An innovative antimicrobial stewardship programme for children in remote and regional areas in Queensland, Australia: optimising antibiotic use through timely intravenous-to-oral switch.

OBJECTIVES: Little is known about the benefits of timely switch from intravenous (IV) to oral antibiotic therapy in children. We evaluated the appropriateness of IV-to-oral switch of antibiotic therapy in remote and regional areas of Australia following the implementation of a multifaceted package of interventions. METHODS: The intervention package, including clinician guidelines, medication review stickers, patient information leaflets and educational resources, was implemented in seven facilities in Queensland, Australia. Children with community-acquired pneumonia and skin and soft-tissue infections were switched to oral therapy if they met the required 'IV-to-oral switch' criteria. Data were collected for a 7-month period from May to November for the baseline (2018) and intervention (2019) phases. RESULTS: A total of 357 patients were enrolled in the study, including 178 in the baseline phase and 179 in the intervention phase. The percentage of patients who switched to oral therapy or stopped IV antibiotics, within 24 h of eligibility, increased from 87.6% (156/178) in the baseline phase to 97.2% (174/179) in the intervention phase (P = 0.003). The average number of extra IV days decreased from 0.45 days in the baseline period to 0.18 days in the intervention period (P < 0.001). The median patient length of stay was 2 days for both phases. The only adverse events recorded were line-associated infiltration, with a decrease from 34.3% (61/178) (baseline) to 17.9% (32/179) (intervention) (P < 0.001). CONCLUSION: A multifaceted intervention package to enhance timely IV-to-oral switch of antibiotic therapy for children in remote and regional facilities is effective.

Polymerase chain reaction for human parechovirus on blood samples improves detection of clinical infections in infants.

Human parechovirus (HPeV) is an emerging pathogen for infants. Improved diagnostics are needed due to the non-specific clinical presentation. Real-time reverse transcription polymerase chain reaction (RT-PCR) on blood samples may be an adjunct to diagnosis. A retrospective cohort of HPeV-affected infants was used to assess sensitivity and specificity of a HPeV RT-PCR on blood and cerebrospinal fluid (CSF). As a secondary analysis, the Ct value of the PCR results was compared to clinical correlates of severity. Between 2017 and 2018 blood samples were obtained from 97 infants of whom 44 had HPeV clinical and laboratory proven infection. Eighty-three concurrent CSF samples were available. Sensitivity was 93.3% [95% CI 82-99] for blood HPeV RT-PCR and 85% [95% CI 73.9-96.1] for CSF HPeV RT-PCR. Blood HPeV RT-PCR Ct values < 25 cycles were associated with age < 28 days and < 3 days of symptoms. No statistical associations were identified between potential clinical markers of severity and Ct value. HPeV RT-PCR on blood is a valuable adjunct to diagnostic testing for acute HPeV-related illness in infants. Results can be expected to be robust until at least day 5 of symptoms, with optimal sampling occurring close to onset of symptoms.

The impact of duration on effectiveness of exercise, the implication for periodization of training and goal setting for individuals who are overfat, a meta-analysis.

Given the assumption that all methods of exercise, e.g., endurance (ET), resistance (RT), or combination of both (E+R), can induce a beneficial effect size (ES) for changes in body composition and health status of individuals who are overfat. Thus the aim and purpose of this study is to evaluate the current body of knowledge to address the question as to the impact that the duration of exercise has on its relative effectiveness for inducing health and body compositional changes in individuals who are overfat to assist with developing periodized exercise protocols and establishing short and long term goals. A tiered meta-analysis of 92-studies and 200-exercise groupings were used for establishing pooled ES within and between groupings based on the increments of 4-week of duration and study designs of ≤8, 9-16, 17-23, 24-36, and ≥36 weeks. Analysis based on random-effect of response indicates a continuum of effectiveness within and between ET, RT and E+R based on duration. Where beneficial effectiveness is not indicated for any measures until after 8-weeks of continuous training with progressive effectiveness being noted in changes to cardiorespiratory fitness, inflammatory cytokines, and alteration of metabolic status from 12-weeks through 32-weeks of continuous training. Results indicate a greater ES for RT and E+R versus ET early in intervention that equalizes with longer durations. Supporting the use of RT and E+R within a periodized program. And secondarily, goals should be established first on performance gains and second body composition or health status modifications for the individual who is overfat.

Preventing the contamination of hospital personnel by cytotoxic agents: evaluation and training of the para-professional healthcare workers in oncology units.

This study was specifically focused on para-professional healthcare workers (PHCWs) who handle cytotoxic drugs and contaminated wastes at the Public Teaching Hospitals of Marseille (AP-HM), France. It first aimed at evaluating the knowledge and professional practice of the PHCWs who belong to a personnel category among the less informed and protected in hospitals. In a second time, this study also proposed to raise awareness, educate and train the staff on protective measures to minimise the exposure of the PHCWs to the potential toxicity of anticancer chemotherapy agents (or metabolites) when cleaning and handling both cytotoxic drugs and wastes. Among the 11 oncology units evaluated, 82% completed an assessment survey, 63% of which were PHCWs. Out of nine oncology units assessed, 89% reported limited knowledge of the general risk and of the safe handling of cytotoxic drugs, 89% reported using vinyl gloves which are the less protective ones. Forty-four per cent of the units used wet sweeping techniques for cleaning the floors, and 11% of the units did not have specific procedures for cleaning the equipments used for collecting contaminated excreta. Protective outer apparel was not always worn and chemotherapy wastes were not managed consistently between all units. Standardized procedures and guidelines to prevent occupational exposure were not used by PHCWs. More education and training are needed to improve safety.

The role of resistance training for treatment of obesity related health issues and for changing health status of the individual who is overfat or obese: a review.

While there is reinforcement of the idea that loss of body mass (BM) will lead to an improvement in overall health status for the individual that is overfat, or obese. The long held recommendation for reduction of BM focusing solely on establishing a reduction on caloric intake, via caloric restriction (CR) in diet alone tends to limited impact on overall health status changes for these individuals. In contrast, the reduction of BM attained through employment of therapeutic exercises produces a significant change in the health status of individuals that are overfat, or obese. While endurance training (ET) is readily recommended, it may be far less effective at correcting these underlying issues relative to changes noted in response resistance training (RT) programs. Therefore this review will examine the differential responses seen with the application of RT related to the positive adaptations in BM modifications, regardless of changes in Body Mass Index (BMI), and proper hormonal responses leads to modifications of health status and eventually returning the individual who is overfat, or obese, back to a normal health status with the employment of RT in a therapeutic exercise program.

Does the type of intervention method really matter for combating childhood obesity? A systematic review and meta-analysis.

With the epidemic rise in obesity and related health issues in children and adolescents there have been numerous types of treatments established to slow or reverse this trend. In an effort to examine the effect of responses to the methods used for treatment, a systematic review of the current literature was performed. From 32 included studies, 120 distinct treatment groups were selected based on the treatment methods used to assess the effect for that treatment, with effect for each treatment based on the effect size (ES) for eliciting changes in body morphology, blood lipid profiles, and hormones (insulin, leptin, adiponectin) that have been linked to metabolic issues. Additionally, treatments were compared for effectiveness in eliciting changes in the aerobic capacity and for eliciting changes in caloric balance. In total three distinct ES patterns were observed, the first based on treatment and therapeutic ES the use of patterns of physical activity and exercise (endurance, ET, or resistance, RT) are more effective than dieting alone. The second, including organized exercise, showed to be a more effective treatment than a general physical activity program. The third including those treatments that were most effective in eliciting a caloric deficit which did not show the greatest impact on effectiveness of improving health status (e.g., hormone levels, blood lipids, and cardiorespiratory fitness). Thus, children and adolescent who are overweight should be encouraged to engage in organized bouts of physical activity that is meant to establish chronic stimulus for physiological response to the exercise stimulus and not rely solely on the establishment of an acute caloric deficit.

Developmental co-ordination disorder in socially disadvantaged Brazilian children.

BACKGROUND: The consequences of developmental co-ordination disorder (DCD) indicate a need for identification in order to provide adequate intervention. The goals of the study were to investigate DCD prevalence across age bands, gender, race and school performance; the motor difficulties of children with DCD, at-risk and typically developing children in the Movement Assessment Battery for Children (MABC) sub-tests across age bands and gender; and the relationship between motor outcomes, age, gender and socio-economic status (SES) in socially disadvantaged Brazilian children. METHODS: The MABC was administered to 1056 Brazilian children from 4 to 10 years old. RESULTS: Eighteen per cent of the children were screened as probable DCD (≤5th percentile) and a further 15% as at risk for DCD (>5th and ≤15th percentile). Significantly more children were screened with probable DCD at age 9-10 years (AB3: P = 0.00), whereas at risk classification was equally distributed across age bands (P = 0.12). Boys showed lower prevalence than girls of probable DCD and at risk for DCD (P = 0.04). Children (9-10 years) showed higher motor impairment in the manual dexterity test results. Children with probable DCD and at risk of DCD showed, in general, poor performance in balance and manual dexterity tasks. SES was the strongest predictor of motor outcomes, accounting for 21% of the variance in the MABC percentile scores. CONCLUSIONS: The prevalence of probable and at-risk DCD cases as well as the percentage of female were higher than those found in the previous studies, and low SES enhances the risk of poor motor development.

Management of paediatric tuberculosis in leading UK centres: unveiling consensus and discrepancies.

SETTING: Large specialist paediatric TB clinics in the UK. OBJECTIVE: To evaluate clinical practice and compare with national and international guidelines. DESIGN: A survey based on an electronic questionnaire on the management of latent tuberculous infection (LTBI) and tuberculosis (TB) disease was conducted in 13 specialist paediatric TB clinics. The consensus and discrepancies were evaluated by descriptive analysis. RESULTS: Practice was reportedly different when choosing age limits for preventive treatment for TB contacts with initially negative tuberculin skin tests (TSTs), interpretation of TST results and use of interferon-gamma release assays (IGRAs) in the context of LTBI. In relation to management of children with TB disease, practices varied for duration of treatment of osteoarticular TB, monitoring for ethambutol ocular toxicity and use of pyridoxine. There was limited experience with multidrug-resistant TB (MDR-TB), and over half of the clinics monitored MDR-TB contacts without giving preventive treatment. CONCLUSIONS: The survey showed heterogeneity in several aspects of clinical care for children with TB. Available paediatric TB guidelines differ substantially, explaining the wide variations in management of childhood TB. Prospective paediatric studies are urgently required to inform and standardise clinical practice, especially in the context of evolving drug resistance.

Toxic shock syndrome surveillance in UK children.

BACKGROUND: Toxic shock syndrome (TSS) is an acute toxin-mediated illness caused by toxin-producing strains of Staphylococcus aureus and Streptococcus pyogenes. There is no recent data regarding incidence, management and mortality of TSS in UK children. METHODS: Consultants from paediatric and burns units in the UK and Ireland, reported cases of TSS seen between November 2008 and December 2009, via the British Paediatric Surveillance Unit. Respondents were sent questionnaires requesting detailed information about TSS cases. Established criteria were used to divide cases into staphylococcal or streptococcal TSS. RESULTS: Forty-nine cases were identified overall; 29 cases of streptococcal TSS (18 confirmed and 11 probable) and 20 cases of staphylococcal TSS (15 confirmed and 5 probable). The incidence of TSS children in the UK & the Republic of Ireland was calculated to be 0.38 per 100 000 children. Children with staphylococcal TSS were older than those with streptococcal TSS (9.5 vs 3.8 years; p<0.003). Paediatric intensive care facilities were used for 78% of cases (invasive ventilatory support 69%; inotropic support 67%; haemofiltration 12%). Agents with antitoxin effects were underused; clindamycin 67%, intravenous immunoglobulin (IVIG) 20%, fresh frozen plasma 40%. There were eight deaths, all in the streptococcal group (28% of streptococcal cases)-none were given IVIG. CONCLUSIONS: Streptococcal TSS was as frequent as staphylococcal TSS, contrasting with previous literature. Children with streptococcal TSS had a higher mortality than those with staphylococcal TSS (28% vs 0%; p<0.05). Recommended immunomodulatory agents (IVIG and clindamycin) were underused. This study highlights the need for a guideline to improve management of TSS in children.

Spatial variation in the risk of hospitalization with childhood pneumonia and empyema in the North of England.

The aim of this study was to investigate spatial variation in risk of hospitalization in childhood pneumonia and empyema in the North of England and associated risk factors. Data on childhood (0-14 years) hospital admissions with a diagnosis pneumonia or empyema were linked to postcode districts. Bayesian conditional autoregressive models were used to evaluate spatial variation and the relevance of specific spatial covariates in an area-based study using postcode as the areal unit. There was a sixfold variation in the risk of hospitalization due to pneumonia across the study region. Variation in risk was associated with material deprivation, Child Well-being Index (CWI) health domain score, number of children requiring local authority support, and distance to hospital. No significant spatial variation in risk for empyema was found.

Impact of the 7-valent pneumococcal conjugate vaccine on the incidence of childhood pneumonia.

In September 2006, the 7-valent pneumococcal conjugate vaccine (PCV7) was added to the UK immunization programme. We aimed to evaluate the impact of PCV7 on the incidence of all-cause community-acquired pneumonia (CAP) in children. A prospective survey was undertaken in 2008-2009 at 11 hospitals in North East England of children aged 0-16 years with radiologically confirmed pneumonia. Data were compared to those from a similar survey undertaken in the same hospitals in 2001-2002. A total of 542 children were enrolled, of which 74% were aged <5 years. PCV7 uptake was 90∙7%. The incidence of pneumonia was 11∙8/10,000 [95% confidence interval (CI) 10∙9-12∙9], and the hospitalization rate was 9∙9/10,000 (95% CI 9∙0-10∙9). Compared to 2001, there was a 19% (95% CI 8-29) reduction in the rate of CAP in those aged <5 years, and in those <2 years a 33∙1% (95% CI 20-45) reduction in the incidence of CAP and 38∙1% (95% CI 24-50) reduction in hospitalization rates. However, for those unvaccinated aged ≥5 years, there was no difference in the incidence of CAP and hospitalization rate between both surveys. Since 2001, the overall reduction in incidence was 17∙7% (95% CI 8-26) and for hospitalization 18∙5% (95% CI 8-28). For the <5 years age group there was a lower incidence of CAP in PCV7-vaccinated children (25∙2/10,000, 95% CI 22∙6-28∙2) than in those that were not vaccinated (37∙4/10,000, 95% CI 29∙2-47∙1). In conclusion, PCV7 has reduced both incidence and rate of hospitalization of pneumonia in children, particularly in the <2 years age group.

Auditory-motor coupling of bilateral finger tapping in children with and without DCD compared to adults.

The ability to modulate bilateral finger tapping in time to different frequencies of an auditory beat was studied. Twenty children, 7 years of age, 10 with and 10 without developmental coordination disorder (DCD), and 10 adults tapped their left index and right middle fingers in an alternating pattern in time with an auditory signal for 15s (four trials each, randomly, at 0.8, 1.6, 2.4, 3.2 Hz per finger). Dominant and non-dominant finger data were collapsed since no differences emerged. All three groups were able to modulate their finger frequency across trials to closely approximate the signal frequency but children with DCD were unable to slow down to the lowest frequency. Children with DCD were more variable in tap accuracy (SD of relative phase) and between finger coordination than typically developing children who were respectively more variable than the adults. Children with DCD were unable to consistently synchronize their finger with the beat. Adults were tightly synchronized and often ahead of the beat while children without DCD tended to be behind the beat. Overall, these results indicated that children with DCD can only broadly match their finger movements to an auditory signal with variability and poor synchronicity as key features of their auditory-fine-motor control. Individual inspection of the data revealed that five children with DCD had difficulty matching the slowest frequencies and that these children also had higher variability and lower percentile MABC scores from the movement assessment battery for children (MABC) than other children with DCD. Three children with DCD were more variable only at higher frequencies and two performed like typically developing children.

Potential effect of NICE tuberculosis guidelines on paediatric tuberculosis screening.

OBJECTIVE: Assays based on interferon gamma (IFNgamma) are an exciting new development for screening for latent tuberculosis infection (LTBI) in adults, but there are limited data on their effectiveness in children. Nevertheless new National Institute for Health and Clinical Excellence (NICE) guidelines recommend their use when screening paediatric tuberculosis (TB) contacts. We evaluated the potential effect of the new NICE guidelines on current paediatric practice. DESIGN: Children screened for TB who had had an IFNgamma assay performed (QuantiFERON-TB Gold (QFG)) were included. Actual outcomes from existing guidelines were compared with those that would have been obtained using NICE guidelines. RESULTS: QFG assays were performed on 120 children, 103 as part of TB contact tracing. Six of the 120 (5%) were QFG positive, and seven of the 120 (6%) were indeterminate. Where both Mantoux and QFG results were available, these agreed in 62/104 (60%) of cases. QFG tests were more likely to correlate with a negative Mantoux (98% agreement) than with a positive Mantoux (11% agreement). Management outcomes differed for 23/103 children seen as part of TB contact tracing. Only one (1%) of these had an indeterminate QFG result. 17 (85%) fewer children would have been given LTBI treatment (chemoprophylaxis) and two (2%) children with possible TB would not have been identified using NICE guidelines. CONCLUSION: New NICE guidelines for the use of IFNgamma-based tests for TB screening will reduce the number of children treated for presumed LTBI. Long-term prospective studies are needed to determine the number of children with positive Mantoux tests but negative IFNgamma results who are not given LTBI treatment yet later develop TB.

Value of bronchoalveolar lavage before haematopoietic stem cell transplantation for primary immunodeficiency or autoimmune diseases.

Pulmonary infection, often insidious, is frequent in primary immunodeficiency (PID) and acquired immunodeficiency. Pulmonary complications are serious obstacles to success of haematopoietic SCT (HSCT) for these conditions. Bronchoalveolar lavage (BAL) permits identification of lower respiratory tract pathogens that may direct specific treatment and influence prognosis. There are no reports about the utility of pre-HSCT BAL for immunodeficient patients. We prospectively studied the value of 'routine' BAL before commencing transplantation in patients undergoing HSCT for severe immunological disease. Routine non-bronchoscopic BAL was performed under general anaesthetic, a few days before commencing pre-HSCT cytoreductive chemotherapy. Patients were categorized as symptomatic or asymptomatic with respect to pulmonary disease or infection. Samples were sent for microbiological processing. Complications arising from the procedure, pathogens isolated and treatments instituted were recorded. Results were available from 69/75 patients transplanted during the study period; 26 (38%) had pathogens identified (six asymptomatic patients), 10 (14.5%) developed complications post-procedure (two asymptomatic patients)-all recovered, 21 had management changes. There was no statistically significant difference in the number of positive isolates from severe combined or other immunodeficient patients, or of symptomatic or asymptomatic patients. Routine non-bronchoscopic BAL is safe in immunodeficient patients about to undergo HSCT, and leads to management changes.

Epidemiology of community-acquired pneumonia in children seen in hospital.

There is little UK data on hospital admission rates for childhood pneumonia, lobar pneumonia, severity or risk factors. From 13 hospitals serving the catchment population, demographic and clinical details were prospectively collected between 2001 and 2002 for children aged 0-15 years, seen by a paediatrician with community-acquired pneumonia (CAP) and consistent chest X-ray changes. From 750 children assessed in hospital, incidence of CAP was 14.4 (95% CI 13.4-15.4)/10,000 children per year and 33.8 (95% CI 31.1-36.7) for <5-year-olds; with an incidence for admission to hospital of 12.2 (95% CI 11.3-13.2) and 28.7 (95% CI 26.2-31.4) respectively. Where ascertainment was confirmed, incidence of CAP assessed in hospital was 16.1 (95% CI 14.9-17.3) and 41.0 (95% CI 37.7-44.5) in the 0-4 years age group, whilst incidence for hospital admission was 13.5 (95% CI 12.4-14.6) and 32 (95% CI 29.1-35.1) respectively. In the <5 years age group incidence of lobar pneumonia was 5.6 (95% CI 4.5-6.8)/10,000 per year and severe disease 19.4 (95% CI 17.4-21.7)/10,000 per year. Risk of severe CAP was significantly increased for those aged <5 years (OR 1.50, 95% CI 1.07-2.11) and with prematurity, OR 4.02 (95% CI 1.16-13.85). It also varied significantly by county of residence. This is a unique insight into the burden of hospital assessments and admissions caused by childhood pneumonia in the United Kingdom and will help inform future preventative strategies.

Perception-action coupling in children with and without DCD: Frequency locking between task-relevant auditory signals and motor responses in a dual-motor task.

BACKGROUND: The current research examines the relationship between perceptual and motor processes, known as perception-action or sensorimotor coupling, and the potential differences in perception-action coupling among children with and without Developmental Coordination Disorder (DCD) and adults in a gross-motor co-ordination task (clapping while marching) when a task-relevant driving sensory signal is present. METHODS: Ten children with DCD (7.32 + 0.23 years), eight typically developing (TD) children who were age-, gender- and racially/ethnically matched (6.91 + 0.24 years) and 10 college-aged adults were participants in this study. Participants clapped and marched to an auditory beat at four different frequencies: 0.8, 1.2,1.6 and 2.0 Hz. The relative timing measures of mean relative phase (MRP) and variability of relative phase (VRP) were calculated and compared using 3 (group) x 4 (frequency) x 2 (limb) anovas. Qualitatively, participants were assessed for the presence of absolute coupling (100% + 15% MRP). RESULTS: Statistically significant differences in MRP occurred for coupling, frequency and group, and post hoc analysis indicated that the adult group differed from both the DCD and TD groups, who did not differ from each other. In VRP, there were significant main effects for coupling and group, and a significant interaction between group and frequency, with post hoc analysis indicating the DCD group to be different from the TD and adult groups. Qualitatively, both the adult and TD groups increased in the number of participants who adopt absolute coupling as frequency increases. In contrast, the DCD participants adopt this absolute coupling far less frequently overall; in fact, the number of participants adopting this pattern decreases as frequency increases. CONCLUSIONS: These results indicate that children with DCD have difficulties with both the co-ordination and the control of their perception-action coupling for this particular task.

Abrupt, but not gradual visuomotor distortion facilitates adaptation in children with developmental coordination disorder.

A previous experiment investigating visuomotor adaptation in typically developing children and children with Developmental Coordination Disorder (DCD) suggested poor adaptation to an abruptly induced visuomotor perturbation. In the current study, using a similar center-out drawing task, but administering either an abrupt or a gradual perturbation, and twice as many adaptation trials, we show that typically developing children are well able to successfully update an existing internal model in response to a 60 degrees rotation of the visual feedback, independent of the perturbation condition. Children with DCD, however, updated their internal map more effectively during exposure to an abrupt visuomotor perturbation than to a gradual one. This may suggest that the adaptation process in children with DCD responds differently to small vs. large steps of visuomotor discrepancies. Given the known role of the cerebellum in providing an error signal necessary for updating the internal model in response to a gradual visuomotor distortion, the results of our study add to the growing body of evidence implicating compromised cerebellar function in DCD.

Effects of increased complexity of visuo-motor transformations on children's arm movements.

The effects of increasing complexity of visuo-motor transformations on movement were examined in 4-, 6-, and 8-year-old children and adults. Participants performed a 'center-out' drawing task under three increasingly complex conditions: (1) Normal transformation: The target, line path and hand position were fully visible, in the horizontal plane, throughout the movement. (2) Aligned transformation: The target and line path were displayed horizontally above the workspace, with vision of the arm/hand occluded. (3) Vertical transformation: The target and line paths were presented on a vertical computer monitor with vision of the arm/hand occluded. Results showed that with increasing age, movements became faster, straighter, and smoother. The 4- and 6-year-old children were more variable in their specification of movement direction than the 8-year-old children and the adults, and were also more affected by the complexity of the transformation. This suggested that besides the complexity of the visual transformation, the familiarity/experienced environment might also play a role in 'sharpening' the transformation maps represented in movement planning.

Enhanced vascular responses to adrenomedullin in mice overexpressing receptor-activity-modifying protein 2.

Adrenomedullin (AM) levels are elevated in cardiovascular disease, but little is known of the role of specific receptor components. AM acts via the calcitonin receptor-like receptor (CLR) interacting with a receptor-activity-modifying protein (RAMP). The AM1 receptor is composed of CLR and RAMP2, and the calcitonin gene-related peptide (CGRP) receptor of CLR and RAMP1, as determined by molecular and cell-based analysis. This study examines the relevance of RAMP2 in vivo. Transgenic (TG) mice that overexpress RAMP2 in smooth muscle were generated. The role of RAMP2 in the regulation of blood pressure and in vascular function was investigated. Basal blood pressure, acute angiotensin II-raised blood pressure, and cardiovascular properties were similar in wild-type (WT) and TG mice. However, the hypotensive effect of IV AM, unlike CGRP, was enhanced in TG mice (P<0.05), whereas a negative inotropic action was excluded by left-ventricular pressure-volume analysis. In aorta relaxation studies, TG vessels responded in a more sensitive manner to AM (EC50, 8.0+/-1.5 nmol/L) than WT (EC50, 17.9+/-3.6 nmol/L). These responses were attenuated by the AM receptor antagonist, AM(22-52), such that residual responses were identical in all mice. Remaining relaxations were further inhibited by CGRP receptor antagonists, although neither affected AM responses when given alone. Mesenteric and cutaneous resistance vessels were also more sensitive to AM in TG than WT mice. Thus RAMP2 plays a key role in the sensitivity and potency of AM-induced hypotensive responses via the AM1 receptor, providing evidence that this receptor is a selective target for novel therapeutic approaches.