To provide a detailed phenotype/genotype characterization of Bietti crystalline dystrophy (BCD).
Observational case series.
Twenty patients from 17 families recruited from a multiethnic British ...population.
Patients underwent color fundus photography, near-infrared (NIR) imaging, fundus autofluorescence (FAF) imaging, spectral domain optical coherence tomography (SD-OCT), and electroretinogram (ERG) assessment. The gene CYP4V2 was sequenced.
Clinical, imaging, electrophysiologic, and molecular genetics findings.
Patients ranged in age from 19 to 72 years (median, 40 years), with a visual acuity of 6/5 to perception of light (median, 6/12). There was wide intrafamilial and interfamilial variability in clinical severity. The FAF imaging showed well-defined areas of retinal pigment epithelium (RPE) loss that corresponded on SD-OCT to well-demarcated areas of outer retinal atrophy. Retinal crystals were not evident on FAF imaging and were best visualized with NIR imaging. Spectral domain OCT showed them to be principally located on or in the RPE/Bruch's membrane complex. Disappearance of the crystals, revealed by serial recording, was associated with severe disruption and thinning of the RPE/Bruch's membrane complex. Cases with extensive RPE degeneration (N = 5) had ERGs consistent with generalized rod and cone dysfunction, but those with more focal RPE atrophy showed amplitude reduction without delay (N = 3), consistent with restricted loss of function, or that was normal (N = 2). Likely disease-causing variants were identified in 34 chromosomes from 17 families. Seven were novel, including p.Met66Arg, found in all 11 patients from 8 families of South Asian descent. This mutation appears to be associated with earlier onset (median age, 30 years) compared with other substitutions (median age, 41 years). Deletions of exon 7 were associated with more severe disease.
The phenotype is highly variable. Several novel variants are reported, including a highly prevalent substitution in patients of South Asian descent that is associated with earlier-onset disease. Autofluorescence showed sharply demarcated areas of RPE loss that coincided with abrupt edges of outer retinal atrophy on SD-OCT; crystals were generally situated on or in the RPE/Bruch's complex but could disappear over time with associated RPE disruption. These results support a role for the RPE in disease pathogenesis.
Background Ventilator-associated pneumonia (VAP) is characterized by neutrophils infiltrating the alveolar space. VAP is associated with high mortality, and accurate diagnosis remains difficult. We ...hypothesized that proteolytic enzymes from neutrophils would be significantly increased and locally produced inhibitors of human neutrophil elastase (HNE) would be decreased in BAL fluid (BALF) from patients with confirmed VAP. We postulated that in suspected VAP, neutrophil proteases in BALF may help identify “true” VAP. Methods BAL was performed in 55 patients with suspected VAP and in 18 control subjects. Isolation of a pathogen(s) at > 104 colony-forming units/mL of BALF dichotomized patients into VAP (n = 12) and non-VAP (n = 43) groups. Matrix metalloproteinases (MMPs), HNE, inhibitors of HNE, and tissue inhibitors of matrix metalloproteinases (TIMPs) were quantified. Plasminogen activator (PA) activity was estimated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and zymography. Results Neutrophil-derived proteases HNE, MMP-8, and MMP-9 were significantly increased in cell-free BALF from patients with VAP as compared with those without VAP (median values: HNE, 2,708 ng/mL vs 294 ng/mL, P < .01; MMP-8, 184 ng/mL vs 5 ng/mL, P < .01; MMP-9, 310 ng/mL vs 11 ng/mL, P < .01). HNE activity was also significantly increased in VAP (0.45 vs 0.01 arbitrary units; P < .05). In contrast, no significant differences were observed for protease inhibitors, TIMPs, or PAs. HNE in BALF, at a cutoff of 670 ng/mL, identified VAP with a sensitivity of 93% and specificity of 79%. Conclusions Neutrophil proteases are significantly elevated in the alveolar space in VAP and may contribute to pathogenesis. Neutrophil proteases appear to have potential in suspected VAP for distinguishing true cases from “non–VAP” cases.
To describe the phenotypic presentation of a cohort of individuals with homozygous disease-associated ABCA4 variants.
Retrospective case series.
Eighteen affected individuals from 13 families ...ascertained from a total cohort of 214 families with ABCA4-related retinal disease presenting to a single center.
A detailed history was obtained, and color fundus photography, autofluorescence (AF) imaging, optical coherence tomography (OCT), and electrophysiologic assessment were performed. Phenotypes based on ophthalmoscopy, AF, and electrophysiology were assigned using previously reported characteristics. ABCA4 mutation detection was performed using the ABCR400 microarray (Asper Biotech, Tartu, Estonia) and high-throughput DNA sequencing, with direct sequencing used to assess segregation.
Detailed clinical, electrophysiologic, and molecular genetic findings.
Eleven disease-associated homozygous ABCA4 alleles were identified, including 1 frame shift, 2 stops, 1 intronic variant causing splice-site alteration, 2 complex missense variants, and 5 missense variants: p.Glu905fsX916, p.Arg1300X, p.Gln2220X, c.4253+4 C>T, p.Leu541Pro and p.Ala1038Val (homozygosity for complex allele), p.Val931Met and p.Arg1705Gln (complex allele), p.Arg212Cys, p.Cys1488Arg, p.Arg1640Trp, p.Gly1961Glu, and p.Leu2027Phe. Eight of these 11 homozygous alleles have not been reported previously. Six of 7 patients with homozygous null alleles had early-onset (<10 years) disease, with all 7 having a severe phenotype. Two patients with homozygous missense variants (p.Leu541Pro and p.Ala1038Val complex, and p.Arg1640Trp) presented with a severe phenotype. Three patients with homozygous p.Gly1961Glu had adult-onset disease and a mild phenotype. One patient with homozygous p.Leu2027Phe showed a spared fovea and preserved visual acuity.
The phenotypes represented in patients identified as homozygous for presumed disease-associated ABCA4 variants gives insight into the effect of individual alleles. Null alleles have severe functional effects, and certain missense variants are similar to nulls, suggesting complete abrogation of protein function. The common alleles identified, p.Gly1961Glu and p. Leu2027Phe, both have a mild structural and functional effect on the adult retina; the latter is associated with relatively retained photoreceptor architecture and function at the fovea.
The use of large, pulsatile left ventricular assist devices (LVADs) has been limited in women because of their small body size.
We compared the survival outcomes, quality of life, and adverse events ...in 465 patients (104 women, 361 men) with advanced systolic heart failure in their first 18 months of support with the HeartMate II (Thoratec Corp, Pleasanton, CA) continuous-flow LVAD for bridge to transplantation.
During the first 18 months, there were no differences in survival between women and men while on LVAD support (73% ± 3% vs 73% ± 5%, p = 0.855) but fewer women (40%) underwent heart transplantation than did men (55%; p = 0.001). More women continued on support after 18 months (p = 0.007). Median duration of support was 238 days for women and 184 days for men (p = 0.003). Mortality was 20% for women and 19% for men (p = 0.89). Adverse events were similar, with the exception of hemorrhagic stroke, which occurred more frequently in women (0.10 vs 0.04 events/patient-year, p = 0.02), and device-related infections, which occurred less frequently in women (0.23 vs 0.44, p = 0.006). Functional capacity and quality of life at 6 months improved significantly in women and men.
Continuous-flow left ventricular assistance as a bridge to transplantation is associated with similar survival rates in women and men. Differences observed in higher stroke rates and fewer infections among women require further study.
Heart and lung transplant recipients have among of the highest incidence rates of post-transplant lymphoproliferative disease (PTLD). Despite this, there is a paucity of data specific to this group. ...We collated data on heart, lung and heart-lung transplant recipients with PTLD to identify disease features and prognostic factors unique to this group of patients.
Seventy cases of PTLD were identified from a single institution (41 heart, 22 lung, 6 heart-lung and 1 heart-kidney transplant) from 1984 to 2013. Demographics, immunosuppression, treatment, response, complications and survival data were analyzed. Uni- and multivariate Cox regression analyses were performed to identify prognostic factors.
The incidence of PTLD was 7.59% in heart-lung, 5.37% in heart and 3.1% in lung transplant recipients. Extranodal disease (82%) with diffuse large B-cell lymphoma (72%) was the most common presentation. Bone marrow involvement (13%) and central nervous system disease (3%) were uncommon. Heart transplant recipients had later onset of PTLD (>1 year post-transplant), with less allograft involvement, compared with lung and heart-lung recipients. Poor prognostic markers were bone marrow involvement (HR 6.75, p < 0.001) and serum albumin <30 g/liter (HR 3.18, p = 0.006). Improved survival was seen with a complete response within 3 months of treatment (HR 0.08, p < 0.001). Five-year overall survival was 29%.
This analysis is the largest to date on PTLD in heart and lung transplant recipients. It provides a detailed analysis of the disease in this group of patients and identifies unique prognostic features to aid risk stratification and guide treatment allocation.
Enhanced S-cone syndrome (ESCS), also known as Goldmann-Favre syndrome, is a progressive retinal degeneration that frequently presents with night blindness and nummular pigment clumping around the ...vascular arcades and is caused by recessive mutations in the photoreceptor-specific NR2E3 transcription factor. A unique feature of this disease is the development of retinoschisis of the macula. This study used fine anatomic and functional assessments within this region to determine whether the loss of retinal function was due to progressive schisis or a primary photoreceptor loss, similar to other rod-cone dystrophies.
Cross-sectional, prospective study.
Nine probands (n=18 eyes) and 3 controls (n=6 eyes) were studied at Moorfields Eye Hospital in London, United Kingdom.
Histories were obtained and visual acuity was measured using Early Treatment Diabetic Retinopathy Study protocol. Autofluorescence (AF), fundus photography, and spectral domain optical coherence tomography (OCT) imaging were co-registered to detailed microperimetry (Nidek MP1; NAVIS software version 1.7.2; Nidek Technologies, Padova, Italy) data for statistical analysis.
Retinal sensitivity (decibels) in a customized test grid of the macula; retinal structure assessed with OCT and AF.
Patients were divided into 3 cohorts roughly based on life span and documentation of schisis: (1) no schisis, childhood; (2) macular schisis, young adults; (3) resolved schisis, older adults. Retinal sensitivity was significantly attenuated in those with schisis and did not recover in those whose schisis had resolved despite retinal thickness comparable to that of controls. All probands exhibited loss of AF peripherally (and corresponding loss of retinal sensitivity), but there was relative preservation of AF within the macula.
Development of macular retinoschisis in ESCS is an important feature of the disease and contributes to attenuated retinal sensitivity that persists after resolution of retinoschisis. The central macula appears to be compromised more by foveoschisis than photoreceptor loss. In contrast, the peripheral retina (ordinarily a rod-rich region) is affected early in the disease process and degenerates rapidly because of photoreceptor loss. Thus, 2 distinct mechanisms of retinal degeneration may exist in ESCS, corresponding to regions of the retina that may experience either normal or abnormal photoreceptor development.
Abstract Objective Accurate and complete long-term postoperative outcome data are critical to improving value in health care delivery. The Society for Vascular Surgery Vascular Quality Initiative ...(VQI) is an important tool to achieve this goal in vascular surgery. To improve on the capture of long-term outcomes after vascular surgery procedures for patients in the VQI, we sought to match VQI data to Medicare claims for comprehensive capture of major clinical outcomes in the first several years after vascular procedures. Methods Patient and procedure characteristics for abdominal aortic aneurysm procedures captured in the Society for Vascular Surgery VQI between January 1, 2002, and December 31, 2013, were matched to Medicare claims data using an indirect identifier methodology. Late outcomes captured in the VQI and in Medicare claims were compared. Results Matching procedures yielded 9895 endovascular aneurysm repair (EVAR) patients (82.4% of eligible VQI patients) and 3405 open aneurysm repair (OAR) patients (74.4% of eligible). Comparison of patients who did and did not match to a Medicare claim demonstrated similar patient and procedure characteristics. Evaluation of late outcomes revealed good patient-level agreement on mortality for both EVAR (κ, 0.64) and OAR (κ, 0.82). Postoperative reintervention rates demonstrated lower agreement for both EVAR (κ, 0.26) and OAR (κ, 0.16). Conclusions This work demonstrates the feasibility of an algorithm using indirect identifiers to match VQI patients and procedures to Medicare claims data. The refinement of this strategy will focus on establishing and improving algorithms related to identifying and categorizing late events after EVAR and may serve as a mechanism to ensure that the best quality follow-up information is achieved within the VQI.
Objectives To determine if nephrolithiasis-associated atherosclerosis has pediatric origins and to consider possible association between kidney stones and atherosclerosis-related proteins. Study ...design We matched children aged 12-17 years with kidney stones and without kidney stones. Carotid artery intima-media thickness (cIMT) was measured by ultrasound. Participants' urine was investigated by enzyme-linked immunosorbent assay for the atherosclerosis-related proteins fibronectin 1, macrophage scavenger receptor 1, osteopontin, and vascular cell adhesion molecule 1 levels, and normalized to urine creatinine levels. Results Subjects with nephrolithiasis had higher cIMT in the right common carotid artery and overall mean measurement. Urine osteopontin and fibronectin 1 were significant predictors of cIMT. Conclusions We have provided initial preliminary evidence that nephrolithiasis-associated atherosclerosis has pediatric origins and performed studies that begin to identify potential reasons for the association of nephrolithiasis and vascular disease.
Background Respiratory syncytial virus (RSV) is a major health care burden with a particularly high worldwide morbidity and mortality rate among infants. Data suggest that severe RSV-associated ...illness is in part caused by immunopathology associated with a robust type 2 response. Objective We sought to determine the capacity of RSV infection to stimulate group 2 innate lymphoid cells (ILC2s) and the associated mechanism in a murine model. Methods Wild-type (WT) BALB/c, thymic stromal lymphopoietin receptor (TSLPR) knockout (KO), or WT mice receiving an anti-TSLP neutralizing antibody were infected with the RSV strain 01/2-20. During the first 4 to 6 days of infection, lungs were collected for evaluation of viral load, protein concentration, airway mucus, airway reactivity, or ILC2 numbers. Results were confirmed with 2 additional RSV clinical isolates, 12/11-19 and 12/12-6, with known human pathogenic potential. Results RSV induced a 3-fold increase in the number of IL-13–producing ILC2s at day 4 after infection, with a concurrent increase in total lung IL-13 levels. Both thymic stromal lymphopoietin (TSLP) and IL-33 levels were increased 12 hours after infection. TSLPR KO mice did not mount an IL-13–producing ILC2 response to RSV infection. Additionally, neutralization of TSLP significantly attenuated the RSV-induced IL-13–producing ILC2 response. TSLPR KO mice displayed reduced lung IL-13 protein levels, decreased airway mucus and reactivity, attenuated weight loss, and similar viral loads as WT mice. Both 12/11-19 and 12/12-6 similarly induced IL-13–producing ILC2s through a TSLP-dependent mechanism. Conclusion These data demonstrate that multiple pathogenic strains of RSV induce IL-13–producing ILC2 proliferation and activation through a TSLP-dependent mechanism in a murine model and suggest the potential therapeutic targeting of TSLP during severe RSV infection.
Abstract Background A limitation of aspirin is that some patients, particularly those with diabetes, may not have an optimal antiplatelet effect. Objectives The goal of this study was to determine if ...oral bioavailability mediates nonresponsiveness. Methods The rate and extent of serum thromboxane generation and aspirin pharmacokinetics were measured in 40 patients with diabetes in a randomized, single-blind, triple-crossover study. Patients were exposed to three 325-mg aspirin formulations: plain aspirin, PL2200 (a modified-release lipid-based aspirin), and a delayed-release enteric-coated (EC) aspirin. Onset of antiplatelet activity was determined by the rate and extent of inhibition of serum thromboxane B2 (TXB2 ) generation. Aspirin nonresponsiveness was defined as a level of residual serum TXB2 associated with elevated thrombotic risk (<99.0% inhibition or TXB2 >3.1 ng/ml) within 72 h after 3 daily aspirin doses. Results The rate of aspirin nonresponsiveness was 15.8%, 8.1%, and 52.8% for plain aspirin, PL2200, and EC aspirin, respectively (p < 0.001 for both comparisons vs. EC aspirin; p = 0.30 for comparison between plain aspirin and PL2200). Similarly, 56% of EC aspirin–treated subjects had serum TXB2 levels >3.1 ng/ml, compared with 18% and 11% of subjects after administration of plain aspirin and PL2200 (p < 0.0001). Compared with findings for plain aspirin and PL2200, this high rate of nonresponsiveness with EC aspirin was associated with lower exposure to acetylsalicylic acid (63% and 70% lower geometric mean maximum plasma concentration and 77% and 82% lower AUC0–t area under the curve from time 0 to the last time measured) and 66% and 72% lower maximal decrease of TXB2 , with marked interindividual variability. Conclusions A high proportion of patients treated with EC aspirin failed to achieve complete inhibition of TXB2 generation due to incomplete absorption. Reduced bioavailability may contribute to “aspirin resistance” in patients with diabetes. (Pharmacodynamic Evaluation of PL2200 Versus Enteric-Coated and Immediate Release Aspirin in Diabetic Patients; NCT01515657 )
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