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.

Synaptic transmission block by presynaptic injection of oligomeric amyloid beta

Early Alzheimer`s disease (AD) pathophysiology is characterized by synaptic changes induced by degradation products of amyloid precursor protein (APP). The exact mechanisms of such modulation are unknown. Here, we report that nanomolar concentrations of intraaxonal oligomeric (o)A beta 42, but not oA beta 40 or extracellular oA beta 42, acutely inhibited synaptic transmission at the squid giant synapse. Further characterization of this phenotype demonstrated that presynaptic calcium currents were unaffected. However, electron microscopy experiments revealed diminished docked synaptic vesicles in oA beta 42-microinjected terminals, without affecting clathrin-coated vesicles. The molecular events of this modulation involved casein kinase 2 and the synaptic vesicle rapid endocytosis pathway. These findings open the possibility of a new therapeutic target aimed at ameliorating synaptic dysfunction in AD.

Role of Rab27 in synaptic transmission at the squid giant synapse

Small GTPase Rab is a member of a large family of Ras-related proteins, highly conserved in eukaryotic cells, and thought to regulate specific type(s) and/or specific step(s) in intracellular membrane trafficking. Given our interest in synaptic transmission, we addressed the possibility that Rab27 (a close isoform of Rab3) could be involved in cytosolic synaptic vesicle mobilization. Indeed, preterminal injection of a specific antibody against squid Rab27 (anti-sqRab27 antibody) combined with confocal microscopy demonstrated that Rab27 is present on squid synaptic vesicles. Electrophysiological study of injected synapses showed that the anti-sqRab27 antibody inhibited synaptic release in a stimulation-dependent manner without affecting presynaptic action potentials or inward Ca2+ current. This result was confirmed in in vitro synaptosomes by using total internal reflection fluorescence microscopy. Thus, synaptosomal Ca2+-stimulated release of FM1-43 dye was greatly impaired by intraterminal anti-sqRab27 antibody. Ultrastructural analysis of the injected giant preterminal further showed a reduced number of docked synaptic vesicles and an increase in nondocked vesicular profiles distant from the active zone. These results, taken together, indicate that Rab27 is primarily involved in the maturation of recycled vesicles and/or their transport to the presynaptic active zone in the squid giant synapse.

Subclinical hyperthyroidism and sudden unexpected death in epilepsy

Epilepsy is the most common serious neurological condition and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Information concerning risk factors for SUDEP is conflicting, but high seizure frequency is a potential risk factor. Additionally, potential pathomechanisms for SUDEP are unknown, but it is very probable that cardiac arrhythmias during and between seizures or transmission of epileptic activity to the heart via the autonomic nervous system potentially play a role. In parallel, several studies have shown a link between hormones and epilepsy. However, exact knowledge regarding the association of thyroid hormones and epilepsy is lacking. As subclinical hyperthyroidism has been linked with increased risk of cardiovascular disease, we propose in this paper that SUDEP, at least in some cases, could be related with subclinical thyroid dysfunction. (C) 2009 Elsevier Ltd. All rights reserved.

Phrenic nerve diabetic neuropathy in rats: unmyelinated fibers morphometry

We have demonstrated that phrenic nerves` large myelinated fibers in streptozotocin (STZ)-induced diabetic rats show axonal atrophy, which is reversed by insulin treatment. However, studies on structural abnormalities of the small myelinated and the unmyelinated fibers in the STZ-model of neuropathy are limited. Also, structural changes in the endoneural vasculature are not clearly described in this model and require detailed study. We have undertaken morphometric studies of the phrenic nerve in insulin-treated and untreated STZ-diabetic rats and non-diabetic control animals over a 12-week period. The presence of neuropathy was assessed by means of transmission electron microscopy, and morphometry of the unmyelinated fibers was performed. The most striking finding was the morphological evidence of small myelinated fiber neuropathy due to the STZ injection, which was not protected or reversed by conventional insulin treatment. This neuropathy was clearly associated with severe damage of the endoneural vessels present on both STZ groups, besides the insulin treatment. The STZ-diabetes model is widely used to investigate experimental diabetic neuropathies, but few studies have performed a detailed assessment of either unmyelinated fibers or capillary morphology in this animal model. The present study adds useful information for further investigations on the ultrastructural basis of nerve function in diabetes.

Acute chagasic myocardiopathy after orthotopic liver transplantation with donor and recipient serologically negative for Trypanosoma cruzi: A case report

Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi. Chagas disease following solid-organ transplantation has occurred in Latin America. This report presents the occurrence of Chagas disease despite negative serological tests in both the donor and the recipient, as well as the effectiveness of treatment. A 21-year-old woman from the state of Sao Paulo (Brazil) underwent cadaveric donor liver transplantation in November 2005, due to cirrhosis of autoimmune etiology. Ten months after liver transplantation, she developed signs and symptoms of congestive heart failure (New York Heart Association functional class IV). The echocardiogram, which was normal preoperatively, showed dilated cardiac chambers, depressed left ventricular systolic function (ejection fraction = 35%) and moderate pulmonary hypertension. Clinical investigation discarded ischemic heart disease and autoimmune and other causes for heart failure. Immuno fluorescence (immunoglobulin M and immunoglobulin G) and hemagglutination tests for T cruzi were positive, and abundant T cruzi amastigotes were readily identified in myocardial biopsy specimens. Treatment with benznidazole for 2 months yielded an excellent clinical response. At the moment of submission, the patient remains in functional class I. This case highlighted that more appropriate screening for T cruzi infection is mandatory in potential donors and recipients of solid-organ transplants in regions where Chagas disease is prevalent. Moreover, it stressed that this diagnosis should always be considered in recipients who develop cardiac complications, since negative serological tests do not completely discard the possibility of disease transmission and since good results can be achieved with prompt trypanocidal therapy.

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.

Masticatory muscle function three years after surgical correction of class III dentofacial deformity

Individuals with dentofacial deformities have masticatory muscle changes. The objective of the present study was to determine the effect of interdisciplinary treatment in patients with dentofacial deformities regarding electromyographic activity (EMG) of masticatory muscles three years after surgical correction. Thirteen patients with class III dentofacial deformities were studied, considered as group PI (before surgery) and group P3 (3 years to 3 years and 8 months after surgery). Fifteen individuals with no changes in facial morphology or dental occlusion were studied as controls. The participants underwent EMG examination of the temporal and masseter muscles during mastication and biting. Evaluation of the amplitude interval of EMG activity revealed a difference between P1 and P3 and no difference between P3 and the control group. In contrast, evaluation of root mean square revealed that, in general, P3 values were higher only when compared with PI and differed from the control group. There was an improvement in the EMG activity of the masticatory muscles, mainly observed in the masseter muscle, with values close to those of the control group in one of the analyses.

Effects of Inspiratory Muscle Training on Muscular and Pulmonary Function After Bariatric Surgery in Obese Patients

This study seeks to assess the effect of inspiratory muscle training (IMT) on pulmonary function, respiratory muscle strength, and endurance in morbidly obese patients submitted to bariatric surgery. Thirty patients were randomly assigned to sham muscular training, or to IMT with a threshold device (40% of maximum inspiratory pressure, MIP), for 30 min/day, from the 2nd until 30th postoperative (PO) day. All of them were submitted to a standard respiratory kinesiotherapy and early deambulation protocol. Data on spirometry, maximum static respiratory pressures, and respiratory muscle endurance were collected on the PO days 2, 7, 14, and 30 in a blinded matter. IMT enabled increases in PO MIP and endurance, and an earlier recovery of the spirometry parameters FEV(1), PEF, and FEF(25-75%). Comparing to preoperative values, MIP was increased by 13% at the 30th PO day in the trained group, whereas control group had a reduction of 8%, with higher values for the IMT group (30th PO, IMT-130.6 +/- 22.9 cmH(2)O; controls-112.9 +/- 25.1 cmH(2)O; p < 0.05). Muscular endurance at the 30th PO day was increased in the trained group comparing to preoperative value (61.5 +/- 39.6 s vs 114.9 +/- 55.2 s; p < 0.05), a finding not observed in the control group (81.7 +/- 44.3 vs 95.2 +/- 42.0 s). IMT improves inspiratory muscle strength and endurance and accounts for an earlier recovery of pulmonary airflows in morbidly obese patients submitted to bariatric surgery.