Comorbid asthma is associated with rhinitis severity in children exposed to air pollutants.

BACKGROUND: The impact of asthma on the severity of rhinitis when children with allergic rhinitis (AR) are exposed to air pollutants has not been studied. METHODS: Children with AR (65 with asthma, 208 without asthma), aged 6-13 years, were recruited from a hospital in Taichung, Taiwan, between 2007 and 2011. Correlations between Pediatric-Rhinoconjunctivitis-Quality-of-Life score, nasal peak expiratory flow, and air pollutants were compared. With the same age, research time, and form the same city, children with AR (660 with asthma, 3174 without asthma) were selected from a database. Correlations between clinical visit times for AR and air pollutants were compared. RESULTS: In male children with AR and asthma, both clinical and database studies revealed a correlation between higher rhinitis discomfort (quality-of-life score), higher visit times for AR, and higher PM10, PM2.5, NO2, NMHC concentrations. Correlations between higher nasal inflammation/obstruction (lower expiratory flow) and higher air pollutant concentrations were observed in male children with AR and asthma. CONCLUSION: In children with AR, comorbid asthma was associated with increased rhinitis severity when they were exposed to air pollutants, and the association was only noted in males. Increased nasal obstruction/inflammation from exposure to air pollutants may be the mechanisms underlying this association. IMPACT STATEMENT: The influence of asthma on the severity of rhinitis when children with allergic rhinitis (AR) are exposed to air pollutants has not been studied. In children with AR, the correlation between higher rhinitis discomfort, higher number of clinical visits for AR, and higher PM10, PM2.5, NO2, NMHC concentrations were only noted in those who also had asthma. The correlation was only noted in male. Comorbid asthma was associated with higher rhinitis severity when children with AR are exposed to air pollutants The association was only noted in male.

Maternal Exposure to Air Pollution Is Associated with Neonatal Jaundice: A Retrospective Cohort Study.

OBJECTIVE: To evaluate the association between maternal ambient pollutant exposure and neonatal jaundice in multiple pollutant species and examine sex differences. STUDY DESIGN: Epidemiologic study: Records of 13 297 newborns (6153 male, 7144 female) born in Taichung, Taiwan were obtained from a national database. Average concentrations of prenatal air pollutants 3 months prior to birth were divided into low, middle, and high levels. Neonatal jaundice phototherapy rates between mothers who suffered varying air pollutant levels were compared. Clinical study: Three hundred seventy-six newborns (189 male, 187 female) born and received jaundice treatment with phototherapy in a hospital in Taichung, Taiwan were recruited. The correlation between prenatal exposure to air pollutants 3 months prior to birth, newborn's serum bilirubin, and serum hemoglobin were calculated. RESULTS: Epidemiologic study: Male newborns born to mothers exposed to high carbon monoxide (CO), nitric oxide (NO), nitrogen dioxide (NO2), and methane (CH4) levels had higher phototherapy rates. In female newborns, the same was noted for CO and CH4. Clinical study: Male newborns had a positive correlation between CO, ≤2.5 µm diameter particles, ≤10 µm diameter particles, NO, NO2, nonmethane hydrocarbon, and CH4 exposure 3 months prior to birth and serum bilirubin levels. Female newborns had a positive correlation for CH4. A positive correlation between CO, ≤2.5 µm diameter particles, ≤10 µm diameter particles, NO2, nonmethane hydrocarbon, CH4 exposure, and serum hemoglobin levels was noted in male newborns. CONCLUSION: Maternal exposure to air pollutants may increase neonatal jaundice treatment rates for phototherapy and higher neonatal serum total bilirubin level. Higher hemoglobin levels because of higher pollutant exposures may explain our findings. The association was more obvious in male newborns.

Early Gut Microbiota Changes in Preterm Infants with Bronchopulmonary Dysplasia: A Pilot Case-Control Study.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a complex chronic lung disease that primarily affects premature or critically ill infants. This pilot study investigated early changes in gut microbiota composition in BPD patients and explored the potential risk factors associated with these changes. STUDY DESIGN: Preterm infants admitted to our neonatal intensive care unit with a gestational age of 26 to 32 weeks were prospectively surveyed and eligible for stool collection on days 7 and 28 of postnatal age between February 2016 and June 2017. A 16S rRNA sequencing approach was applied to compare the gut microbiota composition between the BPD group and controls. Multiple linear regression analysis was used to identify the predictor variables. RESULTS: Eight subjects in the BPD group and 10 subjects in the preterm group were analyzed during the observation period. Actinobacteria, Proteobacteria, Bacteroidetes, and Firmicutes were the four dominant bacteria phyla of intestinal microflora. A significantly lower diversity of gut microbiota was observed in the BPD group compared with the preterm group on day 28 (number of observed operational taxonomic units, p = 0.034; abundance-based coverage estimator, p = 0.022; Shannon index, p = 0.028). Multiple linear regression analysis revealed that high Neonatal Therapeutic Intervention Scoring System score (≧19) at 24 hours was statistically significant in predicting the proportion of aerobic with facultative anaerobic bacteria on day 28 (p = 0.002). CONCLUSION: Infants with BPD are prone to develop gut dysbiosis in early life. A higher severity of illness and treatment intensity may indicate a higher risk of disrupting an anaerobic environment in the gut during the first month of life. KEY POINTS: · BPD patients are prone to develop gut dysbiosis.. · Lower diversity of gut microbiota.. · Higher risk of disrupting anaerobic environment..

Association between allergic disease, sleep-disordered breathing, and childhood nocturnal enuresis: a population-based case-control study.

BACKGROUND: Little is known about the associations between allergic disease, sleep-disordered breathing (SDB), and childhood nocturnal enuresis (NE). We examined whether allergic disease and SDB were associated with childhood NE. METHODS: Data were assessed from the 2007-2012 Taiwan National Health Insurance Research Database. We enrolled 4308 children aged 5-18 years having NE diagnosis and age- and sex-matched 4308 children as the control group. The odds ratios of NE were calculated to determine an association with preexisting allergic disease and SDB. RESULTS: A total of 8616 children were included in the analysis. Prevalence of allergic diseases and SDB was significantly higher for the NE group than the control group (all p < 0.001). After adjusting odds ratios for potential confounding factors, except asthma, children with allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and obstructive sleep apnea (OSA) had significantly higher odds of NE compared with children never diagnosed. With stratification for sex, girls with allergic rhinitis, atopic dermatitis, allergic conjunctivitis, OSA, and snoring had significantly higher odds of NE, compared with girls never diagnosed. Only boys with allergic rhinitis and OSA were associated with increased odds of NE. With stratification for age, children aged 5-12 years with allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and OSA had significantly higher odds of NE compared with those never diagnosed. Odds of NE increased with the number of comorbid allergic diseases. CONCLUSIONS: Allergic diseases and SDB are associated with increased odds of childhood NE. The odds of NE increased with the number of comorbid allergic diseases present.

Neurological images and the predictors for neurological sequelae of epidemic herpangina/hand-foot-mouth disease with encephalomyelitis.

Since 1998 in Taiwan, enterovirus (EV) 71 epidemics have caused encephalomyelitis and placed a significant burden on parents and physicians. In this study, we present clinical manifestations, magnetic resonance (MR) imaging findings, and neurological sequelae on epidemic EV-infected patients with encephalomyelitis. Of the 46 patients, 14 patients presented with neurological sequelae; of them, 3 patients suffered from complications of mental regression. Predictors of unfavorable neurological sequelae were myoclonic jerks (> 4 times/night) and pleocytosis (167/µL) of the cerebrospinal fluid (CSF). Results from viral culture and MR imaging indicated that positive identification of EV71 infection was associated significantly with lesions on MR imaging. Our results show that hand-foot-mouth disease carries a higher risk of encephalomyelitis and that frequent myoclonic jerks and pleocytosis of the CSF are risk factors for subsequent neurological sequelae. Positive identification of EV71 might be useful as a predictor of lesions in MR imaging.

Diagnostic performance of procalcitonin for hospitalised children with acute pyelonephritis presenting to the paediatric emergency department.

OBJECTIVES: Urinary tract infection (UTI) is a common bacterial infection in children that can result in permanent renal damage. This study prospectively assessed the diagnostic performance of procalcitonin (PCT) for predicting acute pyelonephritis (APN) among children with febrile UTI presenting to the paediatric emergency department (ED). METHODS: Children aged ≤10 years with febrile UTI admitted to hospital from the paediatric ED were prospectively studied. Blood PCT, C reactive protein (CRP) and white blood cell (WBC) count were measured in the ED. Sensitivity, specificity, predictive values, multilevel likelihood ratios, receiver operating characteristic (ROC) curve analysis and multivariate logistic regression were used to assess quantitative variables for diagnosing APN. RESULTS: The 136 enrolled patients (56 boys and 80 girls; age range 1 month to 10 years) were divided into APN (n=87) and lower UTI (n=49) groups according to (99m)Tc-dimercaptosuccinic acid scan results. The cut-off value for maximum diagnostic performance of PCT was 1.3 ng/ml (sensitivity 86.2%, specificity 89.8%). By multivariate regression analysis, only PCT and CRP were retained as significant predictors of APN. Comparing ROC curves, PCT had a significantly greater area under the curve than CRP, WBC count and fever for differentiating between APN and lower UTI. CONCLUSIONS: PCT has better sensitivity and specificity than CRP and WBC count for distinguishing between APN and lower UTI. PCT is a valuable marker for predicting APN in children with febrile UTI. It may be considered in the initial investigation and therapeutic strategies for children presenting to the ED.

Allergic rhinitis children with obesity are more vulnerable to air pollution: a cross sectional study.

The association between air pollution, allergic rhinitis (AR), and obesity has not been studied. From 2007 to 2011, 52 obese and 152 non-obese children (7-17 years old) with AR were recruited. Pediatric-Rhinoconjunctivitis-Quality-of-Life Questionnaire (PRQLQ) and nasal peak expiratory flow (NPEF) were tested. Association between the scores and rates of the two tests and mean air pollutant concentrations within 7 days before the tests were compared. When exposed to higher concentrations of CO, PM10, and PM2.5, the rates of worse nasal discomfort were 39.4%, 44.4% and 39.3% in obese children; and 18.0%, 21.9% and 19.7% in non-obese children, respectively. Compare to non-obese children, the rates in obese children were higher for CO (odds ratio (OR) 3.54, 95% confidence interval (CI) 1.15 ~ 10.92); PM10 (OR 3.26, 95% CI 1.01 ~ 10.57) and PM2.5 (OR 3.30; 95% CI 1.03 ~ 10.54). In obese children, correlations between higher concentrations of CO, PM10, PM2.5 and higher nasal discomfort (higher PRQLQ); and correlations between higher concentrations of CO, PM10, PM2.5, NMHC (non-methane hydrocarbon) and higher nasal mucosa inflammation (lower NPEF) were noted. Obesity negatively affected AR severity when AR children experienced higher concentrations of CO, PM10, and PM2.5. Increased nasal inflammation induced by air pollutants might be the underlying mechanism.

Diagnostic performance of serum interleukin-6 and interleukin-10 levels and clinical predictors in children with rotavirus and norovirus gastroenteritis.

OBJECTIVES: Rotavirus and norovirus are the two most common causes of acute viral gastroenteritis in children. This study aimed to explore the association of serum interleukin-6 (IL-6) and interleukin-10 (IL-10) levels and the clinical features in children with rotavirus and norovirus gastroenteritis. METHODS: This prospective study enrolled 168 acute gastroenteritis patients admitted to a tertiary care center. Peripheral blood samples were collected for IL-6 and IL-10 assays within the first 72 h of illness. The diagnostic performance of clinical tests was estimated using the receiver operating characteristic (ROC) analysis. Binary logistic regression modeling was performed to examine the predictive variables. RESULTS: Serum IL-6 and IL-10 were measured in children with rotavirus infection (n=30), norovirus infection (n=25), Salmonella infection (n=26), and in 11 healthy controls. There were significant higher degrees of severity of illness and levels of IL-10 in the rotavirus group as compared to the norovirus group. The binary logistic regression analysis revealed that both the ANC and maximum body temperature (BT) were significant clinical predictors for discriminating rotavirus and norovirus gastroenteritis. The ROC curve to evaluate the accuracy of logistic regression model had an AUC of 0.847 (95% CI: 0.741-0.952, p<0.001). CONCLUSIONS: IL-10 shows a significant discriminating ability between rotavirus and norovirus infection. A model incorporating maximum BT and ANC can help pediatricians to distinguish between rotavirus and norovirus in children with a suspected viral gastroenteritis.

SOXs in human prostate cancer: implication as progression and prognosis factors.

BACKGROUND: SOX genes play an important role in a number of developmental processes. Potential roles of SOXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the involvement of SOXs in the progression and prognosis of human prostate cancer (PCa). METHODS: The gene expression changes of SOXs in human PCa tissues compared with non-cancerous prostate tissues was detected using gene expression microarray, and confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) analysis and immunohositochemistry. The roles of these genes in castration resistance were investigated in LNCaP xenograft model of PCa. RESULTS: The microarray analysis identified three genes (SOX7, SOX9 and SOX10) of SOX family that were significantly dis-regulated in common among four PCa specimens. Consistent with the results of the microarray, differential mRNA and protein levels of three selected genes were found in PCa tissues by QRT-PCR analysis and immunohistochemistry. Additionally, we found that the immunohistochemical staining scores of SOX7 in PCa tissues with higher serum PSA level (P = 0.02) and metastasis (P = 0.03) were significantly lower than those with lower serum PSA level and without metastasis; the increased SOX9 protein expression was frequently found in PCa tissues with higher Gleason score (P = 0.02) and higher clinical stage (P < 0.0001); the down-regulation of SOX10 tend to be found in PCa tissues with higher serum PSA levels (P = 0.03) and advanced pathological stage (P = 0.01). Moreover, both univariate and multivariate analyses showed that the down-regulation of SOX7 and the up-regulation of SOX9 were independent predictors of shorter biochemical recurrence-free survival. Furthermore, we discovered that SOX7 was significantly down-regulated and SOX9 was significantly up-regulated during the progression to castration resistance. CONCLUSIONS: Our data offer the convince evidence that the dis-regulation of SOX7, SOX9 and SOX10 may be associated with the aggressive progression of PCa. SOX7 and SOX9 may be potential markers for prognosis in PCa patients. Interestingly, the down-regulation of SOX7 and the up-regulation of SOX9 may be important mechanisms for castration-resistant progression of PCa.

A 12-year-old boy with an infected ectopic ureter presenting with acute appendicitis-like symptoms and acute scrotum.

An ectopic ureter draining into the seminal vesicle or vas deferens in males is a very rare anomaly and is usually associated with renal dysplasia or agenesis. An ectopic ureter associated with a dysplastic kidney is not usually a suspected cause during clinical evaluation of children with abdominal pain. This report presents a rare case of an ectopic ureter associated with a dysplastic kidney with an acute infection in a previously healthy 12-year-old boy, demonstrated by magnetic resonance imaging. He presented with abdominal pain that mimicked acute appendicitis-like symptoms which was subsequently complicated by epididymitis manifesting as an acute scrotum. Clinicians should consider including an ectopic ureter in the differential diagnosis of children presenting with acute abdomen.

Life-threatening rhabdomyolysis induced by Streptococcus bovis sepsis in a 6-year-old girl presented to the pediatric emergency department.

Streptococcus bovis infection is an uncommon disease during infancy and childhood. Rhabdomyolysis is frequently a complication of a viral infection in children and typically has a benign course. It has rarely been reported as a complication in cases of bacterial infection, especially those caused by S. bovis. We describe a case of life-threatening rhabdomyolysis after a bacterial infection caused by S. bovis sepsis in a previously healthy 6-year-old girl who presented to our pediatric emergency department. She had an unusually high serum creatine kinase value (peak value, 436,449 IU/L), and she was successfully treated with adequate antibiotic treatment and effective renal replacement therapy. This case illustrates that, although uncommon, S. bovis can cause serious infections during childhood. Pediatric emergency physicians should be aware that uncommon organisms may be able to cause severe infections in susceptible children associated with life-threatening rhabdomyolysis.

Bladder agenesis and bilateral ectopic ureters draining into the vagina in a female infant: demonstrated by MR imaging.

Complete agenesis of the bladder and urethra is an extremely rare congenital anomaly and most of these patients are stillborn or die during infancy. We report the case of a 1-month-old female infant with bladder and urethral agenesis who presented with bilateral dilated and tortuous ectopic ureters draining into the vagina diagnosed using MR imaging. Our patient was maintained on antibiotic prophylaxis and she remained well during the 3-year follow-up. MR imaging can be used as a valuable modality for genitourinary abnormalities, particularly in cases of inconclusive ultrasound or retrograde pyelography findings.

The role of procalcitonin for acute pyelonephritis and subsequent renal scarring in infants and young children.

PURPOSE: We assessed the usefulness of procalcitonin as a biological marker in diagnosing acute pyelonephritis and for predicting subsequent renal scarring in young children with a first febrile urinary tract infection. MATERIALS AND METHODS: Children 2 years old or younger with a first febrile urinary tract infection were prospectively studied. Renal parenchymal involvement was assessed by (99m)Tc-dimercaptosuccinic acid scan within 5 days of admission and after 6 months. Serum samples from all patients were tested for procalcitonin, C-reactive protein and white blood cell count measurements. RESULTS: The 112 enrolled patients (age range 24 days to 24 months old) were divided into acute pyelonephritis (76) and lower urinary tract infection (36) groups according to the results of (99m)Tc-dimercaptosuccinic acid scans. Median values of procalcitonin, C-reactive protein and white blood cell count at hospitalization were significantly higher in patients with acute pyelonephritis than in those with lower urinary tract infection. The area under receiver operating characteristic curves showed that procalcitonin was superior to C-reactive protein and white blood cell count as a marker for diagnosing acute pyelonephritis. Initial and post-antibiotic treatment procalcitonin values were significantly higher in children with renal scarring than in those without scarring (p <0.001). Procalcitonin values at hospitalization and after treatment were independent predictors of later renal scarring on logistic regression analysis. CONCLUSIONS: Our results indicate the superior diagnostic accuracy of procalcitonin for predicting acute pyelonephritis in children 2 years old or younger. Higher initial and posttreatment procalcitonin values are independent risk factors for later renal scarring.

The Risk of Developing Constipation After Neonatal Necrotizing Enterocolitis.

Background: Neonatal necrotizing enterocolitis (NEC) is a complex and lethal inflammatory bowel necrosis that primarily affects premature infants. Gut dysbiosis has been implicated in the pathogenesis of NEC. We aim to assess the association between NEC and two other diseases in children, including allergic diseases and constipation, considered to be associated with the alterations in gut microbiota composition. Methods: This retrospective population-based cohort study was conducted using the Taiwan Birth Registration Database, Birth Certificate Application, and National Health Insurance Research Database to inter-link the medical claims of neonates and their mothers. A total of 2,650,634 delivery events were retrieved from 2005 to 2015. We identified a NEC cohort and selected a comparison cohort according to propensity score matching (1:1). Cox proportional hazard regression models were used to determine possible associations of predictors and to obtain adjusted hazard ratios (aHRs). Results: A total of 1,145 subjects in the NEC cohort and 1,145 subjects in the matched cohort were analyzed during the observation period. No significant difference was observed in the incidence of allergic diseases between the two groups. NEC patients had a significant 30.7% increased risk of developing constipation (aHR = 1.307; 95% CI 1.089-1.568). The cumulative incidence of constipation was significantly higher in the NEC cohort than in the matched cohort by the end of follow-up (log-rank test P = 0.003). Conclusion: Infants with NEC have a significantly higher incidence rate of developing constipation and FTT but no increased risk of allergic diseases.

The synergistic tumor growth-inhibitory effect of probiotic Lactobacillus on transgenic mouse model of pancreatic cancer treated with gemcitabine.

Pancreatic cancer is one of the most lethal and chemo-resistant cancers worldwide. Growing evidence supports the theory that the gut microbiota plays an essential role in modulating the host response to anti-cancer therapy. The present study aimed to explore the effect of probiotics as an adjuvant during chemotherapy for pancreatic cancer. An LSL-KrasG12D/--Pdx-1-Cre mouse model of pancreatic ductal adenocarcinoma (PDAC) was created to study the effects of using four-week multi-strain probiotics (Lactobacillus paracasei GMNL-133 and Lactobacillus reuteri GMNL-89) as an adjuvant therapy for controlling cancer progression. At 12 weeks of age, pancreatitis was induced in the mice by two intraperitoneal injection with caerulein (25 µg/kg 2 days apart). Over the next 4 weeks the mice were treated with intraperitoneal injections of gemcitabine in combination with the oral administration of probiotics. The pancreas was then harvested for analysis. Following caerulein treatment, the pancreases of the LSL-KrasG12D/--Pdx-1-Cre transgenic mice exhibited more extensive pancreatic intraepithelial neoplasia (PanIN) formation. Combined treatment with gemcitabine and probiotics revealed a lower grade of PanIN formation and a decrease in the expression of vimentin and Ki-67. Mice that received gemcitabine in combination with probiotics had lower aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Notably, the use of high-dose probiotics alone without gemcitabine also had an inhibitory effect on PanIN changes and serum liver enzyme elevation. These findings suggest that probiotics are able to make standard chemotherapy more effective and could help improve the patient's tolerance of chemotherapy.

Minimally invasive surfactant therapy versus intubation for surfactant administration in very low birth weight infants with respiratory distress syndrome.

BACKGROUND: Minimally invasive surfactant therapy (MIST) is a new mode of surfactant administration without intubation to spontaneously breathing preterm infants with respiratory distress syndrome (RDS). The aims of this study were to assess the feasibility, efficacy and safety of using MIST to give surfactant for very low birth weight (VLBW) infants with RDS. METHODS: In total, 53 VLBW infants who were born before 32 gestational weeks with spontaneous breathing, respiratory distress, and requiring surfactant therapy were divided into two groups. The infants in group A (n = 29) were intubated and received surfactant replacement therapy via endotracheal tube, followed by mechanical ventilation (MV). The infants in group B (n = 24) received tracheal instillation of surfactant via a semirigid vascular catheter during spontaneous breathing under nasal continuous positive airway pressure (nCPAP). After surfactant instillation, the infants in group B were still placed on nCPAP. RESULTS: Our data showed that infants in group B (MIST group) had significantly lower rate (P < 0.05) of composite outcome of death or bronchopulmonary dysplasia (BPD), duration of intermittent positive airway pressure ventilation (IPPV) or MV, drug treatment of patent ductus arteriosus (PDA), and surgical ligation of PDA than group A. CONCLUSION: MIST is feasible, safe and it may reduce the composite outcome of death or BPD for VLBW infants with RDS requiring surfactant replacement therapy.

Lactobacillus Attenuate the Progression of Pancreatic Cancer Promoted by Porphyromonas Gingivalis in K-rasG12D Transgenic Mice.

Accumulating evidence suggests that there is a link between the host microbiome and pancreatic carcinogenesis, and that Porphyromonas gingivalis (P. gingivalis) increases the risk of developing pancreatic cancer. The aim of the current study was to clarify the role of P. gingivalis in the pathogenesis of pancreatic cancer and the potential immune modulatory effects of probiotics. The six-week-old LSL-K-rasG12D; Pdx-1-cre (KC) mice smeared P. gingivalis on the gums, causing pancreatic intraepithelial neoplasia (PanIN) after four weeks to be similar to the extent of lesions in untreated KC mice at 24 weeks. The oral inoculation of P. gingivalis of six-week-old LSL-K-rasG12D; Pdx-1-cre (KC) mice caused significantly pancreatic intraepithelial neoplasia (PanIN) after treatment four weeks is similar to the extent of lesions in untreated KC mice at 24 weeks. The pancreas weights of P. gingivalis plus probiotic-treated mice were significantly lower than the mice treated with P. gingivalis alone (P = 0.0028). The histological expressions of Snail-1, ZEB-1, collagen fibers, Galectin-3, and PD-L1 staining in the pancreas were also notably lower. In addition, probiotic administration reduced the histological expression of Smad3 and phosphorylated Smad3 in P. gingivalis treated KC mice. We demonstrated that oral exposure to P. gingivalis can accelerate the development of PanIN lesions. Probiotics are likely to have a beneficial effect by reducing cancer cell proliferation and viability, inhibiting PanIN progression, and cancer cell metastasis (Epithelial-mesenchymal transition, EMT). The transforming growth factor-ß signaling pathway may be involved in the tumor suppressive effects of probiotics.