Girish Hiremath

Prebiotic and Probiotic Fortified Milk in Prevention of Morbidities among Children: Community-Based, Randomized, Double-Blind, Controlled Trial

Background Recent reviews suggest common infectious diseases continue to be a major cause of death among preschool children in developing countries. Identification of feasible strategies to combat this disease burden is an important public health need. We evaluated the efficacy of adding prebiotic oligosaccharide and probiotic Bifidobacterium lactis HN019 to milk, in preventing diarrhea, respiratory infections and severe illnesses, in children aged 1–4 years as part of a four group study design, running two studies simultaneously. Methods and Findings In a community based double-masked, randomized controlled trial, children 1–3 years of age, willing to participate, were randomly allocated to receive either control milk (Co; n = 312) or the same milk fortified with 2.4 g/day of prebiotic oligosaccharide and 1.9×107 colony forming unit (c.f.u)/day of probiotic Bifidobacterium lactis HN019 (PP; n = 312). Children were followed up for 1 year providing data for 1–4 years. Biweekly household surveillance was conducted to gather information on compliance and morbidity. Both study groups were comparable at baseline; compliance to intervention was similar. Overall, there was no effect of prebiotic and probiotic on diarrhea (6% reduction, 95% Confidence Interval [CI]: −1 to 12%; p = 0.08). Incidence of dysentery episodes was reduced by 21% (95% CI: 0 to 38%; p = 0.05). Incidence of pneumonia was reduced by 24% (95% CI: 0 to 42%; p = 0.05) and severe acute lower respiratory infection (ALRI) by 35% (95% CI: 0 to 58%; p = 0.05). Compared to children in Co group, children in PP group had 16% (95% CI: 5 to 26%, p = 0.004) and 5% (95% CI: 0 to 10%; p = 0.05) reduction in days with severe illness and high fever respectively. Conclusions/Significance Milk can be a good medium for delivery of prebiotic and probiotic and resulted in significant reduction of dysentery, respiratory morbidity and febrile illness. Overall, impact of diarrhea was not significant. These findings need confirmation in other settings. Trial Registration ClinicalTrials.gov NCT00255385

Micronutrient Fortified Milk Improves Iron Status, Anemia and Growth among Children 1–4 Years: A Double Masked, Randomized, Controlled Trial

Background Multiple micronutrient deficiencies are highly prevalent among preschool children and often lead to anemia and growth faltering. Given the limited success of supplementation and health education programs, fortification of foods could be a viable and sustainable option. We report results from a community based double-masked, randomized trial among children 1–4 years evaluating the effects of micronutrients (especially of zinc and iron) delivered through fortified milk on growth, anemia and iron status markers as part of a four group study design, running two studies simultaneously. Methods and Findings Enrolled children (n = 633) were randomly allocated to receive either micronutrients fortified milk (MN = 316) or control milk (Co = 317). Intervention of MN milk provided additional 7.8 mg zinc, 9.6 mg iron, 4.2 µg selenium, 0.27 mg copper, 156 µg vitamin A, 40.2 mg vitamin C, and 7.5 mg vitamin E per day (three serves) for one year. Anthropometry was recorded at baseline, mid- and end-study. Hematological parameters were estimated at baseline and end-study. Both groups were comparable at baseline. Compliance was over 85% and did not vary between groups. Compared to children consuming Co milk, children consuming MN milk showed significant improvement in weight gain (difference of mean: 0.21 kg/year; 95% confidence interval [CI] 0.12 to 0.31, p<0.001) and height gain (difference of mean: 0.51 cm/year; 95% CI 0.27 to 0.75, p<0.001). Mean hemoglobin (Hb) (difference of 13.6 g/L; 95% CI 11.1 to 16.0, p<0.001) and serum ferritin levels (difference of 7.9 µg/L; 95% CI 5.4 to 10.5, p<0.001) also improved. Children in MN group had 88% (odds ratio = 0.12, 95% CI 0.08 to 0.20, p<0.001) lower risk of iron deficiency anemia. Conclusions/Significance Milk provides an acceptable and effective vehicle for delivery of specific micronutrients, especially zinc and iron. Micronutrient bundle improved growth and iron status and reduced anemia in children 1–4 years old. Trial Registration ClinicalTrials.gov NCT00255385

Reproducibility of high-resolution optical coherence tomography in multiple sclerosis

Optical coherence tomography (OCT) is a non-invasive method to quantify neurodegeneration as an outcome in multiple sclerosis clinical trials; however, no data exist on Cirrus spectral domain optical coherence tomography (SD-OCT) reproducibility in patients with multiple sclerosis. The objective of this study was to determine the protocol for achieving optimal inter-visit, inter-rater, and intra-rater reproducibility for studies performed on healthy controls and multiple sclerosis patients utilizing novel high-definition SD-OCT. This is a prospective study of inter-visit, inter-rater, and intra-rater reproducibility in multiple sclerosis patients (n = 58) and healthy controls (n = 32) on Cirrus-HD SD-OCT. Excellent reproducibility of average and quadrantic retinal nerve fiber layer (RNFL) thickness values, average macular thickness (AMT), and total macular volume (TMV) [measured by intraclass correlation coefficient (ICC)] was found for inter-visit (healthy controls: mean RNFL = 0.97, quadrant range = 0.92—0.97, AMT = 0.97, TMV = 0.92), inter-rater (MS: mean RNFL = 0.97, quadrant = 0.94—0.98, AMT = 0.99, TMV = 0.96; healthy controls: mean RNFL = 0.97, quadrant = 0.94—0.97, AMT = 0.98, TMV = 0.99), and intra-rater (MS patients: mean RNFL = 0.99, quadrant = 0.83—0.99, AMT = 0.97, TMV = 0.98) reproducibility. The reproducibility of retinal measures derived by Cirrus HD-OCT, especially quadrantic values, is excellent. Specific procedures for OCT acquisition and analysis of retinal imaging metrics using SD-OCT technology may improve the application of this novel technology in multiple sclerosis.

Effects of fortified milk on morbidity in young children in north India: community based, randomised, double masked placebo controlled trial

Objective To evaluate the efficacy of milk fortified with specific multiple micronutrients on morbidity in children compared with the same milk without fortification. Design Community based, double masked, individually randomised trial. Setting Peri-urban settlement in north India. Participants Children (n=633) aged 1-3 randomly allocated to receive fortified milk (n=316) or control milk (n=317). Intervention One year of fortified milk providing additional 7.8 mg zinc, 9.6 mg iron, 4.2 �g selenium, 0.27 mg copper, 156 �g vitamin A, 40.2 mg vitamin C, 7.5 mg vitamin E per day (three feeds). Main outcome measures Days with severe illnesses, incidence and prevalence of diarrhoea, and acute lower respiratory illness. Results Study groups were comparable at baseline; compliance in the groups was similar. Mean number of episodes of diarrhoea per child was 4.46 (SD 3.8) in the intervention (fortified milk) group and 5.36 (SD 4.1) in the control group. Mean number of episodes of acute lower respiratory illness was 0.62 (SD 1.1) and 0.83 (SD 1.4), respectively. The fortified milk reduced the odds for days with severe illnesses by 15% (95% confidence interval 5% to 24%), the incidence of diarrhoea by 18% (7% to 27%), and the incidence of acute lower respiratory illness by 26% (3% to 43%). Consistently greater beneficial effects were observed in children aged ≤24 months than in older children. Conclusion Milk is well accepted as a means of delivery of micronutrients. Consumption of milk fortified with specific micronutrients can significantly reduce the burden of common morbidities among preschool children, especially in the first two years of life. Trial registration NCT00255385.

Vitamin D status and effect of low-dose cholecalciferol and high-dose ergocalciferol supplementation in multiple sclerosis

Background Vitamin D is important for bone health and immune regulation, and has been shown to be low in multiple sclerosis (MS). We sought to determine the effect of over the counter low dose cholecalciferol (LDC) and high dose ergocalciferol (HDE) on the vitamin D levels in MS patients. Methods We retrospectively evaluated serum 25-hydroxy-vitamin D [25(OH)D] levels of 199 patients (CIS, n = 32; RRMS, n = 115; PPMS, n = 10; SPMS, n = 16; Transverse Myelitis (TM), n = 9; other neurological diseases, n = 16) attending our clinic between 2004 and 2008. We examined the change in 25(OH)D levels in 40 MS patients who took either LDC (≤800 IU/day) or HDE (50,000 IU/day for 7-10 days, followed by 50,000 IU weekly or biweekly). Results The average 25(OH)D level was 71 ± 39 nmol/L (Mean ± SD), and 167(84%) patients had insufficient levels (≤100 nmol/L) of 25(OH)D. The patients supplemented with LDC did not have a significant increase in their 25(OH)D levels. However, 25(OH)D levels increased by 42 nmol/L (P = 0.01) in the patients originally taking LDC and then prescribed HDE. Optimal levels (≥100 nmol/L) were only achieved in less than 40% of patients. Conclusions We conclude that large numbers of patients with MS and TM in our cohort are deficient in vitamin D. HDE significantly elevated 25(OH)D levels in MS patients and was more effective at increasing 25(OH)D levels than LDC. Prospective studies are required to determine appropriate dosing regimen to achieve optimal levels in the majority of MS patients and to ascertain the safety, immunological response, and ultimately the clinical efficacy of vitamin D replacement therapy.

The Impact of Utilizing Different Optical Coherence Tomography Devices for Clinical Purposes and in Multiple Sclerosis Trials

Optical coherence tomography (OCT) derived retinal measures, particularly peri-papillary retinal nerve fiber layer (RNFL) thickness, have been proposed as outcome measures in remyelinating and neuroprotective trials in multiple sclerosis (MS). With increasing utilization of multiple centers to improve power, elucidation of the impact of different OCT technologies is crucial to the design and interpretation of such studies. In this study, we assessed relation and agreement between RNFL thickness and total macular volume (in MS and healthy controls) derived from three commonly used OCT devices: Stratus time-domain OCT, and Cirrus HD-OCT and Spectralis, two spectral-domain (SD) OCT devices. OCT was performed on both Cirrus HD-OCT and Stratus in 229 participants and on both Cirrus HD-OCT and Spectralis in a separate cohort of 102 participants. Pearson correlation and Bland-Altman analyses were used to assess correlation and agreement between devices. All OCT retinal measures correlated highly between devices. The mean RNFL thickness was 7.4 µm lower on Cirrus HD-OCT than Stratus, indicating overall poor agreement for this measurement between these machines. Further, the limits of agreement (LOA) between Cirrus HD-OCT and Stratus were wide (−4.1 to 18.9 µm), indicating poor agreement at an individual subject level. The mean RNFL thickness was 1.94 µm (LOA: −5.74 to 9.62 µm) higher on Spectralis compared to Cirrus HD-OCT, indicating excellent agreement for this measurement across this cohort. Although these data indicate that these three devices agree poorly at an individual subject level (evidenced by wide LOA in both study cohorts) precluding their co-utilization in everyday practice, the small difference for mean measurements between Cirrus HD-OCT and Spectralis indicate pooled results from these two SD-devices could be used as outcome measures in clinical trials, provided patients are scanned on the same machine throughout the trial, similar to the utilization of multiple different MRI platforms in MS clinical trials.

Effects of Bifidobacterium lactis HN019 and prebiotic oligosaccharide added to milk on iron status, anemia, and growth among children 1 to 4 years old.

Objective: To evaluate the effect of Bifidobacterium lactis HN019 and prebiotic-fortified milk on iron status, anemia, and growth among 1- to 4-year-old children. Patients and Methods: In a community-based double-masked, controlled trial in a periurban population, 624 children were enrolled and randomly allocated to receive either milk fortified with additional probiotic and prebiotic (n = 312) or control milk (n = 312) for 1 year. Probiotic and prebiotic milk contained an additional 1.9 × 107 colony-forming units per day of probiotic B lactis HN019 and 2.4 g/day of prebiotic oligosaccharides milk. Hematological parameters were estimated at baseline and at the end of the study. Height and weight measurements were recorded at baseline, mid study, and the end of the study. Difference of means and multivariate regression models was used to examine the effect of intervention. Results: Both study groups were similar at baseline. Compliance was high (>85%) and did not vary by intervention groups. As compared with non-fortified milk, consumption of probiotic- and prebiotic-fortified milk for a period of 1 year reduced the risk of being anemic and iron deficient by 45% (95% CI 11%, 66%; P = 0.01) and increased weight gain by 0.13 kg/year (95% CI 0.03, 0.23; P = 0.02). Conclusions: Preschoolers are usually fed milk, which has good acceptance and can be easily fortified for delivery of probiotics. Consumption of B lactis HN019 and prebiotic-fortified milk resulted in a smaller number of iron-deficient preschoolers and increased weight gain.

A Meta-Analysis of Studies Comparing the Respiratory Route with the Subcutaneous Route of Measles Vaccine Administration

The respiratory tract has been suggested as an optimal alternative site to target measles vaccine delivery. We performed a meta-analysis to evaluate the efficacy of measles vaccine administered through the respiratory route compared to the subcutaneous route. We analyzed 20 reported results from sixteen eligible studies. Seroresponse was 4% higher amongst vaccinees in the respiratory group compared to the subcutaneous group (M-H pooled RR = 1.04; 95% CI = 0.98–1.10). For vaccinees over 9 months of age, seroresponse was 15% higher in the respiratory group (M-H pooled RR = 1.15; 95% CI = 1.08 to 1.17). When Edmonston Zagreb (EZ) strain was used, the vaccine was found to be neither more nor less efficacious when administered through respiratory route (M-H pooled RR=1.00; 95% CI = 0.94 to 1.08). Seroresponse in the vaccinees receiving aerosol measles vaccine was 10% higher (M-H pooled RR = 1.10, 95% CI = 1.04–1.17) compared to those who received measles vaccine through the subcutaneous route. Seroresponse due to aerosolized EZ vaccine was 9% higher than subcutaneous EZ vaccine (M-H pooled RR = 1.09; 95% CI = 1.02–1.16). The seroresponse among seropositive vaccinees was 60 % higher (M-H RR = 1.60; 95 % CI = 1.40 to 1.80). The results suggest that the respiratory route of delivery of measles vaccine is at least as efficacious as measles vaccine administered through the subcutaneous route. However, more research is required on standardization of dosage, administration equipments, efficacy, and safety of respiratory (aerosol) route of administration of measles vaccine.

Infliximab-induced psoriasis in children with inflammatory bowel disease.

Infliximab is frequently used to treat both inflammatory bowel disease (IBD) and psoriasis. We reviewed the medical records of 73 children with IBD receiving infliximab therapy and identified 6 (8%) cases of infliximab-induced psoriasis. Five (83%) had Crohn disease and 4 (67%) were girls. The psoriatic lesions appeared on the face (n = 5; 83%) and perineum (n = 1; 17%). A median of 13 doses were administered during a median duration of 21 months. All of the patients were continued on infliximab to maintain clinical remission of IBD. Educating children with IBD and their caregivers about this paradoxical phenomenon and periodic dermatology evaluation may promote patient care.

Bone Mass in Rett Syndrome: Association with Clinical Parameters and MECP2 Mutations

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. In 49 female RTT children, aged 1.9–17 y, bone mass was assessed and correlated with clinical parameters and mutations involving the MECP2 gene. We also studied five adult females, aged 20–33 y, and one male child, aged 6 y. Lumbar spine bone mineral content (BMC) and bone mineral density (BMD) were correlated with weight, height, BMI, clinical severity, degree of scoliosis, use of anticonvulsants, and ambulatory status. L1-L4 BMD and BMC showed that 48.9% of them had BMD values >2 SD below age-related norms. BMD values were in the osteoporotic range in the five adult females with RTT. Eleven percent of the children and adults with RTT experienced fractures. Low bone mass was correlated with marginal significance to clinical severity and ambulation but not to scoliosis or anticonvulsant use. Lowest bone mass occurred in patients with T158M or R270X mutations but without statistical significance. Studies in a murine model of RTT confirmed low bone mass as an inherent component of this syndrome. MECP2 mutations and clinical parameters impact bone mass in RTT, but an association with a specific mutation was not demonstrable.