What kind of illness is anorexia nervosa? Revisited: some preliminary thoughts to finding a cure.

Two decades have elapsed since our publication of 'What kind of illness is anorexia nervosa?'. The question remains whether our understanding of anorexia nervosa and its treatment thereof has evolved over this time. The verdict is disappointing at best. Our current gold standard treatments remain over-valued and clinical outcomes are modest at best. Those in our field are haunted by the constant reminder that anorexia nervosa carries the highest mortality rate of any psychiatric disorder. This cannot continue and demands immediate action. In this essay, we tackle the myths that bedevil our field and explore a deeper phenotyping of anorexia nervosa. We argue that we can no longer declare agnostic views of the disorder or conceive treatments that are "brainless": it is incumbent upon us to challenge the prevailing zeitgeist and reconceptualise anorexia nervosa. Here we provide a roadmap for the future.

Examining bi-directional change in sleep and depression symptoms in individuals receiving routine psychological treatment.

BACKGROUND: Sleep disturbance is a common symptom of depression. There is conflicting evidence whether improvements in sleep might impact depressive symptoms, or whether treating the core depressive symptoms might improve sleep disturbance. This study explored the bi-directional impact of sleep and depressive symptom change among individuals receiving psychological treatment. METHODS: Session-by-session change in sleep disturbance and depressive symptom severity scores were explored in patients receiving psychological therapy for depression from Improving Access to Psychological Therapies services in England. Bi-directional change in sleep disturbance and depressive symptoms was modelled using random-intercept cross-lagged panel models with items from the PHQ-9. RESULTS: The sample included 17,732 adults that had received three or more treatment sessions. Both depressive symptoms and sleep disturbance scores decreased. Between initial timepoints, higher sleep disturbance was associated with lower depression scores, but after this point positive cross-lagged effects were observed for both the impact of sleep disturbance on later depressive symptoms, and depressive symptoms on later sleep disturbance scores. The magnitude of effects suggested depressive symptoms may have more impact on sleep than the reverse, and this effect was larger in sensitivity analyses. CONCLUSIONS: Findings provide evidence that psychological therapy for depression results in improvements in core depressive symptoms and sleep disturbance. There was some evidence that depressive symptoms may have more impact on sleep disturbance scores at the next therapy session, than sleep disturbance does on later depressive symptoms. Targeting the core symptoms of depression initially may optimise outcomes, but further research is needed to elucidate these relationships.

Transdiagnostic symptom dynamics during psychotherapy.

Psychotherapy is an effective treatment for many common mental health problems, but the mechanisms of action and processes of change are unclear, perhaps driven by the focus on a single diagnosis which does not reflect the heterogeneous symptom experiences of many patients. The objective of this study was to better understand therapeutic change, by illustrating how symptoms evolve and interact during psychotherapy. Data from 113,608 patients from psychological therapy services who completed depression and anxiety symptom measures across three to six therapy sessions were analysed. A panel graphical vector-autoregression model was estimated in a model development sample (N = 68,165) and generalizability was tested in a confirmatory model, fitted to a separate (hold-out) sample of patients (N = 45,443). The model displayed an excellent fit and replicated in the confirmatory holdout sample. First, we found that nearly all symptoms were statistically related to each other (i.e. dense connectivity), indicating that no one symptom or association drives change. Second, the structure of symptom interrelations which emerged did not change across sessions. These findings provide a dynamic view of the process of symptom change during psychotherapy and give rise to several causal hypotheses relating to structure, mechanism, and process.

Translating evidence-based treatment for digital health delivery: a protocol for family-based treatment for anorexia nervosa using telemedicine.

BACKGROUND: Family-based treatment (FBT) is an efficacious outpatient intervention for young people diagnosed with Anorexia Nervosa (AN). To date, treatment to protocol has relied on standard face-to-face delivery. Face-to-face therapy is subject to geographic, temporal and human factors, rendering it particularly susceptible to inequities and disruption. This has resulted in poorer service provision for rural and regional families, and recently a significant challenge to providing face-to-face services during the COVID-19 global pandemic. The present study examines whether FBT for AN can be successfully translated to a digital delivery platform to address these access issues. METHOD: Forty young people aged 12 to 18 years who meet DSM-5 diagnostic criteria for AN, and live in a rural or regional setting, will along with their family be recruited to the study. Trained therapists will provide 18 sessions of FBT over 9 months via telemedicine to the home of the young person and their family. The analysis will examine treatment effectiveness, feasibility, acceptability, and cost-effectiveness. DISCUSSION: The study addresses the treatment needs of families not able to attend face-to-face clinical services for evidence-based treatment for eating disorders. This might be due to several barriers, including a lack of local services or long travel distances to services. There has been a recent and unprecedented demand for telemedicine to facilitate the continuity of care during COVID-19 despite geographical circumstances. If delivering treatment in this modality is clinically and economically effective and feasible, it will facilitate access to potentially lifesaving, evidence-based treatments for families formerly unable to access such care and provide evidence for the continuity of services when and where face-to-face treatment is not feasible.

Adapting IAPT services to support frontline NHS staff during the Covid-19 pandemic: the Homerton Covid Psychological Support (HCPS) pathway.

The Coronavirus (Covid-19) pandemic is exerting unprecedented pressure on NHS Health and Social Care provisions, with frontline staff, such as those of critical care units, encountering vast practical and emotional challenges on a daily basis. Although staff are being supported through organisational provisions, facilitated by those in leadership roles, the emergence of mental health difficulties or the exacerbation of existing ones amongst these members of staff is a cause for concern. Acknowledging this, academics and healthcare professionals alike are calling for psychological support for frontline staff, which not only addresses distress during the initial phases of the outbreak but also over the months, if not years, that follow. Fortunately, mental health services and psychology professional bodies across the United Kingdom have issued guidance to meet these needs. An attempt has been made to translate these sets of guidance into clinical provisions via the recently established Homerton Covid Psychological Support (HCPS) pathway delivered by Talk Changes (Hackney & City IAPT). This article describes the phased, stepped-care and evidence-based approach that has been adopted by the service to support local frontline NHS staff. We wish to share our service design and pathway of care with other Improving Access to Psychological Therapies (IAPT) services who may also seek to support hospital frontline staff within their associated NHS Trusts and in doing so, lay the foundations of a coordinated response. KEY LEARNING AIMS: (1)To understand the ways staff can be psychologically and emotionally impacted by working on the frontline of disease outbreaks.(2)To understand the ways in which IAPT services have previously supported populations exposed to crises.(3)To learn ways of delivering psychological support and interventions during a pandemic context based on existing guidance and research.

Time-intensive behavioural activation for depression: A multiple baseline study.

BACKGROUND AND OBJECTIVES: Depression is the second leading cause of disability, worldwide, and increasing access to its effective/preferred treatment requires more attention. Behavioural activation and time-intensive treatment delivery both show promise in this regard, yet research into their combination is limited. This study aimed to investigate the feasibility, effectiveness, and acceptability of time-intensive behavioural activation (BA) for depression METHODS: Eight adults with major depressive disorder were recruited from three outpatient IAPT services in London. The study employed a single case experimental design with multiple baselines. All participants completed time-intensive BA, consisting of up to seven twice weekly sessions with daily prompting in-between and three optional booster sessions. Idiographic, standardised and process measures of depression symptomatology were collected. RESULTS: Treatment recruitment and retention indicated that the intervention was feasible. Visual and statistical analyses showed that relative to baseline, 6 out of 8 participants made significant improvements in all idiographic symptoms of depression following the intervention. According to standardised measures of depression, four out of eight participants were considered treatment responders. Five participants completed follow-up measures and the majority of progress was maintained after the withdrawal of the intervention. The intervention was also considered highly acceptable by participants and therapists. LIMITATIONS: Conclusions cannot be drawn about the generalizability or the long-term durability of the findings CONCLUSIONS: Overall this study provides new, but tentative evidence highlighting the potential of time-intensive BA as a feasible, effective and acceptable treatment for some adult outpatients with depression. The findings now warrant further, more rigorous evaluation of the treatment.

A randomized controlled trial of in-patient treatment for anorexia nervosa in medically unstable adolescents.

BACKGROUND: Anorexia nervosa (AN) is a serious disorder incurring high costs due to hospitalization. International treatments vary, with prolonged hospitalizations in Europe and shorter hospitalizations in the USA. Uncontrolled studies suggest that longer initial hospitalizations that normalize weight produce better outcomes and fewer admissions than shorter hospitalizations with lower discharge weights. This study aimed to compare the effectiveness of hospitalization for weight restoration (WR) to medical stabilization (MS) in adolescent AN. METHOD: We performed a randomized controlled trial (RCT) with 82 adolescents, aged 12-18 years, with a DSM-IV diagnosis of AN and medical instability, admitted to two pediatric units in Australia. Participants were randomized to shorter hospitalization for MS or longer hospitalization for WR to 90% expected body weight (EBW) for gender, age and height, both followed by 20 sessions of out-patient, manualized family-based treatment (FBT). RESULTS: The primary outcome was the number of hospital days, following initial admission, at the 12-month follow-up. Secondary outcomes were the total number of hospital days used up to 12 months and full remission, defined as healthy weight (>95% EBW) and a global Eating Disorder Examination (EDE) score within 1 standard deviation (s.d.) of published means. There was no significant difference between groups in hospital days following initial admission. There were significantly more total hospital days used and post-protocol FBT sessions in the WR group. There were no moderators of primary outcome but participants with higher eating psychopathology and compulsive features reported better clinical outcomes in the MS group. CONCLUSIONS: Outcomes are similar with hospitalizations for MS or WR when combined with FBT. Cost savings would result from combining shorter hospitalization with FBT.

Response characteristics for thermal and pressure devices commonly used for monitoring nasal and oral airflow during sleep studies.

We examined thermocouple and pressure cannulae responses to oral and nasal airflow using a polyester model of a human face, with patent nasal and oral orifices instrumented with a dual thermocouple (F-ONT2A, Grass) or a dual cannula (0588, Braebon) pressure transducer (± 10 cm H2O, Celesco) system. Tidal airflow was generated using a dual compartment facemask with pneumotachographs (Fleisch 2) connected to the model orifices. During nasal breathing: thermocouple amplitude = 0.38 Ln [pneumotachograph amplitude] + 1.31 and pressure cannula amplitude = 0.93 [pneumotachograph amplitude](2.15); during oral breathing: thermocouple amplitude = 0.44 Ln [pneumotachograph amplitude] + 1.07 and pressure cannula amplitude = 0.33 [pneumotachograph amplitude](1.72); (all range ∼ 0.1-∼ 4.0 L s(-1); r(2) > 0.7). For pneumotachograph amplitudes <1 L s(-1) (linear model) change in thermocouple amplitude/unit change in pneumotachograph amplitude was similar for nasal and oral airflow, whereas nasal pressure cannula amplitude/unit change in pneumotachograph amplitude was almost four times that for oral. Increasing oral orifice area from 0.33 cm(2) to 2.15 cm(2) increased oral thermocouple amplitude/unit change in pneumotachograph amplitude by ∼ 58% but decreased pressure cannula amplitude/unit change in pneumotachograph amplitude by 49%. For pneumotachograph amplitudes up to 1 L s(-1), alterations in inspiratory/expiratory ratios or total respiratory time did not affect the sensitivity of either nasal or oral pressure cannulae or the nasal thermocouple, but the oral thermocouple sensitivity was influenced by respiratory cycle time. Different nasal and oral responses influence the ability of these systems to quantitatively assess nasal and oral airflow and oro-nasal airflow partitioning.

Pitot-tube flowmeter for quantification of airflow during sleep.

The gold-standard pneumotachograph is not routinely used to quantify airflow during overnight polysomnography due to the size, weight, bulkiness and discomfort of the equipment that must be worn. To overcome these deficiencies that have precluded the use of a pneumotachograph in routine sleep studies, our group developed a lightweight, low dead space 'pitot flowmeter' (based on pitot-tube principle) for use during sleep. We aimed to examine the characteristics and validate the flowmeter for quantifying airflow and detecting hypopneas during polysomnography by performing a head-to-head comparison with a pneumotachograph. Four experimental paradigms were utilized to determine the technical performance characteristics and the clinical usefulness of the pitot flowmeter in a head-to-head comparison with a pneumotachograph. In each study (1-4), the pitot flowmeter was connected in series with a pneumotachograph under either static flow (flow generator inline or on a face model) or dynamic flow (subject breathing via a polyester face model or on a nasal mask) conditions. The technical characteristics of the pitot flowmeter showed that, (1) the airflow resistance ranged from 0.065 ± 0.002 to 0.279 ± 0.004 cm H(2)O L(-1) s(-1) over the airflow rates of 10 to 50 L min(-1). (2) On the polyester face model there was a linear relationship between airflow as measured by the pitot flowmeter output voltage and the calibrated pneumotachograph signal a (ß(1) = 1.08 V L(-1) s(-1); ß(0) = 2.45 V). The clinically relevant performance characteristics (hypopnea detection) showed that (3) when the pitot flowmeter was connected via a mask to the human face model, both the sensitivity and specificity for detecting a 50% decrease in peak-to-peak airflow amplitude was 99.2%. When tested in sleeping human subjects, (4) the pitot flowmeter signal displayed 94.5% sensitivity and 91.5% specificity for the detection of 50% peak-to-peak reductions in pneumotachograph-measured airflow. Our data validate the pitot flowmeter for quantification of airflow and detecting breathing reduction during polysomnographic sleep studies. We speculate that quantifying airflow during sleep can differentiate phenotypic traits related to sleep disordered breathing.

Saliva production and surface tension: influences on patency of the passive upper airway.

Pharyngeal patency is influenced by the surface tension (gamma) of the upper airway lining liquid (UAL), of which saliva is a major component. We investigated the influences of saliva production on gamma of the UAL, and upper airway re-opening and closing pressures. In 10 supine, male, anaesthetized, tracheostomised, mechanically ventilated New Zealand White rabbits, we measured re-opening and closing of the passive isolated upper airway at baseline and following graded (cumulative) doses of methacholine or atropine. Upper airway liquid volume index (UALVI) was assessed using a standardized suction procedure (secretion weight obtained per second) expressed as the natural logarithm (LnUALVI). The gamma of UAL samples were measured using the 'pull-off' force technique. Across all animals, baseline values were: LnUALVI -6.2 (-8.6 to -5.4) median (interquartile range), gamma of UAL 58.9 (56.6-59.9) mN m(-1), re-opening 8.6 (6.9-11.1) cmH(2)O, and closing pressures 3.2 (1.8-5.7) cmH(2)O. LnUALVI increased by approximately 0.17 per microg kg(-1) methacholine and decreased by approximately 0.14 per 100 microg kg(-1) atropine (both P < 0.03, linear mixed effects modelling). Surface tension was unchanged by methacholine but increased by approximately 0.6 mN m(-1) per 100 microg kg(-1) atropine (P < 0.004). When data were analysed across all animals, both re-opening and closing pressures increased as surface tension increased (by approximately 0.4 cmH(2)O mN(-1) and by approximately 0.7 cmH(2)O mN(-1), respectively; both P < 0.05). We conclude that saliva production influences upper airway mechanical properties partly via alterations in gamma of UAL. We speculate that in obstructive sleep apnoea, altered autonomic activity may reduce saliva production and increase surface tension of the upper airway lining liquid, thus increasing the likelihood of upper airway obstruction.

Initiating oral breathing in response to nasal loading: asthmatics versus healthy subjects.

Factors influencing nasal versus oral breathing in asthmatics are not well understood. The current authors hypothesised that asthmatic subjects have enhanced perception of nasal threshold loads, and switch from nasal to oral breathing at a lower load than healthy subjects. In total, 15 mild asthmatic and 20 healthy control subjects breathed nasally via an inspiratory threshold loading device. Nasal loading was progressively increased until subjects switched to oral breathing. Load perception at switching was rated using a Borg scale. Nasal resistance was measured using posterior rhinomanometry. The protocol was repeated before and after nasal decongestant administration in subgroups of 10 healthy control and six asthmatic subjects. Inspiratory nasal resistance was within normal limits for most subjects and was not significantly different between asthmatics and healthy controls. Compared with controls, asthmatics switched to oral breathing at a significantly lower nasal load but rated "difficulty breathing in" at the same level. Decongestant significantly lowered nasal resistance but did not change the nasal load initiating switching in either subgroup. Enhanced perception of nasal loading may trigger increased oral breathing in asthmatics, potentially enhancing exposure to nonconditioned inhaled gas and contributing to the occurrence and/or severity of bronchoconstrictive exacerbations.

Traditional and patient-centred outcomes with three classes of asthma medication.

Lung function is commonly used as the primary endpoint in asthma clinical trials, but it may not reflect changes which are important to patients. The present study compared changes in, and relationships between, traditional and patient-centred end-points during treatment with three classes of asthma medication. Subjects with mild-to-moderate asthma were randomised to double-blind, double-dummy crossover treatment with eformoterol 12 microg b.i.d. or montelukast 10 mg q.d., then single-blind treatment with fluticasone 250 microg b.i.d./placebo capsules, with 6-week treatment periods and 1-week washouts. Individual "traditional" end-points (symptoms, reliever use, forced expiratory volume in one second per cent predicted, morning peak expiratory flow, airway hyperresponsiveness) and "patient-centred" end-points (asthma control questionnaire, quality of life, patient global assessments) were assessed. Principal component analysis and linear modelling were used to explore overall rank orders for treatment, and relationships between outcomes. A total of 58 subjects were randomised. The rank order of benefit from eformoterol and fluticasone differed for three factors derived from principal component analysis (eformoterol>fluticasone for symptom/reliever use factor, fluticasone>eformoterol for lung function factor, eformoterol=fluticasone for patient-centred factor). Montelukast was ranked third for all three factors. A significant relationship between patient-based variables and lung function was found only for montelukast treatment. In asthma treatment, traditional end-points do not fully capture patient-centred benefits, and the relationship between end-points differs with medication class.

Sensitivity of human gamma interferon assay and tuberculin skin testing for detecting infection with Mycobacterium tuberculosis in patients with culture positive tuberculosis.

SETTING: Nine university-affiliated chest clinics in Australia. OBJECTIVE: To evaluate the sensitivity of a whole blood human gamma-interferon assay (HGIA, QuantiFERON-TB) for specific T lymphocyte responses and Tuberculin skin testing (TST) for the detection of Mycobacterium tuberculosis infection in subjects with culture-proven M. tuberculosis disease (TBCP). DESIGN: Prospective testing of 129 patients with recent TBCP and 100 patients with non-tuberculosis lung disease (NTBLD). RESULTS: Using a defined level of specific IFN-gamma production and TST 10mm as positive cut-offs, the sensitivity of HGIA was 81% compared to 89% for TST (p=0.06). When positive responses in both TST and HGIA were combined, 96% of TB patients were detected. For the NTBLD group, 43% of whom were born overseas, 73% were negative for both the HGIA and TST. Prior immunization with M. bovis (bacille Calmette-Guerin) (BCG) or the type of TB had no effect on the sensitivities of the assays. For those treated for <2 months, the sensitivities for both assays were 84%, but for those treated for >2 months the sensitivity of TST (90%) tended to be higher than for HGIA (81%) (p=0.07). The distribution of TST results in TB patients showed a broad peak between 10 and 25 mm, while the results in the HGIA were bimodal in both TB and NTBLD patients. CONCLUSION: HGIA may prove an alternative to skin testing for detecting M. tuberculosis infection in certain settings.

Older individuals have increased oro-nasal breathing during sleep.

Breathing route during sleep has been studied very little, however, it has potential importance in the pathophysiology of sleep disordered breathing. Using overnight polysomnography, with separate nasal and oral thermocouple probes, data were obtained from 41 subjects (snorers and nonsnorers; 25 male and 16 female; aged 20-66 yrs). Awake, upright, inspiratory nasal resistance (Rn) was measured using posterior rhinomanometry. Each 30-s sleep epoch (not affected by apnoeas/hypopnoeas) was scored for presence of nasal and/or oral breathing. Overnight, seven subjects breathed nasally, one subject oro-nasally and the remainder switched between nasal and oro-nasal breathing. Oral-only breathing rarely occurred. Nasal breathing epochs were 55.79 (69.78) per cent of total sleep epochs (%TSE; median (interquartile range)), a value not significantly different to that for oro-nasal (TSE: 44.21 (68.66)%). Oro-nasal breathing was not related to snoring, sleep stage, posture, body mass index, height, weight, Rn (2.19 (1.77) cm H2O x L(-1) x sec(-1)) or sex, but was positively associated with age. Subjects > or = 40 yrs were approximately six times more likely than younger subjects to spend >50% of sleep epochs utilising oro-nasal breathing. Ageing is associated with an increasing occurrence of oro-nasal breathing during sleep.

Specific targeting, biodistribution, and lack of immunogenicity of chimeric anti-GD3 monoclonal antibody KM871 in patients with metastatic melanoma: results of a phase I trial.

PURPOSE: KM871 is a chimeric monoclonal antibody against the ganglioside antigen GD3, which is highly expressed on melanoma cells. We conducted an open-label, dose escalation phase I trial of KM871 in patients with metastatic melanoma. PATIENTS AND METHODS: Seventeen patients were entered onto one of five dose levels (1, 5, 10, 20, and 40 mg/m2). Patients received three infusions of KM871 at 2-week intervals, with the first infusion of KM871 trace-labeled with indium-111 (111In) to enable assessment of biodistribution in vivo. Biopsies of metastatic melanoma sites were performed on days 7 to 10. RESULTS: Fifteen of 17 patients completed a cycle of three infusions of KM871. No dose-limiting toxicity was observed during the trial; the maximum-tolerated dose was therefore not reached. Three patients (at the 1-, 5-, and 40-mg/m2 dose levels) developed pain and/or erythema at tumor sites consistent with an inflammatory response. No normal tissue uptake of 111In-KM871 was observed, and tumor uptake of 111In-KM871 was observed in all lesions greater than 1.5 cm (tumor biopsy 111KM871 uptake results: range, 0.001% to 0.026% injected dose/g). The ratio of maximum tumor to normal tissue was 15:1. Pharmacokinetic analysis revealed a 111In-KM871 terminal half-life of 7.68 +/- 2.94 days. One patient had a clinical partial response that lasted 11 months. There was no serologic evidence of human antichimeric antibody in any patient, including one patient who received 16 infusions over a 12-month period. CONCLUSION: This study is the first to demonstrate the biodistribution and specific targeting of an anti-GD3 antibody to metastatic melanoma in patients. The long half-life and lack of immunogenicity of KM871 makes this antibody an attractive potential therapy for patients with metastatic melanoma.

Hypertonic saline alters ion transport across the human airway epithelium.

Aerosolized hypertonic saline is currently being investigated as a new agent for the treatment of impaired mucociliary clearance which occurs in many respiratory diseases. Mannitol aerosols, in particular dry powder inhalers, have been proposed as an alternative treatment to saline, offering the same osmotic load with other benefits. However, the effects of these hypertonic aerosols on airway epithelial ion transport processes have not been tested in human subjects in vivo. This report examines the effect of these solutions on airway ion transport using the nasal potential difference (PD) technique. Seven healthy nonsmoking adult volunteers were studied. On different days, a dose-response curve was constructed for the saline added to Krebs N-[2-hydroxyethyl] piperazine-N'-[2-ethanesulphonic acid] (HEPES) diluent. The reversibility of this saline effect was measured, and the response to additional saline (500 mM) and mannitol (1 M) compared. Hypertonic saline decreased nasal PD in a dose-related manner, with mean (SEM) decreases in PD (less negative) of 6.6 (1.5), 7.6 (1.6), 10.0 (2.0), 13.1 (2.9) and 14.8 (3.2) mV (n =4) for addition of 150 mM, 250 mM, 500 mM, 1,200 mM and 2,000 mM NaCl to the Krebs HEPES diluent, respectively. The effect of hypertonic saline was fully reversible with washout for 3 min (presaline 15.9 (0.5) mV, postwashout 15.8 (1.1) mV, (n=4)). The hypertonic saline response was rapid in onset, sustained for at least 4 min, and decreased PD from 13.7 (1.7) mV to 5.1 (1.3) mV (n = 7, p < 0.001). In contrast, addition of mannitol to the perfusate did not significantly alter nasal PD, with a nonsignificant trend towards an increase (more negative) in the PD, (premannitol 13.9 (1.6) mV, postmannitol 15.3 (2.0) mV, n=7). As the osmotic stimulus of the 1 M mannitol is similar to that of the 500 mM sodium chloride, the divergent nasal potential difference responses suggest that the response to the saline was specific to the sodium chloride itself and not the simultaneous change in osmolarity. This demonstrates that the human airway epithelium in vivo can respond to topical hypertonic saline independent of the altered osmolarity.

Synthesis of a statistically exhaustive fluorescent peptide substrate library for profiling protease specificity.

A statistically exhaustive, 8800 compound tripeptidal amidomethylcoumarin library was synthesized as discreet compounds using solid-phase combinatorial chemistry. A subset of the compounds was purified by HPLC and tested in a high-throughput fluorometric assay against several known serine and cysteine proteases to demonstrate the utility of this library for profiling protease substrate specificity.

Nasal resistance and flow resistive work of nasal breathing during exercise: effects of a nasal dilator strip.

Using posterior rhinomanometry, we measured nasal airflow resistance (Rn) and flow-resistive work of nasal breathing (WONB), with an external nasal dilator strip (ENDS) and without (control), in 15 healthy adults (6 men, 9 women) during exclusive nasal breathing and graded (50-230 W) exercise on a cycle ergometer. ENDS decreased resting inspiratory and/or expiratory Rn (at 0.4 l/s) by >0.5 cmH(2)O. l(-1). s in 11 subjects ("responders"). Inspired ventilation (VI) increased with external work rate, but tended to be greater with ENDS. Inspiratory and expiratory Rn (at 0.4 l/s) decreased as VI increased but, in responders, tended to remain lower with ENDS. Inspiratory (but not expiratory) Rn at peak nasal airflow (Vn) increased as VI increased but, again, was lower with ENDS. At a VI of approximately 35 l/min, ENDS decreased flow limitation and hysteresis of the inspiratory transnasal pressure-flow curve. In responders, ENDS reduced inspiratory WONB per breath and inspiratory nasal power values during exercise. We conclude that ENDS stiffens the lateral nasal vestibule walls and, in responders, may reduce the energy required for nasal ventilation during exercise.