The t(4;14) translocation in multiple myeloma (MM) simultaneously dysregulates two apparent oncogenes: fibroblast growth factor receptor 3 (FGFR3) controlled by the 3' immunoglobulin heavy chain ...enhancer on der(14) and MMSET controlled by the intronic Emu enhancer on der(4). Although all MM tumors and cell lines with a t(4;14) translocation have dysregulated MMSET, about 25% do not express FGFR3. Therefore, the function of dysregulated wild-type (WT) FGFR3 in the pathogenesis of MM remains unclear. We developed a murine transgenic (TG) model in which WT FGFR3 is overexpressed in B lymphoid cells. Although high levels of FGFR3 resulted in lymphoid hyperplasia in about one-third of older mice, no increase in tumorigenesis was observed. However, double TG FGFR3/Myc mice develop mature B lymphoma tumors that occur with a higher penetrance and shorter latency than in single TG Myc mice (P=0.006). We conclude that expression of high levels of WT FGFR3 can be oncogenic and cooperate with MYC to generate B lymphoid tumors. This suggests that dysregulated FGFR3 expression is likely to be essential at least for the early stages of pathogenesis of MM tumors that have a t(4;14) translocation.
Lipids and Age-related Macular Degeneration Kishan, Amar U., BA; Modjtahedi, Bobeck S., MD; Martins, Elisabeth N., MD ...
Survey of ophthalmology,
05/2011, Letnik:
56, Številka:
3
Journal Article
Recenzirano
Abstract Given the considerable public health burden imposed by age-related macular degeneration (AMD), much effort has been directed towards elucidating principles of pathogenesis in order to ...identify risk factors and develop preventive measures and treatments. Together with epidemiological evidence linking cardiovascular risk factors with AMD risk and basic science work examining the role of lipid metabolism in AMD, numerous human studies have assayed a potential relationship between dietary lipids and the development of AMD. We examine the evidence for a role for lipid metabolism in AMD, highlighting key basic biochemical principles, work in animal models, and relevant human studies. The topics of lipoprotein modulation and omega-3 fatty acid intake receive special attention from both a basic science and clinical study standpoint. The evidence suggests that consumption of omega-3 fatty acids, perhaps in concert with antioxidants, may constitute a rational preventative strategy against AMD development, though, absent an appropriately developed double-blind, randomized control trial, insufficient data exist to recommend implementation in the clinical setting at this time.
To evaluate the morphologic changes in the macula of subjects with repaired macula-off retinal detachment (RD) using high-resolution Fourier-domain optical coherence tomography (FD OCT) and to ...perform functional correlation in a subset of patients using microperimetry (MP-1).
Prospective observational case series.
Seventeen eyes from 17 subjects who had undergone anatomically successful repair for macula-off, rhegmatogenous RD at least 3 months earlier and without visually significant maculopathy on funduscopy.
FD OCT with axial and transverse resolution of 4.5 mum and 10 to 15 mum, respectively, was used to obtain rapid serial B-scans of the macula, which were compared with that from Stratus OCT. The FD OCT B-scans were used to create a 3-dimensional volume, from which en face C-scans were created. Among 11 patients, MP-1 was performed to correlate morphologic changes with visual function.
Stratus OCT scans, FD OCT scans, and MP-1 data.
Stratus OCT and FD OCT images of the macula were obtained 3 to 30 months (mean 7 months) postoperatively in all eyes. Although Stratus OCT revealed photoreceptor disruption in 2 eyes (12%), FD OCT showed photoreceptor disruption in 13 eyes (76%). This difference was statistically significant (P<0.001, chi(2)). Both imaging modalities revealed persistent subretinal fluid in 2 eyes (12%) and lamellar hole in 1 eye. Among 7 subjects who had reliable MP-1 data, areas of abnormal function corresponded to areas of photoreceptor layer disruptions or persistent subretinal fluid in 5 subjects (71%); one subject had normal FD OCT and MP-1.
Photoreceptor disruption after macula-off RD repair is a common abnormality in the macula that is detected better with FD OCT than Stratus OCT. A good correlation between MP-1 abnormality and presence of photoreceptor disruption or subretinal fluid on FD OCT demonstrates that these anatomic abnormalities contribute to decreased visual function after successful repair.
Recent advances in the field of clinical biomarkers suggest that quantification of serum proteins could play an important role in the diagnosis, classification, prognosis, and treatment response of ...smoking-related parenchymal lung diseases. COPD and idiopathic pulmonary fibrosis (IPF), two common chronic progressive parenchymal lung diseases, share cigarette smoke exposure as a common dominant risk factor for their development. We have recently shown that COPD and interstitial lung disease may represent distinct outcomes of chronic tobacco use, whereas others have demonstrated that both diseases coexist in some individuals. In this perspective, we examine the potential role of peripheral blood biomarkers in predicting which individuals will develop COPD or IPF, as well as their usefulness in tracking disease progression and exacerbations. Additionally, given the current lack of sensitive and effective metrics to determine an individual's response to treatment, we evaluate the potential role of biomarkers as surrogate markers of clinical outcomes. Finally, we examine the possibility that changes in levels of select protein biomarkers can provide mechanistic insight into the common origins and unique individual susceptibilities that lead to the development of smoking-related parenchymal lung diseases. This discussion is framed by a consideration of the properties of ideal biomarkers for different clinical and research purposes and the best uses for those biomarkers that have already been proposed and investigated.
To evaluate the psychometric properties of the Spinal Cord Injury-Functional Index/Assistive Technology (SCI-FI/AT) short forms (SFs) in the domains of basic mobility, self-care, fine motor function, ...and ambulation based on internal consistency; correlations between SFs and full item banks, and a 10-item computerized adaptive test (CAT) version; magnitude of ceiling and floor effects; and measurement precision across a broad range of function in a sample of adults with spinal cord injury (SCI).
Cross-sectional cohort study.
Nine national Spinal Cord Injury Model Systems programs.
A sample of adults with traumatic SCI (N=460) stratified by level of injury (paraplegia/tetraplegia), completeness of injury, and time since SCI.
Not applicable.
SCI-FI/AT full item bank, 10-item CAT, and SFs (with separate Self-Care and Fine Motor Function SFs for persons with tetraplegia and paraplegia).
The SCI-FI/AT SFs demonstrated very good internal consistency, group-level reliability, and excellent correlations between SFs and scores based on the CAT version and the total item bank. Ceiling and floor effects are acceptable (except for unacceptable ceiling effects for persons with paraplegia on the Self-Care and Fine Motor Function SFs). The test information functions are excellent across a broad range of functioning typical of persons with paraplegia and tetraplegia.
Clinicians and researchers should consider using the SCI-FI/AT SFs to assess functioning with the use of assistive technology when CAT applications are not available.
Abstract Autoimmune pancreatitis is a benign process characterized by inflammation and fibrosis. It is now known that cases of “autoimmune pancreatitis” actually consist of two distinct pathologic ...entities. Type 1 autoimmune pancreatitis is a manifestation of a systemic process, immunoglobulin G subclass 4 (IgG4)-related disease. IgG4-related disease can affect virtually every organ system in the body. Type 1 affects older patients and is characterized by an elevated serum IgG4 level and sites of extrapancreatic disease. Type 2 autoimmune pancreatitis is a disease process confined to the pancreas. It affects younger patients and is associated with inflammatory bowel disease. Type 2 is not associated with elevated IgG4 levels or extrapancreatic disease. Both subtypes can mimic malignancy, particularly pancreatic cancer. Awareness of the clinical and imaging features of the subtypes of autoimmune pancreatitis is important to avoid an incorrect diagnosis of malignancy.
Abstract Background Sleep disorders are common are common following traumatic brain injury. Methods In this article we review the spectrum and proposed mechanisms of traumatic brain injury associated ...sleep disorders and discuss the clinical approach to diagnosis and management of these disorders. Result Disordered sleep and wakefulness after traumatic brain injury is common. Sleep disruption contributes to morbidity, such as the development of neurocognitive and neurobehavioral deficits, and prolongs the recovery phase after injury. Early recognition and correction of these problems may limit the secondary effects of traumatic brain injury and improve patient outcomes. Conclusion Evaluating sleep disorders in traumatic brain injury should be an important component of post-traumatic brain injury assessment and management.
Background Although established for metastatic colorectal (CR) and neuroendocrine (NE) malignancies, the role of partial hepatectomy in management of metastases from other primaries (NCRNE) is not ...well-defined. Study design The objective of this retrospective study is to compare outcomes after partial hepatectomy for NCRNE, NE, and CR metastases and to identify factors associated with longterm survival for patients with NCRNE diseases. Tumor characteristics, treatments, and outcomes of 360 consecutive patients undergoing resection of NCRNE (n = 82), CR (n = 245), and NE (n = 33) hepatic metastases from 1995 to 2005 were analyzed. NCRNE tumors included breast (n = 20), sarcomas (n = 19), genitourinary (n = 18), melanoma (n = 11), and other (n = 14) cancers. The start date for followup and survival analyses was the date of partial hepatectomy. Results For patients with NCRNE, CR, and NE tumors, there were no marked differences in postoperative mortality (4%, 4%, and 9%) or complication (30%, 42%, and 42%) rates. Median overall survival was longest for NE patients (not yet reached) versus NCRNE and CR (both 44 months) patients (p < 0.05, log-rank test). NCRNE patients had shorter disease-free survival than CR counterparts (13 versus 16 months), p < 0.05 (log-rank test). After median followup of 59 months for NCRNE patients, actuarial 5-year overall and disease-free survival was 37% and 16%, respectively, with 15 5-year survivors. Multivariable analysis suggests that interval from discovery of liver metastases to resection > 6 months (p = 0.08) and administration of chemoradiotherapy after resection (p = 0.06) might be associated with improved overall survival. Conclusions In selected patients, resection of NCRNE liver metastases can be done safely with survival similar to CR metastases. Delay of liver resection for at least 6 months and treatment with chemoradiotherapy after resection might be associated with improved longterm survival after partial hepatectomy.
Abstract Background Sepsis-induced cardiomyopathy (SIC) is thought to be the result of detrimental effects of inflammatory mediators on the cardiac muscle. Here we studied the effects of prolonged ...(24 ± 4 h) exposure of adult rat ventricular myocytes (ARVM) to bacterial lipopolysaccharide (LPS) and inflammatory cytokines tumor necrosis factor (TNF) and interleukins-1 (IL-1) and IL-6. Materials and methods We measured sarcomere shortening (SS) and cellular calcium (Ca2+ ) transients (ΔCai , with fura-2 AM) in isolated cardiomyocytes externally paced at 5 Hz at 37°C. Results SS decreased after incubation with LPS (100 μg/mL), IL-1 (100 ng/mL), and IL-6 (30 ng/mL), but not with lesser doses of these mediators, or TNF (10–100 ng/mL). A combination of LPS (100 μg/mL), TNF, IL-1, and IL-6 (each 100 ng/mL; i.e., “Cytomix-100”) induced a maximal decrease in SS and ΔCai . Sarcoplasmic reticulum (SR) Ca2+ load (CaSR , measured with caffeine) was unchanged by Cytomix-100; however, SR fractional release (ΔCai /CaSR ) was decreased. Underlying these effects, Ca2+ influx into the cell (via L-type Ca2+ channels, LTCC) and Ca2+ extrusion via Na+ /Ca2+ exchange were decreased by Cytomix-100. SR Ca2+ pump (SERCA) (SR Ca2+ ATPase) was not affected. Conclusions Prolonged exposure of ARVM to a mixture of LPS and inflammatory cytokines inhibits cell contractility. The effect is mediated by the inhibition of Ca2+ influx via LTCC, and partially opposed by the inhibition of Na+ /Ca2+ exchange. Because both mechanisms are commonly seen in animal models of SIC, we conclude that prolonged challenge with Cytomix-100 of ARVM may represent an accurate in vitro model for SIC.
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