Tissue-specific compensatory mechanisms maintain tissue architecture and body size independent of cell size in polyploid zebrafish.

Genome duplications and ploidy transitions have occurred in nearly every major taxon of eukaryotes, but they are far more common in plants than in animals. Due to the conservation of the nuclear:cytoplasmic volume ratio increased DNA content results in larger cells. In plants, polyploid organisms are larger than diploids as cell number remains relatively constant. Conversely, vertebrate body size does not correlate with cell size and ploidy as vertebrates compensate for increased cell size to maintain tissue architecture and body size. This has historically been explained by a simple reduction in cell number that matches the increase in cell size maintaining body size as ploidy increases, but here we show that the compensatory mechanisms that maintain body size in triploid zebrafish are tissue-specific: A) erythrocytes respond in the classical pattern with a reduced number of larger erythrocytes in circulation, B) muscle, a tissue comprised of polynucleated muscle fibers, compensates by reducing the number of larger nuclei such that myofiber and myotome size in unaffected by ploidy, and C) vascular tissue compensates by thickening blood vessel walls, possibly at the expense of luminal diameter. Understanding the physiological implications of ploidy on tissue function requires a detailed description of the specific mechanisms of morphological compensation occurring in each tissue to understand how ploidy changes affect development and physiology.

Acute postoperative pain management.

BACKGROUND: Acute postoperative pain is common. Nearly 20 per cent of patients experience severe pain in the first 24 h after surgery, a figure that has remained largely unchanged in the past 30 years. This review aims to present key considerations for postoperative pain management. METHODS: A narrative review of postoperative pain strategies was undertaken. Searches of the Cochrane Library, PubMed and Google Scholar databases were performed using the terms postoperative care, psychological factor, pain management, acute pain service, analgesia, acute pain and pain assessment. RESULTS: Information on service provision, preoperative planning, pain assessment, and pharmacological and non-pharmacological strategies relevant to acute postoperative pain management in adults is presented, with a focus on enhanced recovery after surgery pathways. CONCLUSION: Adequate perioperative pain management is integral to patient care and outcomes. Each of the biological, psychological and social dimensions of the pain experience should be considered and understood in order to provide optimum pain management in the postoperative setting.

ANTECEDENTES: El dolor agudo postoperatorio es frecuente. Casi el 20% de los pacientes experimentan dolor intenso durante las primeras 24 horas después de la cirugía, una cifra que se ha mantenido prácticamente sin cambios en los últimos 30 años. Esta revisión tiene como objetivo presentar las consideraciones clave a tener en cuenta en el tratamiento del dolor postoperatorio. MÉTODOS: Se realizó una revisión descriptiva de las estrategias para el tratamiento del dolor postoperatorio. Se efectuó una búsqueda bibliográfica en las bases de datos Cochrane Library, PubMed y Google Scholar utilizando los términos: 'cuidado postoperatorio' (postoperative care); 'factor psicológico' (psychological factor); 'tratamiento del dolor' (pain management); 'servicio de dolor agudo' (acute pain service); 'analgesia' (analgesia); 'dolor agudo' (acute pain); y 'evaluación del dolor' (pain assessment). RESULTADOS: En el tratamiento del dolor agudo postoperatorio en adultos son relevantes: la prestación de servicios, la planificación preoperatoria, la evaluación del dolor y los tratamientos farmacológicos y no farmacológicos haciendo énfasis en los programas de rehabilitación multimodal tras la cirugía. CONCLUSIÓN: El tratamiento adecuado del dolor perioperatorio es parte integral en la atención del paciente y en los resultados obtenidos. Se deben considerar y entender cada una de las dimensiones biológica, psicológica y social del dolor para proporcionar un tratamiento óptimo durante el postoperatorio.

(ICORG 05-03): prospective randomized non-inferiority phase III trial comparing two radiation schedules in malignant spinal cord compression (not proceeding with surgical decompression); the quality of life analysis.

BACKGROUND: The optimal primary external beam radiation therapy (EBRT) radiation schedule for malignant epidural spinal cord compression (MSCC) remains to be determined. The ICORG 05-03 trial assessed if a 10 Gy single fraction radiation schedule was not inferior to one with 20 Gray (Gy) in five daily fractions, in terms of functional motor outcome, for the treatment of MSCC in patients not proceeding with surgical decompression. This article reports on two of the secondary endpoints, Quality of life (QoL), assessed according to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) version 3.0 (EORTC Data Center, Brussels, Belgium) and pain control assessed using a visual analog scale. METHODS: A randomized, parallel group, multicenter phase III trial was conducted by Cancer Trials Ireland (formerly All-Ireland Cooperative Oncology Research Group, ICORG), across five hospital sites in Ireland and Northern Ireland. Patients were randomized to 10 Gy single fraction of EBRT or 20 Gy in five fractions in a 1:1 ratio. Patients with baseline and 5-week follow up QoL data are included in this analysis. FINDINGS: From 2006 to 2014, 112 eligible patients were enrolled for whom 57 were evaluated for this secondary analysis. After adjusting for pre-intervention scores, there was no statistically significant difference in post-treatment Summary scores (excl. FI and QL), or pain scores between the two RT schedules at 5 weeks and 3 months following EBRT. There was a statistically significant relationship between the pretreatment and post-treatment Summary scores (p = .002) but not between the pre-treatment and post-treatment pain scores. INTERPRETATION: Primary radiotherapy for the treatment of MSCC significantly improves QoL in patients not proceeding with surgical decompression. After adjusting for pre-intervention scores, there was no statistically significant difference between a 10 Gy single fraction radiation schedule and one with 20 Gy in five daily fractions on post-treatment QoL Summary scores. For most patients, an effective treatment with low burden would be desirable. A single fraction schedule should be considered for this group of patients.

Neuropathic pain treatment and research: experiences from the United Kingdom mission to Afghanistan and future prospects.

The Defence Medical Services (DMS) of the United Kingdom (UK) assumed command of the Role 3 Medical Treatment Facility field hospital during Operation HERRICK in Afghanistan from April 2006 until the final drawdown in November 2014. The signature injury sustained by coalition personnel during this period was traumatic amputation from improvised explosive devices. Many patients who had suffered extensive tissue damage experienced both nociceptive and neuropathic pain (NeuP). This presented as a heterogeneous collection of symptoms that are resistant to treatment. This paper discusses the relationship of NeuP in the context of ballistic injury, drawing in particular on clinical experience from the UK mission to Afghanistan, Operation HERRICK. The role of this paper is to describe the difficulties of assessment, treatment and research of NeuP and make recommendations for future progress within the DMS.

The ASSURE study: HIV-1 suppression is maintained with bone and renal biomarker improvement 48 weeks after ritonavir discontinuation and randomized switch to abacavir/lamivudine + atazanavir.

OBJECTIVES: HIV treatment guidelines endorse switching or simplification of antiretroviral therapy in therapy-experienced patients with suppressed viraemia; ritonavir discontinuation may also enhance tolerability and reduce long-term adverse events (AEs). This open-label, multicentre, noninferiority study enrolled HIV-1-infected, treatment-experienced adults with confirmed HIV-1 RNA ≤ 75 HIV-1 RNA copies/mL currently receiving tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC + ATV/r) for ≥ 6 months with no reported history of virological failure. METHODS: Participants were randomized 1:2 to continue current treatment or switch to abacavir/lamivudine + atazanavir (ABC/3TC + ATV). Endpoints included the proportion of participants with HIV-1 RNA < 50 copies/mL by time to loss of virological response (TLOVR), AEs, fasting lipids, and inflammatory, coagulation, bone and renal biomarkers. RESULTS: After 48 weeks, 76% (152 of 199) of ABC/3TC + ATV-treated and 79% (77 of 97) of TDF/FTC + ATV/r-treated participants had HIV-1 RNA < 50 copies/mL (TLOVR; P = 0.564). Other efficacy analyses yielded similar results. Rates of new grade 2-4 AEs were 45% in both groups, but an excess of hyperbilirubinaemia made the rate of treatment-emergent grade 3-4 laboratory abnormalities higher with TDF/FTC + ATV/r (36%) compared with ABC/3TC + ATV (19%). Most fasting lipid levels remained stable over time; high-density lipoprotein (HDL) cholesterol increased modestly in ABC/3TC + ATV-treated participants. Bone and renal biomarkers improved significantly between baseline and week 48 in participants taking ABC/3TC + ATV and were stable in participants taking TDF/FTC + ATV/r. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups. CONCLUSIONS: The ABC/3TC + ATV treatment-switch group had similar viral suppression rates up to 48 weeks to the TDF/FTC + ATV/r comparator group, with lower rates of moderate- to high-grade hyperbilirubinaemia and improvements in bone and renal biomarkers.

Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error.

BACKGROUND: Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation. METHODS: Prostatectomy samples from a large patient cohort with long follow-up were blindly assessed by expert pathologists who identified the tissue regions with the highest and lowest Gleason grade from each patient. To simulate biopsy-sampling error, a core from a high- and a low-Gleason area from each patient sample was used to generate a 'high' and a 'low' tumour microarray, respectively. RESULTS: Using a quantitative proteomics approach, we identified from 160 candidates 12 biomarkers that predicted prostate cancer aggressiveness (surgical Gleason and TNM stage) and lethal outcome robustly in both high- and low-Gleason areas. Conversely, a previously reported lethal outcome-predictive marker signature for prostatectomy tissue was unable to perform under circumstances of maximal sampling error. CONCLUSIONS: Our results have important implications for cancer biomarker discovery in general and development of a sampling error-resistant clinical biopsy test for prediction of prostate cancer aggressiveness.

A survey of post-amputation pains in serving military personnel.

INTRODUCTION: Amputation is a common injury in survivors of current military conflicts. The primary aim of this study was to establish the prevalence rate of phantom limb pain (PLP) in military personnel undergoing rehabilitation at the UK's Defence Medical Rehabilitation Centre. The secondary aims were to establish treatment failure rates and prevalence rates of phantom limb sensations (PLS) and residual limb pains (RLP). METHOD: A questionnaire survey was developed from that used in a previous study of pains in veterans. Questions were asked of the intensity of PLP, RLP and PLS over the previous month and the entire time since amputation. Treatment failure was defined as greater than 'mild' pain. A literature review for similar studies was undertaken. RESULTS: There were 48 responders with 65 amputations. PLP in the previous month was reported by 49% of respondents and 20% were classed as treatment failures; 76% had PLP at some point and 56% were analgesic failures. PLS was commoner with 70% reported over the previous month and 66% at any time. 65% had RLP over the previous month, 31% were treatment failures and 80% had experienced RLP at some point and 63% of these were failures of treatment. Eight other papers were found for comparison. CONCLUSIONS: This is the first paper that describes prevalence of pains associated with amputation in a serving military population. It also describes the use of analgesic failure as a concept and provides an encouraging rate of as low as 20% in this population.

Educational inequalities in the co-occurrence of mental health and substance use problems, and its adult socio-economic consequences: a longitudinal study of young adults in a community sample.

OBJECTIVES: To examine the relationship between the co-occurrence of mental health and substance use problems and socio-economic status (SES). STUDY DESIGN: A prospective longitudinal study of 808 males and females followed to age 30. METHODS: Survey data were used to derive latent classes (profiles) of mental health (depression, anxiety) and substance use (alcohol, nicotine, and marijuana [cannabis]) problems at age 27. Analyses examined the associations of these profiles with earlier educational attainment (high school diploma) and indicators of SES at age 30. RESULTS: Latent Class Analysis produced four profiles: a low disorder symptoms group, a licit substance use disorder symptoms group (alcohol and nicotine), a mental health disorder symptoms group, and a comorbid group. Earning a high school diploma by age 21 decreased the odds of belonging to the comorbid group or the licit substance use disorder symptoms group when compared to the low disorder symptoms group. These disorder profiles also were found to adversely impact subsequent adult SES. The adverse impact was more evident in income maintenance and wealth accumulation by age 30 than market or non-market labour force participation. CONCLUSIONS: Earning a high school diploma lessens the risk of co-occurring mental health and substance use problems which contribute to economic instability in young adulthood. Findings underscore the importance of public health programmes to reduce the incidence of mental health and substance use problems and their associated high costs to individuals and to society.

Portfolios in practice: Developing advancing practice within a musculoskeletal competency-based model.

INTRODUCTION: The development of professional portfolios and the relevance of this within professional practice, competency and capability is gaining significant credibility in line with professional requirements. Nursing and medicine in terms of historical perspectives have long held the need for clinicians to maintain a portfolio for professional validation, whilst in other professional groups it is a requirement of registration. The allied health professionals, physiotherapy and ultimately musculoskeletal practice within this context are rapidly developing advancing and consultant practice. This professional development further requires appropriate verification and validation of practice, and achieving this can be through formal and non-formal routes. PURPOSE: This paper looks to explore this and give direction to professionals developing portfolios whilst placing the requirements in context to contemporary practice in the U.K. Universities, professional bodies and special interest groups are now aligning in the need to support practice in a multi-format way, that moves away from traditional methods of evaluation into more diverse models of competency-based assessment. IMPLICATIONS: With improvement in technology, the development of national frameworks and standards, portfolios in practice although commonly considered as standard practice will be a requirement not only of registration but as a criteria of maintaining status, career development and expansion of roles. BACKGROUND: Musculoskeletal (MSK) physiotherapy in the U.K. has moved forward significantly in the last 20 years. Sitting within a clinical reasoned framework, the introduction of additional skills such is image requesting, injection therapies, and non-medical prescribing has further underpinned the advanced practice agenda (Langridge et al., 2015). While these advancements in practice are driving the profession forward, challenges remain in providing the workforce with a clear process of career development. Alongside developing professional pathways methods of evidencing advanced knowledge and skills acquired outside formal routes are required to support practitioners' career pathway into advancing practice.

A survey in the West Midlands of the United Kingdom of current practice in managing hypotension in lower segment caesarean section under spinal anaesthesia.

BACKGROUND: Spinal anaesthesia, the most common form of anaesthesia for caesarean section, leads to sympathetic blockade and profound maternal hypotension resulting in adverse maternal and neonatal outcomes. Hypotension, nausea and vomiting remain common but until the publication of the National Institute of Health and Care Excellence (NICE) 2021 guidance, no national guideline existed on how best to manage maternal hypotension following spinal anaesthesia for caesarean section. A 2017 international consensus statement recommended prophylactic vasopressor administration to maintain a systolic blood pressure of >90% of an accurate pre-spinal value, and to avoid a drop to <80% of this value. This survey aimed to assess regional adherence to these recommendations, the presence of local guidelines for management of hypotension during caesarean section under spinal anaesthesia, and the individual clinician's treatment thresholds for maternal hypotension and tachycardia. METHODS: The West Midlands Trainee-led Research in Anaesthesia and Intensive Care Network co-ordinated surveys of obstetric anaesthetic departments and consultant obstetric anaesthetists across 11 National Health Service Trusts in the Midlands, England. RESULTS: One-hundred-and-two consultant obstetric anaesthetists returned the survey and 73% of sites had a policy for vasopressor use; 91% used phenylephrine as the first-line drug but a wide range of recommended delivery methods was noted and target blood pressure was only listed in 50% of policies. Significant variation existed in both vasopressor delivery methods and target blood pressures. CONCLUSIONS: Although NICE has since recommended prophylactic phenylephrine infusion and a target blood pressure, the previous international consensus statement was not adhered to routinely.

The genetics and genomics of Syngnathidae: pipefishes, seahorses and seadragons.

The goal of this review was to provide a historical overview of how molecular techniques have increased the understanding of the ecology and evolution of the family Syngnathidae (pipefishes, seahorses and seadragons). Molecular studies based primarily on mitochondrial DNA markers have proved their worth by elucidating complex phylogenetic relationships within the family. Phylogeographic studies, which have revealed how life-history traits and past climatic events shape geographic distributions and patterns of genetic variation within syngnathid species, also provide interesting case studies for the conservation and management of threatened species. The application of microsatellite DNA markers has opened a floodgate of studies concerned with the breeding biology of these fishes, which are interesting due to their unique reproductive mode of male pregnancy. Research in this area has contributed significantly to the understanding of mating patterns and sexual selection. Molecular markers may also be employed in studies of demography, migration and local breeding population sizes. Genomic studies have identified genes that are probably involved in male pregnancy and promise additional insights into various aspects of syngnathid biology at the level of the gene. Despite these advances, much more remains to be explored. Goals for future research should include: (1) a more inclusive phylogeny to resolve outstanding issues concerning the relationships within the family and higher order taxa, (2) a broader use of molecular studies to aid management and conservation efforts, (3) the inclusion of more genera in comparative behavioural studies and (4) the continued development of genomic resources for syngnathids to facilitate comparative genomic work.

The influence of ridge migration on the magmatic segmentation of mid-ocean ridges.

The Earth's mid-ocean ridges display systematic changes in depth and shape, which subdivide the ridges into discrete spreading segments bounded by transform faults and smaller non-transform offsets of the axis. These morphological changes have been attributed to spatial variations in the supply of magma from the mantle, although the origin of the variations is poorly understood. Here we show that magmatic segmentation of ridges with fast and intermediate spreading rates is directly related to the migration velocity of the spreading axis over the mantle. For over 9,500 km of mid-ocean ridge examined, leading ridge segments in the 'hotspot' reference frame coincide with the shallow magmatically robust segments across 86 per cent of all transform faults and 73 per cent of all second-order discontinuities. We attribute this relationship to asymmetric mantle upwelling and melt production due to ridge migration, with focusing of melt towards ridge segments across discontinuities. The model is consistent with variations in crustal structure across discontinuities of the East Pacific Rise, and may explain variations in depth of melting and the distribution of enriched lavas.

Perioperative and early rehabilitation outcomes following osseointegration in UK military amputees.

INTRODUCTION: This paper examines the pain management, from surgery to specialist rehabilitation, of the first seven military transfemoral amputee patients treated in the UK with femoral osseointegration. All the patients had sustained complex ballistic injuries on the battlefield. The patients were characterised by long-standing problems with functional rehabilitation due to limitations with conventional prostheses, including stump soft tissue issues and impaired biomechanics. METHODS: A prospective service investigation was undertaken to evaluate the effectiveness of the pain management of patients undergoing osseointegration. Data were collected by daily direct patient contact, supplemented by a focused review of perioperative and rehabilitation case notes. Physiological and medication details were recorded with specific reference to systemic and regional analgesia and the impact of postoperative complications, including infection and accidental injury. RESULTS: Seven patients underwent femoral osseointegration and were followed up for a period of up to 3 years following surgery. The perioperative recovery was associated with significant escalation of analgesic requirements. Postoperative systemic inflammatory response syndrome was identified in six patients, with wound infection persisting in some cases into the rehabilitation phase. Three patients suffered femoral fractures following accidental injuries secondary to increased mobilisation following surgery. CONCLUSIONS: Successful surgical outcomes were achieved in a difficult patient cohort disadvantaged by previously restricted functional recovery from complex injuries. The importance of supporting the operative and recovery phases with a multidisciplinary pain service is emphasised. We offer this data and the lessons learnt to assist clinicians contemplating the establishment and service development of osseointegration services.

Coordinated changes in energy intake and expenditure following hypothalamic administration of neuropeptides involved in energy balance.

OBJECTIVE: The hypothalamic control of energy balance is regulated by a complex network of neuropeptide-releasing neurons. Although the effect of these neuropeptides on individual aspects of energy homoeostasis has been studied, the coordinated response of these effects has not been comprehensively investigated. We have simultaneously monitored a number of metabolic parameters following intracerebroventricular (ICV) administration of 1 and 3 nmol of neuropeptides with established roles in the regulation of feeding, activity and metabolism. Ad libitum- fed rats received the orexigenic neuropeptides neuropeptide Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin-A. Overnight-food-deprived rats received an ICV injection of the anorectic peptides alpha-melanocyte-stimulating hormone (MSH), corticotrophin-releasing factor (CRF) or neuromedin U (NMU). RESULTS: Our results reveal the temporal sequence of the effects of these neuropeptides on both energy intake and expenditure, highlighting key differences in their function as mediators of energy balance. NPY and AgRP increased feeding and decreased oxygen consumption, with the effects of AgRP being more prolonged. In contrast, orexin-A increased both feeding and oxygen consumption, consistent with an observed increase in activity. The potent anorexigenic effects of CRF were accompanied by a prolonged increase in activity, whereas NMU injection resulted in significant but short-lasting inhibition of food intake, ambulatory activity and oxygen consumption. alpha-MSH injection resulted in significant increases in both ambulatory activity and oxygen consumption, and reduced food intake following administration of 3 nmol of the peptide. CONCLUSION: We have for the first time, simultaneously measured several metabolic parameters following hypothalamic administration of a number of neuropeptides within the same experimental system. This work has shown the interrelated effects of these neuropeotides on activity, energy expenditure and food intake, thus facilitating comparison between the different hypothalamic systems.

Co-administration of SR141716 with peptide YY3-36 or oxyntomodulin has additive effects on food intake in mice.

BACKGROUND: SR141716 has been shown to significantly inhibit food intake and reduce body weight by antagonizing CB(1) receptors. The gut hormones peptide YY(3-36) (PYY(3-36)) and oxyntomodulin (OXM) inhibit food intake through Y(2) and Glucagon-Like-Peptide (GLP)-1 receptors respectively. OBJECTIVE: To determine the effects of co-administration of SR141716 with either PYY(3-36) or OXM in mice on food intake. METHODS: Mice (n = 14 per group) were fasted for 16 h prior to study days and given two intraperitoneal injections: study 1, vehicle-saline, SR141716-saline, vehicle-PYY3-36 or SR141716-PYY3-36; study 2: vehicle-saline, SR141716-saline, vehicle-OXM or SR141716-OXM. Food was returned and measured following injections. RESULTS: Co-administration of SR141716-PYY(3-36) or SR141716-OXM showed greater inhibition in food intake when compared with administration of SR141716, PYY(3-36) or OXM alone. CONCLUSION: Our data show that SR141716 in combination with PYY(3-36) or OXM reduces food intake additively in mice.

Glucagon-like peptide-1 stimulates luteinizing hormone-releasing hormone secretion in a rodent hypothalamic neuronal cell line.

To examine the influence of the putative satiety factor (GLP-1) on the hypothalamo-pituitary-gonadal axis, we used GT1-7 cells as a model of neuronal luteinizing hormone- releasing hormone (LHRH) release. GLP-1 caused a concentration-dependent increase in LHRH release from GT1-7 cells. Specific, saturable GLP-1 binding sites were demonstrated on these cells. The binding of [125I]GLP-1 was time-dependent and consistent with a single binding site (Kd = 0.07+/-0.016 nM; binding capacity = 160+/-11 fmol/mg protein). The specific GLP-1 receptor agonists, exendin-3 and exendin-4, also showed high affinity (Ki = 0.3+/-0.05 and 0.32+/-0.06 nM, respectively) as did the antagonist exendin-(9-39) (Ki = 0.98+/-0.24 nM). At concentrations that increased LHRH release, GLP-1 (0.5-10 nM) also caused an increase in intracellular cAMP in GT1-7 cells (10 nM GLP-1: 7.66+/-0.4 vs. control: 0.23+/-0.02 nmol/mg protein; P < 0.001). Intracerebroventricular injection of GLP-1 at a single concentration (10 microg) produced a prompt increase in the plasma luteinizing hormone concentration in male rats (GLP-1: 1.09+/-0.11 vs. saline: 0.69+/-0.06 ng/ml; P < 0.005). GLP-1 levels in the hypothalami of 48-h-fasted male rats showed a decrease, indicating a possible association of the satiety factor with the low luteinizing hormone levels in animals with a negative energy balance.

The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin.

Prolonged fasting is associated with a downregulation of the hypothalamo-pituitary thyroid (H-P-T) axis, which is reversed by administration of leptin. The hypothalamic melanocortin system regulates energy balance and mediates a number of central effects of leptin. In this study, we show that hypothalamic melanocortins can stimulate the thyroid axis and that their antagonist, agouti-related peptide (Agrp), can inhibit it. Intracerebroventricular (ICV) administration of Agrp (83-132) decreased plasma thyroid stimulating hormone (TSH) in fed male rats. Intraparaventricular nuclear administration of Agrp (83-132) produced a long-lasting suppression of plasma TSH, and plasma T4. ICV administration of a stable alpha-MSH analogue increased plasma TSH in 24-hour-fasted rats. In vitro, alpha-MSH increased thyrotropin releasing hormone (TRH) release from hypothalamic explants. Agrp (83-132) alone caused no change in TRH release but antagonized the effect of alpha-MSH on TRH release. Leptin increased TRH release from hypothalami harvested from 48-hour-fasted rats. Agrp (83-132) blocked this effect. These data suggest a role for the hypothalamic melanocortin system in the fasting-induced suppression of the H-P-T axis.

Adjuvant Radiotherapy Use by US Radiation Oncologists After Radical Cystectomy for Muscle-invasive Bladder Cancer.

AIMS: Historic trials suggested significant toxicity with adjuvant radiotherapy (ART) after radical cystectomy for muscle-invasive bladder cancer (MIBC). However, recent trials have found improved locoregional control and the 2016 National Comprehensive Cancer Network (NCCN) guidelines recommend ART consideration for select patients at high risk of local recurrence. ART practice patterns among US radiation oncologists are unknown and we carried out a survey to explore current trends. MATERIALS AND METHODS: We conducted a survey of US radiation oncologists regarding the management of patients with cT2-3N0M0 transitional cell MIBC. Responses were reported using descriptive statistics. Chi-square and univariate logistic regression of clinical and demographic covariates were conducted, followed by multivariable logistic regression analysis to identify factors predicting for ART use. RESULTS: In total, 277 radiation oncologists completed our survey. Nearly half (46%) have used ART for MIBC at least once in the past. In ART users, indications for ART include gross residual disease (93%), positive margins (92%), pathological nodal involvement (64%), pT3 or T4 disease (46%), lymphovascular invasion (16%) and high-grade disease (13%). On univariate logistic regression, ART use was associated with the number of years in practice (P=0.04), pre-cystectomy radiation oncology consultation (P=0.004), primarily treating MIBC patients fit for cystectomy (P=0.01) and intensity-modulated radiotherapy use (P=0.01). On multivariable logistic regression analysis, routine pre-cystectomy radiation oncology consultation (odds ratio 1.91, 95% confidence interval 1.04-3.51; P=0.04) and intensity-modulated radiotherapy use (odds ratio 2.77, 95% confidence interval 1.48-5.22; P=0.002) remained associated with ART use. CONCLUSIONS: ART use is controversial in bladder cancer, yet unexpectedly has commonly been used among US radiation oncologists treating patients with MIBC after radical cystectomy. NRG-GU001 was a randomised trial in the US randomizing patients with high-risk pathological findings for observation or ART after cystectomy. However, due to poor accrual it recently closed and thus it will be up to other international trials to clarify the role of ART and identify patients benefiting form this adjuvant therapy.