Pilot feasibility study to detect mesenchymal stem cell biomarkers of bronchopulmonary dysplasia in the tracheal aspirate fluid of preterm infants.

OBJECTIVE: This study aimed to detect novel mesenchymal stem cell peptides/biomarkers of bronchopulmonary dysplasia (BPD) in the tracheal aspirate fluid (TAF) of preterm infants. STUDY DESIGN: Participants included infants less than 32 weeks' gestational age or birth weight under 1500 grams who required endotracheal intubation and mechanical ventilation within first 24 hours of life. TAF sample collection was performed at the time of the first clinically indicated routine suctioning. Standardization curves for human levels of osteopontin (Opn), macrophage colony stimulating factor 1 (Csf1), transforming growth factor beta 1 (TGF-ß1), and secretory immunoglobulin A (sIgA) were generated for 15 enrolled participants. RESULTS: We demonstrated that stem cell biomarkers are secreted into the TAF of preterm infants and their concentrations can be easily measured during the first week of life. CONCLUSIONS: Further studies are warranted to determine a causal relationship between these biomarkers and BPD development and severity.

Genotype-phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia.

Valosin containing protein (VCP) disease associated with inclusion body myopathy, Paget disease of the bone and frontotemporal dementia is a progressive autosomal dominant disorder caused by mutations in Valosin containing protein gene. To establish genotype-phenotype correlations we analyzed clinical and biochemical markers from a database of 190 members in 27 families harboring 10 missense mutations. Individuals were grouped into three categories: symptomatic, presymptomatic carriers and noncarriers. The symptomatic families were further divided into ten groups based on their VCP mutations. There was marked intra and inter-familial variation; and significant genotype-phenotype correlations were difficult to establish because of small numbers. Nevertheless when comparing the two most common mutations, R155C mutation was found to be more severe, with an earlier onset of myopathy and Paget (p = 0.03). Survival analysis of all subjects revealed an average life span after diagnosis of myopathy and Paget of 18 and 19 years respectively, and after dementia only 6 years. R155C had a reduced survival compared to the R155H mutation (p = 0.03).We identified amyotrophic lateral sclerosis (ALS) was diagnosed in 13 individuals (8.9%) and Parkinson's disease in five individuals (3%); however, there was no genotypic correlation. This study represents the largest dataset of patients with VCP disease and expands our understanding of the natural history and provides genotype-phenotype correlations in this unique disease.

Slow development of ALS-like spinal cord pathology in mutant valosin-containing protein gene knock-in mice.

Pathological features of amyotrophic lateral sclerosis (ALS) include, in addition to selective motor neuron (MN) degeneration, the occurrence of protein aggregates, mitochondrial dysfunction and astrogliosis. SOD1 mutations cause rare familial forms of ALS and have provided the most widely studied animal models. Relatively recent studies implicating another protein, TDP-43, in familial and sporadic forms of ALS have led to the development of new animal models. More recently, mutations in the valosin-containing protein (VCP) gene linked to the human genetic disease, Inclusion Body Myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD), were found also to be associated with ALS in some patients. A heterozygous knock-in VCP mouse model of IBMPFD (VCP(R155H/+)) exhibited muscle, bone and brain pathology characteristic of the human disease. We have undertaken studies of spinal cord pathology in VCP(R155H/+) mice and find age-dependent degeneration of ventral horn MNs, TDP-43-positive cytosolic inclusions, mitochondrial aggregation and progressive astrogliosis. Aged animals (~24-27 months) show electromyography evidence of denervation consistent with the observed MN loss. Although these animals do not develop rapidly progressive fatal ALS-like disease during their lifespans, they recapitulate key pathological features of both human disease and other animal models of ALS, and may provide a valuable new model for studying events preceding onset of catastrophic disease.

Interleukin-17 and systemic lupus erythematosus: current concepts.

The emerging role of interleukin (IL)-17 as a hallmark proinflammatory cytokine of the adaptive immune system, produced primarily by a new T helper cell subset termed 'Th17', has received considerable attention. Differentiation of Th17 cells is driven by the simultaneous presence of transforming growth factor-beta and certain inflammatory cytokines (e.g. IL-6, IL-21), and recent studies have shown that inflammation instigated by IL-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. In this review, we focus on the information regarding IL-17 and systemic lupus erythematosus (SLE), a chronic autoimmune disease. The work that has explored the development and behaviour of IL-17-producing cells in SLE is discussed, and different mechanisms by which IL-17 could potentially augment inflammation and autoantibody production in the context of SLE are proposed.

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control.

Coexistence of pulmonary tuberculosis (TB) and lung cancer in clinic poses significant challenges for the diagnostic and treatment of both diseases. Although association of chronic inflammation and cancer is well-documented, causal relationship between TB infection and lung cancer are not understood. We present experimental evidence that chronic TB infection induces cell dysplasia and squamous cell carcinoma (SCC) in a lung-specific manner. First, squamous cell aggregates consistently appeared within the lung tissue associated with chronic TB lesions, and in some cases resembled SCCs. A transplantable tumor was established after the transfer of cells isolated from TB lung lesions into syngeneic recipients. Second, the (Mycobacterium tuberculosis) MTB-infected macrophages play a pivotal role in TB-induced carcinogenesis by inducing DNA damage in their vicinity and by the production of a potent epidermal growth factor epiregulin, which may serve as a paracrine survival and growth factor responsible for squamous metaplasia and tumorigenesis. Third, lung carcinogenesis during the course of chronic TB infection was more pronounced in animals with severe lung tissue damage mediated by TB-susceptibility locus sst1. Together, our experimental findings showed a causal link between pulmonary TB and lung tumorigenesis and established a genetic model for further analysis of carcinogenic mechanisms activated by TB infection.

Registration of images from sequential MR studies of the brain.

For sequential studies of patients with brain tumors, the authors have designed an automated registration procedure for intra- and interexamination alignment of magnetic resonance images. This was evaluated with artificially misregistered data and data from repeat studies of six healthy volunteers and six brain tumor patients. In a subset of cases, a manual procedure based on matching of neuroanatomic landmarks was also applied for comparison. The results showed that the technique is robust and reproducible, giving an accuracy in the range of 1-2 mm, which corresponded to the spatial resolution of the images. Subject motion between imaging sequences within the same study was negligible, although adjustments (one to two section thicknesses) were required in the z direction to correlate multisection and volume images and to allow accurate image segmentation. For alignment between sequential volunteer and patient examinations, translations of up to 22 mm and rotations in the x, y, and z axes of up to 9 degrees were required. This alignment procedure may be valuable in numerous aspects of treatment planning and patient follow-up.

[Effect of cryopreservation of thyroid parenchyma on iodoamino acid composition of thyroglobulin and its iodination]. / Vliianie kriokonservatsii tireoidnoi parenkhimy na iodaminokislotnyi sostav tireoglobulina i ego iodirovanie.

The content and distribution of iodoamino acids in thyroglobulin of the cryopreserved thyrotoxically-changed thyroid parenchyma were studied, as was thyroglobulin iodination. Thyroid tissue obtained during operations of patients with diffuse-toxic goiter was investigated. The thyroid parenchyma was cryopreserved according to the method developed at the Institute of Cryobiology and Cryomedicine Problems, Academy of Sciences of the Ukrainian SSR. The tissues were stored for 4-6 months. Thyroglobulin was isolated by gel filtration of the thyroid saline extract through a column packed with Sephadex G-200. Thyroglobulin was iodinated with KI + I2 water solution, pH 9.2, at 37 C for 30 min. The amount of iodine added was 100 moles of I2 per protein mole. Protein concentration was determined by the biuret reaction. Thyroglobulin iodoamino acid composition was determined by direct spectrophotometry. Absorption spectra were measured by an EPS-3T recording spectrophotometer ("Hitachi", Japan). The processes of freezing (-196 degrees C) and thawing of the thyroid parenchyma were shown to induce no changes in the thyroglobulin iodoamino acid composition. Cryopreservation of the thyroid parenchyma considerably affected iodine incorporation and formation of iodoamino acids in the thyroglobulin during its in vitro iodination. It may be supposed that cryopreservation of the thyroid tissue affects the thyroglobulin conformational status, that results in increased iodination of this iodoprotein.

[Electrophoretic characteristics of the protein composition of mutant forms of pea nodular bacteria]. / Elektroforeticheskaia kharakteristika belkovogo sostava mutantnykh form kluben'kovykh bakterii gorokha.

A water-soluble protein fraction was studied by gel electrophoresis in the parent and mutant forms of the nodule bacterium Rhizobium leguminosarum. The composition of this fraction changed under the action of NTG. Changes in the composition of protein components in the mutants as compared with that of the parent strain are caused presumably by their modified specificity.