Feasibility and safety of biventricular repair in neonates with hypoplastic left heart complex.

Hypoplastic left heart syndrome is a spectrum of structural cardiac malformations characterized by variable underdevelopment of the left heart-aorta complex. A minority of patients having a milder degree of left ventricular hypoplasia, described as hypoplastic left heart complex (HLHC), may be selected for biventricular repair. The objective of this study was to assess the outcome of the biventricular approach in HLHC. We evaluated retrospectively 30 neonates diagnosed with HLHC from the "12 de Octubre" University Hospital, following established criteria. We analyzed the echocardiographic data recorded just after birth and at last follow-up after surgery. All patients were operated on in the neonatal period using various surgical techniques. There were no early deaths and only 1 late death after a mean follow-up of 62.9 ± 43.8 months. All patients presented a significant growth of the left ventricular structures, with a Z-score increase of 1.17 ± 1.05 for mitral annulus, 1.72 ± 1.23 for aortic annulus, and 1.33 ± 1.46 for left ventricular end-diastolic diameter. Postoperatively, 18 patients showed a left valvular stenosis, and 17 patients underwent a reoperation and/or an interventional procedure. Freedom from surgery or interventional catheterizations at 1, 3 and 5 years was 53, 49 and 43%, respectively. The 29 current survivors are all in a good functional status. In our experience, we achieved good results from biventricular repair in patients with HLHC, with a significant growth of left heart structures and an excellent clinical status at a medium-term follow-up. Nevertheless, there was a high rate of reoperations and/or interventional catheterizations.

[Study of the right ventricle using magnetic resonance imaging]. / Estudio del ventrículo derecho mediante resonancia magnética.

Magnetic resonance (MR) imaging has proven efficacy in the study of the heart. Its clinical applications are directed primarily at the study of the left ventricle, and the right ventricle is relegated to the background. This article reviews the anatomy and physiology of the right ventricle, as well as the manifestations of most common diseases affecting this chamber of the heart: infarction, cardiomyopathy, masses, and right heart failure. Knowing the distinctive features of the right ventricle with respect to the left and the particularities of the MR imaging protocol results in better technical performance in cases in which the reason for the examination or imaging findings point to the right ventricle. The importance of the right ventricle in the management of cardiopulmonary disease is growing and MR imaging can provide clinicians with the support they need.

Non-invasive pressure support ventilation versus conventional oxygen therapy in acute cardiogenic pulmonary oedema: a randomised trial.

BACKGROUND: Non-invasive pressure support ventilation (NIPSV) is an effective treatment for acute respiratory failure in patients with chronic obstructive pulmonary disease. We assessed the efficacy of this therapy in acute cardiogenic pulmonary oedema in a randomised comparison with conventional oxygen therapy. METHODS: 40 patients were randomly assigned conventional oxygen therapy or NIPSV supplied by a standard ventilator through a face mask, with adjustment of tidal volume and pressure support in addition to a positive end-expiratory pressure of 5 cm water. Physiological measurements were obtained in the first 2 h and at 3 h, 4 h, and 10 h. The main endpoints were intubation rate and resolution time. Analyses were by intention to treat. FINDINGS: Three patients were withdrawn on the basis of clinical and chest radiography results. Endotracheal intubation was required in one (5%) of 19 patients assigned NIPSV and in six (33%) of 18 assigned conventional oxygen therapy (p=0.037). Resolution time (defined as a clinical improvement with oxygen saturation of 96% or more and respiratory rate less than 30 breaths/min) was significantly shorter in the NIPSV group (median 30 [IQR 15-53] vs 105 [50-230] min, p=0.002). NIPSV led to a rapid improvement in oxygenation in the first 2 h. There were no differences in hospital length of stay or mortality. INTERPRETATION: In this study of acute cardiogenic pulmonary oedema, NIPSV was superior to conventional oxygen therapy. Further studies should compare NIPSV with continuous positive airway pressure.

Analysis of the Stargardt disease gene (ABCR) in age-related macular degeneration.

PURPOSE: Age-related macular degeneration (AMD) is a complex genetic disorder and the leading cause of severe vision loss in the elderly. The Stargardt disease gene (ABCR) has been proposed as a major genetic risk factor in AMD. The purpose of this study was to evaluate the authors' AMD population for the specific ABCR variants proposed previously as genetic risk factors for AMD. METHODS: The authors screened their AMD population (159 familial cases from 112 multiplex families and 53 sporadic cases) and 56 racially matched individuals with no known history of AMD from the same clinic population for evidence of the ABCR variants. Grading of disease severity was performed according to a standard protocol. Patients with extensive intermediate drusen or large soft drusen, drusenoid retinal pigment epithelial (RPE) detachments, geographic atrophy of the RPE, or evidence of exudative maculopathy were considered affected. Analysis for variants was performed by polymerase chain reaction amplification of individual exons of the ABCR gene with flanking primers and a combination of single-strand conformation polymorphism, heteroduplex analysis, and high-performance liquid chromatography. All abnormal conformers detected using these techniques were characterized by direct sequencing. RESULTS: The authors identified only two of the previously reported variants in their study population. Both variants occurred in sporadic cases, and none was found in familial cases or the randomly selected population. In addition, the authors identified several newly described polymorphisms and variants in both the AMD and control populations. CONCLUSIONS: Based on these initial findings, the authors suggest that ABCR is not a major genetic risk factor for AMD in their study population. Additional genetic studies are needed to more fully evaluate the role of ABCR in AMD.

Gln368STOP myocilin mutation in families with late-onset primary open-angle glaucoma.

PURPOSE: To examine families ascertained for late-onset primary open-angle glaucoma (POAG) to determine mutations in the gene coding for myocilin. METHODS: The diagnosis of late-onset POAG was defined as age at diagnosis more than 35 years, intraocular pressure (IOP) 22 mm Hg or more in both eyes or 19 mm Hg or more while the patient was taking two glaucoma medications, glaucomatous optic neuropathy in both eyes, and visual field loss consistent with optic nerve damage in at least one eye of the proband. Two of three criteria were required in other family members. DNA from all families was screened for polymorphisms in myocilin using single-strand conformation polymorphism analysis. All polymorphisms were sequenced for mutations. RESULTS: Eighty-three affected people in 29 families with late-onset POAG were screened for mutations. Three mutations, two novel missense (Thr377Met and Glu352Lys) and one nonsense (Gln368STOP), were identified. The missense mutations did not segregate with the disease phenotype in these families. The nonsense mutation was found in 3 of 29 unrelated families with POAG. All affected family members and 8 of 12 in whom glaucoma was suspected had the Gln368STOP mutation. All people with this mutation had elevated IOP, and 78% had POAG by age 70. CONCLUSIONS: Three mutations were identified in the gene coding for myocilin in families with late-onset POAG. Of these, the Gln368STOP mutation was highly associated with the development of glaucoma. All people with this mutation had glaucoma or elevated IOP by age 70. In the United States, the Gln368STOP mutation in myocilin is strongly associated with the development of late-onset POAG. However, factors in addition to the presence of this mutation seem to play a role in the development of ocular hypertension and glaucoma in these families.

Matrix metalloproteinases and their inhibitors in human vitreous.

PURPOSE: To conduct zymographic analysis to study the matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in vitreous samples of patients undergoing pars plana vitrectomy as part of the treatment of vitreoretinal disease. METHODS: Forty-two vitreous samples were collected at the time of pars plana vitrectomy. Diagnoses included severe (exudative) age-related macular degeneration (AMD) (12), macular hole (10), presumed ocular histoplasmosis syndrome (6), proliferative diabetic retinopathy (PDR) (5), epiretinal membrane (4), vitreomacular traction syndrome (2), macroaneurysm with subretinal hemorrhage (1), central retinal vein occlusion with vitreous hemorrhage (1), and proliferative vitreoretinopathy (1). Gelatin zymography, reverse gelatin-zymography, carboxymethylated transferrin zymography, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis were performed on the liquid vitreous samples to assess for MMP and TIMP activity. RESULTS: Progelatinase A occurred in all vitrectomy samples. In addition, a band consistent with TIMP-2 occurred in all samples on reverse zymography. An inhibitor of MMP of a lower molecular weight than TIMP-1 was found in all the samples. A serine proteinase with a broad band around 180 kDa was found in 2 of the 11 AMD vitreous samples. A 75-kDa metalloproteinase was found in several AMD samples, but it was much more abundant in the PDR samples. CONCLUSIONS: Metalloproteinases and their endogenous inhibitors are present in human vitreous and may be involved in the pathogenesis of PDR and other vitreoretinal diseases.

[Importance of the early diagnosis of malignant neuroleptic syndrome: report of 2 cases]. / Importancia del diagnóstico precoz del síndrome neuroléptico maligno a propósito de dos casos.

Two cases of neuroleptic malignant syndrome presented in a psychiatry inpatient unit are commented, as well as their positive evolution.

Exclusion of TIMP3 as a candidate locus in age-related macular degeneration.

PURPOSE: Age-related macular degeneration (AMD) is a genetically complex disorder. Tissue inhibitor of metalloproteinases-3 (TIMP3) on chromosome 22 has been identified as a gene that is mutated in Sosby's fundus dystrophy, an autosomal-dominant macular dystrophy that phenotypically resembles AMD. The purpose of this study was to determine whether TIMP3 is a major susceptibility gene for the AMD phenotype. METHODS: Thirty-eight multiplex families with AMD were identified in Massachusetts and North Carolina. The macular findings were graded according to a modification of the grading system used in the Age-Related Eye Disease Study, and persons with extensive intermediate drusen, any large drusen, geographic atrophy, or evidence of exudative maculopathy were coded as affected for the purpose of the analysis. Linkage analysis was performed using both model-dependent (lod score) and model-independent (sibpair) methods. For the lod score analysis, both autosomal-dominant as well as recessive low penetrance "affecteds only" analyses were examined. Three markers, D22S280, D22S529, and D225268, linked tightly and flanking the TIMP3 locus, were chosen for the analysis. Association studies were performed by examining one randomly chosen affected person per family and comparing the patients with AMD with a series of age, gender, and ethnically matched control subjects with no known history of AMD. RESULTS: Lod score analysis excluded linkage in these data for an approximately 10-cm interval surrounding the TIMP3 gene for all models tested. In addition, no significant findings were observed with either the sibpair or the association study. CONCLUSIONS: No evidence of linkage or association or both was found between AMD and TIMP3 in these 38 families. These data suggest that although clinically similar, the genetic defect in Sorsby's fundus dystrophy is of a different cause than the majority of the genetic causes of AMD.

Alterations in stimulus-induced integrin expression in peripheral blood neutrophils of patients with diabetic retinopathy.

Adhesion molecule expression on peripheral blood leukocytes from diabetic patients with severe retinopathy and age-matched control subjects was assessed. Expression of CD11b, CD18, and L-selectin was measured on granulocytes and lymphocytes in whole blood within 1 hour of blood collection. Adhesion molecule expression was determined at 4 degrees C, 37 degrees C, and after stimulation with one of the chemotactic peptides, N-formyl-methionyl-leucyl-phenyl-alanine or beta-phorbol 12-myristate 13-acetate. There were no differences between diabetics and controls in CD11b expression in neutrophils at 4 degrees C, 37 degrees C, or after N-formyl-methionyl-leucyl-phenylalanine stimulation. However, during stimulation with beta-phorbol 12-myristate 13-acetate, the increase in CD11b expression in neutrophils from patients with diabetes was significantly less than in controls. In neutrophils, there was no difference between the control and diabetic participants in CD18 expression at 4 degrees C, but after warming the cells to 37 degrees C, the expression was significantly higher in patients with diabetes. The difference became even more apparent after N-formyl-methionyl-leucyl-phenyl-alanine stimulation. The increase in CD18 expression after beta-phorbol 12-myristate 13-acetate stimulation of neutrophils was similar in control and diabetic participants. There was no difference in L-selectin expression in neutrophils under any conditions. There was no difference in adhesion molecule expression on lymphocytes under similar conditions. In summary, these observations indicate that integrin expression of neutrophils from patients with diabetes and retinopathy is altered after stimulation with neutrophil-activating agents. The changes were integrin-, stimulus-, and cell-specific, which suggests that the signal transduction mechanisms may be altered in diabetic neutrophils. These alterations may be responsible for abnormal leukocyte/endothelial interactions and microvascular complications in diabetic retinopathy.

Phenotypic heterogeneity in families with age-related macular degeneration.

PURPOSE: To evaluate the ophthalmic phenotype in families with three or more individuals who have age-related maculopathy. METHODS: Eight families were identified at academic centers in Massachusetts and North Carolina. Macular findings were graded based on a modification of the grading system used in the Age-Related Eye Disease Study (AREDS). RESULTS: All families had at least three members with stage 3 (extensive drusen change) or higher maculopathy in at least one eye, and six families had at least two members with advanced maculopathy (stage 4, geographic atrophy of the retinal pigment epithelium, or stage 5, exudative maculopathy). Both stages 4 and 5 maculopathy were observed among different individuals in four families. Individuals with stage 3 maculopathy were members of families with more advanced maculopathy (six families) and were of similar age as more severely affected family members but tended to be older than those with stage 2. CONCLUSION: The phenotypic appearance of the macula in families with multiple affected individuals is heterogeneous and representative of the spectrum of macular findings typically associated with age-related maculopathy.

Effect of age on superoxide dismutase activity of human trabecular meshwork.

PURPOSE: It has been hypothesized that accelerated aging of the trabecular meshwork, perhaps because of oxidative damage, is involved in the pathogenesis of primary open angle glaucoma. The authors sought to evaluate the effect of donor age on the specific activity of superoxide dismutase and catalase in normal fresh human cadaver trabecular meshwork. METHODS: Total superoxide dismutase and catalase were assayed in tissue extracts generated from fresh human trabecular meshwork. Cadaver tissue was obtained from 19 donors (18 paired) of a wide age range (30 to 91 years). The assays were performed within 6 hours of enucleation and within 36 hours of donor death. Enzyme-specific activities were calculated using protein concentration of the extract as the denominator. RESULTS: Multiple regression analysis modeled with age and time from death until the beginning of the experiment was performed. The specific activity of superoxide dismutase declined with age (P = 0.00022; r2 = 0.67). There was no effect of age on catalase specific activity (P = 0.24; r2 = 0.16). The time from donor death until the beginning of the experiment was not a significant factor (P > 0.28). CONCLUSIONS: The specific activity of superoxide dismutase, but not catalase, demonstrates an age-dependent decline in normal cadaver human trabecular meshwork. The potential role of superoxide dismutase in primary open angle glaucoma, a disorder of the aging trabecular meshwork, warrants further investigation.

The catalysis of redox cycling by pyrroloquinoline quinone (PQQ), PQQ derivatives, and isomers and the specificity of inhibitors.

Pyrroloquinoline quinone (PQQ) is a widely distributed redox-active cofactor and essential nutrient. For its detection in protein-free ultrafiltrates or dialysates, a highly sensitive amplification assay was developed on the basis of PQQ's ability to catalyze redox cycling at pH 10 in the presence of excess glycine, oxygen, and nitro blue tetrazolium. Herein, we examine the propensities of PQQ, PQQ triester, and its various isomers, and certain PQQ triester derivatives, to catalyze glycine-fueled redox cycling and show that PQQ is the most capable of catalyzing redox cycling. Furthermore, PQQ has a unique pattern of inhibition induced by a series of PQQ antagonists of different potencies. The data indicate that putative PQQ from a biological sample, separated by HPLC and detected by the glycine-fueled redox-cycling assay, can be further identified as PQQ based on the profile of inhibition it displays with the antagonists such as those employed in this study. The methodology presented here should facilitate the specific detection of PQQ in biological samples.

Red blood cell antioxidant enzymes in age-related macular degeneration.

AIMS/BACKGROUND: Oxidative damage has been proposed to be involved in the pathogenesis of age-related macular degeneration (ARMD). The purpose of this study was to evaluate whether red blood cell antioxidant enzyme activity correlates with severity of aging maculopathy in affected individuals. METHODS: Blood samples were obtained from 54 patients with varying severity of aging maculopathy and 12 similarly aged individuals with normal ophthalmoscopic examination. Macular findings were graded according to a modification of the method described for the Age-Related Eye Disease Study. (AREDS). The activities of superoxide dismutase, catalase, glucose-6-phosphate dehydrogenase, glutathione peroxidase, and glutathione reductase were measured in red blood cells. Haemoglobin content of whole blood was measured, and enzyme activity was determined per mg haemoglobin. RESULTS: Multiple regression analysis and ordinal logistic regression analysis were performed to determine whether antioxidant enzyme activity was associated with severity of ARMD. No significant association between disease severity of ARMD and antioxidant enzyme activity was identified for any of the enzymes. CONCLUSION: These results do not provide evidence for a relation between oxidative stress, as measured by antioxidant enzyme activity in red blood cells, and disease severity in ARMD.

Antioxidant enzymes of the human retina: effect of age on enzyme activity of macula and periphery.

The purpose of this research was to evaluate the effect of age on protective antioxidant enzyme activity of normal fresh cadaver human retina of the macula and periphery. Antioxidant enzymes were assayed in tissue extracts generated from 5 mm trephined punches of retina obtained centered over the macula and the superior midperiphery of normal fresh human cadaver retina. Cadaver tissue was obtained from donors of a wide age range (age 7 to 85 years). The assays were performed within 6 h of enucleation and within 24 h of donor death. Antioxidant enzymes assayed included superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Hexokinase and glucose-6-phosphate dehydrogenase, enzymes not directly involved in protection against oxidative damage, were assayed for comparison. Enzyme specific activities were calculated for the macula and periphery using protein concentration of the extract as the denominator. Using linear regression analysis, over the age range of 25 to 75 years, superoxide dismutase activity of the periphery but not the macula tended to decline with age (p = 0.04, R2 = 0.21). Interindividual variability was high, and variability increased with age. The difference between the macular and peripheral enzyme activities for glutathione peroxidase tended to decline with increasing donor age (p = 0.025, R2 = 0.33). There was no effect of age on the specific activities of catalase, glucose-6-phosphate dehydrogenase, and glutathione reductase. The specific activity of hexokinase from the macula declined with increasing donor age (p = 0.022, R2 = 0.43). Time from death to enucleation or beginning of experiment was not a significant factor. In summary, age does not have an effect on the activity of major antioxidant enzymes of the macula in normal human retina. There is a tendency for an effect of age on peripheral superoxide dismutase activity and the difference between macular and peripheral glutathione peroxidase activity. High interindividual variability of antioxidant enzyme activity exists in humans.

Fundus manifestations of orbital disease and treatment of orbital disease.

Disorders of the orbit can secondarily involve the eye. Although nonspecific, changes which can be noted on funduscopic examination including abnormalities of the retina, choroid, and optic nerve, can be secondary to an underlying orbital process. Awareness of these findings and their association with orbital disease is of great importance to the practicing ophthalmologist, since many orbital disorders are treatable and indeed, some are life-threatening. In addition, treatment of these disorders can potentially result in a variety of ocular complications. An understanding of the potential risks is of the utmost importance in planning treatment of an orbital disease.

Inhibition of redox cycling of methoxatin (PQQ), and of superoxide release by phagocytic white cells.

The iodonium compounds diphenyleneiodonium and diphenyliodonium, and the amine compounds, 4,5-dimethyl phenylene diamine, N,N-dimethyl 1,4-phenylene diamine, 1,2-diamino-4,5-methyleneoxybenzene, and aminomalononitrile inhibit methoxatin's (PQQ's) redox activity in vitro, that is, the methoxatin-coupled oxidation of glycine and reduction of nitroblue tetrazolium to formazan. The compounds mentioned above also inhibit phorbol myristate acetate (PMA) stimulated superoxide release by phagocytic white cells--determined mainly as the superoxide dismutase sensitive reduction of ferricytochrome C. Related compounds, 3,4-diaminopyridine and 4-dimethylamino-benzylamine, did not inhibit redox activity of PQQ in vitro, nor did they inhibit PMA stimulated superoxide production in monocytes or neutrophils. Thus, there is a correlation between an agent's ability to inhibit PQQ redox cycling and its ability to inhibit superoxide release by phagocytes. The findings are a further indication that PQQ is involved in the respiratory burst of phagocytic cells.