The association of geographic atrophy and decreased renal function in patients with age-related macular degeneration.

PurposeThe purpose of the study was to investigate the association between area and presence of geographic atrophy (GA) and renal function, as measured by glomerular filtration rate (GFR).Patients and methodsWe retrospectively identified patients aged 50-90 years who were assigned an ICD-9 diagnosis code for age-related macular generation (AMD) between January 2012 and January 2016. Patients met inclusion criteria if they had at least one macular spectral domain optical coherence tomography volume scan, one provider note, and one GFR value in the electronic medical record. Images were evaluated for the presence of GA, area of GA, drusen, and subretinal drusenoid deposits (SDD) and for subfoveal choroidal thickness (CTh) by standard criteria. Imaging findings were correlated with the most recent GFR from the patient's chart.ResultsWe identified 107 patients who met our inclusion criteria (mean age=74 years, range 50-90 years). Overall, we found a significant correlation between the presence of GA and reduced GFR (P=0.002), which was maintained even after accounting for age and other confounders. No association between GFR and GA area was found. CTh was significantly lower in patients with GA (P=0.038) and those with decreased GFR (P=0.004). Within the SDD-positive population, GA was associated with reduced GFR (P=0.007) but only trended toward significance after controlling for age.ConclusionOur study findings demonstrate an association between impaired renal function and the presence, but not area, of GA within an AMD population. These findings may shed light on common pathogenic mechanisms for these two diseases.

Optimisation of an automated drusen-quantifying software for the analysis of drusen distribution in patients with age-related macular degeneration.

PURPOSE: The purpose of this study is to optimise the settings of the Retinal Image Analysis Laboratory (RIALAB), a semi-automatic drusen quantification software, in planning for high-throughput quantification of drusen in clinical studies of age-related macular degeneration (AMD). PATIENTS AND METHODS: A comparison of five different settings in RIALAB was made on 67 images from the Rotterdam eye study (population-based study) and 56 images from the fellow eye of patients with active neovascular AMD in King's College Hospital, London (hospital-based study). RESULTS: The 'Few Outer' setting was the best setting, with it being most appropriate for 52 (77.6%) of the Rotterdam cohort and 47 (83.9%) for the London cohort. Pearson's χ(2)-test revealed both results to be statistically significant (P<0.0001). CONCLUSIONS: RIALAB is a viable algorithm and software package that can detect, quantify, and analyse drusen efficiently in both population-based and hospital-based studies. We have shown that the 'Few Outer' drusen setting can be employed as the default setting, with fine-tuning only needed in a minority of cases, thus helping to speed up workflow.

In vivo snapshot hyperspectral image analysis of age-related macular degeneration.

Drusen, the hallmark lesions of age related macular degeneration (AMD), are biochemically heterogeneous and the identification of their biochemical distribution is key to the understanding of AMD. Yet the challenges are to develop imaging technology and analytics, which respect the physical generation of the hyperspectral signal in the presence of noise, artifacts, and multiple mixed sources while maximally exploiting the full data dimensionality to uncover clinically relevant spectral signatures. This paper reports on the statistical analysis of hyperspectral signatures of drusen and anatomical regions of interest using snapshot hyperspectral imaging and non-negative matrix factorization (NMF). We propose physical meaningful priors as initialization schemes to NMF for finding low-rank decompositions that capture the underlying physiology of drusen and the macular pigment. Preliminary results show that snapshot hyperspectral imaging in combination with NMF is able to detect biochemically meaningful components of drusen and the macular pigment. To our knowledge, this is the first reported demonstration in vivo of the separate absorbance peaks for lutein and zeaxanthin in macular pigment.

An interinstitutional comparative study and validation of computer aided drusen quantification.

AIMS: To assess the portability and clinical applicability of a software program based on Photoshop (Adobe Systems Inc, San Jose, CA, USA) for digital drusen quantification. METHODS: Independent graders from the Digital Fundus Photo Reading Center of Columbia University and King's College Hospital used macular background levelling software to quantify the percentage of drusen in the central and middle Wisconsin subfields. 100 images of consecutive patients with choroidal neovascularisation in one eye and significant drusen in the other eye were analysed to determine suitability, and 10 were chosen for assessment by this software. RESULTS: Of the 10 images used in the interinstitutional validation, the random effects ANOVA for the central and middle subfields showed a high degree of interobserver agreement. The ICC for interobserver reliability was 0.83 (95% CI: 67 to 95) for the central subfield and 0.84 (95% CI: 69 to 99) for the middle subfield. Overall agreement with the manual grading results was good and the within patient coefficient of variation was about 20% for all the pairwise comparisons between observers and the manual stereo gradings. Of the 100 images used to assess practical applicability of the software, 79 were suitable for semiautomated analysis. 13 had extensive mixed retinal pigment epithelial (RPE) changes limiting drusen identification, five had a significant number of reticular drusen, which are poorly identified by the software, and three had multiple small areas of RPE atrophy, which are difficult to distinguish from drusen. CONCLUSIONS: The software was successfully used by two institutions demonstrating portability, with good correlation between graders and to the manual stereo grading. Digital drusen quantification was possible in 79% of the images analysed.

A method of drusen measurement based on reconstruction of fundus background reflectance.

BACKGROUND: The hallmarks of age related macular degeneration (AMD) are the subretinal deposits known as drusen. Current manual methods of drusen segmentation and quantification are laborious and subjective. The authors introduced a digital method and tested it for accuracy and reliability. METHODS: Fourteen eyes with drusen were selected. The authors digitally reconstructed the macular background using normal background areas ("dots") fitted to quadratic polynomials in two zones. The model was used to level the reflectance for the purpose of segmenting drusen by a global threshold. Measurements of drusen areas were compared with those of a semi-automated background levelling technique and manual drawings from stereo pairs. RESULTS: Intraobserver reproducibility had standard deviations from 0.1% to 4.1%. Interobserver reproducibility yielded 95% limits of agreement of -2.7% to 6.3%. The dots method compared with manual drawings and with the semi-automated method had 95% limits of agreement of -8.3% to 2.8% and -7.1% to 4.8%, respectively. CONCLUSIONS: The dots method was reproducible and accurate with respect to validated methods. It provided less total operating time and greater precision than that of standard fundus photo grading. With implementation of commercial software, this technique for macular image analysis has potential for use in clinical research.

Evaluation of the ARMD1 locus on 1q25-31 in patients with age-related maculopathy: genetic variation in laminin genes and in exon 104 of HEMICENTIN-1.

The age-related maculopathy (ARM) genetics program at Columbia University utilizes comprehensive genetic analysis of candidate genes in large case-control studies to determine genotypes associated with the ARM complex trait. Genes encoding laminins, a class of extracellular matrix proteins, represent attractive candidates for two reasons. First, the presence of laminins in the basal lamina of the retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris suggests a possible role in the pathophysiology of ARM. Second, three laminin genes, LAMC1, LAMC2, and LAMB3, are located in the 1q25-31 region, within the previously mapped ARMD1 locus. The entire open reading frame of the three laminin genes was screened for variants by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing in at least 92, and up to 368 ARM patients and matched unaffected controls. Sixty-nine sequence variants were detected in the 69 exons of the LAMC1, LAMC2, and LAMB3 genes. Screening of exon 104 of the recently proposed ARMD1 gene, HEMICENTIN-1, residing in the 1q25-31 locus, did not detect the suggested causal variant, Q5345R, in 632 study subjects. Overall, we did not find statistically significant differences in the frequency of variants between ARM-affected individuals and age-matched controls. Four rare, non-synonymous, variants were detected in single cases of ARM patients. Our data on relatively limited numbers of study subjects do not suggest a significant role for genetic variation in the three laminin genes and in exon 104 of HEMICENTIN-1 in predisposing individuals to ARM. However, as in many instances in similar studies, involvement of rare amino acid-changing variants in a fraction of ARM cannot be ruled out.

Bone-loading response varies with strain magnitude and cycle number.

Mechanical loading stimulates bone formation and regulates bone size, shape, and strength. It is recognized that strain magnitude, strain rate, and frequency are variables that explain bone stimulation. Early loading studies have shown that a low number (36) of cycles/day (cyc) induced maximal bone formation when strains were high (2,000 microepsilon) (Rubin CT and Lanyon LE. J Bone Joint Surg Am 66: 397-402, 1984). This study examines whether cycle number directly affects the bone response to loading and whether cycle number for activation of formation varies with load magnitude at low frequency. The adult rat tibiae were loaded in four-point bending at 25 (-800 microepsilon) or 30 N (-1,000 microepsilon) for 0, 40, 120, or 400 cyc at 2 Hz for 3 wk. Differences in periosteal and endocortical formation were examined by histomorphometry. Loading did not stimulate bone formation at 40 cyc. Compared with control tibiae, tibiae loaded at -800 microepsilon showed 2.8-fold greater periosteal bone formation rate at 400 cyc but no differences in endocortical formation. Tibiae loaded at -1,000 microepsilon and 120 or 400 cyc had 8- to 10-fold greater periosteal formation rate, 2- to 3-fold greater formation surface, and 1-fold greater endocortical formation surface than control. As applied load or strain magnitude decreased, the number of cyc required for activation of formation increased. We conclude that, at constant frequency, the number of cyc required to activate formation is dependent on strain and that, as number of cyc increases, the bone response increases.

Time course for bone formation with long-term external mechanical loading.

Increased mechanical loading of bone with the rat tibia four-point bending device stimulates bone formation on periosteal and endocortical surfaces. With long-term loading cell activity diminishes, and it has been reported that early gains in bone size may reverse. This study examined the time course for bone cellular and structural response after 6, 12, and 18 wk of loading at 1,200-1, 700 microstrain (muepsilon). Bone formation rates, measured by histomorphometry, were compared within groups, between loaded and contralateral nonloaded tibiae, and between weeks. Formation surface, mineral apposition rate, and bone formation rate on periosteal and endocortical surfaces were elevated after 6 wk of loading. By 12 wk of loading, periosteal and endocortical formation surface and endocortical mineral apposition rates were elevated. By 18 wk of loading, periosteal adaptation appeared complete, whereas endocortical mineral apposition rate remained elevated. No periosteal resorption was observed. Average thickness of new bone formed, from baseline to collection, was greater in loaded than nonloaded tibiae by week 6 and was maintained through week 18. Early increases in bone formation result in periosteal apposition of new bone that persists after formation ceases.

Purified donor T cells alone activate transplantation immunity to the male antigen but induce tolerance in combination with Mac-1+ donor cells.

BACKGROUND: In most experimental systems examined, "professional" antigen-presenting cells (APCs), such as dendritic cells, have been found to activate T cells, whereas "nonprofessional" antigen-bearing cells (nonAPC) may induce tolerance. Some recent studies have suggested that nonAPCs may under certain conditions prime a T-cell immune response. We have attempted to separate the roles of transplanted T cells and monocytic/dendritic cells in activating or tolerizing antigen-specific T cells in vivo, by examining the consequences of parenteral exposure to male antigen in anti-male TCR transgenic female mice. METHODS: Qualitative and quantitative changes in the large population of male-reactive transgenic T cells to various male donor cell populations in transgenic female mice were followed after injections of highly purified male lymphoid cells. Changes in male-reactive T cells with time and the long-term outcome of male skin grafts were measured. RESULTS: When a nonAPC population consisting of highly purified male T cells alone was injected intravenously into H-Y antigen-specific TCR transgenic female mice, the number of host transgenic T cells was sustainably increased, and male graft rejection was accelerated. Injection of a combination of purified T cells and purified Mac-l+ cells induced massive and permanent deletion of the host male-reactive T-cell population and permanent graft tolerance. Mac-l+ cells alone gave no appreciable change in responsive T cells or graft rejection times. CONCLUSIONS: The data indicate that highly purified T cells engrafted alone induce rapid sensitization toward the male antigen. They also show that both male donor T cells and a population of male monocytic/ dendritic cells are required to induce peripheral tolerance toward this antigen and that this tolerance is related to permanent peripheral deletion of male-reactive T cells.

The personal experience of pregnancy for African-American women.

This study describes the personal experiences of pregnancy for African-American women. Data were obtained from two group interviews with four African-American nurse-midwives who had experienced pregnancy and had extensive professional experience in the provision of health care services to pregnant African Americans. Three major themes were constructed from the interview narratives. The first concerned the experience of pregnancy as a transition experience from childhood to adulthood and from womanhood to motherhood, involving heightened senses of maturity, self-esteem, and intimacy. The second identified stresses experienced by African-American women, including the lack of material resources and emotional support. The last theme concerned the provision of effective support in pregnancy. The significance of interpersonal relationships with the pregnant women's mothers, other significant women, and their partners was described. Implications for practice included suggestions for the provision of effective emotional support from health care professionals such as attentive listening and the elimination of environmental factors that communicate lowered personal value.

All or none peripheral tolerance induction in H-Y antigen-specific TCR transgenic mice.

In in vivo tolerance induction, the dose of tolerogen injected is generally linearly correlated to the length of tolerance induced. Small, medium and large doses are related to no, partial and long-term tolerance, respectively. However, even with injection of substantially large doses of tolerogen, the length of tolerance induced varies over a wide range. Most of the recipients can still reject donor grafts. In this study, it is shown that the linear dose-response can be altered into an all or nothing response in a H-Y antigen-specific TCR transgenic (Tg) mouse model. In thymectomized female Tg mice, injection of 3, 30 and 100 x 10(6) male spleen cells was correlated to no, partial and massive deletion of Tg (alpha T beta T) CD8 cells, respectively. When the thymectomized Tg mice were injected with 9 x 10(6) T cell-enriched (T+) male cells, one half of the recipients showed no deletion of alpha T beta T cells, and in the other half massive deletion occurred. In complete correlation with deletion, all male skin grafts were rejected in the undeleted group as PBS-injected controls, whereas with massive deletion they were indefinitely tolerized. Thus, partial deletion and partial tolerance can be avoided. Injection of 18 x 10(6) male T+ cells induced long-term tolerance in all the recipients. The all or none T cell deletion and long-term tolerance induction has not only significant implications in understanding the mechanism of peripheral tolerance induction, but also in tolerance induction in transplantation, gene therapy and the prevention and treatment of autoimmune diseases.

Prethymic expression of a transgenic TCR beta chain on a precursor of T-cells.

Mice carrying a rearranged TCR Vbeta 8.2 transgene express the Vbeta protein on the vast majority of peripheral T-cells. The bone marrow and peripheral blood, as well as other lymphoid organs of both untreated animals and animals depleted of T-cells by neonatal thymectomy and/or injection from birth of monoclonal anti-TCR antibodies, contain a small population of cells that express low levels of the Vbeta transgene product, but no T-cell or other detectable lineage-specific phenotypic markers. When such TG-bearing BM cells are purified and injected directly into the non-TG thymus, they show the phenotypic maturation sequences of intrathymic T-cell development and, subsequently, mature TG-bearing peripheral T-cells. However, this population failed to support long-term recovery from lethal irradiation. Both Vbeta 8.2 TG and CD3delta mRNA transcripts are strongly expressed in the cell population, but no CD3gamma, CD3epsilon, CD3zeta, CD4, CD8beta, pre-Talpha, or RAG-1 transcript was detected. The transgene-encoded TCR component is not bound to the cell membrane exclusively by a phosphatidylinositol linkage. The data show that the fully rearranged TCR transgene and transcripts for at least one of the associated CD3 components, CD3delta, can be expressed on a subpopulation of BM and PBL cells that has not passed through the thymus. The phenotypic characteristics of this cell population resemble those described for the earliest thymocyte described by others. The TG protein molecule in this model may provide a specific developmental marker for a prothymocyte lineage subset that lacks pluripotential properties.

Resource support and heart patient recovery.

This prospective study examines the effects of resources utilized by myocardial infarction (MI) and coronary artery bypass (BY) patients in the recovery process. The resource support model incorporates formal (institutionalized) and semi-formal (mutual aid) services along with informal assistance (social networks). Patient interview data were collected on 147 MI and 159 BY patients at hospitalization and at 3 months. Sociodemographic, illness and resource data were obtained, and hospital records were abstracted. Two outcomes were evaluated: activity limitations and work capacity. Bivariate and multivariate analyses were used to assess individual and resource effects. Multivariate analyses revealed that, for MI patients, a higher level of activity prior to hospitalization and a shorter hospital stay were significantly related to recovery. A smaller social network with greater frequency of contact enhanced recovery. For BY patients, recovery was significantly associated with higher social class higher level of activity prior to hospitalization and fewer health care visits. Outcome based on work capacity revealed that MI patients who were younger in age, male sex and who had fewer prescribed medications were more likely to recover. By patients had a similar pattern as that observed for MI patients in terms of age and sex. Co-morbidity had a negative effect on recovery. Those with less affective informal support were more likely to have recovered. The resource support model employed in this prospective study proved to have mixed results. However, the model may be a useful multifactorial framework for examining the effects on patient recovery over a longer duration.

A randomized trial of an empirically-derived social support intervention to prevent low birthweight among African American women.

Previous clinical trials of social support interventions to reduce low birthweight (LBW) have not fully capitalized on findings from social science research, and therefore have not used empirically-derived criteria to define a low social support population or to develop the intervention. To overcome limitations of previous studies, this randomized clinical trial tested the hypothesis that an empirically-derived social support intervention would reduce LBW among African American women. Based on prior work, African American women were identified as at-risk for LBW due to inadequate social support if they lacked support from their mothers or male partners. Focus groups were used in this study to develop a culturally-relevant intervention. Adult low-income African American pregnant women (n = 319) were tested for inadequate social support in mid-pregnancy. Of these, 114 (36%) low-support women were identified and randomly assigned to the intervention group (n = 56) or control group (n = 58). The intervention was designed to provide the support usually provided by the pregnant woman's mother or male partner. It consisted of four standardized face-to-face sessions at two week intervals and telephone contact in the intervening weeks. Birthweight was obtained blinded from charts or birth certificates, with 99% follow-up. The rate of LBW (below 2500 grams) was 9.1% in the intervention group compared to 22.4% in the control group (P < 0.05). Contrary to previous studies, this social support intervention was effective in reducing the rate of LBW. It is promising that this intervention was successful for African Americans because the rate of LBW is twice as high among African Americans than among Caucasians.

Case report: haemangiopericytoma of the oesophagus.

Haemangiopericytomas are rare, vascular soft tissue sarcomas typically located in the retroperitoneum, pelvis or lower extremities. To our knowledge this neoplasm within the oesophagus has not been reported previously. We present a patient with a haemangiopericytoma of the oesophagus and discuss the radiographic and pathological findings.

The barrier function in neodymium-YAG laser capsulotomy.

BACKGROUND: Complications following neodymium (Nd)-YAG laser capsulotomy have been attributed to damage to the capsule and vitreous face. OBJECTIVES: To measure the disruption of the anterior-posterior extracapsular barrier complex induced by Nd-YAG laser capsulotomy and to determine how it might be minimized, using a fluorophotometer. DESIGN: Prospective study of 21 eyes undergoing Nd-YAG laser capsulotomy and cross-sectional comparison with 15 pseudophakic eyes with clear capsules. SETTING: University-based clinical practice. INTERVENTION: Neodymium-YAG laser posterior capsulotomy per study protocol. MAIN OUTCOME MEASURE: Change in extracapsular barrier efficiency as measured by fluorophotometry. RESULTS: Multivariate regression demonstrated that both anterior vitreous disruption and absence of a posterior chamber intraocular lens (aphakia) were significantly correlated with loss of barrier efficiency, whereas capsulotomy size was not. The anterior vitreous was judged to be undamaged in 67% of eyes treated by the study protocol. However, all myopic eyes sustained damage. Opacification of the posterior capsule itself was also associated with mild loss of barrier function even before capsulotomy, compared with the clear-capsule group. Glaucoma occurred more frequently when barrier efficiency was lost postoperatively. CONCLUSION: Damage to the extracapsular barrier complex by Nd-YAG laser capsulotomy is minimized when the anterior vitreous is preserved. The study treatment protocol may be useful in limiting this damage and in reducing complications.

Cancer and the immune system.

Early expectations for control of cancer through immunologic intervention are still unrealized. Increased knowledge of tumor immunity has broadened the understanding of the tumor and host relationship. This article reviews the evidence for an immune response to tumors, tumor antigens, immunologic intervention in cancer, insufficiency of the immune system to eliminate tumor growth, and immunologic approaches to the diagnosis of tumors.

The evaluation of dual cement resins in orthodontic bonding.

Dual-cement resins are composite resins that are both light activated and chemically cured. They can be cured completely with a visible light source or by the catalyst and base reaction of the material. With the control of setting time, dual cements appear to offer clinicians advantages in orthodontic bonding. The purposes of the present research are to compare various dual cements in regard to orthodontic bonding and to evaluate them in relation to currently used chemically cured and light-cured composite resins for bonding stainless steel mesh-backed orthodontic brackets. Seven currently available orthodontic bonding systems (three light cured and four chemically cured) and three dual cements were evaluated. Each of the 10 groups contained 15 noncarious mandibular incisors. Mandibular incisor brackets were bonded to the teeth in accordance with the manufacturer's recommendation. After bonding, the teeth were stored for 5 days in water at 37 degrees C. An Instron machine (Instron Corp., Canton, Mass.) was used to test samples. All samples were compared with Concise orthodontic bonding composite (3M, St. Paul, Minn.). The results of this investigation show that it is possible to bond solid, mesh-backed metal orthodontic brackets to teeth with a dual cement. The shear bond strengths of the dual cements, as tested in the laboratory, should be adequate to withstand normal orthodontic forces. Increased control of the setting time of the dual cements will allow the clinician more time to correctly position brackets and to remove excess resin before curing. In addition, the clinician can be assured of complete polymerization with the chemical properties of the dual cement resins.

Diketocamphane enantiomer-specific 'Baeyer-Villiger' monooxygenases from camphor-grown Pseudomonas putida ATCC 17453.

Pseudomonas putida ATCC 17453 grew with either (+)- or (-)-camphor as sole carbon source. Enantiomer-specific 'biological Baeyer-Villiger' monooxygenases were synthesized irrespective of the camphor isomer used for growth. The two enzymes are probably the products of separate genes but showed many similarities. Each consisted of two electrophoretically identical subunits, bound flavin mononucleotide (FMN) non-covalently and accepted electrons from an induced NADH dehydrogenase which interacted with the FMN bound to the oxygenating component. They showed minor differences in M(r) with 3,6-diketocamphane 1,6-monooxygenase being the smaller enzyme. Isoelectric focussing showed the two enzymes to have different acidic pI values. Polyclonal antibodies raised against 3,6-diketocamphane 1,6-monooxygenase also cross-reacted with 2,5-diketocamphane 1,2-monooxygenase and its subunits.

Familial amyloidotic polyneuropathy presenting with carpal tunnel syndrome and a new transthyretin mutation, asparagine 70.

We report familial amyloidotic polyneuropathy in a pedigree of German ancestry residing in New Jersey. Eight affected subjects presented in the third to seventh decade with carpal tunnel syndrome (CTS) and one subject presented with vitreous opacification. Transmission was autosomal dominant and survival was prolonged. Affected subjects were heterozygous for a novel mutation in serum transthyretin (TTR), resulting in an asparagine for lysine substitution at residue 70 of the TTR monomer. We report two methods for rapid identification of the mutation based on the polymerase chain reaction. This pedigree further emphasizes the evolving phenotypic and genotypic heterogeneity of the transthyretinopathies. Familial or sporadic CTS or unexplained vitreous opacification suggest the possibility of TTR amyloidosis and should prompt a search for TTR mutations.