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 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.

The impact of anatomical location and sun exposure on the dermoscopic recognition of atypical nevi and early melanomas: usefulness of an integrated clinical-dermoscopic method (iDScore).

BACKGROUND: The anatomical location of atypical melanocytic skin lesion (aMSL) was never combined into an algorithm for discriminating early melanomas (EM) from atypical nevi (AN). AIMS: To investigate the impact of body location on the intuitive diagnosis performed in teledermoscopy by dermatologists of different skill levels. A further aim was to evaluate how the integration of the body location could improve an algorithm-aided diagnosis. METHODS: We retrospectively collected 980 standardized dermoscopic images of aMSL cases (663 AN, 317 EM): data on the anatomical location were collected according to 15 body sites classified into 4 macro-areas of chronically/frequently/seldom/rarely exposure. Through a teledermatology web platform, 111 variously skilled dermoscopists performed either the intuitive diagnosis and 3 algorithm-assisted diagnostic tests (i.e. iDScore, 7-point checklist, ABCD rule) on each case, for a total of 3330 examinations. RESULTS: In the rarely photoexposed area (side, bottom, abdomen), AN were the most tricky (i.e. highest quote of false positives), due to a frequent recognition of dermoscopic features usually considered as suggestive for melanoma in these lesions; the EM at these sites received the highest quote of false negatives, being generally interpreted as 'featureless' according to these traditional parameters, that were more frequently displayed on the chronically photoexposed area. In rarely and seldom photoexposed area, intuitive diagnosis fails to achieve adequate accuracy for all aMSLs, as the ABCD rule and the 7-point checklist; by applying the iDScore algorithm the diagnostic performance was increased by 15% in young and 17% in experts. CONCLUSIONS: The body location of an aMSL can affect the quality of intuitive dermoscopic diagnosis, especially in sun-protected areas. Accuracy can be improved by using the iDScore algorithm that assigns a different partial score of each body site.

Validation of an integrated dermoscopic scoring method in an European teledermoscopy web platform: the iDScore project for early detection of melanoma.

BACKGROUND: Although live and teledermoscopic examination has been successfully used to achieve non-invasive diagnosis of melanocytic skin lesions (MSLs), early melanoma (EM) and atypical nevi (AN) continue to be a challenge, and none of the various algorithms proposed have been sufficiently accurate. We designed a scoring classifier diagnostic method, the iDScore that combines clinical data of the patient with dermoscopic features of the MSL. OBJECTIVE: To test the accuracy of the iDScore in differentiating EM from AN in a teledermoscopy setting and to compare it with intuitive diagnosis, the ABCD rule and the seven-point checklist. MATERIALS AND METHODS: A dedicated teledermoscopy web platform was designed. This involved the following: (i) collecting a large integrated clinical-historical-dermoscopic data set of difficult MSLs from eight European dermatology centres; (ii) online testing, education and training in using the iDScore. A total of 904 images were combined with age, sex, lesion diameter and body site data and evaluated on the platform by 111 participants with four levels of skill in dermoscopy. Each testing session consisted of 30 blind cases to examine consecutively by the above four methods. 'Management decisions' and personal participant data were also recorded. RESULTS: iDScore-aided diagnosis achieved satisfactory diagnostic accuracy for all lesions, irrespective of centre of affiliation, showing an average AUC of 0.776 in all participant testing sessions. All skill groups improved their accuracy by 10-16% with respect to intuitive diagnosis and the other methods, showing high concordance and avoiding wrong management decisions. CONCLUSION: We demonstrated the validity of the iDScore method for managing suspicious MSLs in a large multicentric data set and a teledermoscopic setting. The platform designed for the iDScore project provides ready support for physicians of any dermoscopy skill level and is useful for education and training.

Neonatal and adult gonadal hormone manipulations enhance morphine analgesia elicited from the ventrolateral periaqueductal gray in female rats.

Male rodents displayed greater magnitudes of analgesia following systemic, ventricular, and intracerebral administration of mu-opioid receptor agonists than female rodents. Whereas neonatal castration of male rat pups produced reductions in systemic and central morphine analgesia as adults, neonatal androgenization of female rat pups treated with testosterone propionate (TP) displayed enhancements in systemic and central morphine analgesia as adults. Adult gonadectomy minimally affected mu-opioid analgesia, except if less potent mu agonists were employed, or if morphine was directly administered into the ventrolateral periaqueductal gray (vlPAG). Adult ovariectomy failed to appreciably alter the enhanced analgesia following systemic morphine in female rats with neonatal androgenization. Because the vlPAG elicited morphine analgesia that was sensitive to both neonatal and adult gonadal hormone manipulations, the present study examined morphine analgesia elicited from the vlPAG in female rats receiving neonatal treatment with TP or vehicle and subsequently exposed to adult ovariectomy or sham surgery as well as intact male rats. Intact male rats displayed significantly greater magnitudes and potencies in vlPAG morphine analgesia than female rats receiving neonatal treatment with either vehicle or TP. In turn, neonatal androgenization significantly enhanced vlPAG morphine analgesia relative to neonatal vehicle treatment in females. Adult ovariectomy significantly enhanced the magnitude of vlPAG morphine analgesia in female rats receiving neonatal treatment with either vehicle or TP. This demonstrates a strong interaction between neonatal and adult gonadal hormone manipulations in the mediation of vlPAG morphine analgesia in female rats.

High-resolution spectroscopy of Lambda16N by electroproduction.

An experimental study of the (16)O(e,e'K(+))(Lambda)(16)N reaction has been performed at Jefferson Lab. A thin film of falling water was used as a target. This permitted a simultaneous measurement of the p(e,e'K(+))Lambda, Sigma(0) exclusive reactions and a precise calibration of the energy scale. A ground-state binding energy of 13.76+/-0.16 MeV was obtained for (Lambda)(16)N with better precision than previous measurements on the mirror hypernucleus (Lambda)(16)O. Precise energies have been determined for peaks arising from a Lambda in s and p orbits coupled to the p(1/2) and p(3/2) hole states of the (15)N core nucleus.

High resolution spectroscopy of (lambda)(12)B by electroproduction.

An experiment measuring electroproduction of hypernuclei has been performed in hall A at Jefferson Lab on a 12C target. In order to increase counting rates and provide unambiguous kaon identification two superconducting septum magnets and a ring imaging Cherenkov detector were added to the hall A standard equipment. An unprecedented energy resolution of less than 700 keV FWHM has been achieved. Thus, the observed (Lambda)(12)B spectrum shows for the first time identifiable strength in the core-excited region between the ground-state s-wave Lambda peak and the 11 MeV p-wave Lambda peak.

Organizational manipulation of gonadal hormones and systemic morphine analgesia in female rats: effects of adult ovariectomy and estradiol replacement.

Previous research has indicated the importance of sex in mediating the larger magnitude of mu-opioid receptor agonist-induced analgesia in male relative to female rodents. Whereas manipulations involving the adult activational effects of gonadal hormones minimally alter these analgesic sex differences, manipulations involving neonatal organizational effects of gonadal hormones have previously been shown to profoundly affect morphine analgesia. Thus, adult male rats neonatally castrated on the first day after birth displayed reductions in morphine analgesia relative to sham-operated males, and adult female rats neonatally treated with testosterone propionate on the first day after birth displayed enhancements in morphine analgesia relative to vehicle-treated females. Because neonatal androgenization in female rats produces an anovulatory syndrome that could change their adult hormonal milieu, the present study examined whether adult ovariectomy altered the magnitude of systemic morphine analgesia (1-5 mg/kg) in neonatal androgenized female rats relative to neonatal vehicle-treated female rats as well as gonadal steroid hormone replacement with estradiol benzoate. Intact male rats displayed significantly greater magnitudes and potencies (2- to 2.3-fold leftward shift) of systemic morphine analgesia than female rats treated neonatally with either vehicle (1-5 mg/kg) or testosterone (1.7-5 mg/kg). In turn, neonatal androgenized female rats displayed significantly greater magnitudes of systemic morphine (1, 5 mg/kg) analgesia than vehicle-treated female rats accompanied by a smaller 20% leftward shift in potency. Adult ovariectomy minimally affected morphine analgesia in neonatal vehicle-treated females, while significantly reducing the magnitude (1 mg/kg), but not the potency of morphine analgesia in neonatal androgenized female rats. Estradiol replacement therapy significantly increased the magnitude of morphine analgesia in both groups at some doses, but only changed the potency (20-30%) in females treated neonatally with vehicle. Taken together, these data suggest a limited organizational-activational gonadal hormone interaction in the mediation of systemic morphine analgesia in female rats.

Baseline transition sleep and associated sleep episodes are related to the learning ability of rats.

The EEGs of 18 adult male Wistar rats were recorded during a baseline session lasting 7 h (day 1). The following day, rats were trained for a 2-way active avoidance task in an automated shuttle-box. A retention test was scheduled on the third day. On the basis of the number of avoidances scored during the training and retention sessions, rats were assigned to a fast-learning group (FL; achieving criterion during the training session), a slow-learning group (SL; achieving criterion in the retention test session), and a nonlearning group (NL; failing to achieve criterion). Vigilance states were determined by analyzing EEG data in 5-s epochs and calculating EEG power spectra of consecutive time intervals as short as 1 s. This high-resolution method led to the identification of transition sleep episodes that followed slow-wave sleep (SS) and were followed by waking (TS-->W) or by paradoxical sleep (TS-->PS). Comparison of the baseline sleep variables of the 3 behavioral groups revealed the presence of several significant differences. These observations were confirmed by the results of correlative analyses between baseline sleep variables and number of avoidances scored during the training and retention sessions. The most reliable indices of the capacity to learn the avoidance task were the amounts of SS preceding the TS-->W or the TS-->PS sequence, and the amounts of either component of the latter sequence. These variables displayed markedly higher values in FL rats. In addition, the amount of SS preceding TS-->W and the amount of TS-->(W) were significantly correlated with the number of avoidances scored during the training session. On the other hand, 1' SS-->(PS) and (SS)-->PS episodes were longer in NL rats than in SL or FL rats, respectively; and 2, the duration of SS-->(PS) episodes was inversely correlated with the number of avoidances of the first training period. The data are interpreted to suggest that TS and associated sleep episodes may predict the acquisition of the avoidance task, and the episodes of SS-->PS not associated with TS may predict the retention of innate responses, such as freezings or escapes.

Indobufen compared with aspirin and dipyridamole on graft patency after coronary artery bypass surgery: results of a combined analysis.

BACKGROUND: Two prospective, randomized, double-blind clinical trials, performed in the UK and Italy, showed that indobufen, a reversible cyclo-oxygenase inhibitor, is as effective as, and safer than, a combination of aspirin with dipyridamole in preventing occlusion of saphenous vein coronary artery bypass grafts (CABG) 1 year after surgery. OBJECTIVE: To obtain, in a larger patient population, a more precise estimate of the possible differences in efficacy and safety between the two treatments. METHODS: We performed a combined analysis of the results of the two studies, based on the 1-year angiography data, on a total of 934 patients with 2258 saphenous vein distal anastomoses. RESULTS: Patients in the UK and Italy had similar baseline clinical characteristics. The analysis confirmed that there were no significant differences between the two treatment groups in the proportion of patients with one or more occluded grafts and in the proportion of occluded distal anastomoses. The combined analysis showed that the difference in response frequency (indobufen compared with aspirin and dipyridamole) was close to 0: 2.0% (95% confidence interval (CI) -4.2 to 8.2) in terms of patients, and 0.8% (95% CI -2.5 to 4.2) in terms of distal anastomoses. The 1-year incidence of postoperative major cardiovascular events was not statistically different between the treatment groups (19/694 indobufen compared with 25/678 aspirin and dipyridamole). CONCLUSIONS: Two multicentre CABG studies performed in different countries in patients with similar characteristics showed similar results in terms of graft patency. On the basis of the combined analysis, the two treatments can reasonably be considered to be equally effective in the prevention of graft occlusion.

CAD-CAM ceramic inlays and onlays: using an indirect technique.

A time-sharing technique for a CAD-CAM unit can avoid scheduling difficulties and lengthy appointments. Dentists can also share the cost of expensive equipment and involve staff in learning the steps of this computer-aided design and manufacture.

[Angina pectoris induced by oral administration of dipyridamole]. / Angina pectoris indotta dalla somministrazione orale di dipiridamolo.

Five cases scheduled for myocardial elective coronary artery bypass (CAB), who developed angina and ischemic electrocardiographic changes, after oral administration of dipyridamole (100 mg) are reported. Dipyridamole induced myocardial ischemia has been demonstrated in subjects with coronary artery disease, if this drug is administered intravenously. To our knowledge, only one study reported this side effect, after oral route, in four patients awaiting urgent CAB, for unstable angina. Based on our and other Authors experience, preoperative dipyridamole should be used with caution, especially in patients with unstable angina.

Acid adaptation and survival of Listeria monocytogenes in Italian-style soft cheeses.

AIMS: The ability of Listeria monocytogenes to survive and grow at high salt concentrations and low pH makes it a potential hazard after the consumption of milk and dairy products, often implicated in severe outbreaks of listeriosis. This study was designed to evaluate the behaviour of L. monocytogenes in traditional acid and salted Italian-style soft cheeses and to investigate whether Listeria occurrence and growth in these environments may represent a potential increase of hazard. METHODS AND RESULTS: A first approach was addressed to in vitro evaluate survival, acid tolerance response, ability to produce biofilm, and capability to invade intestinal-like cells of a L. monocytogenes strain grown under experimental conditions mimicking environmental features that this pathogen encounters in soft cheeses (such as acid pH and high NaCl content). A second set of experiments was performed to monitor, during the storage at 4 degrees C, the survival of acid-adapted and nonadapted Listeriae in artificially contaminated soft cheeses. Both acid tolerance response and invasion efficiency of acid-adapted bacteria resulted in an increase, even when bacteria were simultaneously pre-exposed to increasing salt stress. The contamination of cheeses with acid-adapted and nonadapted bacteria evidenced in all products a good survival. A significant increased survival, the recovery of bacterial cells highly resistant to lethal pH exposure, and the prevalence of filamentous structures were observed in crescenza cheese during the storage. CONCLUSIONS: The Listeria survival and acid pH tolerance observed during refrigerated storage are probably related to the intrinsic acid and saline features of soft cheeses analysed. SIGNIFICANCE AND IMPACT OF THE STUDY: Italian soft cheeses tested may represent a potential hazard for the recovery of acid-adapted L. monocytogenes cells with enhanced ability to adhere to inert surfaces and/or to penetrate host cells.

Manejo multidisciplinario de la acromegalia / Multidisciplinary management of acromegaly

Acromegaly is a chronic disease caused in most cases by hypophysiary adenoma. It is of complex management due to the high variability of the causing lesion and its clinical repercussion. Surgical outcomes are poor with remission rates of 80 percent for microadenomas and 50 percent for macroadenomas. The author's experience in treating 38 patients with this pathology as well as the remission results of the illness and the complications are presented herein. Handling alternatives and associated complications are discussed and a clinical case is presented to show the therapeutical options in more complex cases.

La acromegalia es una enfermedad crónica causada en la mayoría de los casos por un adenoma hipofisario. Su manejo es complejo por la gran variabilidad de la lesión causante y su repercusión clínica. Los resultados quirúrgicos son pobres, con tasas de remisión de la enfermedad en promedio de un 80 por ciento en microadenomas y 50 por ciento en macroadenomas. Se presenta la experiencia del autor en el manejo de esta patología en 38 pacientes, los resultados de remisión de la enfermedad. Se discute las alternativas de manejo, complicaciones asociadas y se ilustra con un caso clínico para demostrar las opciones terapéuticas en los casos más complejos.

Síndrome de fenilquetonuria materna, un nuevo desafío para Chile / Maternal phenylketonuria syndrome, a new challenge for Chile

Phenylquetonuria (PKU) is a hereditary disease, caused by the deficiency or absence of the enzyme phenylalanine hydroxylase, which produces an abnormal conversion of phenylalanine (Phe) to tyrosine. If PKU is not diagnosed and treated during the neonatal period, blood accumulation of Phe causes neurological damage. Chile has a neonatal screening program for PKU and congenital hypothyroidism since 1992; this program has diagnosed 162 PKU patients in Chile, which are being followed-up in INTA, Universidad de Chile. Nowadays, there are 20 PKU patients in adolescence, so we face a new challenge such as maternal PKU syndrome. This syndrome refers to the teratogenic effect of Phe in a pregnant PKU female. The most frequent anomalies are intrauterine growth retardation, microcephaly, global development retardation and congenital heart defects. Their occurrence is directly related to maternal Phe during pregnancy. In order to assure a normal pregnancy and to prevent this syndrome, levels of Phe in blood should be kept between 2 and 6 mgldl prior to conception and throughout pregnancy. Considering this challenge, INTA has proposed a strict protocol of follow-up to improve the compliance to nutritional therapy and prevent maternal PKU syndrome.

La fenilquetonuria (PKU) es una patología hereditaria, producida por la deficiencia o ausencia de la enzima fenilalanina hidroxilasa, lo que impide la metabolización normal de la fenilalanina (FA) a tirosina. La acumulación de fenilalanina en la sangre ocasiona daño neurológico si no es diagnosticada y tratada desde el periodo neonatal. Desde 1992 Chile tiene un programa de pesquisa neonatal de PKU e hipotiroidismo congénito, lo que ha permitido diagnosticar 162 casos con PKU, los que mantienen un seguimiento integral en el INTA, de la Universidad de Chile. Actualmente hay 20 PKU en etapa de adolescencia, por lo que nos enfrentamos a un nuevo desafío, el síndrome de PKU materna. Este síndrome se refiere al efecto teratogénico de la FA en una embarazada con PKU. Las alteraciones más características son el retraso del crecimiento intrauterino, la microcefalia, el retraso global del desarrollo y los defectos cardiacos congénitos. La presencia de estas alteraciones está directamente relacionada con los niveles de FA de la madre durante el embarazo. Para asegurar un embarazo normal y prevenir este síndrome se recomienda la mantención de niveles de FA entre 2 y 6 mg/dl, desde el período preconcepcional y durante todo el embarazo. El INTA considerando este desafío, ha propuesto un protocolo de seguimiento estricto preconcepcional y durante el embarazo con el objetivo de favorecer la adherencia al tratamiento nutricional y prevenir el síndrome de PKU materna.

[Long-term clinical results after intervention using aorto-coronary bypass]. / Risultati clinici a lungo termine dopo intervento di bypass aortocoronarico.

The survival and symptoms of 294 consecutive patients discharged from the hospital after isolated coronary artery bypass grafting from 1970 to 1975 were evaluated 6 to 10 years after surgery. The actuarial 10 years expectancy of cardiac death as 10.0 +/- 2.4% the non fatal myocardial infarction one was 11.2 +/- 2.8; the yearly probability of severe ischemic event therefore was 2.1%. One year after surgery, 56% patients were free from angina, 31% improved and only 7% symptomatically unchanged. These percentages became 45%, 26% and 13% respectively at the end of the follow-up, thus showing a definite though slight deterioration. Clinical status one year after operation was predictive of further evolution: only 6.2% of the symptom-free patients developed severe ischemic events, as opposed to 20% of the highly symptomatic ones. The actuarially determined curve of recurrence of angina in the patients asymptomatic at the first control shows, after 2 years of steady state, a progressive upslope which reaches 40% by the 7th year and 90% at the 10th year of follow-up. Subgroup analysis indicated that long term prognosis is influenced by the presence of left main stenosis and by perioperative myocardial damage. Clinical results at one year are influenced by completeness of revascularization, graft patency and perioperative myocardial infarction. The tendency of symptoms to recur in patients who are free from angina one year after intervention, is similar in the various subgroups and is adversely influenced only by perioperative myocardial damage. These results show that coronary artery bypass grafting has a true clinical impact, although symptomatic improvement is somewhat temporary.

Factors influencing 1-year patency of coronary artery saphenous vein grafts. Studio Indobufene nel Bypass Aortocoronarico (SINBA).

BACKGROUND: To evaluate the possible influence of a series of clinical angiographic and surgical variables on the 1-year patency of saphenous vein (SV) coronary graft, data collected prospectively in a multicenter randomized clinical trial were analyzed. METHODS AND RESULTS: The study group included 349 patients--847 SV distal anastomoses--who underwent angiography at a median time of 374 days after surgery. By logistic binomial regression analysis, age, sex, smoking habits, hypertension, high cholesterol, previous myocardial infarction, and angina were not found to be significant factors leading to graft occlusion. Among the angiographic and surgical variables, the following were retained as predictive of higher occlusion risk: (1) vessel diameter (< or = 1.5 mm versus > 1.5 mm, odds ratio (OR) = 2.46); (2) the location of the grafted vessel, namely, the right coronary artery versus the left anterior descending (OR = 2.15); and (3) the wall motion of the vessel-dependent myocardial region (altered versus normal: OR = 2.12). The presence of two or three risk factors multiplied the occlusion risk up to 11-fold. CONCLUSIONS: The study suggests that vessel diameter, wall motion of the vessel-dependent myocardial region, and location of the grafted vessel are the main determinants of SV coronary graft patency during the first postoperative year. Knowledge of these artery-specific factors may provide a basis for estimating the risk of graft occlusion, thereby modifying surgical strategy and postoperative surveillance.