Kidney Function and 24-Hour Proteinuria in Patients with Fabry Disease during 36 Months of Agalsidase Alfa Enzyme Replacement Therapy: A Brazilian Experience

Background. Prior to the introduction of enzyme replacement therapy (ERT), management of Fabry disease (FD) consisted of symptomatic and palliative measures. ERT has been available for several years using recombinant human agalsidase alfa, an analogue of alpha-galactosidase A (GALA). However, the limitations of ERT in improving kidney function have not been established. This study evaluates the safety and therapeutic effect of agalsidase alfa replacement in terms of kidney function and reduction in 24-hour proteinuria. Methods. During the period between January 1, 2002, and August 1, 2005, nine Fabry patients (7 male, 2 female) were treated according to protocol, receiving 0.2 mg/kg agalsidase alfa IV every two weeks. Kidney function was evaluated by measuring the glomerular filtration rate (GFR) using chromium ethylene diamine tetra-acetate clearance ((51)Cr-EDTA mL/min/1.73 m(2)) at baseline, 12, 24, and 36 months. 24-hour proteinuria was measured at baseline, 3, 6, 12, 18, 24, and 36 months of ERT. Kidney disease was classified according to National Kidney Foundation Disease Outcome Quality Initiative (NKF/DOQI) Advisory Board criteria, which define stage I chronic kidney disease (CKD) as GFR >= 90mL/min/1.73 m(2), stage II as 60-89 mL/min/1.73m(2), stage III as 30-59 mL/min/1.73 m(2), stage IV as 15-29 mL/min/1.73m(2), and stage V as < 15 mL/min/1.73m(2). Results. Six patients completed 36 months of therapy, 2 patients completed 18 months, and 1 patient completed 12 months. Mean patient age at baseline was 34.6 +/- 11.3 years. During the study period, kidney function remained stable in patients with stages I, II, or III CKD. One patient, who entered the study with stage IV CKD, progressed to end-stage chronic kidney disease, beginning hemodialysis after 7 months and receiving a kidney transplant after 12 months of ERT. Proteinuria also remained stable in the group of patients with pathologic proteinuria. The use of agalsidase alfa was well tolerated in 99.5% of the infusions administered. Conclusion. Over the course of 36 months of ERT, there was no change in kidney function and 24-hour proteinuria. This suggests thatagalsidase alfa may slow or halt the progression of kidney disease when used before extensive kidney damage occurs. No significant side effects were observed with ERT during the course of the study.

New SMS mutation leads to a striking reduction in spermine synthase protein function and a severe form of Snyder-Robinson X-linked recessive mental retardation syndrome

We report the identification of a novel mutation at a highly conserved residue within the N-terminal region of spermine synthase (SMS) in a second family with Snyder-Robinson X-linked mental retardation syndrome ( OMIM 309583). This missense mutation, p.G56S, greatly reduces SMS activity and leads to severe epilepsy and cognitive impairment. Our findings contribute to a better delineation and expansion of the clinical spectrum of Snyder-Robinson syndrome, support the important role of the N-terminus in the function of the SMS protein, and provide further evidence for the importance of SMS activity in the development of intellectual processing and other aspects of human development.

The role of BPH, lower urinary tract symptoms, and PSA levels on erectile function of Brazilian men who undergo prostate cancer screening

Introduction. Lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are common problems in middle-aged and older men. Recently, epidemiologic studies have shown significant associations between severity of LUTS and male sexual dysfunction. Aim. We analyzed the role of prostate enlargement, LUTS, and prostate specific antigen (PSA) levels in the erectile function of Brazilian men who underwent prostate cancer (PCa) screening. Method. We analyzed data from 1,008 consecutive patients enrolled in a PCa screening program. Benign prostatic hyperplasia (BPH) was defined as a prostate weight greater than 30 g as defined by digital rectal examination. For statistical analysis, we used the chi-squared and analysis of variance tests. The odds ratios (OR) for correlation of ED with prostate volume LUTS and PSA were estimated using logistic regression models. Main Outcome Measure. The American Urological Association (AUA) symptom score for LUTS and the International Index of Erectile Function. Results. Mean patient age was 61.2 years (45-87) and median PSA value was 1.9 ng/mL. BPH was identified in 48.5% of patients. Mild, moderate, and severe LUTS were found in 52.3%, 30.9%, and 16.8% of cases, respectively. ED was classified as absent, mild, mild to moderate, moderate, and severe in 18.6%, 23.1%, 18.6%, 15.2%, and 24.5%, respectively. While only 5.4% of the patients with no ED presented severe LUTS, this finding was observed in 27.1% of patients with severe ED (P<0.001). Univariate logistic regression analysis demonstrated that age, prostate volume, AUA symptom score, and PSA levels were significant predictors of ED. However, when controlled for patient age, only LUTS remained as an independent predictor of ED. Conclusions. Controlling for patient age, LUTS are independent risk factors for the development of ED among Brazilian men who undergo PCa screening.

Quantitative parameters of facial motor evoked potential during vestibular schwannoma surgery predict postoperative facial nerve function

Background Facial motor evoked potential (FMEP) amplitude ratio reduction at the end of the surgery has been identified as a good predictor for postoperative facial nerve outcome. We sought to investigate variations in FMEP amplitude and waveform morphology during vestibular schwannoma (VS) resection and to correlate these measures with postoperative facial function immediately after surgery and at the last follow-up. Methods Intraoperative orbicularis oculi and oris muscles FMEP data from 35 patients undergoing surgery for VS resection were collected, then analysed by surgical stage: initial, dural opening, tumour dissection (TuDis), tumour resection (TuRes) and final. Findings Immediately after surgery, postoperative facial function correlated significantly with the FMEP amplitude ratio during TuDis, TuRes and final stages in both the orbicularis oculi (p = 0.003, 0.055 and 0.028, respectively) and oris muscles (p = 0.002, 0.104 and 0.014, respectively). At the last follow-up, however, facial function correlated significantly with the FMEP amplitude ratio only during the TuDis (p = 0.005) and final (p = 0.102) stages for the orbicularis oris muscle. At both time points, postoperative facial paresis correlated significantly with FMEP waveform deterioration in orbicularis oculi during the final stage (immediate, p = 0.023; follow-up, p = 0.116) and in orbicularis oris during the TuDis, TuRes and final stages (immediate, p = 0.071, 0.000 and 0.001, respectively; follow-up, p = 0.015, 0.001 and 0.01, respectively). Conclusions FMEP amplitude ratio and waveform morphology during VS resection seem to represent independent quantitative parameters that can be used to predict postoperative facial function. Event-to-baseline FMEP monitoring is quite useful to dictate when intraoperative changes in surgical strategy are warranted to reduce the chances of facial nerve injury.

Altered endothelial function following the Fontan procedure

Objective: Thrombosis has been widely described after the Fontan procedure. The vascular endothelium plays a central role in the control of coagulation and fibrinolysis. The aim of this study was to investigate if patients undergoing a modified Fontan procedure have impaired endothelial function and fibrinolysis in the late postoperative course. Patients and methods: We compared 23 patients aged from 7 to 26 years with age-matched healthy volunteers, collecting blood samples prior to and following standardized venous occlusion testing. Plasma levels of von Willebrand factor antigen, tissue-type plasminogen activator antigen, plasminogen activator inhibitor-1, and D-dimer were measured with enzyme-linked immunosorbent assay. Results: We found increased plasma levels of von Willebrand factor antigen in patients when compared to controls (p = 0.003). At the basal condition, concentrations of tissue-type plasminogen activator antigen and plasminogen activator inhibitor-1 antigen in the plasma, as well as their activity, were not significantly different between patients and controls. Following venous occlusion, concentrations of tissue-type plasminogen activator antigen in the plasma were significantly increased both in patients and controls, compared to pre-occlusion values. D-dimer was within the reference range. Multivariate discriminant analysis differentiated patients and their controls on the basis of differences for plasminogen activator inhibitor-1 and von Willebrand factor antigen (p = 0.0016). Conclusions: Our data suggest that patients with the Fontan circulation may have endothelial dysfunction, as indicated by raised levels of von Willebrand factor. Fibrinolysis seems to be relatively preserved, as suggested by appropriate response to venous occlusion.

Evaluation of renal function in leprosy: a study of 59 consecutive patients

Background. Renal abnormalities in leprosy have been largely described in medical literature, but there are few studies evaluating renal function in these patients. Methods. This is a cross-sectional study in 59 consecutive paucibacillary (PB) and multibacillary (MB) leprosy patients. Glomerular filtration rate (GFR) was estimated by simplified-MDRD formula. Microalbuminuria was determined by 24 h urine collection. Urinary acidification capacity was measured after water deprivation and acid-loading with CaCl2. Urinary concentration capacity was evaluated after desmopressin acetate administration, using the urinary to plasma osmolality (U/P-osm) ratio. All parameters except microalbuminuria were measured in a control group of 18 healthy volunteers. Results. Age and gender were similar between leprosy (MB or PB) and control groups. GFR <= 80 ml/min/1.73 m(2) was observed in 50% of the leprosy patients. GFR and U/P-osm in leprosy patients were significantly lower than in controls (P < 0.001). Urinary acidification defect was found in 32% of PB and in 29% of MB patients and urinary concentrating ability was abnormal in 83% of PB and 85% of MB patients. Microalbuminuria was found in 4 patients (8.5%), leukocyturia was found in 13 (22%) and haematuria was present in 16 patients (27%). Plasma creatinine (P-cr) > 1.2 mg/dl was observed in 17.9% of MB patients and in none of the controls (P = 0.020). A negative correlation was observed between GFR and time of treatment (r = -0.339; P = 0.002). Age and time of treatment were independent risk factors for GFR <= 80 ml/min/1.73 m(2) in multivariate analysis. Conclusions. Asymptomatic GFR changes and renal tubular dysfunction, including urine concentration defect and impaired acidifying mechanisms, can be caused by leprosy on specific treatment and without any reaction episodes.

Pulmonary function testing in quadriplegic subjects

Study design: Cross-sectional study. Objective: Pulmonary functional capacity in 23 Brazilian quadriplegic subjects (ASIA A), aged 30 (9.5) years, weight 66 (10.75) kg, height 176 (7) cm, was investigated at 42 ( 64) months postinjury. Setting: University Hospital-UNICAMP, Campinas, Brazil. Method: Subjects performed forced vital capacity ( FVC) and maximal voluntary ventilation (MVV) tests while seated in their standard wheelchairs. Forced Expired Volume after 1 s (FEV1) and FVC/FEV1 ratio were calculated from these tests. Values obtained were compared to three prediction equations from the literature that are used specifically for spinal cord subjects and include different variables in their formulae, such as age, gender, height, postinjury time and injury level. Data are expressed as median (interquartile interval). Differences between values were demonstrated by median confidence interval with significance level set at a 0.05. Results: Obtained data were statistically different from prediction equation results, with FVC 3.11 ( 0.81), 4.46 (0.28), 4.16 (0.33), 4.26 (0.42); FEV1 2.77 (1.03), 3.67 (0.21), 3.66 (0.30), 3.45 (0.39) and MVV 92 (27), 154.2 (11.9), 156.6 (14),157.3 (16.8), where the first value is obtained experimentally and the second, third and fourth values correspond to predicted values. The results obtained from spirometry test in this study differed significantly from the results obtained when prediction equations were used. Conclusion: The use of prediction equations developed to estimate pulmonary function in wheelchair users significantly overestimates pulmonary function of quadriplegic individuals with complete lesions (ASIA group A), in comparison to measured values.

Tyrosines in the Carboxyl Terminus Regulate Syk Kinase Activity and Function

The Syk tyrosine kinase family plays an essential role in immunoreceptor tyrosine-based activation motif (ITAM) signaling. The binding of Syk to tyrosine-phosphorylated ITAM subunits of immunoreceptors, such as Fc epsilon RI on mast cells, results in a conformational change, with an increase of enzymatic activity of Syk. This conformational change exposes the COOH-terminal tail of Syk, which has three conserved Tyr residues (Tyr-623, Tyr-624, and Tyr-625 of rat Syk). To understand the role of these residues in signaling, wild-type and mutant Syk with these three Tyr mutated to Phe was expressed in Syk-deficient mast cells. There was decreased Fc epsilon RI-induced degranulation, nuclear factor for T cell activation and NF kappa B activation with the mutated Syk together with reduced phosphorylation of MAP kinases p38 and p42/44 ERK. In non-stimulated cells, the mutated Syk was more tyrosine phosphorylated predominantly as a result of autophosphorylation. In vitro, there was reduced binding of mutated Syk to phosphorylated ITAM due to this increased phosphorylation. This mutated Syk from non-stimulated cells had significantly reduced kinase activity toward an exogenous substrate, whereas its autophosphorylation capacity was not affected. However, the kinase activity and the autophosphorylation capacity of this mutated Syk were dramatically decreased when the protein was dephosphorylated before the in vitro kinase reaction. Furthermore, mutation of these tyrosines in the COOH-terminal region of Syk transforms it to an enzyme, similar to its homolog ZAP-70, which depends on other tyrosine kinases for optimal activation. In testing Syk mutated singly at each one of the tyrosines, Tyr-624 but especially Tyr-625 had the major role in these reactions. Therefore, these results indicate that these tyrosines in the tail region play a critical role in regulating the kinase activity and function of Syk.

Changes in Myocardial Perfusion Correlate With Deterioration of Left Ventricular Systolic Function in Chronic Chagas` Cardiomyopathy

OBJECTIVES This study aimed at analyzing the association between myocardial perfusion changes and the progression of left ventricular systolic dysfunction in patients with chronic Chagas` cardiomyopathy (CCC). BACKGROUND Pathological and experimental studies have suggested that coronary microvascular derangement, and consequent myocardial perfusion disturbance, may cause myocardial damage in CCC. METHODS Patients with CCC (n = 36, ages 57 +/- 10 years, 17 males), previously having undergone myocardial perfusion single-positron emission computed tomography and 2-dimensional echocardiography, prospectively underwent a new evaluation after an interval of 5.6 +/- 1.5 years. Stress and rest myocardial perfusion defects were quantified using polar maps and normal database comparison. RESULTS Between the first and final evaluations, a significant reduction of left ventricular ejection fraction was observed (55 +/- 11% and 50 +/- 13%, respectively; p = 0.0001), as well as an increase in the area of the perfusion defect at rest (18.8 +/- 14.1% and 26.5 +/- 19.1%, respectively; p = 0.0075). The individual increase in the perfusion defect area at rest was significantly correlated with the reduction in left ventricular ejection fraction (R = 0.4211, p = 0.0105). Twenty patients with normal coronary arteries (56%) showed reversible perfusion defects involving 10.2 +/- 9.7% of the left ventricle. A significant topographic correlation was found between reversible defects and the appearance of new rest perfusion defects at the final evaluation. Of the 47 segments presenting reversible perfusion defects in the initial study, 32 (68%) progressed to perfusion defects at rest, and of the 469 segments not showing reversibility in the initial study, only 41 (8.7%) had the same progression (p < 0.0001, Fisher exact test). CONCLUSIONS In CCC patients, the progression of left ventricular systolic dysfunction was associated with both the presence of reversible perfusion defects and the increase in perfusion defects at rest. These results support the notion that myocardial perfusion disturbances participate in the pathogenesis of myocardial injury in CCC. (J Am Coll Cardiol Img 2009;2:164-72) (c) 2009 by the American College of Cardiology Foundation

Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome

Context: Physiological activation of the prokineticin pathway has a critical role in olfactory bulb morphogenesis and GnRH secretion in mice. Objective: To investigate PROK2 and PROKR2 mutations in patients with hypogonadotropic hypogonadism (HH) associated or not with olfactory abnormalities. Design: We studied 107 Brazilian patients with HH (63 with Kallmann syndrome and 44 with normosmic HH) and 100 control individuals. The coding regions of PROK2 and PROKR2 were amplified by PCR followed by direct automatic sequencing. Results: In PROK2, two known frameshift mutations were identified. Two brothers with Kallmann syndrome harbored the homozygous p. G100fsX121 mutation, whereas one male with normosmic HH harbored the heterozygous p. I55fsX56 mutation. In PROKR2, four distinct mutations (p. R80C, p. Y140X, p. L173R, and p. R268C) were identified in five patients with Kallmann syndrome and in one patient with normosmic HH. These mutations were not found in the control group. The p. R80C, p. L173R, and p. R268C missense mutations were identified in the heterozygous state in the HH patients and in their asymptomatic first-degree relatives. In addition, nomutations of FGFR1, KAL1, GnRHR, KiSS-1, or GPR54 were identified in these patients. Notably, the new nonsense mutation (p. Y140X) was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous for this severe defect. Conclusion: We expanded the repertoire of PROK2 and PROKR2 mutations in patients with HH. In addition, we show that PROKR2 haploinsufficiency is not sufficient to cause Kallmann syndrome or normosmic HH, whereas homozygous loss-of-function mutations either in PROKR2 or PROK2 are sufficient to cause disease phenotype, in accordance with the Prokr2 and Prok2 knockout mouse models.

Effects of acute magnesium loading on pulmonary function of stable COPD patients

Background: Magnesium (Mg) use has the potential to promote bronchodilatation and to improve lung function in obstructive diseases. IV administration of Mg during exacerbations of chronic obstructive pulmonary disease (COPD) has led to improved peak flow. This study aimed to investigate the effects of acute IV Mg loading on respiratory parameters of stable COPD patients. Material/Methods: This was a randomized, double-blind, placebo-controlled crossover study. Twenty-two male COPD patients (64 +/- 6 years old, FEV1: 49 +/- 20%) received an IV infusion of 2 g of magnesium sulfate or placebo on two distinct occasions. Spirometry and mouth maximal respiratory pressures were obtained before and 45 minutes after the infusions. Results: Mg use led to significant changes in functional respiratory capacity (-0.48 1,95% CI: -0.96, -0.01), inspiratory capacity (0.21 1,95% CI: 0.04, 0.37). The treatment was also associated with a marginally significant decrease in residual volume (-0.47 1,95% CI: -0.96, 0.02, p=0.06). Conclusions: Acute IV Mg loading in stable COPD patients was associated with a reduction in lung hyperinflation and improvement of respiratory muscle strength. The clinical potential for chronic magnesium supplementation in COPD deserves further investigation.

Liver mitochondrial function in familial amyloidotic polyneuropathy

The objective of the present study was to analyze hepatic mitochondrial function in patients with familial amyloidotic polyneuropathy (FAP) undergoing cadaveric donor orthotopic liver transplantation. From February `2005 to May 2007, eight patients with FAP, ranging in age from 34 to 41 years and with Model for End-Stage Liver Disease scores ranging from 24 to 29. Underwent orthotopic transplantation using a liver from a deceased donor by the piggyback method. Immediately before beginning the recipient hepatectomy in a patient with FAP, a biopsy was obtained for analysis of mitochondrial function (FAP group). The control group consisted of 15 patients undergoing hepatic surgery to treat small tumors of the liver. Mitochondrial respiration was determined on the basis of oxygen consumption by energized mitochondria using a polarographic method. The membrane potential of the mitochondria was determined spectrofluorometrically. Data were analyzed statistically by the Mann-Whitney test, with the level of significance set at 5%. State 3 and 4 values, respiratory control ratio, and membrane potential were 47 +/- 8 versus 28 +/- 10 natoms O/min/mg protein (P <.05); 14 +/- 3 vs 17 +/- 7 nat.O/min/ mg.prot.mit. (P >.05); 3.6+/- .5 vs 1.7 +/- 0.7 (P <.05); and 135 +/- 5.2 vs 135 +/- 6 mV (P >.05) for control versus FAP patients, respectively, demonstrating a decreased energy status of the liver in FAP.

Improved Endothelial Function and Reversal of Myocardial Perfusion Defects after Aerobic Physical Training in a Patient with Microvascular Myocardial Ischemia

The objective of this report is to document the effects of an aerobic training program on myocardial perfusion, and endothelial function abnormalities, and on the relief of angina in a patient with microvascular myocardial ischemia. A 53-year-old female patient exhibited precordial pain on effort and angiographically normal coronaries. Her symptoms had been present for 4 yrs despite pharmacologic treatment for the control of risk factors, with myocardial perfusion scintigraphy revealing an extensive reversible perfusion defect. She was submitted to aerobic training for 4 mos, obtaining significant improvement of the anginal symptoms. Additionally, after the aerobic training program, scintigraphy revealed the disappearance of the myocardial perfusion defect, with a marked improvement of endothelium-dependent vasodilatory response and an improved quality-of-life score. These results suggest that aerobic training can improve endothelial function, leading to a reduction of ischemia and an improved quality-of-life in patients with microvascular myocardial ischemia.

Perception of dysphagia: lack of correlation with objective measurements of esophageal function

Background The mechanism underlying increased perception of food bolus passage in the absence of esophageal mechanical obstruction has not been completely elucidated. A correlation between the intensity of the symptom and the severity of esophageal dysfunction, either motility (manometry) or bolus transit (impedance) has not been clearly demonstrated. The aim of this study was to analyze the correlation between objective esophageal function assessment (with manometry and impedance) and perception of bolus passage in healthy volunteers (HV) with normal and pharmacologically-induced esophageal hypocontractility, and in patients with gastro-esophageal reflux disease (GERD) with and without ineffective esophageal motility (IEM). Methods Combined manometry-impedance was performed in 10 HV, 19 GERD patients without IEM and nine patients with IEM. Additionally, nine HV were studied after 50 mg sildenafil, which induced esophageal peristaltic failure. Perception of each 5 mL viscous swallow was evaluated using a 5-point scale. Manometry identified hypocontractility (contractions lower than 30 mmHg) and impedance identified incomplete bolus clearance. Key Results In HV and in GERD patients with and without IEM, there was no association between either manometry or impedance and perception on per swallow analysis (OR: 0.842 and OR: 2.017, respectively), as well as on per subject analysis (P = 0.44 and P = 0.16, respectively). Lack of correlation was also found in HV with esophageal hypocontractility induced by sildenafil. Conclusions & Inferences There is no agreement between objective measurements of esophageal function and subjective perception of bolus passage. These results suggest that increased bolus passage perception in patients without mechanical obstruction might be due to esophageal hypersensitivity.