Very Rapid Improvement in Extended Nitric Oxide Parameters Is Associated With Clinical and Functional Improvement in Patients With Chronic Rhinosinusitis With Nasal Polyps Treated With Dupilumab.

BACKGROUND AND OBJECTIVE: Dupilumab, an anti-IL-4 receptor a monoclonal antibody, was recently approved for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate-to-severe asthma. Onset of its clinical effects is rapid. CRSwNP is characterized by extended type 2 inflammatory involvement that can be assessed using extended nitric oxide analysis. We investigated whether dupilumab was associated with a rapid improvement in extended nitric oxide parameters, lung function, and clinical outcomes in patients with CRSwNP. METHODS: Consecutive patients with CRSwNP and an indication for dupilumab were evaluated for extended nitric oxide analysis (exhaled, FeNO; bronchial, JawNO; alveolar, CalvNO; nasal, nNO) and lung function 15 and 30 days after initiation of treatment and for clinical outcomes (nasal polyps score [NPS], quality of life questionnaires, visual analog scale [VAS] for the main symptoms, and the Asthma Control Test [ACT]) 30 days after initiation of treatment. RESULTS: We enrolled 33 patients. All extended nitric oxide and lung function parameters improved significantly after 15 days of treatment, remaining stable at 30 days. Scores on the NPS, VAS for the main RSwNP symptoms, quality of life questionnaires, and the ACT improved significantly 30 days after initiation of treatment. CONCLUSION: Dupilumab is associated with very rapid improvement in type 2 inflammation in all airway areas. This is associated with improved lung function and clinical parameters in patients with CRSwNP.

Very Rapid Improvement in Extended Nitric Oxide Parameters Is Associated With Clinical and Functional Improvement in Patients With Chronic Rhinosinusitis With Nasal Polyps Treated With Dupilumab

Background: Dupilumab, an anti–IL-4 receptor a monoclonal antibody, was recently approved for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate-to-severe asthma. Onset of its clinical effects is rapid. CRSwNP is characterized by extended type 2 inflammatory involvement that can be assessed using extended nitric oxide analysis. Objectives: We investigated whether dupilumab was associated with a rapid improvement in extended nitric oxide parameters, lung function, and clinical outcomes in patients with CRSwNP. Methods: Consecutive patients with CRSwNP and an indication for dupilumab were evaluated for extended nitric oxide analysis (exhaled, FeNO; bronchial, JawNO; alveolar, CalvNO; nasal, nNO) and lung function 15 and 30 days after initiation of treatment and for clinical outcomes (nasal polyps score [NPS], quality of life questionnaires, visual analog scale [VAS] for the main symptoms, and the Asthma Control Test [ACT]) 30 days after initiation of treatment. Results: We enrolled 33 patients. All extended nitric oxide and lung function parameters improved significantly after 15 days of treatment, remaining stable at 30 days. Scores on the NPS, VAS for the main CRSwNP symptoms, quality of life questionnaires, and the ACT improved significantly 30 days after initiation of treatment. Conclusions: Dupilumab is associated with very rapid improvement in type 2 inflammation in all airway areas. This is associated with improved lung function and clinical parameters in patients with CRSwNP. (AU)

Antecedentes: El dupilumab, un anticuerpo monoclonal anti-IL-4 receptor alfa, ha sido aprobado recientemente para el tratamiento de la rinosinusitis crónica con pólipos nasales (CRSwNP) y asma de moderada a grave, demostrando un inicio rápido de los efectos clínicos. La CRSwNP se caracteriza por un infiltrado extenso inflamatorio de tipo 2 que puede evaluarse mediante el análisis de óxido nítrico exhalado extendido. Objetivos: En este estudio, investigamos si dupilumab se asocia con una mejora rápida en los parámetros de óxido nítrico extendido, la función pulmonar y los resultados clínicos en pacientes con CRSwNP. Métodos: Se incluyeron pacientes consecutivos con CRSwNP e indicación para ser tratados con dupilumab y fueron evaluados mediante el análisis de óxido nítrico extendido (exhalado, FENO; bronquial, JawNO y alveolar, componentes CalvNO; nasal, nNO) y función pulmonar, 15 y 30 días después del inicio del tratamiento; y en el caso de las variables clínicas (puntuación del tamaño de los pólipos nasales [NPS]; cuestionarios de calidad de vida; escalas analógicas visuales [EVA] para los principales síntomas principales, prueba de control del asma [ACT]) solo después de 30 días de iniciado el tratamiento. Resultados: Se incluyeron 33 pacientes. Todos los parámetros del análisis extendido del óxido nítrico y la función pulmonar mejoraron significativamente después de 15 días de tratamiento, permaneciendo estables a los 30 días de tratamiento. El NPS, las EVA para los principales síntomas de CRSwNP, el cuestionario de calidad de vida y el ACT mejoraron significativamente después de 30 días de inicio del tratamiento. Conclusiones: En pacientes con CRSwNP, el tratamiento con dupilumab se asocia con una mejoría muy rápida en la inflamación tipo 2 en todos los compartimentos de las vías respiratorias y esto se asocia con una mejor función pulmonar y los parámetros clínicos. (AU)

Very rapid improvement of extended nitric oxide parameters, associated with clinical and functional betterment, in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) treated with Dupilumab.

BACKGROUND AND OBJECTIVE: Background: Dupilumab, an anti-IL-4 receptor alpha monoclonal antibody, has been recently approved for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate to severe asthma, demonstrating a rapid onset of clinical effects. CRSwNP is characterized by an extended type-2 inflammatory involvement that can be assessed by extended nitric oxide analysis. Objective: In this study we investigated whether Dupilumab is associated with a rapid improvement in extended nitric oxide parameters, lung function and clinical outcomes in patients with CRSwNP. METHODS: : Consecutive patients with CRSwNP and indication to be treated with Dupilumab were evaluated for extended nitric oxide analysis (exhaled, FENO; bronchial, JawNO and alveolar, CalvNO components; nasal, nNO) and lung function 15 and 30 days after treatment initiation, and for clinical outcomes (nasal polyps score, NPS; quality of life questionnaires; visual analogue scales, VAS, for main symptoms, asthma control test, ACT) after 30 days of treatment initiation. RESULTS: 33 patients were enrolled. All extended nitric oxide and lung function parameters significantly improved after 15 days of treatment remaining stable at 30 days. NPS, VAS for main CRSwNP symptoms, quality of life questionnaires and ACT significantly improved after 30 days of treatment initiation. CONCLUSION: Dupilumab is associated with very rapid improvement in type 2 inflammation in all airway districts and this is associated with improved lung function and clinical parameters in patients with CRSwNP.

Comorbid allergic rhinitis and asthma: important clinical considerations.

INTRODUCTION: The numerous links between allergic rhinitis and asthma have been extensively explored in the last two decades, gaining great concern within the scientific community. These two conditions frequently coexist in the same patient and share numerous pathogenetic and pathophysiological mechanisms. AREAS COVERED: We reviewed major pathophysiological, epidemiological, and clinical links between allergic rhinitis and asthma. We also provided a comprehensive discussion of allergic rhinitis treatment according to current guidelines, with a particular focus on the relevance of allergic rhinitis therapies in patients with comorbid asthma. EXPERT OPINION: We believe that there are several unmet needs for our patients, however, there are promising advances forecasted for the future. Although allergic rhinitis is a recognized risk factor for asthma, a proper asthma detection and prevention plan in allergic rhinitis patients is not available. Allergen immunotherapy (AIT) represents a promising preventive strategy and may deserve an earlier positioning in allergic rhinitis management. A multidisciplinary approach should characterize the journey of patients with respiratory allergies, with an adequate referral to specialized Allergy/Asthma centers. Molecular Allergy Diagnosis may provide support for optimal AIT use. Finally, a possible evolution of biological treatment can be envisaged, mainly if biosimilars decrease such therapies' costs.

Free flap microvascular anastomosis in head and neck reconstruction using a 4K three-dimensional exoscope system (VITOM 3D).

The aim of this study was to evaluate the feasibility of microvascular anastomosis using a 4K three-dimensional exoscope system (VITOM 3D) in 10 consecutive cases of free flap head and neck reconstructive surgery. This was a clinical human study of free flap microvascular anastomosis using a VITOM 3D exoscope in 10 consecutive patients undergoing reconstruction after ablative surgery for head and neck carcinoma. Microvascular anastomoses were performed successfully using the exoscope in all patients, without any need for the conventional microscope. Arterial anastomoses were all end-to-end. Venous anastomoses were end-to-end in eight cases and end-to-side with the internal jugular vein in two cases. This study demonstrates the technical feasibility of microvascular anastomosis using a 4K three-dimensional exoscope system (VITOM 3D) in a series of 10 cases.

Nasal cytology: Methodology with application to clinical practice and research.

Nasal cytology is an easy, cheap, non-invasive and point-of-care method to assess nasal inflammation and disease-specific cellular features. By means of nasal cytology, it is possible to distinguish between different inflammatory patterns that are typically associated with specific diseases (ie, allergic and non-allergic rhinitis). Its use is particularly relevant when other clinical information, such as signs, symptoms, time-course and allergic sensitizations, is not enough to recognize which of the different rhinitis phenotypes is involved; for example, it is only by means of nasal cytology that it is possible to distinguish, among the non-allergic rhinitis, those characterized by eosinophilic (NARES), mast cellular (NARMA), mixed eosinophilic-mast cellular (NARESMA) or neutrophilic (NARNE) inflammation. Despite its clinical usefulness, cheapness, non-invasiveness and easiness, nasal cytology is still underused and this is at least partially due to the fact that, as far as now, there is not a consensus or an official recommendation on its methodological issues. We here review the scientific literature about nasal cytology, giving recommendations on how to perform and interpret nasal cytology.

[Treatments of hereditary hemorrhagic telangiectasia of the nasal mucosa]. / Indications et stratégies thérapeutiques des épistaxis dans la maladie de Rendu Osler.

UNLABELLED: Hereditary Hemorrhagic Telangiectasia is a systemic autosomal dominant disorder involving blood vessels. The most common symptom is recurrent epistaxis. The treatments of these epistaxis are numerous but such treatments are often symptomatic and their effects are often not sustained. Some of these treatments may be complicated by visceral vascular malformations. The aim of this study is to propose a treatment plan for these patients with hierarchical organisation of therapeutic options taking into account of their previous therapy. METHOD: H. Plauchu organized in Paris, december 2002 a meeting with any medical specialists of this disease. They have analysed variety of therapies that have been proposed for epistaxis control in Hereditary Haemorrhagic Télangiectasia. RESULTS: Most common use packing of nasal fossa and then hyperselective embolization of the internal maxillary and facial arteries for severe epistaxis. For chronic epistaxis, best treatment use sclerotics products (Ethibloc) and laser. After discussion, primary embolization could be useful to reduce vascularization of nasal fossa. CONCLUSION: Treatment of epistaxis in Hereditary Haemorrhagic Telangiectasia could increase in few years. Use of an index card of for epistaxis in the disease of Rendu-Osler could help to find treatment of choice.

Altered microperfusion at the rectal stump is predictive for rectal anastomotic leak.

PURPOSE: The aim of this study was to evaluate the reliability of intraoperative laser-Doppler measurements in predicting the occurrence of anastomotic leak in patients with colorectal cancer undergoing stapled straight anastomosis to the rectum. METHODS: A prospective study was undertaken on 55 patients with rectal cancer or distal sigmoid cancer programmed for elective curative surgery. In all patients transmural colonic blood flow was measured by laser-Doppler flowmetry technique before bowel manipulation (baseline measurement) and after vascular ligation and division. Comorbidities at admission, intraoperative events, associated surgical procedures, and clinical outcome were tested for any association with anastomotic leak. RESULTS: Postoperative mortality was 1.8 percent (1/55 patients), and the overall morbidity was 21.3 percent. Anastomotic leak occurred in eight patients (14.5 percent). After colonic division a blood flow reduction at the rectal stump was observed in 42 patients (76.3 percent) as compared with baseline measurement. The mean rectal stump flow reduction was 6.2 percent in patients without anastomotic leak, whereas in patients who developed anastomosis breakdown it was 16 percent (P < 0.001). Mean proximal stump flow reduction was 5.1 percent in the uncomplicated patients, whereas in patients who had an anastomosis breakdown it was 12.9 percent (P < 0.01). A positive linear correlation was found between decrease in blood flow and rate of anastomotic leak. CONCLUSION: Blood flow reduction at the rectal stump is associated with an increased risk of anastomotic leak.

Muscarinic cholinergic mediation of the GH response to gamma-hydroxybutyric acid: neuroendocrine evidence in normal and parkinsonian subjects.

We have recently reported that parkinsonian patients show a significant GH response to gamma-hydroxybutyric acid (GHB), but not to gamma-aminobutyric acid (GABA)-ergic drug administration. In order to establish whether muscarinic cholinergic receptors mediate the GH secretion induced by GHB, normal men and parkinsonian patients were tested with GHB both in the absence and in the presence of the anticholinergic agent, pirenzepine. Both normal controls and parkinsonian patients showed a significant serum GH rise in response to GHB (25 mg/kg body weight p.o.) even though a slightly, but significantly lower response was observed in parkinsonian patients. Pretreatment with pirenzepine (100 mg p.o. 2 h before GHB) completely suppressed the GHB-induced GH release in both normal controls and parkinsonian patients. These data indicate that a cholinergic mechanism mediates the GH response to GHB in normal men. In addition the data indicate that this pathway is preserved in the parkinsonian brain.

Orienting of visual attention in Alzheimer's disease: its implication in favor of the interhemispheric balance.

Visual attention in dementia of Alzheimer's disease (AD) has not been investigated as extensively as memory or language. The aim of this research was to study the orienting of attention in patients with AD (which temporo-parietal areas are primarily affected) compared with patients with Parkinson-Dementia, Parkinson's disease, and normal controls, using the Posner paradigm. Subjects were instructed to respond by pressing a response key after the appearance of a target at the same location (valid trial) or at the opposite location (invalid trial) indicated by a central cue (arrow). According to the experimental procedure developed by Posner, it has been hypothesized that parietal lobes are involved in "disengagement operation" (when attention has to move from one location to another in the controlateral field). Results showed no differences between AD and the other groups and between left and right hemifield. In conclusion, the authors did not find any sign of difficulty with disengagement, and results are discussed in terms of Kinsbourne's interpretation of a balance between hemispheres.

ACTH/cortisol involvement in the serotonergic disorder affecting the parkinsonian brain.

In order to establish whether the serotonergic disorder affecting the parkinsonian brain also modifies hypothalamic-pituitary function in Parkinson's disease, 10 patients (aged 57-66 years) and 10 normal controls (aged 55-69 years) were tested with the serotonergic agonist d,l-fenfluramine (60 mg p.o.), with CRH (100 micrograms i.v.) and with placebos. Plasma ACTH/cortisol levels during tests were evaluated and compared. Both groups showed similar levels of ACTH and cortisol in basal conditions and after placebo administration. A slight physiological decline in both ACTH and cortisol levels during the placebo test was observed in normal controls and parkinsonian patients. CRH induced similar ACTH/cortisol increments in all subjects. In contrast, d,l-fenfluramine significantly increased plasma ACTH/cortisol concentrations in the normal controls, but not in the parkinsonian patients. These data show a defective serotonergic control of the pituitary-adrenal axis in Parkinson's disease.

Low-dose ovine corticotropin-releasing hormone stimulation test in diabetes mellitus with or without neuropathy.

The function of the hypothalamic-pituitary-adrenal (HPA) axis was evaluated in insulin-dependent diabetics without (group I, n = 10) or with (group II, n = 10) established symptomatic neuropathy and in age- and weight-matched normal controls (n = 11). Since the corticotropin (ACTH)/cortisol response to the minimal-effective dose of corticotropin-releasing hormone ([CRH] 0.03 microgram/kg body weight) represents a useful tool for HPA axis examination, all subjects were tested with the low-dose ovine CRH stimulation test. Experiments started at 8:30 AM, when CRH was injected after two basal blood samples were withdrawn, and lasted 2 hours. Basal serum levels of ACTH were similar in the three groups. Administration of CRH induced a small but significant increase in ACTH levels in all subjects; however, the CRH-induced ACTH increase was significantly higher in normal controls than in diabetic groups I and II. Furthermore, a significantly lower ACTH response was observed in group II than in group I. In contrast, basal and CRH-induced cortisol levels were significantly higher in diabetics than in normal controls. Comparisons between diabetic groups showed that both basal and stimulated cortisol secretion was significantly higher in group II than in group I. When peak ACTH responses to CRH and basal cortisol levels were combined, a significant negative correlation was found (r = .545, P < .02). These data show that even uncomplicated diabetes mellitus is associated with adrenal hyperfunction. Such an alteration is more pronounced in the presence of neuropathy.

Age at onset and SPECT imaging in Alzheimer's disease.

It is generally accepted that presenile Alzheimer's disease (AD) has faster progression and severer clinical manifestation than senile onset AD. Recently a relative left frontal hypoperfusion was only found in patients with presenile AD by using SPECT imaging. The aim of the present report was to ascertain whether the same conclusion could be drawn matching the population with respect to the severity of the cognitive profile and disease duration. Twenty subjects for each group were studied with SPECT and no differences emerged between groups. It is postulated that presenile and senile onset AD represent aspects of the same biological process.

The correlation between three methods of skin perfusion pressure measurement: radionuclide washout, laser Doppler flow, and photoplethysmography.

The most accurate measurement of skin perfusion pressure is made with use of radioisotopic clearance techniques. We compared the skin perfusion pressure using radioisotope to the skin perfusion pressure measured simultaneously by placing laser Doppler and photoplethysmography probes within a transparent polyvinylchloride plastic blood pressure cuff in 13 subjects. A new device, which was created for this experiment, consisted of a plastic bladder into which light-emitting probes can be placed, so that the pressure applied to the skin was transmitted by the surface of the bladder, rather than by the surface of a rigid probe. The cuff was inflated to a supra-systolic pressure over the intradermal injection site of technetium Tc 99m, then deflated in 10 mm Hg decrements at 3-minute intervals. The pressures at which radioisotope clearance began, at which microcirculatory flow was detected by laser Doppler, and at which deflection of the photoplethysmography (DC mode) output occurred, were recorded as the skin perfusion pressure. The range of radioisotopic determined skin perfusion pressure was 0 to 100; skin perfusion pressure-laser Doppler was 0 to 100; and skin perfusion pressure-photoplethysmography was 60 to 100, with 7 of 13 limbs demonstrating no clear deflection point and thus an unobtainable skin perfusion pressure-photoplethysmography reading. Linear regression revealed a coefficient of correlation of 0.991 for skin perfusion pressure when the radioisotopic and laser Doppler methods were compared. Our study is not in agreement with previous reports of the successful determination of skin perfusion pressure with use of photoplethysmography. This may be due to differences in our technique when compared with previous reports of skin perfusion pressure-photoplethysmography determination.(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiation of the analgesic effects of tryptophan by allopurinol in rats.

The administration to rats of tryptophan (CAS 73-22-3) in high dosage causes a significant increase in pain threshold values. The analgesic effects of tryptophan are potentiated by allopurinol (CAS 315-30-0). The analgesic effects shown by tryptophan injection are associated with increased levels of serotonin and 5-hydroxyindoleacetic acid in some areas of the brain. The combined allopurinol and tryptophan treatment elevates the serotonin levels furtherly when they are compared with the values observed in animals receiving tryptophan only. The analgesia caused by tryptophan administration has been attributed to an increased activity of the serotoninergic system involved in the control of pain transmission.

Fuld's formula and WAIS subtests in differential diagnosis of dementia.

The Fuld formula and the linear discriminant function applied to WAIS subtest scores were tested for their ability to identify Alzheimer's disease and senile dementia of the Alzheimer type in a group of 101 demented subjects. The sensitivity and specificity of Fuld's formula for Alzheimer dementia against other dementias were 44.2% and 73.8% respectively; when compared with an age-matched normal control group specificity was 91.4%. When the linear discriminant function was applied only WAIS subtest scores in "similarities and digit span" and "object assembly" significantly differentiated Alzheimer from other dementias (sensitivity 61.5% and specificity 63.3%). Specificity increased to 97.1% when the function was applied to discriminate Alzheimer from normal controls. Discriminant analysis applied to other WAIS subtests for the two demented groups revealed "picture completion" as significantly differentiating the groups but it did not contribute to diagnostic accuracy. WAIS scores are of limited value in the differential diagnosis of dementias.

2-substituted derivatives of benzimidazole inhibiting gastric acid secretion in rats.

Benzimidazole and its 2-derivatives with amino, carbamonitrile, urea, and guanidine groups have been tested for their activity on gastric secretory process. The carbamonitrile-, urea-, and guanidine compounds decrease gastric acid secretion, basal and stimulated with histamine or betazole, in Shay-rats and depress the guinea pig auricle activity stimulated by betazole. The results suggest that the studied 2-substituted benzimidazole compounds exhibit anti H2-histamine activity.