Enzyme replacement therapy with agalsidase alfa in patients with Fabry's disease: an analysis of registry data.

BACKGROUND: We analysed 5-year treatment with agalsidase alfa enzyme replacement therapy in patients with Fabry's disease who were enrolled in the Fabry Outcome Survey observational database (FOS). METHODS: Baseline and 5-year data were available for up to 181 adults (126 men) in FOS. Serial data for cardiac mass and function, renal function, pain, and quality of life were assessed. Safety and sensitivity analyses were done in patients with baseline and at least one relevant follow-up measurement during the 5 years (n=555 and n=475, respectively). FINDINGS: In patients with baseline cardiac hypertrophy, treatment resulted in a sustained reduction in left ventricular mass (LVM) index after 5 years (from 71.4 [SD 22.5] g/m(2.7) to 64.1 [18.7] g/m(2.7), p=0.0111) and a significant increase in midwall fractional shortening (MFS) from 14.3% (2.3) to 16.0% (3.8) after 3 years (p=0.02). In patients without baseline hypertrophy, LVM index and MFS remained stable. Mean yearly fall in estimated glomerular filtration rate versus baseline after 5 years of enzyme replacement therapy was -3.17 mL/min per 1.73 m(2) for men and -0.89 mL/min per 1.73 m(2) for women. Average pain, measured by Brief Pain Inventory score, improved significantly, from 3.7 (2.3) at baseline to 2.5 (2.4) after 5 years (p=0.0023). Quality of life, measured by deviation scores from normal EuroQol values, improved significantly, from -0.24 (0.3) at baseline to -0.17 (0.3) after 5 years (p=0.0483). Findings were confirmed by sensitivity analysis. No unexpected safety concerns were identified. INTERPRETATION: By comparison with historical natural history data for patients with Fabry's disease who were not treated with enzyme replacement therapy, long-term treatment with agalsidase alfa leads to substantial and sustained clinical benefits. FUNDING: Shire Human Genetic Therapies AB.

Mini-review: the ultrasonographical and serological chanbges and their improvement after praziquantel treatment Schistosoma japonicum infected patients in Leyete, Philippines

We have identified the specific ultrasonographical (US) changes in Schistosoma japonicum infected patients with the serological changes in general liver function markers. The US examination with the following haematological and biochemical serum analysis was performed on 102 patients in Shistosomiasis Hospital, Leyte, Philippines. The US liver images were classified into 4 patterns according to the development of periportal fibrosis and the patterns of echogenic bands. Among various haematological and biochemical serum parameters of liver damage. The serum levels of total bile acid (TBA) and procollagen-III-peptide (P-III-P) correlated well with the development of hepatic fibrosis and the portal hypertension. These patients were subsequently treated with praziquantel (3 x 20 mg/kg), and improvement of the thickening of the portal vein wall and the dintensity of the echogenic band formation was detected 6 months after treatment. The significant US changes could not be detected in the patients with severe hepatic fibrosis caused in the long term infection. The results revealed that the US examination with the serum TBa level would provider a sensitive tool monitor the severity of the infection and also the improvement occured shortly after praziquantel treatment.

Thermogenic effect of bronchodilators in patients with chronic obstructive pulmonary disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are frequently malnourished and have increased resting energy expenditure (REE). An increase in the work of breathing is generally considered to be the main cause of this hypermetabolism, but other factors may also be implicated. Bronchodilators may decrease the work of breathing by reducing airway obstruction, but beta 2 adrenergic agents have a thermogenic effect. The aim of this study was to determine the effect of salbutamol and ipratropium bromide administration on REE in patients with COPD. METHODS: Thirteen patients (10 men) of mean (SD) age 68.3 (7.3) years and forced expiratory volume in one second (FEV1) 39.0 (17.0)% predicted were studied on three consecutive days. The REE was measured by indirect calorimetry at 30, 60, 120, and 180 minutes after double blind nebulisation of either salbutamol, ipratropium bromide, or placebo in random order. RESULTS: FEV1 increased both after salbutamol and after ipratropium. The difference in the mean response between salbutamol and placebo over 180 minutes was +199 ml (95% CI +104 to +295). The difference in mean response between ipratropium and placebo was +78 ml (95% CI +2 to +160). REE increased after salbutamol but was not changed after ipratropium. The difference in mean response between salbutamol and placebo was +4.8% of baseline REE (95% CI +2.2 to +7.4). Heart rate increased after salbutamol but not after ipratropium. The difference in the mean response between salbutamol and placebo was +5.5 beats/ min (95% CI +2.6 to +8.4). CONCLUSION: Salbutamol, but not ipratropium bromide, induces a sustained increase in the REE of patients with COPD despite a reduction in airway obstruction.

Le rein de l'enfant face à la chimiothérapie [The kidney in children under chemotherapy].

Nowadays more and more children survive after an intensive anti-tumoral therapy. The price to pay consists of numerous and relatively frequent long-term sequelae (secondary tumors, neuropsychological deficits, endocrine or cardiac damage). After chemotherapy, we sometimes observe renal side-effects, either tubular (metabolic acidosis, hypokalemia, hypomagnesemia, proteinuria, Fanconi syndrome, rickets) or glomerular (acute or chronic decreased GFR). These renal toxic side-effects are encountered especially after cisplatinum and ifosfamide, less frequently after carboplatin and cyclophosphamide. The pediatrician has to be aware of these toxic nephrologic side-effects, to look out for them and monitor carefully the renal function of all paediatric patients receiving these potentially nephrotoxic chemotherapies.

Diet-induced thermogenesis in chronic obstructive pulmonary disease.

Increased resting energy expenditure and malnutrition are frequently observed in patients with COPD. The aim of this study was to examine the possible contribution of an increased diet-induced thermogenesis (DIT) to weight loss. Eleven patients with COPD in stable clinical state and 11 healthy control subjects were studied. Resting energy expenditure (REE) was measured by standard methods of indirect calorimetry, using a ventilated canopy. Premeal REE was measured after an overnight fast. All subjects then received a balanced liquid test meal with a caloric content that was 0.3 times their REE extrapolated to 24 h. Diet-induced thermogenesis was measured over 130 min. Premeal REE was 109.9 +/- 11.7% of predicted values in the COPD group and 97.5 +/- 9.6% of predicted in the control group (p < 0.01). Seventy minutes after the test meal, REE had increased by 18.8 +/- 8.5% in the COPD group and by 15.1 +/- 5.8% in the control group (NS). After 130 min, REE had increased by 16.4 +/- 7.1% in the COPD group and by 12.4 +/- 5.3% in the control group (NS). The DIT expressed as a percentage of the caloric content of the meal was 4.3 +/- 1.6% in the COPD group and 3.3 +/- 1.4% in the control group (NS). We conclude that patients with stable COPD, although hypermetabolic at rest, do not show an increased DIT.

Are oxygen uptake kinetics modified when using a respiratory snorkel?

PURPOSE: The aim of this study was to compare VO2 kinetics during constant power cycle exercise measured using a conventional facemask (CM) or a respiratory snorkel (RS) designed for breath-by-breath analysis in swimming. METHODS: VO2 kinetics parameters-obtained using CM or RS, in randomized counterbalanced order-were compared in 10 trained triathletes performing two submaximal heavy-intensity cycling square-wave transitions. These VO2 kinetics parameters (ie, time delay: td1, td2; time constant: τ1, τ2; amplitude: A1, A2, for the primary phase and slow component, respectively) were modeled using a double exponential function. In the case of the RS data, this model incorporated an individually determined snorkel delay (ISD). RESULTS: Only td1 (8.9 ± 3.0 vs 13.8 ± 1.8 s, P < .01) differed between CM and RS, whereas all other parameters were not different (τ1 = 24.7 ± 7.6 vs 21.1 ± 6.3 s; A1 = 39.4 ± 5.3 vs 36.8 ± 5.1 mL x min(-1) x kg(-1); td2 = 107.5 ± 87.4 vs 183.5 ± 75.9 s; A2' (relevant slow component amplitude) = 2.6 ± 2.4 vs 3.1 ± 2.6 mL x min(-1) x kg(-1) for CM and RS, respectively). CONCLUSIONS: Although there can be a small mixture of breaths allowed by the volume of the snorkel in the transition to exercise, this does not appear to significantly influence the results. Therefore, given the use of an ISD, the RS is a valid instrument for the determination of VO2 kinetics within submaximal exercise.

Effects of caffeine on energy metabolism, heart rate, and methylxanthine metabolism in lean and obese women.

The magnitude of coffee-induced thermogenesis and the influence of coffee ingestion on substrate oxidation were investigated in 10 lean and 10 obese women, over two 24-h periods in a respiratory chamber. On one occasion the subjects consumed caffeinated coffee and on the other occasion, decaffeinated coffee. The magnitude of thermogenesis was smaller in obese (4.9 +/- 2.0%) than in lean subjects (7.6 +/- 1.3%). The thermogeneic response to caffeine was prolonged during the night in lean women only. The coffee-induced stimulation of energy expenditure was mediated by a concomitant increase in lipid and carbohydrate oxidation. During the next day, in postabsorptive basal conditions, the thermogenic effect of coffee had vanished, but a significant increase in lipid oxidation was observed in both groups. The magnitude of this effect was, however, blunted in obese women (lipid oxidation increased by 29 and 10% in lean and obese women, respectively). Caffeine increased urinary epinephrine excretion. Whereas urinary caffeine excretion was similar in both groups, obese women excreted more theobromine, theophylline, and paraxanthine than lean women. Despite the high levels of urinary methylxanthine excretion, thermogenesis and lipid oxidation were less stimulated in obese than in lean subjects.

Shrinking lung syndrome successfully treated with rituximab and cyclophosphamide.

Shrinking lung syndrome (SLS) is an uncommon feature of systemic lupus erythematosus (SLE) characterized by dyspnea, pleuritic chest pain, diaphragmatic elevation, restrictive ventilatory defect and reduced respiratory muscle strength as measured by volitional tests. We report the case of a 28-year-old woman with overlapping features of SLE and Sjögren syndrome who developed severe SLS while receiving corticosteroids and azathioprine for severe polyarthritis. She was treated with a combination of rituximab and cyclophosphamide, which led to a dramatic improvement in her clinical condition and respiratory function tests. The increase in vital capacity was one of the highest among 35 published cases of SLS. Thus, restoring a near-normal lung function is an achievable goal in SLS, and the use of rituximab, with or without concomitant cyclophosphamide, certainly deserves further study in this setting.

Dual transplant of marginal kidneys. Case report and review of the literature.

INTRODUCTION: Double transplantation is one possible answer to the shortage of donor organs. While each donor kidney would be unsuitable when considered as a single allograft, use of both kidneys should provide sufficient nephron mass for effective glomerular filtration. CASE REPORT: This is the first Swiss report of a dual adult transplant of marginal kidneys in a 46-year-old man, who was transplanted for the fourth time. Follow-up at 6 months is excellent without acute rejection. CONCLUSION: Recent analysis of dual marginal versus single ideal transplant outcomes, found a comparable 1-yr graft survival in both of the procedures. Long term results are still lacking and guidelines to decide between single, double or no transplantation are emerging.

A New Year's Resolution - be smart about your drinking!

Now 2012 has arrived, the Public Health Agency is encouraging people to make a New Year's resolution to know their limits when it comes to alcohol, not to drink excessively and to cut back for a while, especially if the festive period led to a little too much consumption.Owen O'Neill, PHA Health and Social Wellbeing Improvement Manager and drugs and alcohol lead, explained: "The New Year is a great opportunity for us to be positive about our health, making resolutions that make us look and feel better. If people choose to drink, staying within the safe drinking limits is important. Excessive and binge drinking can have lasting effects on health, such as damage to the liver, heart, brain and stomach. Drinking too much can also increase the risk of accidents and antisocial behaviour as well as sexually transmitted infections and unplanned pregnancy. And it doesn't have to be drinking to extremes - regularly drinking over the recommended limits can have a damaging effect."Remember that for each unit you drink over the daily limit, the risk to your health increases. It's important to spread the units throughout the week and not 'save' them for the weekend and to drink plenty of water, ideally matching the amount of alcohol you have consumed."For those who have consumed a lot of alcohol over the festive season, cutting back in the New Year and being careful can have immediate, positive effects particularly on helping you to look and feel better, being less tired during the day, feeling fitter and perhaps losing weight. Longer term, the benefits include improved mood, sleep, memory and general health, particularly improving liver function, immunity to illness and preventing any damage caused by any excessive drinking getting any worse."Daily alcohol limits are recommended by the government to avoid the dangers of excessive and binge drinking in any one session. These are:MenNo more than 3 to 4 units of alcohol a day and no more than 21 units over the course of the week.WomenNo more than 2 to 3 units of alcohol a day and no more than 14 units over the course of the week.Examples of units:Can of extra strong lager - 4 unitsBottle of lager - 1.5 unitsSmall pub bottle of wine - 2.25 unitsPub measure of spirits - 1.5 unitsPint of stout - 2.5 unitsPint of cider - 3 unitsFor further information on sensible drinking and alcohol units visit the Public Health Agency's website www.knowyourlimits.info

Magnetic resonance stress tagging in ischemic heart disease.

High-dose dobutamine magnetic resonance stress testing has been shown to be superior to dobutamine stress echocardiography for diagnosis of coronary artery disease (CAD). We determined the feasibility of quantitative myocardial tagging during low- and high-dose dobutamine stress and tested the ability of global systolic and diastolic quantitative parameters to identify patients with significant CAD. Twenty-five patients suspected of having significant CAD were examined with a standard high-dose dobutamine/atropine stress magnetic resonance protocol (1.5-T scanner, Philips). All patients underwent invasive coronary angiography as the standard of reference for the presence (n = 13) or absence (n = 12) of significant CAD. During low-dose dobutamine stress, systolic (circumferential shortening, systolic rotation, and systolic rotation velocity) and diastolic (velocity of circumferential lengthening and diastolic rotation velocity) parameters changed significantly in patients without CAD (all P < 0.05 vs. rest) but not in patients with CAD. Identification of patients without and with CAD during low-dose stress was possible using the diastolic parameter of "time to peak untwist." At high-dose stress, none of the global systolic or diastolic parameters showed the potential to identify the presence of significant CAD. With myocardial tagging, a quantitative analysis of systolic and diastolic function was feasible during low- and high-dose dobutamine stress. In our study, the diastolic parameter of time to peak untwist as assessed during low-dose dobutamine stress was the most promising global parameter for identification of patients with significant CAD. Thus quantitative myocardial tagging may become a tool that reduces the need for high-dose dobutamine stress.

Asthme a début tardif [Late-onset asthma].

Late-onset asthma is a common disease, with characteristics that differentiate it from childhood asthma persisting in adults, including a heterogeneity of underlying mechanism, a correlation with occupational exposure and the tendency to chronicize. Inadequate perception of the disease importance and difficulties in diagnosis, due to the association to COPD, the broad differential diagnosis spectrum and an atypical clinical manifestation, make this disease entity underdiagnosed and under-treated, with consequences for morbidity and mortality. The treatment of adults with asthma follows the usual guidelines, but must take into account an occasional poor therapeutic response and the risk of side effects in polymorbid patients.

Transfer factor for carbon monoxide: a glance behind the scene.

The transfer factor for carbon monoxide (TLCO) is widely used in pulmonary function laboratories because it represents a unique non-invasive window on pulmonary microcirculation. The TLCO is the product of two primary measurements, the alveolar volume (VA) and the CO transfer coefficient (KCO). This test is most informative when VA and KCO are examined, together with their product TLCO. In a normal lung, a low VA due to incomplete expansion is associated with an elevated KCO, resulting in a mildly reduced TLCO. Thus, in case of low VA, a seemingly "normal KCO" must be interpreted as an abnormal gas transfer. The most common clinical conditions associated with an abnormal TLCO are characterised by a limited number of patterns for VA and KCO: incomplete lung expansion, discrete loss of alveolar units, diffuse loss of alveolar units, emphysema, pulmonary vascular disorders, high pulmonary blood volume, alveolar haemorrhage.

Dexamethasone therapy and cortisol excretion in severe pediatric head injury.

Glucocorticoids are used in an attempt to reduce brain edema secondary to head injury. Nevertheless, their usefulness remains uncertain and contradictory. In a randomized study of 24 children with severe head injury, urinary free cortisol was measured by radioimmunoassay. Twelve patients (group 1) received dexamethasone and 12 (group 2) did not. All patients were treated with a standardized regimen. In group 1 there was complete suppression of endogenous cortisol production. In group 2 free cortisol was up to 20-fold higher than under basal conditions and reached maximum values on days 1-3. Since the excretion of cortisol in urine reflects the production rate closely and is not influenced by liver function and barbiturates, the results in group 2 show that the endogenous production of steroids is an adequate reaction to severe head injury. Exogenous glucocorticoids are thus unlikely to have any more beneficial effects than endogenous cortisol.