Nutraceuticals as immune-stimulating therapy to fight COVID-19. Combination of elements to improve the efficacy.

COVID-19 pandemic has underlined that unknown viral infections, which jump from animals to humans, can be extremely dangerous. In case of new viruses as SARS-CoV2, available drugs can fail to contrast the virus aggressiveness leading patients to death. Long time is necessary to create a vaccine, but immediate solutions are necessary to stop the mortality COVID-19 related. We have learned that the immune-system is the key to reduce the severity of COVID-19 and, through its modulation, it has been possible saving people's life. In this short communication, we discuss the use of nutraceuticals to modulate and stimulate the immune answer for reducing the severity of COVID-19 symptoms. The nutraceuticals are safe and can be administered to all ages. In addition, combination of natural anti-viral elements and immune-stimulating molecules already successfully tested against others upper-respiratory tract infections-could be efficient against SARS-CoV2. We believe that these natural molecules could really be a valid ally against COVID-19, especially in this moment in which a SARS-CoV2 vaccine is still not available.

The effects of oral supplements with Sambucus nigra, Zinc, Tyndallized Lactobacillus acidophilus (HA122), Arabinogalactans, vitamin D, vitamin E and vitamin C in otitis media with effusion in children: a randomized controlled trial.

OBJECTIVE: To evaluate the ability of oral supplements with immune-stimulating molecules (Sambucus nigra, Zinc, Tyndallized Lactobacillus acidophilus (HA122), Arabinogalactans, vitamin D, vitamin E and vitamin C) to reduce the inflammation of the upper airway tract and improve the outcome of otitis media with effusion (OME) in children. PATIENTS AND METHODS: Randomized controlled trial. One-hundred ninety-eight children (CI 95%: 12-96 months) were divided into four groups. Group 1 (48 subjects) received 10 ml of oral supplements (OS) with immune-stimulating molecules for three months (20 days consecutively, then 10 days of suspension - the therapeutic scheme was repeated three times); Group 2 (54 children) underwent treatment with 10 ml of OS for 90 consecutive days; Group 3 (48 subjects) received 15 ml of OS for 45 consecutive days; a control group (48 children) underwent the standard treatment for rhinitis and OME. Outcome measures included otoscopy, tympanometry, fibroendoscopy, and the pure tone audiometry (PTA) at T0 (before treatment), T1 (45 days after treatment), and T2 (90 days after treatment). RESULTS: All children treated with OS showed a reduction of Upper Airway Infection (UAI) episodes and OME compared to the control group independent of the administration method and posology. The three groups treated with OS showed statistically significant differences between T0 and T2 for otoscopy, tympanometry, fibroendoscopy, and PTA. In Group 2, the otoscopy and the tympanometry scores improved at T1. Group 2 and 3 had better PTA results than Group 1. CONCLUSIONS: OS with immune-stimulating molecules should be considered as a supporting therapy in children affected by recurrent episodes of UAI associated with OME due to their capacity to improve the immune response and reduce the inflammatory phenomena. OS can improve the fibroendoscopic findings by restoring middle ear ventilation, in addition to their ability to reduce inflammation in the middle ear.

Endotypes of pollen-food syndrome in children with seasonal allergic rhinoconjunctivitis: a molecular classification.

BACKGROUND: Pollen-food syndrome (PFS) is heterogeneous with regard to triggers, severity, natural history, comorbidities, and response to treatment. Our study aimed to classify different endotypes of PFS based on IgE sensitization to panallergens. METHODS: We examined 1271 Italian children (age 4-18 years) with seasonal allergic rhinoconjunctivitis (SAR). Foods triggering PFS were acquired by questionnaire. Skin prick tests were performed with commercial pollen extracts. IgE to panallergens Phl p 12 (profilin), Bet v 1 (PR-10), and Pru p 3 (nsLTP) were tested by ImmunoCAP FEIA. An unsupervised hierarchical agglomerative clustering method was applied within PFS population. RESULTS: PFS was observed in 300/1271 children (24%). Cluster analysis identified five PFS endotypes linked to panallergen IgE sensitization: (i) cosensitization to ≥2 panallergens ('multi-panallergen PFS'); (ii-iv) sensitization to either profilin, or nsLTP, or PR-10 ('mono-panallergen PFS'); (v) no sensitization to panallergens ('no-panallergen PFS'). These endotypes showed peculiar characteristics: (i) 'multi-panallergen PFS': severe disease with frequent allergic comorbidities and multiple offending foods; (ii) 'profilin PFS': oral allergy syndrome (OAS) triggered by Cucurbitaceae; (iii) 'LTP PFS': living in Southern Italy, OAS triggered by hazelnut and peanut; (iv) 'PR-10 PFS': OAS triggered by Rosaceae; and (v) 'no-panallergen PFS': mild disease and OAS triggered by kiwifruit. CONCLUSIONS: In a Mediterranean country characterized by multiple pollen exposures, PFS is a complex and frequent complication of childhood SAR, with five distinct endotypes marked by peculiar profiles of IgE sensitization to panallergens. Prospective studies in cohorts of patients with PFS are now required to test whether this novel classification may be useful for diagnostic and therapeutic purposes in the clinical practice.

Potent isozyme-selective inhibition of human glutathione S-transferase A1-1 by a novel glutathione S-conjugate.

Elevated levels of glutathione S-transferases (GSTs) are among the factors associated with an increased resistance of tumors to a variety of antineoplastic drugs. Hence a major advancement to overcome GST-mediated detoxification of antineoplastic drugs is the development of GST inhibitors. Two such agents have been synthesized and tested on the human Alpha, Mu and Pi GST classes, which are the most representative targets for inhibitor design. The novel fluorescent glutathione S-conjugate L-gamma-glutamyl-(S-9-fluorenylmethyl)-L-cysteinyl-glycine (4) has been found to be a highly potent inhibitor of human GSTA1-1 in vitro (IC50=0.11+/-0.01 microM). The peptide is also able to inhibit GSTP1-1 and GSTM2-2 isoenzymes efficiently. The backbone-modified analog L-gamma-(gamma-oxa)glutamyl-(S-9-fluorenylmethyl)-L-cysteinyl-glycine (6), containing an urethanic junction as isosteric replacement of the gamma-glutamyl-cysteine peptide bond, has been developed as gamma-glutamyl transpeptidase-resistant mimic of 4 and evaluated in the same inhibition tests. The pseudopeptide 6 was shown to inhibit the GSTA1-1 protein, albeit to a lesser extent than the lead compound, with no effect on the activity of the isoenzymes belonging to the Mu and Pi classes. The comparative loss in biological activity consequent to the isosteric change confirms that the gamma-glutamyl moiety plays an important role in modulating the affinity of the ligands addressed to interact with GSH-dependent proteins. The new specific inhibitors may have a potential in counteracting tumor-protective effects depending upon GSTA1-1 activity.

Relationship between Bet v 1 and Bet v 2 specific IgE and food allergy in children with grass pollen respiratory allergy.

Grass allergy is the most common pollinosis in Northern Italy. Some patients with grass allergy show polysensitization against other pollens and plant-derived foods. In these patients oral allergic syndrome (OAS) is frequently associated. To evaluate the correlation between food allergy or food sensitization and specific IgE against panallergens such as Bet v 1 and Bet v 2, we studied 56 children (mean age: 8 years 5 months) suffering from respiratory allergy due to grass pollens were enrolled. Specific IgE against the most important food, inhalant allergen and Bet v 1, Bet v 2 were performed by ImmunoCAP technology (UniCAP 1000, Pharmacia Diagnostics, Uppsala, Sweden). We found 14 children (25%) sensitized to Bet v 1 and 13 (23%) to Bet v 2; in 24 cases (42.3%) a sensitization to at least one of the 2 panallergens was observed. Five of the 14 cases (36%) sensitized to Bet v 1 showed food allergy and 8 (57%) food sensitization; 6 (46%) of the 13 children sensitized to Bet v 2 showed food allergy and 7 (54%) food sensitization; only one case of Bet v 1 specific IgE without food allergy or sensitization was seen. Sixteen subjects (29%) showed food allergy (group A); 20 children (35.5%) multiple sensitizations to inhalant and at least one plant-derived food (group B); 20 subjects (35.5%) only inhalant allergens (group C). Sensitization to Bet v 1 (P<0.03) and Bet v 2 (P<0.009) is from a statistical point of view significantly higher in groups A and B than in group C. In the 16 patients with food allergy hazelnut was the major triggering food (50%), followed by peanut (38%), kiwi (31%), apple and walnut (19%). Specific IgE for Bet v 1 is more associated with nuts and legumes, while Bet v 2 is more related to fresh fruit and vegetables. In conclusion grass pollinosis is frequently associated with polysensitization to other pollen and food allergens. Bet v 1 and Bet v 2 specific IgE are significantly higher in these patients than in patients with grass monosensitization, and this sensitization may be considered a possible risk factors to evolve later into food allergy. Among the offending foods, legumes and the nut group are mostly related to Bet v 1, while vegetables and fresh fruits to Bet v 2.

A comparison of different allergometric tests, skin prick test, Pharmacia UniCAP and ADVIA Centaur, for diagnosis of allergic diseases in children.

BACKGROUND: The diagnosis of allergic disease is performed by skin prick tests (SPT) or through the demonstration of specific IgE in a blood sample via an in vitro test. The measurement of IgE concentration against allergens provides critical information in clinical allergy. Standardized and reproducible methods contribute to the quality of diagnosis and treatment of allergic disease. METHODS: In this study we evaluated the performance of a new specific IgE method, developed by ALK-Abellò for Bayer Diagnostics to run on their ADVIA Centaur immunoassay system. One hundred and fifty-one children with allergic diseases (both food and inhalant allergies) were tested for specific IgE (sIgE) via SPT and in vitro tests (UniCAP system, Pharmacia, and ADVIA Centaur immunoassay system, Bayer Diagnostics) and the test results were correlated with the clinical data. RESULTS: Statistical analysis revealed no significant difference between the two in vitro tests compared with clinical history. The sensitivities and specificities are similar, but the UniCAP system method has higher sensitivity. In the children with cow's milk allergy, the UniCAP system has sensitivity of 91% and specificity of 70%; the ADVIA Centaur immunoassay has sensitivity of 82% and specificity of 74%. In hen's egg allergy, UniCAP system has 94% sensitivity and 64% specificity, and the ADVIA Centaur system has 88% sensitivity and 52% specificity. In inhalant allergies, the two methods show statistically similar performances for both grass pollen allergies (UniCAP sensitivity 100%, specificity 73%; ADVIA Centaur sensitivity 95%, specificity 79%) and in the dust mites allergies (UniCAP sensitivity 91%, specificity 62%; ADVIA Centaur sensitivity 86%, specificity 64%). In cat allergies, the systems showed equivalent results (UniCAP sensitivity 100%, specificity 71%; ADVIA Centaur sensitivity 100%, specificity 70%). Using the UniCAP system, the geometric mean of sIgE values in children with clinical allergy is significantly higher than in sensitized ones. The ADVIA Centaur system shows a similar trend with the exclusion of cow's milk and Dermatophagoides farinae allergens. With this last method the mean value of sIgE is higher in sensitized than in symptomatic children. CONCLUSION: The new ADVIA Centaur method compares favorably with the results obtained on the UniCAP system. If other studies continue to confirm this data, then the advantages are numerous: the use of only a small quantity of serum (25 micro l per allergen), rapid turnaround time, minimal hands-on time, and no interference from IgG.

"Linear" and "derived" otoacoustic emissions in newborns: a comparative study.

OBJECTIVE: To investigate the effects of a specific aspect of the acquisition procedure, the averaging technique, on the evaluation of click-evoked otoacoustic emissions (CEOAEs) in newborns. DESIGN: CEOAEs were recorded by an Otodynamic ILO88 system from 89 full-term newborns at the third day after delivery. For each ear and in the same test session, CEOAEs were evoked by 75 to 85 dB pSPL acoustic clicks and averaged according to two different modes: the "linear" (classic average) and the "derived" mode, which allows the cancellation of linear behaving components (such as acoustic artifacts). All examined ears had a normal auditory function as assessed by conventional ABR between the ages of 2 and 4 mo. CEOAEs obtained by both averaging techniques were compared on the basis of several quantitative parameters: the waveform similarity; the levels of signal and noise and the inter-test reproducibility of the broadband response and of four different frequency bands centered at 1.6, 2.4, 3.2, and 4 kHz; the amplitude as a function of time; the test time. To eliminate the contribution of the stimulus artifact, linear CEOAEs were windowed 6 to 20 msec, whereas derived emissions were windowed using the default ILO88 window (2.5 to 20 msec). Additionally, CEOAEs were classified as "pass" or "fail" accordingly to screening criteria used in the daily clinical practice. RESULTS: Linear and derived emissions had very similar wave shapes and no time shifts during the first 12.5 msec. On the contrary, clear differences in the waveforms and time shifts were observed at longer latencies. The use of both averaging techniques resulted in identical CEOAE levels for both the broadband response and for the first two tested frequencies. For the last two frequencies, emission levels were lower when averaged with the linear technique owing to the use of the time window 6 to 20 msec, which reduces the amplitudes of high-frequency components. The residual noise in derived traces is 6 dB higher than that from linear traces. Also, derived CEOAEs had a lower inter-test reproducibility in both the broadband compound emission and in the four frequency bands examined here. The greatest difference in reproducibility was observed at the lowest band (1.2 to 2 kHz). Scoring of emissions was influenced by the averaging technique: 14% CEOAEs obtained with linear averaging and scored as passes were classified as fails when averaged with the derived mode. Moreover, if a CEOAE was scored as pass when using the derived technique, it also was scored as pass when using linear averaging. The increased number of false positives most likely was due to the higher noise floor/lower signal to noise ratio (SNR) of CEOAEs obtained with the derived technique. CONCLUSIONS: In the tested newborns and at the levels of stimulation used in this study, the emissions obtained with the derived technique were noisier than those obtained with the linear technique, this being intrinsically due to the type of averaging. Therefore, screening criteria based on the evaluation of the SNR (or similar parameters) could be influenced by the type of averaging used during the acquisition.

[Evaluation of hearing by studying acoustic distortion products in noise-induced hearing loss]. / Prévision de l'audition par les produits de distorsions chez les sourds par le bruit.

In this work, the Authors want to verify the possibility of an objective method of cochlear function evaluation in subjects affected by chronic acoustic trauma, through the study of the acoustic distortion products. Undertaking 46 subjects, the researchers have demonstrated a direct correlation between the tonal acoustic threshold and that of the distortion products. This method was able to show the useful indications of an objective evaluation of acoustic capacity in non collaborating subject. Because of the large variability of intensity of the distortion products and their absence when the acoustic threshold is more than 50-60 dB HL, they by themselves, don't permit exact evaluation of the tonal threshold for a given frequency.

Vitamin A modulation of basement membrane production by purified testicular myoid cells.

Purified myoid cells, isolated from prepubertal rat testes, cultured in a chemically defined medium for up to 1 week do not change their metabolic activities, evaluated as protein synthesis and secretion, during the culture time. We report that fibronectin, collagen IV, and laminin are synthesized and secreted by myoid cells as demonstrated by immunocytochemical and biochemical methods. The deposition of all three proteins was spotty, with different regional localizations. The effect of vitamin A on the synthesis and the secretion of the basement membrane components was also evaluated. Retinol supplementation induces a higher synthesis of fibronectin and laminin, whereas it does not change collagen IV synthesis and secretion. The secretion of the other two molecules is differentially regulated by retinol; in fact fibronectin secretion is increased, whereas laminin secretion is reduced. Similar results were obtained utilizing retinoic acid. The data we report in this paper show, for the first time, that purified testicular myoid cells synthesize and secrete fibronectin, collagen IV, and laminin and that synthesis and secretion of these components of the basement membrane are regulated by retinol. These findings reveal a new effect of vitamin A in the regulation of mammalian spermatogenesis.

[Results and considerations regarding auditory neonatal screening based on the use of transient evoked otoacoustic emission]. / Risultati e considerazioni a proposito di uno screening audiologico neonatale basato sull'impiego delle otoemissioni acustiche evocate transienti.

The authors present a 5-year clinical experience in audiological screening performed at the neonatal center of the Policlinico of Perugia, Italy. The study was performed using an IL088 Otodynamics unit produced by Bray & Kemp. A total of 1328 newborns (2656 ears) were tested on the 4th day of life and during spontaneous sleep. None of the children had any audiological risk factors. The test was repeated one month later for all subjects who lacked Transient Evoked Otoacoustic Emissions and in many cases ABR testing was performed by 3 months of age. The authors present the undoubted advantages of the present method which include the fact that it is a) easy to perform, b) non invasive, c) sensitive and d) effective. They then discuss the main problems which arose during the course of the screening and advance some solutions. For the most part these problems involved the high number of false positives (13.1%) and the high percentage of subjects who were lost to subsequent controls (approximately 6% of the total population). The number of false positives could be reduced by using a linear acoustic stimulation (rather than the non-linear stimulation which is the default parameter for the machine). Such a linear stimulation can improve the signal-to-noise ratio, thus making it possible to adopt a reproducibility index lower than the 70% presently used (however, this brings with it the risk of including a certain number of false negatives). Finally, they discuss the possibility of only retesting those subjects with bilateral lack of TEOAEs, thus reducing the number of check-ups to be performed a month later.

[Otoacoustic distortion products in sensorineural hearing loss in the cochlea]. / I prodotti di distorsione otoacustici nelle ipoacusie neurosensoriali di natura cocleare.

The purpose of the present work was to assess distortion-product otoacoustic emissions (DPOAE) in cochlear hearing loss and in its various morphologies. A total of 19 patients (30 ears) were selected for the study. They showed various pictures of neurosensorial hearing loss which were localized within the frequency range normally examined during audiometric tonal threshold testing. The DPOAEs were recorded using a Bray and Kemp ILO 92 instrument. The DPOAEs of several frequencies (750,1000,1500,2000,3000,4000 and 6000 Hz) were examined using an f2 tone of 696, 1001, 1587, 2002, 3147, 4004 and 6348 Hz, respectively. The results were as follows: a) At certain frequencies the overlap between hearing loss and the absence of, or reduction in, DPOAE amplitude was virtually total. b) There was a modest correlation between the degree of hearing loss and decrease in, or absence of, DPOAEs although there was a spectrum of intermediate hearing losses where the DPOAEs varied widely from one individual to another (this spectrum ranged from 10 to 45 dB HL on the audiometric tonal test). c) The absence of DPOAEs at 750 Hz is unable to predict hearing loss for this frequency as, at this frequency, there can be a lack of DPOAEs even when the 750 Hz audiometric threshold level is normal. Finally, what emerged from this study was that DPOAEs prove quite useful to complement the study of auditory brainstem responses (ABR), now universally accepted as the means for early diagnosis of hearing loss in children. In fact, ABRs provide precise data regarding a frequency field which is socially less important in terms of verbal communication and the development of spoken language. It is, however, unable to explore individual frequencies.

[Evoked otoacoustic emissions using clicks in detection of deafness in young children]. / Les oto-émissions acoustiques provoquées (OEAP) par des transitoires dans le dépistage de la surdité du jeune enfant.

Click-evoked otoacoustic emissions (EOAEs) are sounds emitted by the cochlea due to active outer hair cell contraction following stimulation of the stereocilia. The purpose of this study was to evaluate the use of testing for EOAEs as a valid auditory screening method in newborns, and 1074 healthy fullterm babies (2148 ears) with an Apgar score higher than 8 at birth were examined. EOAEs were elicited 4 days after birth and a correlation index higher than 70% represented normal response criteria. If there was no response, EOAEs and brainstem response potentials were tested at the age of one month. On the fourth day after birth. EOAEs specificity and efficiency were found to be 92.3% and 92.4% respectively, while sensitivity was 100%. Specificity and efficiency at one month were rated at 100%. The use of EOAEs offers numerous advantages over traditional auditory screening methods, thus suggesting that this technique is suitable for the mass-screening of infants.

[The donation of autologous blood in pregnancy. Observations on its safety and the cost-benefit relationship]. / Riserva di sangue autologo in gravidanza. Considerazioni sull'innocuità e sul rapporto costi-benefici.

Experience with the collection of autologous blood during the last part of pregnancy in 57 women is reported. The authors confirm the safety of the autologous transfusion program but come to the conclusion that, with current entrance criteria, the cost-benefit ratio seems unfavourable. Therefore they suggest: a) the sole involvement of women with real potential hemorrhagic complications (placenta previa, multiple pregnancy); b) the collection, when possible, of at least 2 units of autologous blood.

[Short-term reproducibility of acoustic oto-emissions induced by clicks in adults]. / Reproductibilité à court terme des oto-émissions acoustiques provoquées par des clics chez des sujets adultes.

Otoacoustic emissions (OAE) are sounds emitted by the cochlea and recordable in the external ear canal by a miniature microphone. The OAE reflect the existence of an active mechanism within the cochlea. Development of the OAE has spurred much interest because they may used as a valid test for screening and monitoring cochlear changes. The OAE were recorded in 8 normal hearing subjects (15 ears) during nine test sessions under similar conditions. The aim of this work was to study the short-term variability in the amplitude of the emissions. Results of the study indicate that response levels are stable over time in the same ear therefore changes in the response level can be associated with changes in the cochlea.

The effect of gamma-linolenic acid on clinical status, red cell fatty acid composition and membrane microviscosity in infants with atopic dermatitis.

A double blind placebo-controlled study of two doses of gamma-linolenic acid, provided by evening primrose oil (EPO, Epogam, Searle, U.K.), in children with atopic dermatitis was performed: 1) to examine the effect of gamma-linolenic acid administration on the clinical status of children with atopic dermatitis and abnormalities of IgE-mediated immune responses compared to those without such IgE abnormalities; 2) to investigate the effect of gamma-linolenic acid on red cell fatty acid composition and 3) to assess whether treatment with gamma-linolenic acid induced changes in red cell membrane microviscosity. A significant improvement in the overall severity of the clinical condition was seen in children treated with gamma-linolenic acid, independent of whether the children had manifestations of IgE-mediated allergy. Furthermore, gamma-linolenic acid treatment increased the percentage content of n-6 fatty acids in erythrocyte cell membrane; this increase was more marked in the membranes of children treated with high doses of EPO. In the high dose group a significant increase in dihomogamma-linolenic acid (DGLA) occurred. This may be of particular relevance because of the potential importance of DGLA as a precursor of antiinflammatory prostanoids. Red cell membrane microviscosity did not change in any group after treatment with EPO, even in high doses, despite a significant increase in the proportion of long chain polyunsaturated fatty acids.

Evoked otoacoustic emissions behaviour in retinitis pigmentosa.

The hearing function was studied in 26 patients affected by retinitis pigmentosa (RP) and in their relatives. Sixteen patients showed bilateral normal hearing when examined with traditional audiometric methods. In these normoacusic patients evoked otoacoustic emissions (EOE) have been studied. The EOE offer a unique opportunity to measure objectively the function of outer hair cells: they record the amplitude of the energy produced by the outer hair cells of the coclea following an acoustic stimulation. The data have been statistically compared, using the Student's t-test, with those obtained in a homogeneous control-group of normal subjects. In normoacusic subjects with RP the average values of EOE intensity are statistically lower than those of normal subjects in 64 of the 127 frequency bands examined. Moreover, the distribution of the EOE in patients with retinitis pigmentosa proved to be more discontinous than that observed in the normal subjects. The EOE recorded in 14 normoacusic relatives show in some cases small anomalies but the data, on account of the limited sample group, cannot be statistically evaluated. Therefore a subclinical alteration of the Organ of Corti is found in 100% of the patients affected by RP, although they appear to be normoacusic to usual audiometric tests.