Vitamin D and Otitis Media.

PURPOSE OF REVIEW: To examine the relationship between vitamin D and otitis media. RECENT FINDINGS: Vitamin D deficiency has been associated with several respiratory diseases, including otitis media. Vitamin D supplementation may reduce the risk of otitis media. This relationship may be explained by vitamin D supporting the immune system by upregulating antimicrobial peptides which are effective against otopathogens and biofilm formation, supporting a less inflammatory immune response, or promoting beneficial commensal bacteria. This review will explore risk factors of both otitis media and vitamin D deficiency, the evidence of vitamin D being beneficial for various forms of otitis media, and possible mechanisms of action.

Nasal microbial composition and chronic otitis media with effusion: A case-control study.

OBJECTIVES: Chronic otitis media with effusion (COME) in children can cause prolonged hearing loss, which is associated with an increased risk of learning delays and behavioural problems. Dispersal of bacterial pathogens from the nasal passages to the middle ear is implicated in COME. We sought to determine whether there is an association between nasal microbial composition and COME in children. METHODS: A case-control study of children aged 3 and 4 years was conducted. Cases undergoing placement of tympanostomy tubes for COME were compared to healthy controls. Nasal swabs were collected and a questionnaire was administered. The V1-3 region of the 16S rRNA gene was amplified, and sequenced on the Illumina MiSeq. RESULTS: 73 children with COME had a lower Shannon diversity index than 105 healthy controls (1.62 [.80] versus 1.88 [.84], respectively; P = .046). The nasal microbiota of cases and controls differed in composition using Bray-Curtis dissimilarity (p = 0.002). Children with COME had a higher abundance of otopathogens and lower abundance of commensals including alpha haemolytic Streptococci and Lactococcus. Cluster analysis revealed 4 distinct nasal microbial profiles. Profiles that were Corynebacterium-dominated (aOR 4.18 [95%CI, 1.68-10.39], Streptococcus-dominated (aOR 3.12 [95%CI, 1.08-9.06], or Moraxella-dominated (aOR 4.70 [95%CI, 1.73-12.80] were associated with COME, compared to a more mixed microbial profile when controlling for age, ethnicity, and recent antibiotics use. CONCLUSIONS: Children with COME have a less diverse nasal microbial composition with a higher abundance of pathogens, compared to healthy children who have a more mixed bacterial profile with a higher abundance of commensals. Further research is required to determine how nasal microbiota may relate to the pathogenesis or maintenance of COME, and whether modification of the nasal microbiota can prevent or treat children at risk of COME.

Higher serum 25(OH)D concentration is associated with lower risk of chronic otitis media with effusion: a case-control study.

AIM: Vitamin D supplementation and higher 25(OH)-vitamin D concentration are associated with reduced risk of acute respiratory infection. This study examined whether there is a similar association between higher serum 25(OH)D concentration and lower risk of chronic otitis media with effusion (COME). METHODS: In a case-control study, serum 25(OH)D concentration in children referred for tympanostomy tube placement for COME (n = 178) was compared to that of healthy children randomly sampled from primary care practices (n = 179). Subjects aged three and four years were recruited in Auckland, New Zealand between May 2011 and November 2013. Blood samples were collected from the children, and their guardians were interviewed. Odds ratios were calculated using logistic regression. RESULTS: In a multivariable analysis, higher serum 25(OH)D concentration was associated with a lower risk of COME (OR: 0.86 per 10 nmol/L; 95% CI 0.77-0.97) after adjusting for age, sex, deprivation index, ethnicity, tobacco smoke exposure, duration of breastfeeding and season of blood sampling. Further adjustment for eight additional risk factors did not change the result. CONCLUSION: This finding supports further investigation into whether the risk of COME could be reduced by increasing serum 25(OH)D concentration through increased sun exposure, higher dietary intake or vitamin D supplementation.

Determinants of chronic otitis media with effusion in preschool children: a case-control study.

BACKGROUND: Chronic otitis media with effusion (COME) is a prevalent upper airway infection resulting in hearing loss. The aim of this research was to determine risk factors for COME in preschool children. METHODS: A case-control design was conducted in Auckland, New Zealand from May 2011 until November 2013. The cases were children aged 3 and 4 years referred for tympanostomy tube placement due to a diagnosis of COME (n = 178). The controls were a random sample of healthy children aged 3 and 4 years from primary care practices (n = 209). The children's guardians completed an interviewer-administered questionnaire that covered topics including socio-demographic information, pregnancy and birth, infant feeding practices, home environment, and respiratory health. In addition, skin prick tests for atopy were performed. Odds ratios (OR) estimating the risk of COME independently associated with the exposures were calculated using a logistic regression model. RESULTS: Children with COME frequently had nasal obstruction (OR: 4.38 [95% CI: 2.37-8.28]), always snored (OR: 3.64 [95% CI: 1.51-9.15]) or often snored (OR: 2.45 [95% CI: 1.04-5.96]), spent more hours per week in daycare (OR per hour/week: 1.03 [95% CI: 1.00-1.05]), had frequent colds (OR: 2.67 [95% CI: 1.59-4.53]), had siblings who had undergone tympanostomy tube placement (OR: 2.68 [95% CI: 1.22-6.02]), underwent long labour (OR: 2.59 [95% CI: 1.03-6.79]), and had early introduction of cow's milk (OR: 1.76 [95% CI: 1.05-2.97]). Asian ethnicity (OR: 0.20 [95% CI: 0.07-0.53]) and having older siblings (OR: 0.54 [95% CI: 0.31-0.93]) were inversely associated with COME. CONCLUSION: COME in preschool children was associated with pathogen exposure, respiratory infection, and nasal obstruction. Strategies to prevent pathogen transmission warrant investigation. The novel findings of long labour and early cow's milk introduction require replication in future studies.

NOD/SCID-GAMMA mice are an ideal strain to assess the efficacy of therapeutic agents used in the treatment of myeloma bone disease.

Animal models of multiple myeloma vary in terms of consistency of onset, degree of tumour burden and degree of myeloma bone disease. Here we describe five pre-clinical models of myeloma in NOD/SCID-GAMMA mice to specifically study the effects of therapeutic agents on myeloma bone disease. Groups of 7-8 week old female irradiated NOD/SCID-GAMMA mice were injected intravenously via the tail vein with either 1x106 JJN3, U266, XG-1 or OPM-2 human myeloma cell lines or patient-derived myeloma cells. At the first signs of morbidity in each tumour group all animals were sacrificed. Tumour load was measured by histological analysis, and bone disease was assessed by micro-CT and standard histomorphometric methods. Mice injected with JJN3, U266 or OPM-2 cells showed high tumour bone marrow infiltration of the long bones with low variability, resulting in osteolytic lesions. In contrast, mice injected with XG-1 or patient-derived myeloma cells showed lower tumour bone marrow infiltration and less bone disease with high variability. Injection of JJN3 cells into NOD/SCID-GAMMA mice resulted in an aggressive, short-term model of myeloma with mice exhibiting signs of morbidity 3 weeks later. Treating these mice with zoledronic acid at the time of tumour cell injection or once tumour was established prevented JJN3-induced bone disease but did not reduce tumour burden, whereas, carfilzomib treatment given once tumour was established significantly reduced tumour burden. Injection of U266, XG-1, OPM-2 and patient-derived myeloma cells resulted in less aggressive longer-term models of myeloma with mice exhibiting signs of morbidity 8 weeks later. Treating U266-induced disease with zoledronic acid prevented the formation of osteolytic lesions and trabecular bone loss as well as reducing tumour burden whereas, carfilzomib treatment only reduced tumour burden. In summary, JJN3, U266 or OPM-2 cells injected into NOD/SCID-GAMMA mice provide robust models to study anti-myeloma therapies, particularly those targeting myeloma bone disease.

Myeloma bone disease: pathogenesis, current treatments and future targets.

INTRODUCTION: Patients with myeloma develop localized and generalized bone loss leading to hypercalcaemia, accelerated osteoporosis, vertebral wedge fractures, other pathological fractures, spinal cord compression and bone pain. Bone loss is mediated by a variety of biological modifiers including osteoclast-activating factors (OAF) and osteoblast (OB) inhibitory factors produced either directly by malignant plasma cells (MPCs) or as a consequence of their interaction with the bone marrow microenvironment (BMM). Raised levels of OAFs such as receptor activator of nuclear factor-kappa B ligand (RANKL), macrophage inflammatory protein 1 alpha, tumour necrosis factor-alpha and interleukin 6 stimulate bone resorption by recruiting additional osteoclasts. Via opposing mechanisms, increases in OB inhibitory factors, such as dickkopf-1 (Dkk-1), soluble frizzled-related protein-3 and hepatocyte growth factor (HGF), suppress bone formation by inhibiting the differentiation and recruitment of OBs. These changes result in an uncoupling of physiological bone remodelling, leading to myeloma bone disease (MBD). Moreover, the altered BMM provides a fertile ground for the growth and survival of MPCs. Current clinical management of MBD is both reactive (to pain and fractures) and preventive, with bisphosphonates (BPs) being the mainstay of pharmacological treatment. However, side effects and uncertainties associated with BPs warrant the search for more targeted treatments for MBD. This review will summarize recent developments in understanding the intimate relationship between MBD and the BMM and the novel ways in which they are being therapeutically targeted. SOURCES OF DATA: All data included were sourced and referenced from PubMed. AREAS OF AGREEMENT: The clinical utility of BP therapy is well established. However, there is general acknowledgement that BPs are only partially successful in the treatment of MBD. The number of skeletal events attributable to myeloma are reduced by BPs but not totally eliminated. Furthermore, existing damage is not repaired. It is widely recognized that more effective treatments are needed. AREAS OF CONTROVERSY: There remains controversy concerning the duration of BP therapy. Whether denosumab is a viable alternative to BP therapy is also contested. Many of the new therapeutic strategies discussed are yet to translate to clinical practice and demonstrate equal efficacy or superiority to BP therapy. It also remains controversial whether reported anti-tumour effects of bone-modulating therapies are clinically significant. GROWING POINTS: The potential clinical utility of bone anabolic therapies including agents such as anti-Dkk-1, anti-sclerostin and anti-HGF is becoming increasingly recognized. AREAS TIMELY FOR DEVELOPING RESEARCH: Further research effectively targeting the mediators of MBD, targeting both bone resorption and bone formation, is urgently needed. This should translate promptly to clinical trials of combination therapy comprising anti-resorptives and bone anabolic therapies to demonstrate efficacy and improved outcomes over BPs.