and follow-up will be used for VERDICT MRI. DISCUSSION: We expect the combined effect of biomarkers and VERDICT MRI will improve care by better detecting aggressive prostate cancer early and make mp-MRI before biopsy economically viable for universal NHS adoption. TRIAL REGISTRATION: INNOVATE is registered on ClinicalTrials.gov, with reference NCT02689271 .

Collaboration of RAG2 with RAG1-like proteins during the evolution of V(D)J recombination.

The recombination-activating gene 1 (RAG1) and RAG2 proteins initiate V(D)J recombination, the process that assembles the B- and T-lymphocyte antigen receptor genes of jawed vertebrates. RAG1 and RAG2 are thought to have arisen from a transposable element, but the origins of this element are not understood. We show that two ancestral RAG1 proteins, Transib transposase and purple sea urchin RAG1-like, have a latent ability to initiate V(D)J recombination when coexpressed with RAG2 and that in vitro transposition by Transib transposase is stimulated by RAG2. Conversely, we report low levels of V(D)J recombination by RAG1 in the absence of RAG2. Recombination by RAG1 alone differs from canonical V(D)J recombination in having lost the requirement for asymmetric DNA substrates, implicating RAG2 in the origins of the "12/23 rule," a fundamental regulatory feature of the reaction. We propose that evolution of RAG1/RAG2 began with a Transib transposon whose intrinsic recombination activity was enhanced by capture of an ancestral RAG2, allowing for the development of adaptive immunity.

Relationship between self-discrepancy and worries about penis size in men with body dysmorphic disorder.

We explored self-discrepancy in men with body dysmorphic disorder (BDD) concerned about penis size, men without BDD but anxious about penis size, and controls. Men with BDD (n=26) were compared to those with small penis anxiety (SPA; n=31) and controls (n=33), objectively (by measuring) and investigating self-discrepancy: actual size, ideal size, and size they felt they should be according to self and other. Most men under-estimated their penis size, with the BDD group showing the greatest discrepancy between perceived and ideal size. The SPA group showed a larger discrepancy than controls. This was replicated for the perceptions of others, suggesting the BDD group internalised the belief that they should have a larger penis size. There was a significant correlation between symptoms of BDD and this discrepancy. This self-actual and self-ideal/self-should discrepancy and the role of comparing could be targeted in therapy.

Defining the learning curve for multiparametric magnetic resonance imaging (MRI) of the prostate using MRI-transrectal ultrasonography (TRUS) fusion-guided transperineal prostate biopsies as a validation tool.

OBJECTIVES: To determine the accuracy of multiparametric magnetic resonance imaging (mpMRI) during the learning curve of radiologists using MRI targeted, transrectal ultrasonography (TRUS) guided transperineal fusion biopsy (MTTP) for validation. PATIENTS AND METHODS: Prospective data on 340 men who underwent mpMRI (T2-weighted and diffusion-weighted MRI) followed by MTTP prostate biopsy, was collected according to Ginsburg Study Group and Standards for Reporting of Diagnostic Accuracy standards. MRI data were reported by two experienced radiologists and scored on a Likert scale. Biopsies were performed by consultant urologists not 'blinded' to the MRI result and men had both targeted and systematic sector biopsies, which were reviewed by a dedicated uropathologist. The cohorts were divided into groups representing five consecutive time intervals in the study. Sensitivity and specificity of positive MRI reports, prostate cancer detection by positive MRI, distribution of significant Gleason score and negative MRI with false negative for prostate cancer were calculated. Data were sequentially analysed and the learning curve was determined by comparing the first and last group. RESULTS: We detected a positive mpMRI in 64 patients from Group A (91%) and 52 patients from Group E (74%). The prostate cancer detection rate on mpMRI increased from 42% (27/64) in Group A to 81% (42/52) in Group E (P < 0.001). The prostate cancer detection rate by targeted biopsy increased from 27% (17/64) in Group A to 63% (33/52) in Group E (P < 0.001). The negative predictive value of MRI for significant cancer (>Gleason 3+3) was 88.9% in Group E compared with 66.6% in Group A. CONCLUSION: We demonstrate an improvement in detection of prostate cancer for MRI reporting over time, suggesting a learning curve for the technique. With an improved negative predictive value for significant cancer, decision for biopsy should be based on patient/surgeon factors and risk attributes alongside the MRI findings.

Penile Dysmorphic Disorder: Development of a Screening Scale.

Penile dysmorphic disorder (PDD) is shorthand for men diagnosed with body dysmorphic disorder, in whom the size or shape of the penis is their main, if not their exclusive, preoccupation causing significant shame or handicap. There are no specific measures for identifying men with PDD compared to men who are anxious about the size of their penis but do not have PDD. Such a measure might be helpful for treatment planning, reducing unrealistic expectations, and measuring outcome after any psychological or physical intervention. Our aim was, therefore, to validate a specific measure, termed the Cosmetic Procedure Screening Scale for PDD (COPS-P). Eighty-one male participants were divided into three groups: a PDD group (n = 21), a small penis anxiety group (n = 37), and a control group (n = 23). All participants completed the COPS-P as well as standardized measures of depression, anxiety, social phobia, body image, quality of life, and erectile function. Penis size was also measured. The final COPS-P was based on nine items. The scale had good internal reliability and significant convergent validity with measures of related constructs. It discriminated between the PDD group, the small penis anxiety group, and the control group. This is the first study to develop a scale able to discriminate between those with PDD and men anxious about their size who did not have PDD. Clinicians and researchers may use the scale as part of an assessment for men presenting with anxiety about penis size and as an audit or outcome measure after any intervention for this population.

Phenomenology of men with body dysmorphic disorder concerning penis size compared to men anxious about their penis size and to men without concerns: a cohort study.

Men with body dysmorphic disorder (BDD) may be preoccupied with the size or shape of the penis, which may be causing significant shame or impairment. Little is known about the characteristics and phenomenology of such men and whether they can be differentiated from men with small penis anxiety (SPA) (who do not have BDD), and men with no penile concerns. Twenty-six men with BDD, 31 men with SPA, and 33 men without penile concerns were compared on psychopathology, experiences of recurrent imagery, avoidance and safety-seeking behaviours. Men with BDD had significantly higher scores than both the SPA group and no penile concern group for measures of imagery, avoidance, safety seeking and general psychopathology. The groups differed on the phenomenology of BDD specific to penile size preoccupation clearly from the worries of SPA, which in turn were different to those of the men without concerns. The common avoidance and safety seeking behaviours were identified in such men that may be used clinically.

¿Son los agentes biologicos realmente superiores en eficacia a los medicamentos modificadores de la enfermedad (DMARD) incluida la terapia combinada? / ¿Are biologic agent superiors in efficacy to diseases modified agents (DMARD)?

Varios estudios controlados han demostrado los beneficios de la terapia biológica en especial de los antagonistas del factor de necrosis tumoral a e igualmente de los DMARDS en el tratamiento de la artritis reumatoide. Un reciente estudio en artritis reumatoide temprana comparó la eficacia del Etanercept respecto al Metotrexate, el efecto terapéutico del primero fue más rápido a los 6 meses de seguimiento, se equiparó a los 12 meses pero a largo plazo el beneficio clínico y radiológico fue superior respecto al Metotrexate. Esto resalta la importancia de los estudios cabeza a cabeza para definir el papel de una u otra alternativa terapéutica, sin embargo, no dudamos que la terapia biológica es el futuro en el tratamiento de la artritis reumatoide.