Anderson-Fabry disease: Ten-year outcome of enzyme replacement therapy in a renal transplant patient

Anderson‑Fabry disease (AFd) is a rare disorder characterised by the deficiency or absence of lysosomal enzymatic alpha‑galactosidase A activity (α‑Gal A) that leads to progressive and systemic accumulation of glycosphingolipids. The clinical manifestations are variable but kidney disease usually manifests before the fourth decade of life and chronic renal failure rapidly progresses to end‑stage renal disease (ESRD), requiring dialysis and kidney transplantation (KT). In patients with a definite diagnosis, enzyme replacement therapy (ERT) is recommended as soon as there are early clinical signs of kidney, heart or brain involvement. We present a case of a kidney transplant patient who was diagnosed with AFd nine years after KT, confirming the difficulty that may exist in na early diagnosis of this disease even among high‑risk groups. At this stage, in addition to renal damage, the patient already had advanced disease and established organ injury, including ocular, pulmonary, cerebrovascular and cardiac. He started agalsidase beta (Fabrazyme®) intravenously every two weeks at a dose of 1 mg/kg body weight. During ten years of treatment no major adverse events were reported and our experience indicates that ERT is a safe and effective treatment for extra‑renal Fabry manifestations in KT patientsinfo:eu-repo/semantics/publishedVersio

Familial ATTR amyloidosis: microalbuminuria as a predictor of symptomatic disease and clinical nephropathy

Familial ATTR amyloidosis: microalbuminuria as a predictor of symptomatic disease and clinical nephropathy. Lobato L, Beirão I, Silva M, Bravo F, Silvestre F, Guimarães S, Sousa A, Noël LH, Sequeiros J. SourceDepartment of Nephrology and Centro de Estudos de Paramiloidose, Hospital Geral de Santo António and Institute for Molecular and Cell Biology, Porto, Portugal. [email protected] Abstract BACKGROUND: Portuguese type familial amyloid polyneuropathy (FAP) is a neuropathic amyloidosis caused by a mutant transthyretin (TTR). Varying degrees of renal involvement have been reported. Our aim was to assess the value of microalbuminuria (MA) for predicting clinical neurological disease and overt nephropathy in TTR-related amyloidosis. METHODS: All subjects had the TTR Val30Met mutation, and were recruited between 1993 and 1999. We have prospectively evaluated 22 asymptomatic gene carriers (7 male, 15 female; mean age 41.6+/-9.6 years) and 32 patients with neuropathy (14 male, 18 female; 36.8+/-8.8 years, on average, 33.0+/-9.3 years at the onset of neuropathy). We measured urinary albumin excretion every year, if asymptomatic, or every 6 months if already affected. Kidney biopsies were performed in patients with normal urinary albumin excretion, MA, and overt nephropathy, respectively. RESULTS: In asymptomatic carriers, persistent MA was detected in eight (36%) subjects. The presence of MA in asymptomatic gene carriers, compared with those having normal urinary albumin excretion, conferred a 4.8-fold risk of developing neuropathy, usually within the subsequent 3 years. Once neurological signs appeared, nephropathy, manifested as MA, progressed to overt nephropathy in one-half of subjects. In patients with neuropathy, 24 (75%) had MA during follow-up: evolution towards clinical renal disease occurred in 14 (58%) and renal failure occurred in five (21%), always after a course of MA. Proteinuria or renal failure without prior persistent MA were never observed in the present patient cohort. Histopathological evaluation did not reveal glomerular lesions other than amyloid deposits to explain abnormal urinary albumin excretion. The amount of mesangial and vascular-pole amyloid deposits was correlated with the degree of albuminuria. CONCLUSIONS: Microalbuminuria represents the first stage of clinical TTR amyloid nephropathy and is premonitory of neuropathy. Its presence identifies a subgroup of patients who are more prone to develop overt nephropathy. Screening of MA may be important to assess disease onset and to recommend liver transplantation in individuals at risk

End-stage renal disease versus death in a Portuguese cohort of elderly patients: an approach using competing event analysis

Chronic kidney disease (CKD) is higher in elderly, but mortality outweighs the risk of end-stage renal disease (ESRD). Our aim was to identify prognostic markers for ESRD or death in elderly CKD, within a competing-risk analysis. This is a longitudinal study of consecutive newly referred patients with CKD ages 65 years, followed until the time of the first event (ESRD or death), using a competing-risk analysis. A modified Charlson Comorbidity Index (mCCI) was subdivided into subgroups (0-2, 3-4, ≥5). Patients were followed for hospitalizations that occurred prior to the outcomes. Among 416 patients, age 76±8 years, 52% male, median estimated glomerular filtration rate of 32 mL/min per 1.73 m2, 50% had diabetes, and 67% cardiovascular disease. Over a median follow-up of 3.6 years, 36 patients progressed to ESRD (8.7%) and 103 died (24.8%). Older age (subdistribution HR (sHR)=1. 06; p<0.001), creatinine≥1.6 mg/dL (sHR=2.03, p=0.004), hemoglobin <11 g/dL (sHR=1.91, p=0.003), mCCI score≥5 (sHR=3.01, p<0.001) and having one or more hospitalizations (sHR=1.73, p<0.001) were associated with death before ESRD. The independent predictors for ESRD with competing risk of death were: lower age (sHR=0.94; p=0.009), creatinine≥1.6 mg/dL (sHR=3.26, p=0.006), hemoglobin <11 g/dL (sHR=2.15, p=0.027), peripheral vascular disease (sHR=3.45, p=0.001) and having one or more hospitalizations (sHR=1.56, p=0.031). Elderly referred patients with CKD are near threefold more likely to die than progress to ESRD. A competing-risk framework based on available clinical and laboratory data may discriminate between those outcomes and could be used as a decision-making tool

Pressure moderation and effective pressure in Navier-Stokes flows

We study the Cauchy problem of the Navier–Stokes equations by both semi-analytic and classical energy methods. The former approach provides a physical picture of how viscous effects may or may not be able to suppress singularity development. In the latter approach, we examine the pressure term that drives the dynamics of the velocity norms ||u||Lq , for q ≥ 3. A key idea behind this investigation is due to the fact that the pressure p in this term is determined upto a function of both space and |u|, say Ƥ(x, |u|), which may assume relatively broad forms. This allows us to use Ƥ as a pressure moderator in the evolution equation for ||u||Lq , whereby optimal regularity criteria can be sought by varying Ƥ within its admissible classes. New regularity criteria are derived with and without making use of the moderator. The results obtained in the absence of the moderator feature some improvement over existing criteria in the literature. Several criteria are derived in terms of the moderated (effective) pressure p+Ƥ. A simple moderation scheme and the plausibility of the present approach to the problem of Navier–Stokes regularity are discussed.PostprintPeer reviewe

The Ionized Gas in Nearby Galaxies as Traced by the [NII] 122 and 205 \mu m Transitions

The [NII] 122 and 205 \mu m transitions are powerful tracers of the ionized gas in the interstellar medium. By combining data from 21 galaxies selected from the Herschel KINGFISH and Beyond the Peak surveys, we have compiled 141 spatially resolved regions with a typical size of ~1 kiloparsec, with observations of both [NII] far-infrared lines. We measure [NII] 122/205 line ratios in the ~0.6-6 range, which corresponds to electron gas densities $n_e$~1-300 cm$^{-3}$, with a median value of $n_e$=30 cm$^{-3}$. Variations in the electron density within individual galaxies can be as a high as a factor of ~50, frequently with strong radial gradients. We find that $n_e$ increases as a function of infrared color, dust-weighted mean starlight intensity, and star formation rate surface density ($\Sigma_{SFR}$). As the intensity of the [NII] transitions is related to the ionizing photon flux, we investigate their reliability as tracers of the star formation rate (SFR). We derive relations between the [NII] emission and SFR in the low-density limit and in the case of a log-normal distribution of densities. The scatter in the correlation between [NII] surface brightness and $\Sigma_{SFR}$ can be understood as a property of the $n_e$ distribution. For regions with $n_e$ close to or higher than the [NII] line critical densities, the low-density limit [NII]-based SFR calibration systematically underestimates the SFR since [NII] emission is collisionally quenched. Finally, we investigate the relation between [NII] emission, SFR, and $n_e$ by comparing our observations to predictions from the MAPPINGS-III code.Comment: 18 pages, 9 figures, accepted for publication in The Astrophysical Journa

Optimal Sobolev regularity for linear second-order divergence elliptic operators occurring in real-world problems

On bounded three-dimensional domains, we consider divergence-type operators including mixed homogeneous Dirichlet and Neumann boundary conditions and discontinuous coefficient functions. We develop a geometric framework in which it is possible to prove that the operator provides an isomorphism of suitable function spaces. In particular, in these spaces, the gradient of solutions turns out to be integrable with exponent larger than the space dimension three. Relevant examples from real-world applications are provided in great detail

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one

Beyond Genetic Factors in Familial Amyloidotic Polyneuropathy: Protein Glycation and the Loss of Fibrinogen's Chaperone Activity

Familial amyloidotic polyneuropathy (FAP) is a systemic conformational disease characterized by extracellular amyloid fibril formation from plasma transthyretin (TTR). This is a crippling, fatal disease for which liver transplantation is the only effective therapy. More than 80 TTR point mutations are associated with amyloidotic diseases and the most widely accepted disease model relates TTR tetramer instability with TTR point mutations. However, this model fails to explain two observations. First, native TTR also forms amyloid in systemic senile amyloidosis, a geriatric disease. Second, age at disease onset varies by decades for patients bearing the same mutation and some mutation carrier individuals are asymptomatic throughout their lives. Hence, mutations only accelerate the process and non-genetic factors must play a key role in the molecular mechanisms of disease. One of these factors is protein glycation, previously associated with conformational diseases like Alzheimer's and Parkinson's. The glycation hypothesis in FAP is supported by our previous discovery of methylglyoxal-derived glycation of amyloid fibrils in FAP patients. Here we show that plasma proteins are differentially glycated by methylglyoxal in FAP patients and that fibrinogen is the main glycation target. Moreover, we also found that fibrinogen interacts with TTR in plasma. Fibrinogen has chaperone activity which is compromised upon glycation by methylglyoxal. Hence, we propose that methylglyoxal glycation hampers the chaperone activity of fibrinogen, rendering TTR more prone to aggregation, amyloid formation and ultimately, disease