Multiple Disease Associations in Autoimmune Polyglandular Syndrome Type II

ObjectiveAutoimmune polyglandular syndrome type II (APS II) is characterized by adrenal insufficiency (Addison’s disease), autoimmune thyroid disease, and/or type 1 diabetes mellitus (DM1). Multiple other autoimmune diseases have been associated with APS II. Here we report a case of a patient with APS II who over the course of 10 years developed Addison’s disease, hypothyroidism, DM1, Hashimoto’s encephalopathy, vitiligo, celiac disease, seronegative arthritis, and ulcerative colitis. This is a particularly aggressive course of APS II, and this combination of autoimmune diseases has not been previously reported.MethodsA 25-year-old female with a history of ulcerative colitis (UC), celiac disease, and DM1 presented to our institution with mental status changes. She was diagnosed with Hashimoto’s encephalopathy and treated with high-dose steroids and intravenous immunoglobulin (IVIG). She recovered well from her encephalopathy but her posthospitalization course was complicated due to the development of Addison’s disease, vitiligo, seronegative arthritis, and hypothyroidism.ResultsThe current understanding of APS II and its autoimmune disease associations are briefly summarized.Submitted for publication April 10, 2014 Accepted for publication July 10, 2014 The association of UC and Hashimoto’s encephalopathy with APS II is novel and discussed in detail.ConclusionA case of a patient with APS II with a dramatic development of 8 autoimmune diseases over 10 years is described. The novel APS II developments of Hashimoto’s encephalopathy and UC are discussed. This case highlights the potential complexity and severity of the clinical course of APS II. (Endocr Pract. 2014;20:e250-e255)     

Associations between Anticholinergic Burden and Adverse Health Outcomes in Parkinson Disease

Background

Elderly adults should avoid medications with anticholinergic effects since they may increase the risk of adverse events, including falls, delirium, and cognitive impairment. However, data on anticholinergic burden are limited in subpopulations, such as individuals with Parkinson disease (PD). The objective of this study was to determine whether anticholinergic burden was associated with adverse outcomes in a PD inpatient population.

Methods

Using the Cerner Health Facts® database, we retrospectively examined anticholinergic medication use, diagnoses, and hospital revisits within a cohort of 16,302 PD inpatients admitted to a Cerner hospital between 2000 and 2011. Anticholinergic burden was computed using the Anticholinergic Risk Scale (ARS). Primary outcomes were associations between ARS score and diagnosis of fracture and delirium. Secondary outcomes included associations between ARS score and 30-day hospital revisits.

Results

Many individuals (57.8%) were prescribed non-PD medications with moderate to very strong anticholinergic potential. Individuals with the greatest ARS score (≥4) were more likely to be diagnosed with fractures (adjusted odds ratio (AOR): 1.56, 95% CI: 1.29–1.88) and delirium (AOR: 1.61, 95% CI: 1.08–2.40) relative to those with no anticholinergic burden. Similarly, inpatients with the greatest ARS score were more likely to visit the emergency department (adjusted hazard ratio (AHR): 1.32, 95% CI: 1.10–1.58) and be readmitted (AHR: 1.16, 95% CI: 1.01–1.33) within 30-days of discharge.

Conclusions

We found a positive association between increased anticholinergic burden and adverse outcomes among individuals with PD. Additional pharmacovigilance studies are needed to better understand risks associated with anticholinergic medication use in PD.     

An Insight into Cell Elasticity and Load-Bearing Ability. Measurement and Theory

We have studied the elasticity and load bearing ability of plant tissue at the cellular level, using onion (Allium cepa) epidermal cells. The Young's modulus and Poisson's ratio of the cells were obtained by loading a tensile force on onion epidermal peels of different turgor pressures, and measuring the elongation and the lateral contraction of the peels. The Young's moduli and the Poisson's ratios ranged from 3.5 to 8.0 MPa and 0.18 to 0.30, respectively. To determine the effects of cell elasticity and turgor pressure on the cell's ability to bear load, we loaded a small glass ball onto a cell and measured the projected contact area between the ball and the cell. Unlike previous studies, we considered the cell as a whole entity, and utilized the Boussinesq's solution to derive the relevant equations that related the elastic parameters and cell deformation. For cells with a turgor pressure > or = 0.34 MPa, the predicted contact area agreed well with the measured area. The equations could also predict cell turgor pressure with a deviation from the measured value of 0.01 MPa. This study gives strong support to ball tonometry, a new method of measuring cell turgor pressure.     

Insight into Neutral and Disease-Associated Human Genetic Variants through Interpretable Predictors

A variety of methods that predict human nonsynonymous single nucleotide polymorphisms (SNPs) to be neutral or disease-associated have been developed over the last decade. These methods are used for pinpointing disease-associated variants in the many variants obtained with next-generation sequencing technologies. The high performances of current sequence-based predictors indicate that sequence data contains valuable information about a variant being neutral or disease-associated. However, most predictors do not readily disclose this information, and so it remains unclear what sequence properties are most important. Here, we show how we can obtain insight into sequence characteristics of variants and their surroundings by interpreting predictors. We used an extensive range of features derived from the variant itself, its surrounding sequence, sequence conservation, and sequence annotation, and employed linear support vector machine classifiers to enable extracting feature importance from trained predictors. Our approach is useful for providing additional information about what features are most important for the predictions made. Furthermore, for large sets of known variants, it can provide insight into the mechanisms responsible for variants being disease-associated.     

Whole Genome Sequence of Multiple Myeloma-Prone C57BL/KaLwRij Mouse Strain Suggests the Origin of Disease Involves Multiple Cell Types

Monoclonal gammopathy of undetermined significance (MGUS) is the requisite precursor to multiple myeloma (MM), a malignancy of antibody-producing plasma B-cells. The genetic basis of MGUS and its progression to MM remains poorly understood. C57BL/KaLwRij (KaLwRij) is a spontaneously-derived inbred mouse strain with a high frequency of benign idiopathic paraproteinemia (BIP), a phenotype with similarities to MGUS including progression to MM. Using mouse haplotype analysis, human MM SNP array data, and whole exome and whole genome sequencing of KaLwRij mice, we identified novel KaLwRij gene variants, including deletion of Samsn1 and deleterious point mutations in Tnfrsf22 and Tnfrsf23. These variants significantly affected multiple cell types implicated in MM pathogenesis including B-cells, macrophages, and bone marrow stromal cells. These data demonstrate that multiple cell types contribute to MM development prior to the acquisition of somatic driver mutations in KaLwRij mice, and suggest that MM may an inherently non-cell autonomous malignancy.     

Digging through the Obstruction: Insight into the Epithelial Cell Response to Respiratory Virus Infection in Patients with Cystic Fibrosis

Respiratory virus infections are common but generally self-limiting infections in healthy individuals. Although early clinical studies reported low detection rates, the development of molecular diagnostic techniques by PCR has led to an increased recognition that respiratory virus infections are associated with morbidity and acute exacerbations of chronic lung diseases, such as cystic fibrosis (CF). The airway epithelium is the first barrier encountered by respiratory viruses following inhalation and the primary site of respiratory viral replication. Here, we describe how the airway epithelial response to respiratory viral infections contributes to disease progression in patients with CF and other chronic lung diseases, including the role respiratory viral infections play in bacterial acquisition in the CF patient lung.     

Insight into the physiological functions of PDGF through genetic studies in mice

Genetic analyses in mice have contributed significantly to the understanding of the physiological functions of platelet-derived growth factors (PDGFs) and their receptors. Phenotypic analyses of gene knockouts of PDGF-A, PDGF-B, PDGF alpha-receptors (PDGFRalpha) and beta-receptors (PDGFRbeta) have shown that these ligands and receptors play major roles during embryonic development. Conditional and subtle mutations in the same genes and analysis of chimeric mice have provided additional information about the roles of these genes in postnatal development. Transgenic over-expression studies have also demonstrated that PDGF ligands are capable of inducing pathological cell proliferation in a number of different organs. The present review summarizes these findings and discusses their implications for mammalian development and disease.     

Insight into Types I and II nonhost resistance using expression patterns of defense-related genes in tobacco

Plants protect themselves against pathogens using a range of response mechanisms. There are two categories of nonhost resistance: Type I, which does not result in visible cell death; and Type II, which entails localized programmed cell death (or hypersensitive response) in response to nonhost pathogens. The genes responsible for these two systems have not yet been intensively investigated at the molecular level. Using tobacco plants (Nicotiana tabacum), we compared expression of 12 defense-related genes between a Type I (Xanthomonas axonopodis pv. glycines 8ra) nonhost interaction, and two Type II (Pseudomonas syringae pv. syringae 61 and P. syringae pv. phaseolicola NPS3121) nonhost interactions, as well as those expressed during R gene-mediated resistance to Tobacco mosaic virus. In general, expression of most defense-related genes during R gene-mediated resistance was activated 48 h after challenge by TMV; the same genes were upregulated as early as 9 h after infiltration by nonhost pathogens. Surprisingly, X. axonopodis pv. glycines (Type I) elicited the same set of defense-related genes as did two pathovars of P. syringae, despite the absence of visible cell death. In two examples of Type II nonhost interactions, P. syringae pv. phaseolicola NPS3121 produced an expression profile more closely resembling that of X. axonopodis pv. glycines 8ra, than that of P. syringae pv. syringae 61. These results suggest that Type I nonhost resistance may act as a mechanism providing a more specific and active defense response against a broad range of potential pathogens.     

Modeling Disease Severity in Multiple Sclerosis Using Electronic Health Records

Objective

To optimally leverage the scalability and unique features of the electronic health records (EHR) for research that would ultimately improve patient care, we need to accurately identify patients and extract clinically meaningful measures. Using multiple sclerosis (MS) as a proof of principle, we showcased how to leverage routinely collected EHR data to identify patients with a complex neurological disorder and derive an important surrogate measure of disease severity heretofore only available in research settings.

Methods

In a cross-sectional observational study, 5,495 MS patients were identified from the EHR systems of two major referral hospitals using an algorithm that includes codified and narrative information extracted using natural language processing. In the subset of patients who receive neurological care at a MS Center where disease measures have been collected, we used routinely collected EHR data to extract two aggregate indicators of MS severity of clinical relevance multiple sclerosis severity score (MSSS) and brain parenchymal fraction (BPF, a measure of whole brain volume).

Results

The EHR algorithm that identifies MS patients has an area under the curve of 0.958, 83% sensitivity, 92% positive predictive value, and 89% negative predictive value when a 95% specificity threshold is used. The correlation between EHR-derived and true MSSS has a mean R² = 0.38±0.05, and that between EHR-derived and true BPF has a mean R² = 0.22±0.08. To illustrate its clinical relevance, derived MSSS captures the expected difference in disease severity between relapsing-remitting and progressive MS patients after adjusting for sex, age of symptom onset and disease duration (p = 1.56×10⁻¹²).

Conclusion

Incorporation of sophisticated codified and narrative EHR data accurately identifies MS patients and provides estimation of a well-accepted indicator of MS severity that is widely used in research settings but not part of the routine medical records. Similar approaches could be applied to other complex neurological disorders.     

Senescence and declining reproductive potential: Insight into molecular mechanisms through testicular metabolomics

Aging is associated with structural and functional changes in the organism that result in the declining of its functioning. Postponed parenthood has renewed the interest in age-related decline of testicular function and male fertility. Still, little is known about the molecular mechanisms associated with testicular senescence and related decline of fertility. Here we sought to elucidate the molecular basis of metabolic changes associated with testicular aging and reproductive potential using an NMR-based metabolomics approach. Testicular metabolic profiles of rats from 3 to 24?months-of-age were analysed. An age-associated decrease in most antioxidant metabolites, like betaine, creatine and glutathione was observed. Amino acid content changed as early as 6?months-of-age, with an increase in branched chain and aromatic amino acids, accompanied by decrease of nucleotide synthesis (IMP, CMP, ATP). Testicular content of phospholipid precursors (choline, ethanolamine, myo-inositol, glycerol) increased with advanced age and was accompanied by a decrease in the levels of their phosphorylated products, suggesting compromised spermatogenesis. This is the first metabolomics study of testicular tissue of aged rats and we were able to identify metabolites associated with reproductive maturity from the onset to senescence. Our results provide evidence for an influence of aging on global testicular metabolome, as early as 6?months-of-age, with a profound alteration of several key metabolic pathways associated with the male reproductive potential.     

Multiple Single-Cell Genomes Provide Insight into Functions of Uncultured Deltaproteobacteria in the Human Oral Cavity

Despite a long history of investigation, many bacteria associated with the human oral cavity have yet to be cultured. Studies that correlate the presence or abundance of uncultured species with oral health or disease highlight the importance of these community members. Thus, we sequenced several single-cell genomic amplicons from Desulfobulbus and Desulfovibrio (class Deltaproteobacteria) to better understand their function within the human oral community and their association with periodontitis, as well as other systemic diseases. Genomic data from oral Desulfobulbus and Desulfovibrio species were compared to other available deltaproteobacterial genomes, including from a subset of host-associated species. While both groups share a large number of genes with other environmental Deltaproteobacteria genomes, they encode a wide array of unique genes that appear to function in survival in a host environment. Many of these genes are similar to virulence and host adaptation factors of known human pathogens, suggesting that the oral Deltaproteobacteria have the potential to play a role in the etiology of periodontal disease.