Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma.

Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.

Instrumental assessment of dynamic postural stability in patients with unilateral vestibular hypofunction during straight, curved, and blindfolded gait.

PURPOSE: To characterise dynamic postural stability of gait in patients with vestibular hypofunction (PwVH) using a sensor-based assessment while performing dynamic tasks and to correlate the results of this evaluation with clinical scales. METHODS: This cross-sectional study involved 22 adults between 18 and 70 years old from a healthcare hospital centre. Eleven patients suffering from chronic vestibular hypofunction (PwVH) and eleven healthy controls (HC) were evaluated through a combined inertial sensor-based and clinical scale assessment. Participants were equipped with five synchronised inertial measurement units (IMUs) (128 Hz, Opal, APDM, Portland, OR, USA): three IMUs were located on the occipital cranium bone, near the lambdoid suture of the head, at the centre of the sternum, and at L4/L5 level, just above the pelvis, and were used to quantify gait quality parameters, while the other two were located slightly above lateral malleoli and used to perform stride and step segmentation. Three different motor tasks were performed in a randomized order: the 10-m Walk Test (10mWT), the Figure of Eight Walk Test (Fo8WT) and the Fukuda Stepping Test (FST). A set of gait quality parameters related to stability, symmetry and smoothness of gait were extracted from IMU data and correlated with the clinical scale scores. PwVH and HC results were compared to test for significant between-group differences. RESULTS: Significant differences were found for the three motor tasks (10mWT, Fo8WT and FST) when comparing PwVH and HC groups. For the 10mWT and the Fo8WT, significant differences between the PwVH and HC groups were found for the stability indexes. Considering the FST, significant differences between the PwVH and HC groups were also found in the stability and symmetry of gait. A significant correlation was found between the Dizziness Handicap Inventory and gait indices during the Fo8WT. CONCLUSIONS: In this study, we characterized the dynamic postural stability alterations during linear, curved, and blindfolded walking/stepping in PwVH combining an instrumental IMU-based with traditional clinical scales approach. Combining instrumental and clinical evaluation for dynamic stability of gait alterations in PwVH is useful in thoroughly evaluating the effects of unilateral vestibular hypofunction.

The pre-launch on-ground characterization of Ma_MISS spectrometer for ExoMars-Rosalind Franklin Rover mission. II. Radiometric calibration.

The Ma_MISS miniaturized spectrometer is integrated within the Drilling System of the ExoMars Rosalind Franklin Rover for Mars exploration. Here we focus on the on ground calibration campaign to obtain radiometric and linearity calibrations of the Ma_MISS instrument, while the first paper dealt with the spectral calibration [De Angelis et al., Rev. Sci. Instrum. 93, 123704 (2022)]. The experimental setup used to carry out radiometric calibration is described, as are the methods used for data processing and key parameter retrieval. In particular, the Spectrometer Transfer Function (Responsivity), Signal-to-Noise Ratio, and detector linearity are determined. In a third paper [De Sanctis et al., Planet. Sci. J. 3, 142 (2022)], validation of the Ma_MISS calibration results through spectral measurements performed on rock and synthetic targets during the radiometric calibration campaign is described.

Constraining the Rosalind Franklin Rover/Ma_MISS Instrument Capability in the Detection of Organics.

The Mars Multispectral Imager for Subsurface Studies (Ma_MISS) instrument is a miniaturized visible and near-infrared spectrometer that is integrated into the drilling system of the ESA Rosalind Franklin rover, which is devoted to subsurface exploration on Mars. Ma_MISS will acquire spectral data on the Martian subsurface from excavated borehole walls. The spectral data collected by Ma_MISS on unexposed rocks will be crucial for determination of the composition of subsurface rocks and optical and physical properties of materials (i.e., grain size). Ma_MISS will further contribute to a reconstruction of the stratigraphic column and acquire data on subsurface geological processes. Ma_MISS data may also inform with regard to the presence of potential biomarkers in the subsurface, given the presence of organic matter that may affect some spectral parameters. In this framework, we performed a wide range of measurements using the laboratory model of the Ma_MISS to investigate mineral/organic mixtures in different proportions. We prepared mixtures by combining kaolinite and nontronite with glycine, asphaltite, polyoxymethylene, and benzoic acid. These organic compounds show different spectral characteristics in the visible and near-infrared; therefore their presence can be detected by the Ma_MISS instrument. Our results indicate that the Ma_MISS instrument can detect organic material down to abundances of around 1 wt %. In particular, the data collected on low-concentration mixtures show that, by analyzing sediments with a grain size smaller than the Ma_MISS spatial resolution, the instrument can still discern those points where organic matter is present from points with exclusive mineral composition. The results also show that a collection of multiple contiguous measurements on a hypothetical borehole wall could help indicate the presence of organic matter in clay-rich soils if present.

Therapeutic educational workshops for caregivers of patients with severe acquired brain injury.

Abstract: Severe acquired brain injury (sABI) leads to a wide range of functional limitations in cognitive, moto and behavioural abilities. These changes impact the patient's family in terms of the feeling of emotional and physical health, social life and financial condition. Caregivers are often intensely involved in the patient's management exposing them to negative effects of caregiving including stress, mood disorders and decreased quality of life. Implementing forms of active involvement of caregivers in the rehabilitative program could be useful. Thus, in the present study, therapeutic educational workshops (TEWs) for caregivers during the post-acute intensive hospitalization were organized during the post-acute intensive hospitalization of patients with sABI. The caregivers were asked to participate in the workshops to actively involve them in the patient's care and neurorehabilitation program. Each workshop session provided indications regarding the management of the patient with aphasia, neglect, behavioural and swallowing disorders. A questionnaire of 22 items has been designed in order to represent possible indicators of usefulness and effectiveness of the TEWs. The primary aim of this study was to develop a reliable and valid questionnaire able to assess the caregivers' satisfaction with the modalities of carrying out the TEW as a novel activity during the post-acute hospitalization of patients with sABI. The second aim was to assess the caregivers' satisfaction with the utility of the TEW as a tool to enhance their skills in the management of patients' disabilities. 100 caregivers of patients with sABI who attended at least one TEW session and completed the questionnaire were included in the analysis. In conclusion the administered questionnaire has proven to be a valid and reliable tool to evaluate sABI caregivers' satisfaction with TEW. Moreover, caregivers were satisfied with the organization of the TEW and with their usefulness in the management of the patients with sABI.

The pre-launch on-ground characterization of Mars Multispectral Imager for Subsurface Studies (Ma_MISS) spectrometer for ExoMars rover mission: Spectral calibration.

The Ma_MISS spectrometer is integrated within the drilling system of the Rosalind Franklin ExoMars rover. This paper reports the on-ground calibration campaign performed on the spectrometer. Here, we focus on the spectral calibration of the instrument. The experimental setup used to carry out calibration is described, and the methods used for data processing and key parameters retrieval are explained. In particular, the spectral parameters such as (i) pixel central wavelengths, (ii) spectral response function, (iii) spectral resolution, (iv) sampling, and (v) range are determined. In a follow-up paper, the linearity and radiometric calibrations are described, while in De Sanctis et al. [Planet. Sci. J. 3, 142 (2022)], the validation of spectral measurements performed on synthetic and natural rock targets is presented.

Introduction to a community dataset from an infrasound array experiment at Mt. Etna, Italy.

Volcanic activity represents a hazard to population and infrastructure worldwide. The study of acoustic waves in the atmosphere by volcanic activity is growing in popularity as an effective tool to monitor and understand the mechanisms of eruptions. In 2019, we deployed two 6-element infrasound arrays at Mt. Etna, Italy, one of the most active volcanoes in the world. Our experiment captured a range of acoustic signals associated with diverse activity ranging from background degassing to energetic Strombolian explosions, lava flows, and atmospheric injection of volcanic ash. Here, we present a description of this valuable, publicly available, research dataset. We document the design and scope of the experiment, report on data availability, and present a brief summary of the activity observed at Mt. Etna during our deployment aiming to facilitate future use of these valuable data. This dataset is the first example of open data from a multiple infrasound array experiment at Mt. Etna and one of the few available globally.

Clinical comparison of a xenogeneic collagen matrix versus subepithelial autogenous connective tissue graft for augmentation of soft tissue around implants.

Dental implant placement is a predictable therapy for replacing teeth. Nevertheless, mechanical, biological, and aesthetic complications frequently occur. The aim of this study was to compare the clinical outcomes of a xenogeneic collagen matrix (XCM) used at the time of implant placement as an alternative to a subepithelial connective tissue graft (SCTG), for soft tissue augmentation. This was a prospective clinical trial with 12 months of follow-up. In the control group, soft tissue augmentation at the time of implant placement was performed with a SCTG, while in the test group, a XCM was employed. At 12 months postoperative, all xenografts showed no postoperative complications. In both groups, a significantly greater thickness was observed on the buccal and occlusal sides from preoperative to 3 months postoperative (P<0.05). No statistically significant difference in pink aesthetic score (P=0.379, 6 months postoperative) or marginal bone loss (P=0.449 at 3 months postoperative, P=0.778 at 6 months postoperative) was observed between the groups. Statistically significant differences in pain perceived by the patients (P<0.0001) and the time to complete the surgical procedure (P=0.0008) were detected. At 12 months after surgery, XCM provided similar clinical results in terms of soft tissue augmentation on the buccal and occlusal sides as compared with the SCTG.

The effects of aquatic therapy during post-acute neurorehabilitation in patients with severe traumatic brain injury: a preliminary randomized controlled trial.

OBJECTIVE: The primary aim is to verify the effectiveness of an aquatic training (AT) in inpatients with severe Traumatic Brain Injury (sTBI) on balance. The secondary aims are to explore the effects on gait, activities of daily living, and quality of life, comparing to a land-based conventional protocol. METHODS: Two-arm, randomized controlled trial. Twenty inpatients with sTBI, Glasgow Coma Scale score ≤8, and Level of Cognitive Functioning ≥7 were recruited and randomly assigned to the aquatic therapy group (ATG) or to the Conventional Training Group (CTG). Patients underwent 12 individual rehabilitation sessions (3 days/week, 4 weeks), in a rehabilitation pool during the post-acute intensive neurorehabilitation. The primary outcome measure was the Berg Balance Scale (BBS). Secondary outcome measures were the Modified Barthel Index (MBI), Disability Rating Scale (DRS), Tinetti Gait Balance Scale (TBG) and Quality of Life After Brain Injury (QOLIBRI). All the evaluations were performed at the baseline and after 4 weeks of training. RESULTS: The within-subjects analysis showed a significant improvement both in ATG and CTG in MBI, BBS, TBG, and QOLIBRI. CONCLUSION: Our results may support the use of AT during post-acute phase to improve motor functions and quality of life in patients with sTBI.

Effectiveness of a sensor-based technology in upper limb motor recovery in post-acute stroke neurorehabilitation: a randomized controlled trial.

Sensor-based technological therapy devices could be a possible neurorehabilitation strategy for motor rehabilitation in patients with stroke during the post-acute hospitalization, especially for treating upper extremities function limitations. The audio-visual feedback devices are characterized by interactive therapy games that allow training the movement of shoulders, elbows, and wrist, measuring the strength and the active range of motion of upper limb, registering data in an electronic database to quantitatively monitoring measures and therapy progress. This study aimed to investigate the effects of sensor-based motor rehabilitation in add-on to the conventional neurorehabilitation for improving the upper limb functions in patients with subacute stroke. Thirty-seven patients were enrolled in the study and randomly assigned to the experimental group and the control group. The training consisting of twelve sessions of upper limb training compared with twelve sessions of upper limb sensory-motor training, without robotic support. Both rehabilitation programs were performed for 40 minutes three times a week, for 4 weeks, in addition to conventional therapy. All patients were evaluated at the baseline (T0) and after 4 weeks of training (T1). The within-subject analysis showed a statistically significant improvement in both groups in all clinical scales. The analysis of effectiveness revealed that, compared with baseline (T0), the improvement percentage in the Modified Barthel Index was greater in the experimental group than the control group. The use of a sensor-based training with audio-video-feedback could be a useful complementary strategy for improving upper limb motor functions in patients with stroke during post-acute neurorehabilitation.

Design, development, and testing of an environmental P-T cell for infrared spectroscopy measurements.

Water absorption bands due to superficially adsorbed molecules often dominate the near-infrared spectra of particulate minerals and rocks, when measured in the laboratory in the reflectance mode. In order to remove this, the spectral effect is thus necessary to acquire spectra of samples in vacuum and at higher temperatures. With the aim to accomplish this task, we developed an environmental cell to perform infrared spectroscopic measurements at controlled pressure-temperature conditions. Currently the cell allows one to measure reflectance spectra in the temperature range from room values up to 300 °C (573 K), in the pressure range of 103-10-6 mbar. The acquisition of spectra continuously in two distinct phases, namely, during a preliminary pumping stage (at room T) and subsequently during a heating stage (in vacuum), permits to highlight and characterize separately the effect of pressure and temperature on infrared spectra.

Modeling Volcanic Eruption Parameters by Near-Source Internal Gravity Waves.

Volcanic explosions release large amounts of hot gas and ash into the atmosphere to form plumes rising several kilometers above eruptive vents, which can pose serious risk on human health and aviation also at several thousands of kilometers from the volcanic source. However the most sophisticate atmospheric models and eruptive plume dynamics require input parameters such as duration of the ejection phase and total mass erupted to constrain the quantity of ash dispersed in the atmosphere and to efficiently evaluate the related hazard. The sudden ejection of this large quantity of ash can perturb the equilibrium of the whole atmosphere triggering oscillations well below the frequencies of acoustic waves, down to much longer periods typical of gravity waves. We show that atmospheric gravity oscillations induced by volcanic eruptions and recorded by pressure sensors can be modeled as a compact source representing the rate of erupted volcanic mass. We demonstrate the feasibility of using gravity waves to derive eruption source parameters such as duration of the injection and total erupted mass with direct application in constraining plume and ash dispersal models.

Malignant ventricular arrhythmias induction by programmed electrical stimulation of the right ventricular outflow tract only during type 1 Brugada ECG maximization.

OBJECTIVE: The role of electrophysiology study in Brugada syndrome (BS) sudden cardiac death risk stratification remains controversial and seems to depend on the phenotypic expression of the channelopathy. Ajmaline has a key role in the diagnosis of BS. We observed that programmed electrical stimulation (PES) of the right ventricular outflow tract (RVOT), only when type 1 BS ECG is unmasked by ajmaline administration, induces ventricular arrhythmias. CASE REPORT: We describe a case of ventricular fibrillation induction by PES of the RVOT when type 1 BS ECG is revealed by ajmaline, in a patient with a baseline dynamic intermittent type 1 and 2 BS ECG. CONCLUSIONS: The heterogeneous clinical presentations of BS are due to the underlying mechanisms. PES of the RVOT during positive ajmaline test maximizes the channelopathy and therefore sudden cardiac death risk-stratification in BS.

Heart Failure in a Dedicated Outpatient Clinic: Results after 58 Month Follow-Up. Can it be Enough?

Incidence of chronic heart failure (HF) is rapidly increasing, approaching a 10 per 1000 rate after 65 years of age. In the last decades, despite pharmacological, interventional and supportive innovations, HF prognosis remained poor, with about 30% of death within one year from the diagnosis. Current guidelines recommend for these patients management programs providing follow-up through dedicated outpatient clinic. Limits of these programs are represented by great difficulties in getting patients adherence, being still too elevated the rate of abandonments. In this paper, we analyzed the impact of 58 months of activity in our dedicated to heart failure outpatient clinic on mortality, hospitalization and abandonment rate. 477 HF patients (346 M, 72.5%, mean age 69.6 years) were enrolled. Mean follow-up and visit were 18.2 and 2.6 months respectively. Total mortality rate was 11.5%, 4% of patients per year. Total hospitalizations for acute HF were 212 and, among all patients left in follow-up, the number of hospitalizations for acute de-compensation significantly decreased from 0.49/patient/year before enrollment to 0.29/patient/year during follow-up (p=0.015). Patients who abandoned outpatient clinic were 94 (19%, 1 abandonment every 23 days), mostly observed over the first months of activity. In conclusion, our patients experienced a major decrease in rates of acute de-compensation and need of in-hospital admissions.

Ventricular fibrillation induction and diffuse abnormal ST-segment response to ajmaline in a patient with apparent pre-existing dynamic right bundle branch block.

OBJECTIVE: ST-segment elevation in the right precordial electrocardiography (ECG) leads in Brugada syndrome (BS) can be unmasked by class I anti-arrhythmic drugs (sodium channel blockers) administration. It is still debated whether this ECG pattern is better explained by abnormal repolarization or ventricular conduction and depolarization. Conduction diseases can conceal type 1 BS-like ECG in standard V1-V3 leads. ECG alterations were found also in alternative leads. The role of electrophysiology study (EPS) in sudden cardiac death risk stratification remains controversial, and could depend on the phenotypic expression of the cardiac sodium channels disease. CASE REPORT: We describe unmasked diffuse J-point and ST-segment anomalies in peripheral and precordial ECG leads and ventricular fibrillation (VF) induction by EPS after ajmaline administration in a patient with pre-existing atypical right bundle branch block (RBBB) concealing subtle anomalies in standard V1-V3 leads. RBBB was influenced by the underlying BS-like ECG associating repolarization anomaly and pre-existing conduction disease. EPS induced VF when RBBB was associated with BS-like ECG, and failed to induce VF when RBBB was present alone. CONCLUSIONS: BS phenotype heterogeneity requires further studies to improve the knowledge of its pathophysiological mechanisms associated with conduction diseases in order to better identify an individual therapy and prognostic stratification.

Efficacy of calcium channel blockers in the treatment of the myocardial bridging: a pilot study.

BACKGROUND: Myocardial Bridging (MB) is defined as a segment of a major epicardial coronary artery, the "tunnelled artery", that goes intramurally through the myocardium beneath the muscle bridge. MATERIALS AND METHODS: A 69-year-old male patient with a story of arterial hypertension and dyslipidemia in treatment with converting enzyme inhibitors (ACE-I), antiplatelet therapy and HMG-CoA reductase inhibitors and calcium channel blockers, presented with anginal-like chest pain and dyspnea. The coronary angiography showed a myocardial bridging and no hemodynamically significant coronary artery disease. RESULTS: On admission in our Department, the exercise cyclo ergometer test was significant for > 3 mm ST segment depression in the anterior and lateral leads (V3, V4, V5, V6) associated with chest pain. The coronary angiography revealed a 40% stenosis of the distal tract of the right coronary artery (RCA), a 30% stenosis of the proximal tract of the left anterior descending artery (LAD) and 40% of the proximal tract of the first diagonal branch. A 30% stenosis in the middle tract of the left circumflex coronary artery (LCX) was then detected. A marked systolic localized narrowing (90%) on the middle tract of the LAD, after the second diagonal branch (a myocardial bridge) was also detected. After eight months, the exercise cyclo ergometer test using a standard Bruce protocol was normal and, after sixteen months, no significant coronary artery disease (< 50%) and no myocardial bridging were detected by the coronary 64-multislice spiral computed tomography. Two years later, the patient was readmitted to our Department because of angina-like chest pain during light exertion in the last two months. The coronary angiography of the right system revealed a 30% stenosis of the proximal tract and a 50% stenosis of the distal tract of the RCA. The coronary angiography of the left system showed a 30% stenosis of the proximal tract of the LAD and 85% of the middle tract of the first diagonal branch. A 40% stenosis in the middle tract of the left circumflex coronary artery (LCX) was then detected. No MB of the middle tract of the LAD was detected, and a bare metal stent (Presillion 2.5 x 12 mm) was deployed in the middle tract of the first diagonal branch. CONCLUSIONS: After 2 years, the administration of the calcium channel blockers has been effective in the treatment of the MB but no effect on the atherosclerotic plaque growth has been demonstrated.

Functional changes cardiovascular: normobaric activity and microgravity in young healthy human subjects.

BACKGROUND: The cardiovascular system works to maintain homeostasis through a series of adaptive responses to physiological requirements. Different self-regulatory mechanism prevent the effects induced by hydrostatic pressure changes on oncotic pressure caused by postural changes. Gravity exerts a strong influence on the postural changes with implications on the cardiovascular system. In orbit, gravity (+Gz) is responsible of mass redistribution of circulating blood flow. The aim of this study was the evaluation of the adaptive responses of cardiovascular system to postural changes with and without the use of the Lower Body Negative Pressure (LBNP). We considered that pressure changes that occur in human body in orbit can be simulated experimentally with use of Tilt-Test (Clino/ortho; Clino/head-down; head-down/ortho). This investigation could be useful for studying the influence on astronauts of long flights. SUBJECTS AND METHODS: We studied in 12 months, 30 young healthy volunteers (20 males, 10 female) during postural change tests. In the first evaluation they were submitted to tilt-test for 40 minutes, remaining in head-up +60 degrees (this state corresponds to a kind of gravitational stress +Gz) and in head-down to -30 degrees (-Gz) for 20 minutes. During the second assessment (after 5 +/- 1 days) all volunteers wear a device that simulate a state of LBNP at -20 mmHg. Afterwards, they were processed to 20 minutes in Head Down -8 degrees and after 2 hours of rest to 20 minutes at -15 degrees. Volunteers were monitored measuring blood pressure, heart rate and by Transthoracic Echocardiogram (TTE). RESULTS: Collected data were elaborated by a statistical analysis. We observed during orthostatic position for 40 min (+60 degrees) without LBNP, lower diameters and volumes of left and right ventricular (p < 0.05) and an increase in heart rate in comparison with the baseline conditions in clinostatism. Despite the reduction of preload volume, the mean value of cardiac output does not vary significantly. In Trendelemburg (-15 degrees) data show a non-significant variation (p > 0.05) of left and right ventricular diameters and volumes, while cardiac output and systolic blood pressure varies significantly (p < 0.05) compared to clinostatic and orthostatic position. With LBNP in head down to -8 degrees and -15 degrees, systolic and diastolic arterial pressure, ventricular volumes and cardiac output were unchanged if compared to values obtained in clinostatism with and without LBNP. If compared to -30 degrees in Trendelemburg without LBNP, data reached statistical significance (p < 0.05). CONCLUSIONS: The cardiovascular system and the autonomic nervous system, respond to postural changes and to volemia alterations, maintaining the physiological cardiac output, in order to preserve the metabolic requirements of body.

Serum transforming growth factor ß1 during diabetes development in non-obese diabetic mice and humans.

Recent data show that regulatory cells with transforming growth factor (TGF)-ß1-dependent activity are able to restore self-tolerance in overtly diabetic non-obese diabetic (NOD) mice. Thus, TGF-ß1 seems to have a relevant role in protection from autoimmune diabetes. Our aim was to investigate the possible significance of serum TGF-ß1 measurement in the natural history of diabetes in NOD mice, as well as in children positive for at least one islet-related antibody. Serum TGF-ß1 (both total and active) was measured by enzyme-linked immunosorbent assay at monthly intervals in 26 NOD mice during the spontaneous development of diabetes and, on a yearly basis, in nine siblings of patients with type 1 diabetes (T1D) with a follow-up of 4 years. Diabetes appeared between the 12th week of age and the end of the study period (36 weeks) in 17 mice. TGF-ß1 serum level variations occurred in the prediabetic period in both NOD mice and humans and diabetes diagnosis followed a continuing reduction of active TGF-ß1 (aTGF-ß1) serum levels. In mice, aTGF-ß1 serum levels measured at 4 weeks of age correlated positively with severity of insulitis, and negatively with percentage of insulin-positive cells. Our findings suggest that in NOD mice serum TGF-ß1 levels during the natural history of the diabetes reflect the course of islet inflammation. The measurement of aTGF-ß1 in islet-related antibody-positive subjects may provide insights into the natural history of prediabetic phase of T1D.

Inhaled ammonium persulphate inhibits non-adrenergic, non-cholinergic relaxations in the guinea pig isolated trachea.

BACKGROUND: Persulphates can act both as irritants and sensitizers in inducing occupational asthma. A dysfunction of nervous control regulating the airway tone has been hypothesized as a mechanism underlying bronchoconstriction in asthma. OBJECTIVES: It was the aim of this study to investigate whether inhaled ammonium persulphate affects the non-adrenergic, non-cholinergic (NANC) inhibitory innervation, the cholinergic nerve-mediated contraction or the muscular response to the spasmogens, carbachol or histamine, in the guinea pig epithelium-free, isolated trachea. METHODS: Male guinea pigs inhaled aerosols containing ammonium persulphate (10 mg/m(3) for 30 min for 5 days during 3 weeks). Control animals inhaled saline aerosol. NANC relaxations to electrical field stimulation at 3 Hz were evaluated in whole tracheal segments as intraluminal pressure changes. Drugs inactivating peptide transmission, nitric oxide synthase, carbon monoxide production by haem oxygenase-2 and soluble guanylyl cyclase were used to assess the involvement of various inhibitory neurotransmitters. Carbachol and histamine cumulative concentration-response curves were obtained. RESULTS: In both groups, nitric oxide and carbon monoxide participated to the same extent as inhibitory neurotransmitters. In exposed animals, the tracheal NANC relaxations were reduced to 45.9 +/- 12.1% (p < 0.01). The cholinergic nerve-mediated contractions to electrical field stimulation and the muscular response to histamine were not modified by ammonium persulphate exposure. The muscular response to carbachol was unaffected up to 1 microM. Conversely, the response to the maximal concentration of carbachol (3 microM) was increased (p < 0.01). CONCLUSION: Ammonium persulphate inhalation at high concentrations impairs the nervous NANC inhibitory control in the guinea pig airways. This may represent a novel mechanism contributing to persulphate-induced asthma.