Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon ß in dermatomyositis.

BACKGROUND: Dermatomyositis (DM) is an autoimmune disease primarily affecting skin and muscle. OBJECTIVES: The purpose of this study was to determine whether an association exists between clinical skin disease activity as measured by the validated Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and type 1 interferon (IFN) pathway biomarkers in the blood of patients with DM. METHODS: Forty-two patients with DM and 25 healthy volunteers were prospectively enrolled. CDASI scores were obtained, and serum and blood RNA were isolated from all participants. Associations between CDASI activity and type 1 IFN-inducible gene signature were assessed cross-sectionally in all patient samples and longitudinally on 13 paired visits via transcriptional profiling analyses. RESULTS: By RNAseq analysis, type 1 IFN-inducible genes were the most highly differentially regulated. A CDASI activity threshold of 12 was correlated with an elevated type 1 IFN gene signature and with serum IFN-ß, but not with IFN-α protein. Expression analysis showed that all patients with mild disease activity had a low type 1 IFN gene signature, while 93% of patients with moderate-to-high disease activity had elevated gene signature. In longitudinal analysis, changes in CDASI activity showed nonsignificant trends with concordant directional changes in gene signature. CONCLUSIONS: A type 1 IFN pathway signature biomarker in blood is highly correlated with CDASI activity scores in DM, and may be a promising surrogate clinical trial end point. The correlation of serum IFN-ß, but not IFN-α, with both a gene signature and CDASI suggests that IFN-ß drives disease activity in DM.

INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia.

In this study, we investigated the role of inositol polyphosphate-4-phosphatase, type-II (INPP4B) in acute myeloid leukemia (AML). We observed that AML patients with high levels of INPP4B (INPP4B(high)) had poor response to induction therapy, shorter event-free survival and shorter overall survival. Multivariate analyses demonstrated that INPP4B(high) was an independent predictor of poor prognosis, significantly improving current predictive models, where it outperformed conventional biomarkers including FLT3-ITD and NPM1. Furthermore, INPP4B(high) effectively segregated relative risk in AML patients with normal cytogenetics. The role of INPP4B on the biology of leukemic cells was assessed in vitro. Overexpression of INPP4B in AML cell lines enhanced colony formation potential, recapitulated the chemotherapy resistance observed in AML patients and promoted proliferation in a phosphatase-dependent, and Akt-independent manner. These findings reveal that INPP4B(high) has an unexpected role consistent with oncogenesis in AML, in contrast to its previously reported tumor-suppressive role in epithelial cancers. Overall, we propose that INPP4B is a novel prognostic biomarker in AML that has potential to be translated into clinical practice both as a disease marker and therapeutic target.

Relationship between disease activity and type 1 interferon- and other cytokine-inducible gene expression in blood in dermatomyositis and polymyositis.

The objective of this study was to evaluate the relationship between blood mRNA, disease activity and treatment effects in a longitudinal study of patients with dermatomyositis (DM) or polymyositis (PM). In all, 24 patients with DM or PM were followed for up to 6 years (mean of 1.9 years) at 2-7 follow-up visits while receiving standard clinical care. Clinical data and blood samples collected at 80 patient visits were used for the analysis of cytokine-induced gene expression for the signaling pathways of type 1 interferon (IFN), tumor necrosis factor-α, IL-1ß, granulocyte-monocyte colony-stimulating factor, IL-10 and IL-13. A type 1 IFN signature score, but not other cytokine signature scores in the blood of patients with DM or PM, correlated highly with disease activity, decreased significantly with immunomodulatory therapies and showed concordant changes with major changes in disease activity. Type 1 IFN signature score in the blood correlates with disease activity in longitudinal follow-up of individual patients with DM or PM. The type 1 IFN-inducible gene transcripts in the blood have potential utility for monitoring disease activity in patients with DM or PM.

Plasma cells in muscle in inclusion body myositis and polymyositis.

BACKGROUND: Previous immunohistochemical studies of muscle from patients with inclusion body myositis and polymyositis found many more T cells than B cells, suggesting a role for intramuscular cell-mediated immune mechanisms rather than humoral mechanisms. METHODS: Microarray studies were performed on muscle biopsy specimens from 40 patients with inclusion body myositis (IBM; n = 23), polymyositis (PM; n = 6), and without neuromuscular disease (n = 11). Reverse transcription PCR of selected immunoglobulin gene transcripts was performed on two patient samples. Qualitative immunohistochemical studies for B-cell lineage cell surface markers were performed on 28 muscle specimens and quantitative studies performed on a subset of 19 untreated patients with IBM or PM. CD138+ cells were isolated from muscle using laser capture microdissection, and immunoglobulin transcripts were PCR amplified to determine the presence or absence of immunoglobulin gene rearrangements unique to the B-cell lineage. RESULTS: Immunoglobulin gene transcripts accounted for 59% in IBM and 33% in PM of the most stringently defined highest differentially expressed muscle transcripts compared with normal. Plasma cells, terminally differentiated B cells expressing CD138 but not CD19 or CD20, are present in IBM and PM muscle in numbers several times higher than B cells. CONCLUSIONS: There are differentiated B cells in the form of CD138+ plasma cells within the muscle of patients with inclusion body myositis and polymyositis. The principle of linked recognition of B-cell activation predicts several strategies for autoantigen discovery that could not otherwise be pursued through the study of the infiltrating T-cell population alone.

Molecular profiles of inflammatory myopathies.

OBJECTIVE: To describe the use of large-scale gene expression profiles to distinguish broad categories of myopathy and subtypes of inflammatory myopathies (IM) and to provide insight into the pathogenesis of inclusion body myositis (IBM), polymyositis, and dermatomyositis. METHODS: Using Affymetrix GeneChip microarrays, the authors measured the simultaneous expression of approximately 10,000 genes in muscle specimens from 45 patients in four major disease categories (dystrophy, congenital myopathy, inflammatory myopathy, and normal). The authors separately analyzed gene expression in 14 patients limited to the three major subtypes of IM. Bioinformatics techniques were used to classify specimens with similar expression profiles based on global patterns of gene expression and to identify genes with significant differential gene expression compared with normal. RESULTS: Ten of 11 patients with IM, all normals and nemaline myopathies, and 10 of 12 patients with Duchenne muscular dystrophy were correctly classified by this approach. The various subtypes of inflammatory myopathies have distinct gene expression signatures. Specific sets of immune-related genes allow for molecular classification of patients with IBM, polymyositis, and dermatomyositis. Analysis of differential gene expression identifies as relevant to disease pathogenesis previously reported cytokines, major histocompatibility complex class I and II molecules, granzymes, and adhesion molecules, as well as newly identified members of these categories. Increased expression of actin cytoskeleton genes is also identified. CONCLUSIONS: The molecular profiles of muscle tissue in patients with inflammatory myopathies are distinct and represent molecular signatures from which diagnostic insight may follow. Large numbers of differentially expressed genes are rapidly identified.

Inflammatory myopathy associated with mixed connective tissue disease and scleroderma renal crisis.

Mixed connective tissue disease is a rheumatological syndrome with neuromuscular manifestations that may include inflammatory myopathy and carpal tunnel syndrome. We report a patient who presented with an inflammatory myopathy and bilateral carpal tunnel syndrome prior to the diagnosis of a connective tissue disorder. Early in the course of treatment, a syndrome of acute renal failure developed. Knowledge of this syndrome, scleroderma renal crisis, and its possible relation to corticosteroid treatment is important to clinicians involved in the management of patients with inflammatory myopathies.

DNA microarray gene expression analysis technology and its application to neurological disorders.

DNA microarray technology is currently an area of great interest. Also called "genechip" technology, it incorporates molecular genetics and computer science on a massive scale. This technology can rapidly provide a detailed view of the simultaneous expression of entire genomes and provide new insights into gene function, disease pathophysiology, disease classification, and drug development. In this review, the author discusses the basic theory behind genechip and the other biologic chip technologies, their limitations given the current state of biologic knowledge and computational abilities, and their potential applications to the understanding of neurologic disorders.

Methodologic issues in conducting research on hospitalized older people.

OBJECTIVE: To describe challenges in conducting research with hospitalized geriatric patients. DESIGN: Quasi-experimental longitudinal study with inperson interviews at baseline and discharge and a three-month postdischarge telephone interview. Study protocol required baseline interviews within 48 hours of admission for patients or 72 hours for proxies. SETTING: 813-bed urban teaching hospital. PARTICIPANTS: 240 patients, mean age 83.8 years, at moderate to high risk for functional decline during hospitalization, admitted from the emergency room to a general medical unit. MEASUREMENTS: Delays starting or interruptions continuing interviews; patient and environmental conditions potentially affecting data quality; and information on proxy use. RESULTS: Timely access to patients or proxies was a major difficulty, resulting in the screening of only 53.1% of 867 potentially eligible patients. Multiple patient contacts and visits were required to complete interviews. Only 61.3% of baseline and 28.1% of follow-up interviews were completed on the initial day of contact. Despite having on-site interviewers 7 days a week, 29% of discharge interviews were conducted by telephone. Interviews were >90% complete in 487 of 503 of encounters (97%). Baseline delays and interruptions were usually due to the presence of medical staff, off-unit tests, patient illness, nurse unavailability for interview, and need for a proxy. Most in-hospital interviews were conducted with others present. Proxies were required for approximately one-third of patients at all three interviews. CONCLUSION: Conducting clinical research with older adults in the current inpatient setting, where patients are more severely ill yet have shorter lengths of stay now than in the past, proves a challenging yet achievable goal. Effective procedures for negotiating the acute care environment are critical to successful studies.

Dejerine-Sottas disease with sensorineural hearing loss, nystagmus, and peripheral facial nerve weakness: de novo dominant point mutation of the PMP22 gene.

A 32 year old woman with Dejerine-Sottas disease and negative family history is reported. Clinical onset of her condition was with congenital weakness of her distal four extremities, accompanied by peripheral facial nerve weakness, deafness, and nystagmus. She has used a wheelchair all her life. Sural nerve biopsy showed proliferation of Schwann cells, extensive endoneural fibrosis, axon loss, and demyelination. MNCVs showed marked slowing. MRI of the brain was normal. Molecular genetic studies indicated a de novo dominant missense point mutation of exon 3 of the peripheral myelin protein 22 gene at nucleotide 264 causing replacement of serine with leucine.

Pseudochoreoathetosis. Movements associated with loss of proprioception.

OBJECTIVE: To describe seven patients with proprioceptive sensory loss and choreoathetoid movements. DESIGN: Case series. SETTING: Outpatient and inpatient university referral. PATIENTS: Patients with sensory loss and abnormal movements. INTERVENTION: None. MAIN OUTCOME MEASURE: None. RESULTS: One patient had a parietal cortex injury, one had a thalamic infarction, two had spinal cord lesions, two had dorsal root ganglion neuronopathies, and one had an ulnar neuropathy. In each case, the duration of abnormal movements correlated with the duration of proprioceptive sensory loss, and the abnormal movements were restricted to body parts with proprioceptive sensory loss. The movements varied from chorea and athetosis to dystonia. CONCLUSIONS: These cases suggest that proprioceptive sensory loss can lead to a movement disorder, termed pseudochoreoathetosis, which occurs following the appearance of lesions anywhere along proprioceptive sensory pathways, from peripheral nerves to the cerebral cortex. It is hypothesized that pseudochoreoathetosis occurs because of the failure to process limb proprioceptive information in the striatum. Therefore, both choreoathetosis and pseudochoreoathetosis may be manifestations of the failure of the striatum to properly integrate cortical motor and sensory inputs.

Binder's syndrome (nasomaxillary dysplasia): an uncommonly common disorder.

Binder's syndrome or nasomaxillary dysplasia is a disorder characterized by hypoplastic development of the midportion of the midfacial skeleton and its associated soft tissue manifestations. The disorder is probably more common than initially believed with only 40 cases described previous to 1980. However, since 1980, 127 cases have been reported. One case of Binder's syndrome treated with onlay split cranial (calvarial) bone grafts is presented. The technique of using split calvarial bone grafts has become increasingly popular in craniofacial surgery and facial trauma reconstruction. A literature review of Binder's syndrome is outlined and the technique of using split calvarial bone grafts is described. An analysis of the skeleton and soft tissue characteristics of Binder's syndrome is detailed and treatment options discussed.

Temporomandibular joint dysfunction: evaluation and treatment.

Temporomandibular joint dysfunction is a complicated problem requiring interdisciplinary cooperation for diagnosis and treatment. Functional problems including bruxism and psychological disorders frequently occur with joint dysfunction making evaluation more difficult. Many new diagnostic modalities are now available to supplement the history and physical examination to provide an accurate assessment of the joint. Although conservative treatment is successful in a majority of the patients, some form of surgical treatment remains the only option for those who do not respond to conservative management. We have discussed the etiology, diagnosis, and treatment of the pathological conditions of the TMJ and introduced a new modality of treatment, temporalis fascia interpositional arthroplasty. Further work is necessary to elucidate the etiology of TMJ dysfunction and develop treatment modalities that avoid the use of alloplastic materials.

The response of rat brain protein synthesis to ethanol and sodium barbital.

Central nervous system (CNS) depressants such as ethanol and barbiturates under acute or chronic conditions can induce changes in rat brain protein synthesis. While these data demonstrate the individual effects of drugs on protein synthesis, the response of brain protein synthesis to alcohol-drug interactions is not known. The goal of the present study was to determine the individual and combined effects of ethanol and sodium barbital on brain protein synthesis and gain an understanding of the mechanisms by which these alterations in protein synthesis are produced. Specifically, the in vivo and in vitro effects of sodium barbital (one class of barbiturates which is not metabolized by the hepatic tissue) were examined on brain protein synthesis in rats made physically dependent upon ethanol. Using cell free brain polysomal systems isolated from "Control," "Ethanol" and 24 h "Ethanol Withdrawn" rats, data show that sodium barbital, when intubated intragastrically, inhibited the time dependent incorporation of 14(C) leucine into protein by all three groups of ribosomes. Under these conditions, the "Ethanol Withdrawn" group displayed the largest inhibition of the 14(C) leucine incorporation into protein when compared to the "Control" and "Ethanol" groups. In addition, sodium barbital when added at various concentrations in vitro to the incubation medium inhibited the incorporation of 14(C) leucine into protein by "Control" and "Ethanol" polysomes. The inhibitory effects were also obtained following preincubation of ribosomes in the presence of barbital but not cycloheximide. Data suggest that brain protein synthesis, specifically brain polysomes, through interaction with ethanol or barbital are involved in the functional development of tolerance. These interactions may occur through proteins or polypeptide chains or alterations in messenger RNA components associated with the ribosomal units.

Cell-mediated immunity in the uremic rat.

The popliteal node assay of the graft-versus-host reaction in the inbred rat provides a sensitive measure of cell-mediated immunity. Spleen cells from uremic Lewis rats as well as normal cells cultured in uremic serum demonstrated significant immunosuppression which was proportional to the severity of the uremia.