Mia Alessandra Nieto is an 8-year old living with Juvenile Idiopathic Arthritis (JIA) in Austin, Texas. When she was diagnosed at 10 months, she was the youngest child ever diagnosed with JIA in the state of Texas. However, it took 37 days to confirm her condition because there is an immense lack on knowledge in the field of pediatric rheumatology among general practitioners despite the fact that JIA is the most prevalent chronic condition in children in the United States with over 300,000 diagnosed. This is an overview of Mia’s story, along with information regarding the lack of knowledge on the condition not only in the general population but mainly and more importantly among the medical professionals in the United States. / text

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Abstract Hereditary hemochromatosis (HH) is a common autosomal recessive disorder estimated to affect one out of every 250–400 Caucasian individuals. It is a disorder of iron metabolism, in which excessive iron accumulation in the body may induce serious clinical manifestations (e.g. liver cirrhosis, hepatocellular carcinoma, diabetes, and cardiomyopathy). HH is caused by mutations in the HFE gene, and HFE genotyping thus enables early diagnosis of the disease and detection of the individuals at risk for HH. HFE mutations have also been proposed to predispose to certain other diseases, such as various hematological malignancies and cardiomyopathy. The present evaluation of the clinical utility and outcome of HFE genotyping in search for HH was based on data obtained from 137 subjects referred for HFE mutation analysis during the years 1999–2001. The C282Y and H63D mutations were determined for each subject. HFE genotyping was also used to examine the association between HFE mutations with various hematological disorders and idiopathic dilated cardiomyopathy (IDCM). The C282Y and H63D mutations were determined from 232 patients with various hematological disorders and the C282Y, H63D, and S65C mutations from 91 patients with IDCM and 102 control subjects. High frequencies of C282Y homozygotes (16.8%) and C282Y/H63D compound heterozygotes (5.1%) were found among the subjects referred for HFE genotyping, and the rate of positive findings for HH increased steadily over the years 1999–2001. The frequencies of HFE mutations did not differ significantly in patients with various hematological disorders and IDCM compared to controls. At the end of the follow-up period, left ventricular end-diastolic diameter (LVEDD) was significantly higher in IDCM patients carrying the C282Y mutation than in those without this mutation (p = 0.037). The present study supports active testing for the HFE gene mutations C282Y and H63D in public health care. Serum transferrin saturation is considered the most useful test for selecting subjects for such analysis. Although increasing numbers of HH cases are recognized by physicians, it may still be an underdiagnosed disease. HFE mutations do not seem to significantly increase the risk for various hematological disorders or IDCM. The C282Y mutation may, nevertheless, mediate the progression of IDCM by modifying LV dilation and remodeling.

Background: The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare autoimmune diseases comprising of polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). They are characterised primarily by muscle weakness, and can present with extramuscular manifestations such as skin rashes, interstitial lung disease and malignancy. Aims: This aim of this study was to identify novel genetic risk factors in IIM and to further elucidate the relationship between genotype and serotype. Methods: 2,566 IIM samples were collected from 14 countries through the Myositis Genetics Consortium (MYOGEN) and genotyped on the Immunochip, a custom array covering 186 established autoimmune susceptibility loci. SNP2HLA was used to impute classical HLA alleles and constituent amino acids. Results: In a combined IIM analysis, the HLA region and PTPN22 reached genome-wide significance (p<5x10-8). A further nine regions reached suggestive significance (p<2.25x10-5) including UBE2L3, STAT4 and CD28 that have been implicated in autoimmune disease previously. Independent effects were seen within the STAT4 region. In a PM subgroup analysis (n=931), the HLA region and PTPN22 reached genome-wide significance. A further seven regions reached suggestive significance including SLC26A1/IDUA and RGS1. In an adult and juvenile DM analysis (n=1,360), only the HLA region reached genome wide significance. Three loci reached suggestive significance including GSDMB. In the IBM analysis (n=252), only the HLA region reached genome wide significance and 3 loci reached suggestive significance, including the CCR2 locus. Identification of exonic and eQTL SNPs has localised association signals to several potential causal variants. HLA imputation on the combined dataset confirmed that alleles of the 8.1 ancestral haplotype (AH) are most strongly associated with IIM. The cohort was stratified in to clinical subgroups. In PM the strongest effect was found with HLA-DRB1*03:01 with an independent effect with HLA-B*08:01. Amino acid position 74 lies within the peptide binding groove and may explain the risk in HLA-DRB1. HLA-B*08:01 was the most associated variant in both DM and JDM, with independent effects of amino acid position 57 of HLA-DQB1 in DM and HLA-C*02:02 in JDM. In IBM, the strongest associations were with amino acids positions 26 and 11 of HLA-DRB1.HLA imputation was conducted on antibody subgroups. The most associated variant for anti-Jo-1 and anti-PM/Scl antibodies was with amino acid 74 of HLA-DRB1. Alleles of the 8.1 AH were most associated with anti-TIF1-γ, anti-SAE and anti-cN1A antibodies. Alleles independent of the 8.1 AH were replicated such as anti-Mi-2 antibodies and HLA-DRB1*07:01, and anti-HMGCR antibodies and HLA-DRB1*11. Conclusions: This represents the largest study to date in IIM and has considerably expanded our knowledge about the genetic architecture of this rare disease. This study has identified novel disease susceptibility genes for IIM and independent associations with PM and DM, IBM and antibody subgroups that show that stratifying patients in to more homogenous cohorts is important to expand our knowledge of IIM. Ongoing sample collection is required to identify additional genes and environmental risk factors that lead to the development of IIM, and to expand our limited understanding of the pathogenesis of this disease.

Orbital pseudotumor, also known as idiopathic orbital inflammatory disease (IOID), is an idiopathic inflammatory process within the orbit. The potential for permanent visual impairment makes this disease important to diagnose and treat. While oral corticosteroids are the mainstay of therapy, they can have significant toxicity when used for long periods of time. We present a case of IOID that was successfully treated with leflunomide after methotrexate was discontinued for toxicity-related issues. To our knowledge, use of leflunomide for this condition has not previously been reported in the literature.

Indiana University-Purdue University Indianapolis (IUPUI) / Idiopathic urethritis (IU) comprises up to 50% of symptomatic cases of male urethritis in clinical settings. The syndrome is of an unknown etiology but may be due to an as yet unidentified bacterial pathogen(s). We were interested in identifying pathogens that could cause IU using multiple methods. Shotgun metagenomic sequencing or 16S rRNA sequencing methods can provide rich datasets but are limited by the completeness of the corresponding sequence reference databases. We generated metagenomic and 16S datasets from DNA extracted from urethral swabs of men with IU to determine the composition of their urethral microbiome. In order to enrich the corresponding reference databases used to identify the reads in the sequence datasets, I cultivated bacteria from the first void urine (FVU) of men with IU. My goal was to grow and whole genome sequence bacterial isolates that are not currently represented in the reference databases. Of the 216 men we enrolled at the Bell Flower STD clinic in Indianapolis, IN, 59 men had IU. I grew a total of 802 isolates from the FVU of the IU patients and identified those isolates using colony-based 16S rRNA PCR. Based on % sequence similarity to the nearest type strain, I sorted the 16S alleles into four categories: Species (≥98 % identity) (N=264), Genus (≥95 % identity) (N=407), Closest Match (<95 % identity) (N=95), and No Hit (0 % identity) (N=22). There were 24 genera represented in the isolate collection. Of these, the six most abundant genera were Streptococcus, Staphylococcus, Corynebacterium, Haemophilus, Gardnerella, and Prevotella. These six genera composed nearly 80% of all IU-associated isolates. All sequences below 98% sequence similarity represent potentially novel strains of bacteria. We will proceed with whole genome sequencing of bacterial isolates with the goal of improving genome database coverage of bacterial diversity in the male urethra.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease of unknown etiology, in which excessive accumulation of scar tissue in the interstitial spaces of the lung obstruct normal pulmonary function. Currently, the only curative treatment is lung transplantation. While pharmaceutical therapeutics have been recently approved for use in IPF in 2014, they are still unable to provide a truly curative treatment. While genetic risk factors have been identified, the most commonly occurring mutation is only detected in approximately 38% of IPF patients, leaving an uncertainty in the very existence of a common genetic factor in IPF. Cigarette smoke and other environmental particulates have been significantly linked to the diagnosis of IPF, implicating an initial immunological response to trigger the pathogenesis of IPF. Nintedanib, a potent tyrosine kinase receptor inhibitor was first developed in 1998 as a candidate for cancer treatment. Investigation of its effects in fibrosis in the past few decades has led to a significant discovery of its application in IPF. Nintedanib significantly inhibits the fibrotic activity of fibrotic myofibroblasts in the lungs by inhibiting signaling cascades necessary for cell proliferation and progression of the disease. However, nintedanib falls short in that it cannot fully inhibit the advancement of the disease and mortality rates of IPF still remain high. Pirfenidone, the other currently available pharmaceutical therapeutic, was discovered in 1976 as a potent inhibitor of inflammation. Subsequent experiments further reviled its potency as an anti-fibrotic drug. After decades of research, pirfenidone’s mechanism of antifibrotic characteristics were revealed as a potent inhibitor of fibrocyte recruitment and chemotaxis, and as an inhibitor of transcription growth factor beta (a growth factor heavily implicated in the activity of myofibroblasts) mediated pathways. However, like nintedanib, pirfenidone fails as a curative treatment, only delaying the progression of the disease. In the search for new molecular targets for pharmaceutical therapy, forkhead box M1 (FOXM1), programmed cell death protein-1 (PD-1), and prostaglandin E2, have been identified to play a mediatory role in many of the pathways involved in myofibroblast activity. Many of these targets have also been identified in other disease models such as cancer and immunological inflammatory disease. Avasimibe has been recently identified as a potent inhibitor of aldo-ketoreductase through a FOXM1 mediated pathway. Its molecular mechanism in osteosarcoma cancer disease model may prove to be a novel pharmaceutical therapeutic for IPF. BI 853250, a novel focal adhesion kinase (FAK) inhibitor also demonstrates potential to be a new pharmaceutical therapeutic for IPF patients. Exploring signaling pathways that involve these newly found targets and collaborative research with cancer and immunological diseases shows promise in providing steps to cure IPF in the future.

No description available.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Adolescent Idiopathic Scoliosis (AIS) is typically treated surgically by Posterior Spinal Fusion (PSF) surgery. Intravenous analgesics and oral opioids are commonly used for pain management. Several adjunct therapies are used in addition to the standard treatments. One of these therapies is the use of dexmedetomidine (dex). Though dex has been found to be an effective sedative for post‐operative patients, there are also several adverse effects that are associated with its use. The purpose of this study was to investigate the effectiveness and overall benefit of using dex for pain control for patients undergoing PSF for AIS. IRB approval was obtained. A group of 43 patients with AIS undergoing PSF and using Dex for adjunctive pain control were matched with 43 patients who did not use Dex. The groups were matched based on gender, age, height, weight, and level of spinal fusion. During the patients’ post‐operative hospital stay, the total opioid use and clinical pain scores were compared between the two groups using t‐tests, with significance set at p<0.05. Total opiate use was 239.6 morphine equivalent doses in the non‐Dex (control) group and 246.2 in the group that received Dex (p=0.72). The average pain score in the control group was 2.3, and the group that received Dex was 2.6 (p =0.43). There were no differences in the complication rate between the two groups, specifically the oversedation rates and pulmonary complications. Lastly, the average length of stay for the control group was 4.8 days compared to the dex group, which was 5.0 days (p=0.35). Although adjunctive pain modalities may be very useful in the treatment of postoperative pain after PSF in patients with AIS, the use of Dex in this cohort did not improve pain scores, lower opioid use, or lower the LOS. Based on these results, we do not recommend the routine use of dexmedetomidine as an adjunctive pain control modality. Adjunctive modalities are important in pain control in patients with AIS undergoing PSF, but the use of dexmedotomidine was not effective in improving pain control.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Surgical correction of Adolescent Idiopathic Scoliosis (AIS) carries a substantial risk of complication. The literature supports improved perioperative outcomes through the two surgeon strategy in other complex orthopedic procedures. Does the presence of 2 versus 1 attending surgeons affect the perioperative morbidity of posterior spinal fusion (PSF) in patients with AIS curves greater than 70°? We reviewed the database from a large regional children’s hospital of all patients with AIS curves greater than 70° who underwent PSF from 2009‐2014 and divided the cohort into single versus 2‐surgeon groups (28 vs. 19 cases, respectively). We analyzed cases for length of surgery, estimated blood loss, and length of stay. The groups were identical when comparing age, gender, spinal levels fused, and average ASA score. However, the average Cobb angle in the single surgeon group was significantly less than in the 2 surgeon group at 78.4 vs 84.0 degrees, respectively (p=0.049). Mean operative time for single versus 2 surgeons was 238 (SD 48) vs 212 (SD 46) minutes (p=0.078). Mean percent estimated blood loss was 26% (SD 14.1) for single surgeon vs 31% (SD 14.9) for 2 surgeons (p=0.236), and mean estimated blood loss for single surgeon vs 2 surgeons was 830ml (SD 361) vs 1045ml (SD 346) (p=0.052). Mean length of stay was significantly decreased in the 2 surgeon group at 5.16 days (SD 1.7) versus the single surgeon group at 6.82 days (SD 6.82) (p=0.002). The use of 2 surgeons in AIS deformity correction at an experienced regional children’s hospital did not improve clinical outcomes. The average length of stay was reduced in the two‐surgeon group, but there was no significant impact on blood loss or operative time. However, this study does not rule out the potential for positive impact with a two‐surgeon strategy, and given previous supportive data in the literature, this approach should further evaluated to determine its effect on improving perioperative outcomes.