Spirometric abnormalities in patients with Fabry disease and effect of enzyme replacement therapy

Aim: Fabry disease is an X-linked genetic disorder due to deficiency of the lysosomal enzyme a-galactosidase A, which leads to the accumulation of neutral glycosphingolipids within the lysosomes of almost all tissues. Clinical manifestations usually include acroparaesthesia, renal insufficiency and cardiomyopathy. Recently, pulmonary manifestations consisting of progressive obstructive airway disease have been reported. The aim of this study was to analyse the cross-sectional prevalence of airflow obstruction in a Swiss cohort of patients, and in selected cases, to evaluate the impact of enzyme replacement therapy (ERT) with agalsidase alfa (ReplagalTM; TKT - 5S). Methods: Forty-four patients (27 men, 17 women) were included in the study and received pulmonary function testing. Fifteen patients underwent spirometry after ERT. Results: Twelve patients (nine men) had chronic obstructive pulmonary disease according to the Global Obstructive Lung Disease (GOLD) initiative criteria: forced expiratory volume (FEV1)/forced vital capacity (FVC) 50.7), but only one was an active smoker and one a previous smoker. FEV1/ FVC as percentage predicted was weakly correlated with age (r=0.42, p=0.005, calculated by Pearson product-moment correlation), demonstrating that airway obstruction occurs in the late stages of the disease. Median FEV1 in patients with obstruction was 67% of predicted (range, 45-90%). Reversibility of FEV1 after b2-agonist inhalation never exceeded 8% of predicted. Diffusing capacity of the lung for carbon monoxide (DLCO) was measured in 13 individuals with a median of 88% of predicted (range, 39-125%). After 15+9 months of ERT, spirometry measurements were recorded in 15 patients. Decline in FEV1 was -2+5% of predicted. (p40.05, measured by the Wilcoxon signed-rank test). Median change in DLCO was -10% of predicted (-40 to +25%, p40.05). High resolution computed tomography scans demonstrated a moderate thickening of the bronchial wall in affected individuals, without evidence of emphysema. Conclusion: We conclude that Fabry disease can be complicated by significant airway obstruction, particularly in patients in the advanced stages of the disease, and that in the period studied, ERT had no demonstrable impact on pulmonary function.

Cardiac re-synchronization therapy in a patient with isolated ventricular non-compaction: a case report.

Isolated ventricular non-compaction (IVNC) is a rare, congenital, unclassified cardiomyopathy characterized by prominent trabecular meshwork and deep recesses. Major clinical manifestations of IVNC are heart failure, atrial and ventricular arrhythmias, and thrombo-embolic events. We describe a case of a 69-year-old woman in whom the diagnosis of IVNC was discovered late, whereas former echocardiographic examinations were considered normal. She was known for systolic left ventricular dysfunction for 3 years and then became symptomatic (NYHA III). In the past, she suffered from multiple episodes of deep vein thrombosis and pulmonary embolism. Electrocardiogram revealed a wide QRS complex, and transthoracic echocardiography showed typical apical thickening of the left and right ventricular myocardial wall with two distinct layers. The ratio of non-compacted to compacted myocardium was >2:1. Cardiac MRI confirmed the echocardiographic images. Cerebral MRI revealed multiple ischaemic sequellae. In view of the persistent refractory, heart failure in medical treatment of patients with classical criteria for cardiac re-synchronization therapy, as well as the ventricular arrhythmias, a biventricular automatic intracardiac defibrillator (biventricular ICD) was implanted. The 2-year follow-up period was characterized by improvement of NYHA functional class from III to I and increasing in left ventricular function. We hereby present a case of IVNC with favourable outcome after biventricular ICD implantation. Cardiac re-synchronization therapy could be considered in the management of this pathology.

In vivo survival of teicoplanin-resistant Staphylococcus aureus and fitness cost of teicoplanin resistance.

Glycopeptide resistance, in a set of in vitro step-selected teicoplanin-resistant mutants derived from susceptible Staphylococcus aureus SA113, was associated with slower growth, thickening of the bacterial cell wall, increased N-acetylglucosamine incorporation, and decreased hemolysis. Differential transcriptome analysis showed that as resistance increased, some virulence-associated genes became downregulated. In a mouse tissue cage infection model, an inoculum of 10(4) CFU of strain SA113 rapidly produced a high-bacterial-load infection, which triggered MIP-2 release, leukocyte infiltration, and reduced leukocyte viability. In contrast, with the same inoculum of the isogenic glycopeptide-resistant derivative NM67, CFU initially decreased, resulting in the elimination of the mutant in three out of seven cages. In the four cages in which NM67 survived, it partially regained wild-type characteristics, including thinning of the cell wall, reduced N-acetylglucosamine uptake, and increased hemolysis; however, the survivors also became teicoplanin hypersusceptible. The elimination of the teicoplanin-resistant mutants and selection of teicoplanin-hypersusceptible survivors in the tissue cages indicated that glycopeptide resistance imposes a fitness burden on S. aureus and is selected against in vivo, with restoration of fitness incurring the price of resistance loss.

Deficiency symptoms and uptake of micronutrients by castor bean grown in nutrient solution

Castor bean is a nutrient-demanding species, but there is still little information on its micronutrient requirements. The objectives of this study were to evaluate the effects of levels of B (2.5, 12.5 and 25.0 µmol L-1), Cu (0.05, 0.25 and 0.50 µmol L-1), Mn (0.2, 1.0 and 2.0 µmol L-1) and Zn (0.2, 1.0 and 2.0 µmol L-1) in a nutrient solution on plant B, Cu, Mn and Zn concentrations and uptake, vegetative growth and fruit yield of castor bean "Iris", grown in greenhouse. The experiment was arranged in a completely randomized block design with three replicates. The first deficiency symptoms were observed for B, followed by Zn, Cu and Mn. The main changes in the cell ultrastructure due to lack of B were thickening of the cell walls and middle lamellae, distorted chloroplasts and tightly stacked thylakoids, besides the absence of starch grains. The Mn, Zn and Cu deficiencies led to disruption of chloroplasts, disintegration of thylakoids and absence of amyloplasts. The concentration and uptake of B, Cu, Mn, and Zn in castor bean plants increased with micronutrient supply in the solution. Fruit yield was drastically reduced by B and Mn deficiencies. On the other hand, the dry matter yield of the shoot and root of castor bean plants was not. In the treatment with full nutrient solution, the leaves accumulated 56 and 48 % of the total B and Mn taken up by the plants, respectively, and the seeds and roots 85 and 61 % of the total Cu and Zn taken up, respectively. This shows the high demand of castor bean Iris for B and Mn for fruit yield.

Neurofibrome palpébral chez une femme jeune [Eyelid neurofibroma affecting a young woman].

A 43-year-old female patient had an amelanotic single tumor thickening the upper right eyelid and observed since early childhood. Clinically, it appeared as a firm mass, without sharp margins, giving a thickened appearance to the superior eyelid. The ophthalmic clinical examination was normal but some subcutaneous nodules attested to the diffusion of the disease recognized as a limited form of neurofibromatosis 1. Although well tolerated, it gave rise to a cosmetic disturbance and the patient was willing to undergo an excision. A complete surgical excision was performed on the lesions and the pathological study disclosed a typical neurofibroma. Regular observation of the different cutaneous nodules was recommended.

Recurrent left colonic diverticulitis episodes: more severe than the initial diverticulitis?

BACKGROUND: Until recently, it was accepted that the rate of complications and failure of medical therapy were higher during recurrent episodes of diverticulitis. New data and new interpretation of older studies have challenged this opinion. The aim of the present study was to determine whether recurrent diverticulitis in comparison with the initial episode has a different short-term outcome after medical or surgical treatment. METHODS: This was a retrospective cohort study of 271 consecutive patients admitted for diverticulitis confirmed by computed tomography (CT) between 2001 and 2004. Altogether 202 patients had an initial episode (group I), and 69 had recurrent diverticulitis (group R). A total of 20 clinical and 15 radiologic parameters were analyzed and compared between the two groups, including need for surgery, clinical presentation at admission, response to treatment, complications, laboratory parameters, and pathologic CT features (colonic wall thickening, abscess, pneumoperitoneum, free intraperitoneal fluid). An unpaired Student's t-test and Fisher's and Wilcoxon's tests were applied for statistical analysis. RESULTS: None of the clinical or radiologic parameters was statistically different between the two groups. Regarding surgery, 15.8% of the group I patients needed surgery at admission compared to 5.8% in group R (p = 0.04). Conservative treatment failure was similar in the two groups (10.7% vs. 10.0%; p = 0.84). There was 3% mortality at 30 days in group I compared to 0% in group R. CONCLUSIONS: Recurrent episodes of diverticulitis do not lead to more complications and more conservative treatment failure. Moreover, surgery at admission was less frequent among patients who presented with a recurrence.

High-resolution ultrasonography of subretinal structure and assessment of retina degeneration in rat.

The purpose of this work was to evaluate the ability of 80 MHz ultrasonography to differentiate intra-retinal layers and quantitatively assess photoreceptor dystrophy in small animal models. Four groups of 10 RCS rats each (five dystrophic and five controls) were explored at 25, 35, 45 and 55 days post-natal (PN). A series of retina cross-sections were obtained ex vivo from outside intact eyes using an 80 MHz three-dimensional ultrasound backscatter microscope (20-microm-axial resolution). Ultrasound features of normal retina were correlated to those of corresponding histology and thickness measurements of photoreceptor segment and nuclear layers were performed on all groups. To show the ability of 80 MHz ultrasonography to distinguish the retinal degeneration in vivo, one RCS rat was explored at 25 and 55 days post-natal. Ultrasound image of normal retina displayed four distinct layers marked by reflections at neurites/nuclei interfaces and permitted to differentiate the photoreceptor segment and nuclear layers. The backscatter level from the retina was shown to be related to the size, density and organization of the intra-layer structure. Ultrasound thickness measurements highly correlated with histologic measurements. A thinning (p<0.05) of outer nuclear layer (ONL) was detected over time for controls and was thought to be assigned to retina maturation. Retinal degeneration started at PN35 and resulted in a more pronounced ONL thinning (p<0.05) over time. ONL degeneration was accompanied by segment layer thickening (p<0.05) at PN35 and thinning thereafter. These changes may indicate accumulation of outer segment debris at PN35 then progressive destruction. In vivo images of rat intra-retinal structure showed the ability of the method to distinguish the photoreceptor layer changes. Our results indicate that 80 MHz ultrasonography reveals intra-retinal layers and is sensitive to age and degenerative changes of photoreceptors. This technique has great potential to follow-up retinal dystrophy and therapeutic effects in vivo.

Necrotizing fasciitis: contribution and limitations of diagnostic imaging.

Necrotizing fasciitis is a rare, rapidly spreading, deep-seated infection causing thrombosis of the blood vessels located in the fascia. Necrotizing fasciitis is a surgical emergency. The diagnosis typically relies on clinical findings of severe sepsis and intense pain, although subacute forms may be difficult to recognize. Imaging studies can help to differentiate necrotizing fasciitis from infections located more superficially (dermohypodermitis). The presence of gas within the necrotized fasciae is characteristic but may be lacking. The main finding is thickening of the deep fasciae due to fluid accumulation and reactive hyperemia, which can be visualized using computed tomography and, above all, magnetic resonance imaging (high signal on contrast-enhanced T1 images and T2 images, best seen with fat saturation). These findings lack specificity, as they can be seen in non-necrotizing fasciitis and even in non-inflammatory conditions. Signs that support a diagnosis of necrotizing fasciitis include extensive involvement of the deep intermuscular fascias (high sensitivity but low specificity), thickening to more than 3mm, and partial or complete absence on post-gadolinium images of signal enhancement of the thickened fasciae (fairly high sensitivity and specificity). Ultrasonography is not recommended in adults, as the infiltration of the hypodermis blocks ultrasound transmission. Thus, imaging studies in patients with necrotizing fasciitis may be challenging to interpret. Although imaging may help to confirm deep tissue involvement and to evaluate lesion spread, it should never delay emergency surgical treatment in patients with established necrotizing fasciitis.

Shear thinning and thixotropy of HMHEC and HEC water solutions

Steady state viscosity and thixotropy of hydrophobically modified hydroxyethyl cellulose HMHEC and nonassociative cellulose water solutions are studied. Although all the samples are shear thinning, only the HMHEC is thixotropic, since the migration of hydrophobes to micelles is controlled by diffusion. The Cross model fits steady state curves. The Mewis model, a phenomenological model that proposes that the rate of change of viscosity when the shear rate is suddenly changed is related to the difference between the steady state and current values of viscosity raised to an exponent, fits structure construction experiments when the exponent, n, is estimated to be around 2. The Newtonian assumption used by Mewis cannot be used here, however. This seems to be related to the fact that the thickening is due to bridged micelle formation, which is a slow process, and also to topological constraints and entanglements, which are rapid processes. The kinetic parameter was redefined to kn in order to make it independent of initial conditions. So, kn depends only on how the shear affects the structure. kn reaches a plateau at shear rates too low to produce structure destruction and decreases at higher shear rates.

An angiotensin II- and NF-kappaB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension.

AIMS: Connexins (Cxs) play a role in the contractility of the aorta wall. We investigated how connexins of the endothelial cells (ECs; Cx37, Cx40) and smooth muscle cells (SMCs; Cx43, Cx45) of the aorta change during renin-dependent and -independent hypertension. METHODS AND RESULTS: We subjected both wild-type (WT) mice and mice lacking Cx40 (Cx40(-/-)), to either a two-kidney, one-clip procedure or to N-nitro-l-arginine-methyl-ester treatment, which induce renin-dependent and -independent hypertension, respectively. All hypertensive mice featured a thickened aortic wall, increased levels of Cx37 and Cx45 in SMC, and of Cx40 in EC (except in Cx40(-/-) mice). Cx43 was up-regulated, with no effect on its S368 phosphorylation, only in the SMCs of renin-dependent models of hypertension. Blockade of the renin-angiotensin system of Cx40(-/-) mice normalized blood pressure and prevented both aortic thickening and Cx alterations. Ex vivo exposure of WT aortas, carotids, and mesenteric arteries to physiologically relevant levels of angiotensin II (AngII) increased the levels of Cx43, but not of other Cx. In the aortic SMC line of A7r5 cells, AngII activated kinase-dependent pathways and induced binding of the nuclear factor-kappa B (NF-kappaB) to the Cx43 gene promoter, increasing Cx43 expression. CONCLUSION: In both large and small arteries, hypertension differently regulates Cx expression in SMC and EC layers. Cx43 is selectively increased in renin-dependent hypertension via an AngII activation of the extracellular signal-regulated kinase and NF-kappaB pathways.

Incidence of anatomical variations and disease of the maxillary sinuses as identified by cone beam computed tomography: a systematic review.

PURPOSE: To analyze available evidence on the incidence of anatomical variations or disease of the maxillary sinuses as identified by cone beam computed tomography (CBCT) in dentistry. MATERIALS AND METHODS: A focused question was developed to search the electronic databases MEDLINE, EMBASE, the Cochrane Oral Health Group Trials Register, and CENTRAL and identify all relevant papers published between 1980 and January 19, 2013. Unpublished literature at ClinicalTrials.gov, in the National Research Register, and in the Pro-Quest Dissertation Abstracts and Thesis database was also included. Studies were included irrespective of language. These results were supplemented by hand and gray literature searches. RESULTS: Twenty-two studies were identified. Twenty were retrospective cohort studies, one was a prospective cohort study, and one was a case control study. The main indication for CBCT was dental implant treatment planning, and the majority of studies used a small field of view for imaging. The most common anatomical variations included increased thickness of the sinus membrane, the presence of sinus septa, and pneumatization. Reported sinus disease frequency varied widely, ranging from 14.3% to 82%. There was a wide range in the reported prevalence of mucosal thickening related to apical pathology, the degree of lumenal opacification, features of sinusitis, and the presence of retention cysts and polyps. More pathologic findings in the maxillary sinus were reported in men than in women, and the medial wall and sinus floor were most frequently affected. CONCLUSION: CBCT is used primarily to evaluate bony anatomy and to screen for overt pathology of the maxillary sinuses prior to dental implant treatment. Differences in the classification of mucosal findings are problematic in the consistent and valid assessment of health and disease of the maxillary sinus.

Cardiovascular hypertrophy: role of angiotensin II and bradykinin.

Angiotensin II can raise blood pressure rapidly by inducing direct vasoconstriction and by activating the sympathetic nervous system via central and peripheral mechanisms. In addition, this peptide may act as a growth factor to cause vascular and cardiac hypertrophy (CVH). The structural changes caused by hypertension can therefore be amplified by angiotensin II. Blockade of angiotensin II generation with angiotensin-converting enzyme (ACE) inhibitors appears to be particularly effective in preventing the development of cardiovascular hypertrophy. This beneficial effect might be related to some extent to local accumulation of bradykinin. ACE is one of the enzymes physiologically involved in bradykinin degradation. Treatment of hypertensive rats with a selective bradykinin antagonist can attenuate the blood pressure-lowering effect of ACE inhibition and render less effective the prevention of intimal thickening after endothelial removal from the rat carotid artery. Bradykinin is a vasodilator that acts by increasing the release of endothelium-derived factors such as nitric oxide and prostacyclin, which may have antiproliferative activity. However, blockade of the renin-angiotensin system with an angiotensin II subtype 1-receptor antagonist is also effective in preventing cardiac hypertrophy and neointimal proliferation after endothelial injury. Therefore, the exact contribution of bradykinin to the beneficial effects of ACE inhibition on cardiovascular hypertrophy remains to be further explored.

In vivo time-resolved spectroscopy of the human bronchial early cancer autofluorescence.

Time-resolved measurements of tissue autofluorescence (AF) excited at 405 nm were carried out with an optical-fiber-based spectrometer in the bronchi of 11 patients. The objectives consisted of assessing the lifetime as a new tumor/normal (T/N) tissue contrast parameter and trying to explain the origin of the contrasts observed when using AF-based cancer detection imaging systems. No significant change in the AF lifetimes was found. AF bronchoscopy performed in parallel with an imaging device revealed both intensity and spectral contrasts. Our results suggest that the spectral contrast might be due to an enhanced blood concentration just below the epithelial layers of the lesion. The intensity contrast probably results from the thickening of the epithelium in the lesions. The absence of T/N lifetime contrast indicates that the quenching is not at the origin of the fluorescence intensity and spectral contrasts. These lifetimes (6.9 ns, 2.0 ns, and 0.2 ns) were consistent for all the examined sites. The fact that these lifetimes are the same for different emission domains ranging between 430 and 680 nm indicates that there is probably only one dominant fluorophore involved. The measured lifetimes suggest that this fluorophore is elastin.

Electrical signature of modern and ancient tectonic processes in the crust of the Atlas mountains of Morocco.

The Atlas Mountains in Morocco are considered as type examples of intracontinental chains, with high topography that contrasts with moderate crustal shortening and thickening. Whereas recent geological studies and geodynamic modeling have suggested the existence of dynamic topography to explain this apparent contradiction, there is a lack of modern geophysical data at the crustal scale to corroborate this hypothesis. Newly-acquired magnetotelluric data image the electrical resistivity distribution of the crust from the Middle Atlas to the Anti-Atlas, crossing the tabular Moulouya Plain and the High Atlas. All the units show different and unique electrical signatures throughout the crust reflecting the tectonic history of development of each one. In the upper crust electrical resistivity values may be associated to sediment sequences in the Moulouya and Anti-Atlas and to crustal scale fault systems in the High Atlas developed during the Cenozoic times. In the lower crust the low resistivity anomaly found below the Mouluya plain, together with other geophysical (low velocity anomaly, lack of earthquakes and minimum Bouguer anomaly) and geochemical (Neogene-Quaternary intraplate alkaline volcanic fields) evidence, infer the existence of a small degree of partial melt at the base of the lower crust. The low resistivity anomaly found below the Anti-Atlas may be associated with a relict subduction of Precambrian oceanic sediments, or to precipitated minerals during the release of fluids from the mantle during the accretion of the Anti-Atlas to the West African Supercontinent during the Panafrican orogeny ca. 685 Ma).

Cardiovascular Risk Prediction with Ultrasound

This paper addresses primary care physicians, cardiologists, internists, angiologists and doctors desirous of improving vascular risk prediction in primary care. Many cardiovascular risk factors act aggressively on the arterial wall and result in atherosclerosis and atherothrombosis. Cardiovascular prognosis derived from ultrasound imaging is, however, excellent in subjects without formation of intimal thickening or atheromas. Since ultrasound visualises the arterial wall directly, the information derived from the arterial wall may add independent incremental information to the knowledge of risk derived from global risk assessment. This paper provides an overview on plaque imaging for vascular risk prediction in two parts: Part 1: Carotid IMT is frequently used as a surrogate marker for outcome in intervention studies addressing rather large cohorts of subjects. Carotid IMT as a risk prediction tool for the prevention of acute myocardial infarction and stroke has been extensively studied in many patients since 1987, and has yielded incremental hazard ratios for these cardiovascular events independently of established cardiovascular risk factors. However, carotid IMT measurements are not used uniformly and therefore still lack widely accepted standardisation. Hence, at an individual, practicebased level, carotid IMT is not recommended as a risk assessment tool. The total plaque area of the carotid arteries (TPA) is a measure of the global plaque burden within both carotid arteries. It was recently shown in a large Norwegian cohort involving over 6000 subjects that TPA is a very good predictor for future myocardial infarction in women with an area under the curve (AUC) using a receiver operating curves (ROC) value of 0.73 (in men: 0.63). Further, the AUC for risk prediction is high both for vascular death in a vascular prevention clinic group (AUC 0.77) and fatal or nonfatal myocardial infarction in a true primary care group (AUC 0.79). Since TPA has acceptable reproducibility, allows calculation of posttest risk and is easily obtained at low cost, this risk assessment tool may come in for more widespread use in the future and also serve as a tool for atherosclerosis tracking and guidance for intensity of preventive therapy. However, more studies with TPA are needed. Part 2: Carotid and femoral plaque formation as detected by ultrasound offers a global view of the extent of atherosclerosis. Several prospective cohort studies have shown that cardiovascular risk prediction is greater for plaques than for carotid IMT. The number of arterial beds affected by significant atheromas may simply be added numerically to derive additional information on the risk of vascular events. A new atherosclerosis burden score (ABS) simply calculates the sum of carotid and femoral plaques encountered during ultrasound scanning. ABS correlates well and independently with the presence of coronary atherosclerosis and stenosis as measured by invasive coronary angiogram. However, the prognostic power of ABS as an independent marker of risk still needs to be elucidated in prospective studies. In summary, the large number of ways to measure atherosclerosis and related changes in human arteries by ultrasound indicates that this technology is not yet sufficiently perfected and needs more standardisation and workup on clearly defined outcome studies before it can be recommended as a practice-based additional risk modifier.