Probiotics in digestive diseases: focus on Lactobacillus GG.

Probiotics are becoming increasingly important in basic and clinical research, but they are also a subject of considerable economic interest due to their expanding popularity. They are live micro-organisms which, when administered in adequate amounts, confer a health benefit to the host. From this very well-known definition, it is clear that, unlike drugs, probiotics might be useful in healthy subjects to reduce the risk of developing certain diseases or to optimise some physiological functions. They also may offer some advantages in already ill persons in relieving symptoms and signs, e.g. people with acute diarrhea. According to current definitions, probiotics should survive both gastric acid and bile to reach the small intestine and colon, where they exert their effects. Many of these are available in a lyophilized (freeze-dried) pill form, though some are available in yogurt or as packets (sachets), which can be mixed into non-carbonated drinks. The present review focuses on three main issues: 1) understanding why, at present, probiotics are so interesting for doctors and consumers; 2) reviewing the available data on probiotic use in digestive diseases, in particular irritable bowel syndrome (IBS), (prevention of) infectious diarrhea, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD), and colorectal cancer (CRC); 3) highlighting the individual profile of Lactobacillus GG (LGG) in the above contexts, providing an assessment as well as recommendations on its use in gastro-intestinal tract (GIT) disorders. Research studies conducted in animals and humans with the main probiotics strains for GIT diseases, and published from the early 1990s to 2014 have been considered. PubMed, Medline and Ovid were the main sources adopted for data retrieving. The increasing attention on probiotics is a direct consequence of the improvement in the techniques for studying microbiota. Until recently, its composition has been analysed by culture-based methods that use differential media to select for specific populations of bacteria according to their metabolic requirements. Lactobacillus and Bifidobacterium species are by and large the most commonly used probiotics. Strictly speaking, however, the term "probiotic" should be reserved for live microbes that have been shown in controlled human studies to provide a health benefit. Taking into account patients suffering from the most common gastrointestinal diseases, in whose establishment the GI microbiota plays a key role, probiotics have to be considered as very promising agents, capable of beneficially modulating the intestinal ecosystem, which is perturbed in cases of dysbiosis. Although more clinical data are still needed to better assess the clinical relevance of probiotics, to date, procariota such as Bifidobacteria and Lactobacilli strains, and eucariota such as some Saccharomyces strains are among the most widely used agents in GIT disorders. LGG is a well-known probiotic strain that was isolated more than 20 years ago by Goldin and Gorbach from a faecal sample of a healthy adult, based on several selection criteria: high adhesion in vitro, high resistance against gastric acidity and high antimicrobial activity against pathogens such as Salmonella. In vivo studies have also shown a good persistence of LGG in the human GIT. Since its isolation, LGG has become one of the best clinically documented probiotic strains. A growing body of evidence suggests benefits such as prevention and relief of various types of diarrhoea, and treatment of relapsing Clostridium difficile colitis. Thus, with respect to both adaptation to the GIT and probiotic effects, LGG can be regarded as a prototypical probiotic strain.

Nasal congestion in infants and children: a literature review on efficacy and safety of non-pharmacological treatments.

The most common causes of nasal obstruction and runny nose in infants and children are infections, mainly of viral origin, or allergies. In neonates and infants viral upper respiratory tract infections (URTI) are frequently observed during episodes of nasal obstruction. Saline irrigation of the nose is believed to alleviate URTI symptoms by helping to eliminate excess mucus, to reduce congestion and by contributing to improve breathing. Objective of the study was to review the efficacy and safety of non-pharmacological options for the treatment of nasal congestion and its sequelae, in infants and children, with a special focus on hypertonic and isotonic solutions and other medical devices, including nasal aspirators. Available data indicate that nasal symptoms in children with allergic rhinitis or acute sinusitis significantly improved following nasal saline irrigation. The use of medical devices is less documented. Nasal aspiration with a medical device, associated with an isotonic saline solution, during viral rhinitis, has been shown to lower the risk of developing acute otitis media and rhinosinusitis, in comparison with a group treated with physiological saline solution alone. Safety and tolerability have been evaluated and no serious adverse events have been reported. Literature data highlighted the good tolerability. The use of isotonic and hypertonic saline solutions to relief nasal congestion in infants and children is widespread; it is a safe and valuable therapeutic support, and can reduce the use of medications (antihistamines, decongestant, antibiotics, corticosteroids) during the treatment of URTIs.

Role of PHGG as a dietary fiber: a review article.

AIM: Functional and metabolic effects of dietary fiber are recognized by the scientific, clinical and nutritional experts. Dietary fiber plays a very significant role in modifying the intestinal microbiota, exerting prebiotic effects such as stimulating the growth and/or function of beneficial intestinal microorganisms. Changes in the gut microbiota composition are classically considered as one of the many factors involved in the pathogenesis of either inflammatory bowel disease or irritable bowel syndrome. The use of particular food products with a prebiotic effect has thus been tested in clinical trials with the objective to improve the clinical activity and well-being of patients with such disorders. Partially Hydrolyzed Guar Gum (PHGG) is a natural dietary fiber (Benefibra™, Novartis CH Italy): it is a white powder, water-soluble, colorless and transparent in water solution and almost tasteless. PHGG is stable and soluble at various pH levels commonly found in foods as well as resistant to heat, acid, salt, high pressure and digestive enzymes. Low viscosity of PHGG provides a distinct advantage for the use of fiber in enteral feeding products to be administered through feeding tubes. It has been studied in adults, both healthy volunteers and patients, in different disorders such as constipation, irritable bowel syndrome (IBS), enteral nutrition, small intestine bacterial overgrowth (SIBO) and, very recently, in children suffering from functional abdominal pain according to the Rome III Criteria definition for functional gastrointestinal disorders (FGIDs). This review takes stock of the situation concerning what is known to date on PHGG as dietary fiber, in order to give the health care professionals, such as gastroenterologists, dieticians and general practitioners, a complete overview on its intrinsic characteristics, preclinical and clinical evaluations, uses in different situations as supportive therapy in the management of the main intestinal functional disorders both in adults and in children. METHODS: All the papers on PHGG, published from the early 1990s of the Last Century to the Year 2013, have been considered. All types of publications have been included. PubMed, Medline, Ovid were the main sources adopted for data retrieving. RESULTS: PHGG has been studied in both animals and humans; its safety is well known and several clinical uses are well established. Concerning the modulation of metabolism in human, very little has been done to date and the studies have been focused, for the most part, on the functional diseases: PHGG has been proved to be useful in treating both IBS -C and D symptoms, not only in adults but also in children; data on constipation are relatively scarce and what can be deduced from the Literature is that the high concentration of fiber gives the PHGG the possibility of being used effectively in acceptable dosages (up to 22 g/day) even in situations such as chronic constipation. The use in clinical nutrition has revealed the flexibility of the compound which, owing to its peculiar characteristics, does not gel and remains liquid, PHGG can be used successfully in patients in enteral nutrition lowering the incidence of diarrhea. New open horizons can be glimpsed for SIBO treatment, lowering or maximizing the antibiotics use. CONCLUSION: Not all the fibers are the same: this is a fact. Promoting the specific knowledge of their characteristics is very important if healthcare professionals want to give their patients the best options for functional gastrointestinal disorders or nutritional needs. PHGG (Benefiber™ Novartis CH) has been proved to be safe and effective in promoting gut health.

Gastroesophageal reflux in pregnancy: a systematic review on the benefit of raft forming agents.

The prevalence of gastroesophageal reflux disease (GERD) symptoms in pregnancy is very high, up to 80%, with a maximum peak during the third trimester. Together with lifestyle modifications, antacids and antisecretive agents, such as proton pump inhibitors (PPIs) and histamine H2 receptor antagonists (H2RAs), are commonly prescribed in non-pregnant, adult population. In certain Countries these drugs are not allowed in or are allowed only during the late stages of pregnancy. Alginate-based formulations have been used for the symptomatic treatment of heartburn for decades, as they usually contain sodium or potassium bicarbonate. In the presence of gastric acid, a foamy raft is created above the gastric contents. The alginate raft moves into the esophagus in place or ahead of acidic gastric contents during reflux episodes physically preventing reflux of gastric contents into the esophagus. Alginate-based formulations are allowed with no restrictions also in pregnancy: their safety profile make them a very valid option taking into account the risk/benefit ratio for both parturient and unborn baby. This systematic review paper aims to explore the use of medications for treating GERD in pregnancy, including alginate raft-forming-agents, highlighting the benefits for both the mother and the fetus. Electronic search in databases was conducted on databases such as Medline, PubMed, Ovid retrieving data concerning the reflux treatments in pregnancy, with a special focus on alginate raft forming antireflux agents. From the literature on alginate use in pregnancy, no particular risks have been shown to date for both parturient and unborn baby when alginate had been administered during all the pregnancy trimesters. The physical mode of action ensures the maximum esophageal protection by the neutral foam floating in the stomach, maintaining physiological pH values at stomach level, without interfering with the digestive processes. The symptoms' healing has been markedly improved during the weeks of observation; the symptoms monitored in all studies were: heartburn, regurgitation, pain (chest). After four weeks of treatment little or no change was observed in maternal mean sodium or potassium concentrations. No sodium restriction diet has been adopted. No edema of lower limbs or weight gain occurred. No adverse reactions related to the testing drug had been reported and all the authors concluded that alginate was safe for the unborn baby. Nowadays pharmacological treatments for GER are available as OTC drugs, including antacids, antisecretive agents, PPIs and H2RAs, and as medical devices, such as alginate raft forming antireflux agents (i.e.: Reflubloc™, Novartis NCH Italy). On this last product, considering the specific indication in pregnancy and the safety profile, without restrictions of administration during the whole pregnancy period, furthermore the physical mode of action, it gives the gynecologists a very important option in treating GER in pregnancy, taking care of both pregnant and fetus. Raft-forming-antireflux agents are safe and effective in GER treatment during pregnancy.

Observational study on the performance of the Narhinel method (nasal aspirator and physiological saline solution) versus physiological saline solution in the prevention of recurrences of viral rhinitis and associated complications of the upper respiratory tract infections (URTI), with a special focus on acute rhinosinusitis and acute otitis of the middle ear.

AIM: The aim of this study was to assess the validity of Narhinel method in the prevention of recurrences of viral rhinitis and of any associated sequelae, in particular acute otitis of the middle ear (AOM) and acute rhinosinusitis (AR). METHODS: This was a prospective observational study, in children aged from two months to two years, observed for five months during the cold season and carried out by family pediatricians (FIMP association) in Friuli Venezia Giulia, Italy. The study enrolled 435 patients. The observed population consisted of two groups: the first one of 238 children treated with Narhinel method and the second one of 197 patients treated only with the physiological saline solution. In compliance with the guidelines of an observational trial, the children were prescribed the therapeutic treatments used as a routine. The patients were recruited for the trial after the responsible parent had signed the informed consent form. The study protocol had been approved by the Ethics Committee of the area of Pordenone. In order to be recruited, patients had to comply with the following criteria: symptoms suggestive of the common cold; age > or =2 months < or =2 years; male and female. Patients presenting one or more of the following characteristics were not included: systemic diseases; congenital nasal obstruction (choanal atresia); infections of the upper and lower respiratory tracts other than common cold; systemic and/or topical use of antibiotics and/or corticosteroids at the moment of recruitment. During the five months of the observation period, all the therapies that the investigators had decided it was necessary to administer had been included and recorded in the CRF. Patients evaluations were carried out for five months. The clinical assessment was performed at baseline (B), in the first week (Fw) and monthly and described as M1 to 5; several clinical parameters were analyzed (anterior and posterior rhinorrhoea, oral respiration, noisy nasal respiration, and nasally transmitted thoracic sounds) and measured by the pediatrician at all examinations from B to M5. Other parameters were derived from the parents' daily observations, recorded in a diary and made note of the quality of sleep, diet and respiration, and the use of any drug during any relapse of acute rhinitis (common cold episode). Recurrence of AOM and AR was assessed by the pediatrician at M1-2-3-4-5. Safety of use was determined using the Italian Health Ministry incident/near incident report sheets for Medical Device and based on diaries where the parents took note of any events which occurred during the observation period. Parental satisfaction and compliance were assessed through a questionnaire given to the parents at the end of the last visit (M5). RESULTS: In the Narhinel group, the mean age was inferior (statistically significant): 8.9 compared to 11.4 months in the physiological saline solution group. The frequency of recurrences from viral rhinitis was very similar in the two groups and a decrease (statistical significant) was observed from M3 through M5 in both groups. Rhinorrhea, oral breathing, and other upper respiratory symptoms, improved in the two groups even if in the Narhinel one the improvement was more prominent during the first two months of observation. There was no difference in the frequency of AR between the groups: at M4 and M5, there was a statistically significant decrease in the frequency of episodes. The frequency of AOM varied in the two groups considering a comparison intra-groups: at M5 the decrease of episodes was statistically significant in the Narhinel group. In Narhinel group, AR and acute AOM seem to be more markedly controlled (frequency) especially for AOM. The frequency of adverse events (AEs) did not vary in the two groups: in the Narhinel one there was a difference (not statistically significant and not clinically relevant) in the number of patients with AEs, especially crying and nasal bleeding. One serious AE was reported in the physiological saline solution group. A 14-month-old child developed laryngospasm which recovered completely after hospital treatment with adrenaline. This event was not related to treatment with saline solution and causality was assessed as "unlikely" by the investigator. In the Narhinel group, one serious event of moderate convulsion febrile in a male patient (age of 0.9) was reported. The causality relationship was assessed by the investigator as improbable. Parents' satisfaction was higher (statistically significant) in the Narhinel group compared to the physiological saline solution alone group. CONCLUSION: In acute rhinites (common cold) both medical devices are effective nevertheless Narhinel method is valid and shows better results in AOM and AR. Moreover Narhinel method was also more appreciated by parents than physiological saline solution. According to authors' experience, the Narhinel method is safe and its performance is valid in the prevention of AOM and AR in children.

Safety of use, efficacy and degree of parental satisfaction with the nasal aspirator Narhinel in the treatment of nasal congestion in babies.

AIM: The aim of this study was to assess the safety, effectiveness and parental compliance with a medical device on the market in Europe for removing excess nasal secretions by aspiration in babies viral infections of the upper respiratory tract. METHODS: A prospective observational noncomparative cohort study, as part of postmarketing and customer satisfaction surveillance was specifically performed among family paediatricians in Lombardy, Italy. Two hundred and forty patients were admitted from 22 different family pediatricians belonging to the Italian Federation of Paediatricians (Federa-zione Italiana Medici Pediatri, FIMP) in Lombardy. All patients took part in the safety assessment. Two hundred and twelve patients (104 females, 108 males, average age 9.6 months, age range 1.8-27.6 months) also underwent clinical efficacy assessment (28 patients were excluded). Upon admission and at the first outpatient examination (E1), parents were taught by their family pediatrician to clean their babies' noses by nasal aspiration 3 times a day for 7 consecutive days immediately before feeding. At the end of treatment, a second outpatient examination (E2) was carried out at which parents' treatment diaries were collected and the parents answered a satisfaction questionnaire. SAFETY of use was checked using: 1) Italian Health Ministry incident/near incident report forms and 2) treatment diaries where the parents noted any events that had occurred while using the device every day. EFFICACY was assessed by analysing various clinical parameters (anterior and posterior rhinorrhea, oral respiration, noisy nasal respiration, and nasally transmitted chest sounds) measured by the pediatrician at the two examinations (E1 and E2), and the entries in the parents' treatment diary regarding quality of sleep, feeding and respiration, and use of any drugs. Parental satisfaction and compliance were assessed through a questionnaire given to the parents at E2. The device is marketed in 2007 under the name of Narhinel in Italy, Spain and Portugal; Otrisalin in Greece; Prorhinel in France; Rhinomer in the Baltic countries (Lithuania, Latvia, Estonia); Otrivin Baby in Russia and Otri-Baby in Sweden. SAFETY: no incidents were reported to the Italian Ministry of Health. There were 40 cases of mild side effects such as nose bleed (6), protracted crying (30), restlessness/irritation (2), vomiting and others (2). EFFICACY: clear improvements were seen in all the clinical parameters assessed at the post-treatment examination (E2) when compared to E1: anterior rhinorrhea (decreased by 74%), posterior rhinorrhea (decreased by 80%), oral respiration (decreased by 78%), noisy respiration (decreased by 73%), and nasally transmitted chest sounds (decreased by 82%). The entries in the treatment diaries also showed progressive improvement in the children's' conditions during the treatment period: peaceful sleep increased by 67%, quality of feeding increased by 36%, respiration improved by 76%, and the administration of drugs decreased by 41%. The P values for each item (clinicians observations and parents' observations) are statistically significative P<0.001, between the day 1 and the day 8. Satisfaction and compliance were excellent: 92% of parents were satisfied (56% very and 42.7 fairly). Seventy-eight percent reported that the device was simple to use, and 86% of parents judged Narhinel to be more effective than other similar devices. CONCLUSION: Narhinel proved to be a safe, effective and simple to use device. The parents of babies with nasal obstruction caused by upper respiratory infection were extremely satisfied.

Adherent neoplastic cells grown at confluence downregulate HLA class I expression and enhance their susceptibility to lysis mediated by natural killer cells.

The number of HLA class I molecules and the susceptibility to lysis mediated by natural killer (NK) cells were evaluated on cell targets obtained from confluent and sparsely plated cultures of both normal and tumor cell lines. Sparsely plated proliferating cells expressed high amounts of HLA class I molecules and were more resistant to NK cell-mediated lysis than confluent cells, which expressed low amounts of HLA class I antigens. This characteristic could be involved in the control of cancer progression and could also explain the wide variability of assays of lymphocyte-mediated cytotoxic activity.

Intralesional sonographically guided injections of lymphokine-activated killer cells and recombinant interleukin-2 for the treatment of liver tumors: a pilot study.

Primary and metastatic liver cancers have a poor prognosis. At present, sonographically guided alcohol injection results in a partial reduction of cancer masses even if severe toxic effects (including pain and bleeding) are always present. For these reasons, a pilot study was started to evaluate the feasibility of an intralesional adoptive immunotherapeutic approach, using lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2). Nine patients (one with primary hepatocarcinoma and eight with liver metastases) entered the study. Four cycles of weekly injections of LAK cells (ranging from 2 to 9 x 10(8)) and 10(6) IU rIL-2 were performed percutaneously under ultrasonic guidance. In the same period, 3 x 10(6) IU rIL-2/day, for 24 days, was injected subcutaneously. All patients but one completed the therapy. Side effects were limited to grade 1-2 fever and were mostly related to rIL-2 subcutaneous injections. No patients complained of having pain during intralesional therapy. Two complete responses were detected. One partial response, four stable diseases, and one progressive disease were observed. One patient was not evaluable. These preliminary results suggest that sonographically guided intralesional adoptive immunotherapy of liver tumors is feasible, safe, and could offer promising therapeutic advantages in cancers for which conventional treatment is generally unsatisfactory.

Cytotoxic effects of high energy shock waves on cancer cells linked to metallic beads vehicled by monoclonal antibodies.

Previous studies have reported that high energy shock waves (HESW), generated by an electrohydraulic lithotriptor, may have some utility as a cancer treatment modality. Furthermore, it has been described that shock waves propagating in a fluid, show demolitive effects at the level of the interface of a solid fragment immersed in the fluid. In this study, we demonstrate that it is possible to enhance the antineoplastic effects of HESW if treated cells or tissues are linked to monoclonal antibodies (MoAbs) conjugated with metallic beads (MB) (about 1 mu of diameter) and specific for a cancer cell surface determinant. A leukemic cell line was used to study the effects of HESW on cells linked to MB. A fresh human breast cancer specimen was used to perform the assay on tumor tissue. MB linked treated cell viability, growth curve, cloning efficiency and Bromodeoxyuridine incorporation were reduced in comparison to cells treated with HESW alone. Our data suggest that the presence of solid fragments vehicled by MoAbs on a cancer cell surface is able to synergize with the limited antineoplastic effects of HESW.

Selective expansion of circulating CD8+ lymphocytes during cancer immunotherapy with interleukin-2 plus alpha-interferon but not with interleukin-2 alone.

The use of interferons in anti-cancer therapy is justified by the experimental evidence that these cytokines are able to enhance in vitro the expression of some surface molecules such as major histocompatibility complex and tumor associated lymphocytes. Furthermore, a synergism of action of interleukin-2 with alpha-interferon in the treatment of human malignancies has been described. Nevertheless, whether the in vivo role of interferons associated to interleukin-2 as anti-cancer drugs is actually related to the properties of this cytokine of modulating surface molecule expression on target cells, has never been clearly reported. In this report, we describe an immune system cell resetting, during immunotherapy with interleukin-2 plus alpha-interferon, which seems to support this hypothesis.