Fundus autofluorescence in patients with age-related macular degeneration and high risk of visual loss

PURPOSE: To describe fundus autofluorescence (AF) patterns and their change over time in patients with age-related macular degeneration (AMD) and high risk of visual loss participating in the drusen laser study (DLS). DESIGN: Randomized clinical trial. METHODS: The study population consisted of 29 patients (35 eyes) participating in the DLS, which is a prospective, randomized, controlled clinical trial of prophylactic laser therapy in patients with AMD and high risk of neovascular complications. The intervention consisted of 16 eyes having prophylactic laser and 19 receiving no treatment. The main outcome measures were changes in the distribution of drusen and AF. Patients were reviewed for a median follow-up or 24 months (range 12-36 months). RESULTS: At baseline, four patterns of fundus AF were recognized: focal increased AF (n = 18), reticular AF (n = 3), combined focal and reticular AF (n = 2), and homogeneous AF (n = 12). At last follow-up, fundus AF remained unchanged in 15 untreated (78%) and in seven treated (43%) eyes. In only one untreated eye, focal areas of increased AF returned to background levels and were no longer detectable at last follow-up, compared with six treated eyes. This difference was statistically significant (P =.03). Only large foveal soft drusen (drusenoid pigment epithelium detachments) consistently corresponded with focal changes in AF, whereas no obvious correspondence was found between small soft drusen located elsewhere and changes in AF. CONCLUSION: The lack of obvious correspondence between the distribution of drusen and of AF found in this study appears to indicate that drusen and AF represent independent measures of aging in the posterior pole.     

Left ventricular mass in dippers and nondippers with newly diagnosed hypertension

Hypertensive subjects can be subdivided into 2 groups, dippers and nondippers, according to the presence or the lack of a nocturnal fall of blood pressure of more than 10%. Several studies have investigated cardiac organ damage in the 2 groups with discordant results, but they included subjects with different onset, severity, and treatment of hypertension. The authors selected 23 dippers and 17 nondippers affected by newly (< 1 year) diagnosed grades 1 and 2 hypertension, never treated, who underwent 24-hour ambulatory blood pressure monitoring and M-mode echocardiography. They did not find significant differences between the 2 groups as regards the echocardiographic left ventricular and atrial dimensions or regarding the left ventricular mass, left ventricular mass index, or relative wall thickness. Also no significant differences were found in the rate of either left ventricular remodeling or left ventricular hypertrophy. These data suggest that nondipping status is not associated with a higher level of cardiac involvement in the early phases of hypertension compared to dipping status.     

Epidermal growth factor receptor activation: how exon 19 and 21 mutations changed our understanding of the pathway.

The discovery of epidermal growth factor receptor (EGFR) mutations in never-smokers has been the most relevant finding ever in non-small cell lung cancer. When patients whose tumors bear the sensitizing mutations are treated with the tyrosine kinase inhibitors gefitinib or erlotinib, we witness response rates and durations never before reported, including complete responses. At the same time, the presence of EGFR mutations has raised numerous new questions, tantalizing data, and new challenges for treatment. This is particularly true as we try to generalize the findings in lung cancer to other malignancies. The indiscriminate use of gefitinib or erlotinib in the general lung cancer population results in meager survival benefit for patients. Similarly, the tyrosine kinase inhibitors have limited activity in a variety of tumor types with EGFR overexpression. This has led to the question of whether EGFR remains a viable target in patients other than those whose tumors contain mutations, and whether the modest activity of cetuximab in colorectal cancer and head and neck cancer represents all that we can expect from inhibition of this pathway in the absence of mutation. Mechanisms of pathway activation other than mutation have been discovered in recent years, and include overexpression mediated by gene amplification or by amplification of a dinucleotide repeat in the EGFR promoter, mutation of an extracellular region on EGFR generating a mutant protein termed EGFRvIII, and enhanced signaling due to heterodimerization with other members of the EGFR family, particularly overexpression of HER2/HER3. The extent to which these paths to EGFR activation will confer sensitivity to the tyrosine kinase inhibitors or to EGFR monoclonal antibodies is being explored. Thus far, published clinical data suggest that there is little room for the administration of gefitinib or erlotinib in the absence of EGFR mutations. The five articles in this edition of CCR Focus will address the various mechanisms of EGFR pathway activation and provide insight into the potential for translation into clinical relevance.     

Tumor angiogenesis is associated with plasma levels of stromal-derived factor-1alpha in patients with multiple myeloma.

PURPOSE: Multiple myeloma is an incurable hematologic malignancy characterized by increased bone marrow angiogenesis and extensive lytic bone disease. We have previously shown that elevated levels of stromal-derived factor-1alpha (SDF-1alpha) in peripheral blood plasma are associated with osteolysis in multiple myeloma patients. We have now examined whether SDF-1alpha levels also correlate with angiogenesis. EXPERIMENTAL DESIGN: We examined the contribution of multiple myeloma plasma cell-derived SDF-1alpha in the stimulation of in vitro angiogenesis using a tube formation assay. We also collected trephine and peripheral blood plasma samples from patients with multiple myeloma to analyze microvessel density and SDF-1alpha levels, respectively. RESULTS: We show that multiple myeloma plasma cell line-derived conditioned medium containing SDF-1alpha stimulates in vitro angiogenesis. In addition, in a large cohort of patients with multiple myeloma and its precursor condition monoclonal gammopathy of undetermined significance, we confirm previous findings that plasma cell burden correlates with both angiogenesis and plasma levels of SDF-1alpha. We now extend these observations and show the novel finding that peripheral blood plasma levels of SDF-1alpha positively correlate with the degree of bone marrow angiogenesis in multiple myeloma and monoclonal gammopathy of undetermined significance patients. CONCLUSIONS: High levels of SDF-1alpha produced by multiple myeloma plasma cells promote osteolysis and bone marrow angiogenesis. Therefore, we propose that inhibition of SDF-1alpha may be an effective mechanism by which angiogenesis and osteolysis can be reduced in multiple myeloma patients.     

Demarcation laser therapy in the management of macular-sparing persistent subretinal fluid after scleral buckling procedures

Background Persistent or recurrent macular-sparing subretinal fluid (SRF) can sometimes occur following scleral buckling procedures. Observation and reoperation have been used in the management of such cases. Demarcation laser therapy (DLT) has been used to treat macular-sparing retinal detachments in the context of cytomegalovirus retinitis and as primary treatment for selected rhegmatogenous retinal detachments. There are, however, scarce data in the literature regarding its use following primary scleral buckling procedures. The current study explores the use of DLT under the latter circumstances.Methods The medical records of all consecutive patients with persistent SRF sparing the macula following primary rhegmatogenous retinal detachment repair using a scleral buckling procedure were retrospectively reviewed. Only those patients in whom the breaks were localised to the area of indentation and, thus, seemed to be well supported by the buckle were included. Demographics, clinical characteristics of the retinal detachment prior to scleral buckling, extension of the residual SRF observed postoperatively, details of the laser procedure, anatomical and functional outcomes and complications were evaluated.Results Seven patients, all females, with a mean age of 47.9 years (range: 20–81) were included in the study. The retinal detachments were superior (n=3), inferior (n=3) and subtotal, affecting both superior and inferior retina (n=1). Scleral buckling procedures were used to treat the retinal detachments in all cases. Following demarcation laser therapy, the area of SRF remained stable in two patients, and flattened in four. In one patient, extension of SRF occurred requiring further surgery.Conclusions Demarcation laser therapy appears to be a reasonable option in the management of patients with persistent or recurrent SRF sparing the macula following scleral buckling surgery.The authors do not have any proprietary interests in the products or methods utilised in this study     

Ultrastructure of supraspinal dorsal root projections in the toads. I. The obex region

The ultrastructure of the dorsal column nucleus (DCN) has been investigated at the level of the obex region in normal and experimental toads. Large 'isolated' neurons (greater than 20 micrometer) and clusters of small neurons (less than 20 micrometer) have been identified in this region. Synaptic profiles have been classified into three types: large 'en passant' LR boutons, containing round synaptic vesicles and neurofilaments, small R boutons with round vesicles and F boutons with pleomorphic vesicles. The axon terminals exhibited synaptic contacts with cell somata, with dendrites of varying calibers and with other axons. The terminals involved in the axo-axonic contact were the F boutons which were presynaptic to the LR boutons, thus representing the morphological basis for presynaptic inhibition. Transection of the second dorsal root was performed in order to identify the terminals of the primary afferents to the DCN, after different survival periods (16 h--50 days). Only the LR boutons underwent degeneration, thus representing the central endings of the primary dorsal root afferents. The functional significance of these findings was discussed.     

Mammalian cell invasion and intracellular trafficking by Trypanosoma cruzi infective forms

Trypanosoma cruzi, the etiological agent of Chagas disease, occurs as different strains or isolates that may be grouped in two major phylogenetic lineages: T. cruzi I, associated with the sylvatic cycle and T. cruzi II, linked to the human disease. In the mammalian host the parasite has to invade cells and many studies implicated the flagellated trypomastigotes in this process. Several parasite surface components and some of host cell receptors with which they interact have been identified. Our work focused on how amastigotes, usually found growing in the cytoplasm, can invade mammalian cells with infectivities comparable to that of trypomastigotes. We found differences in cellular responses induced by amastigotes and trypomastigotes regarding cytoskeletal components and actin-rich projections. Extracellularly generated amastigotes of T. cruzi I strains may display greater infectivity than metacyclic trypomastigotes towards cultured cell lines as well as target cells that have modified expression of different classes of cellular components. Cultured host cells harboring the bacterium Coxiella burnetii allowed us to gain new insights into the trafficking properties of the different infective forms of T. cruzi, disclosing unexpected requirements for the parasite to transit between the parasitophorous vacuole to its final destination in the host cell cytoplasm.