Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study

Background

Due partly to physicians’ unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression.

Methods

We conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry), muscle function (quick motor function test), and pulmonary function (forced vital capacity in sitting and supine positions) were assessed every 3–6 months and analyzed using repeated-measures ANOVA.

Results

Between October 2004 and August 2009, 94 patients aged between 25 and 75 years were included in the study. Although skeletal muscle weakness was typically distributed in a limb-girdle pattern, many patients had unfamiliar features such as ptosis (23%), bulbar weakness (28%), and scapular winging (33%). During follow-up (average 1.6 years, range 0.5-4.2 years), skeletal muscle strength deteriorated significantly (mean declines of ?1.3% point/year for manual muscle testing and of ?2.6% points/year for hand-held dynamometry; both p<0.001). Longer disease duration (>15 years) and pulmonary involvement (forced vital capacity in sitting position <80%) at study entry predicted faster decline. On average, forced vital capacity in supine position deteriorated by 1.3% points per year (p=0.02). Decline in pulmonary function was consistent across subgroups. Ten percent of patients declined unexpectedly fast.

Conclusions

Recognizing patterns of common and less familiar characteristics in adults with Pompe disease facilitates timely diagnosis. Longer disease duration and reduced pulmonary function stand out as predictors of rapid disease progression, and aid in deciding whether to initiate enzyme replacement therapy, or when.

     

Frequency encoded biochemical regulation is more accurate than amplitude dependent control

It is generally recognised in engineering that encoding information in a frequency provides resistance to degradation by noise and an enhanced precision of control. This paper demonstrates how the same arguments can be applied to biochemical control networks. It shows that the conversion of an analogue demand signal to an oscillation is stable against corruption by noise in the input and even against corruption by certain internal chaotic motions. The paper also argues that intracellular transmission of frequency encoded information is robust against noise. These arguments are proposed as a partial explanation of why so many biological regulatory systems are periodic.     

Expression and prognostic value of glucose transporters and hexokinases in tonsil and mobile tongue squamous cell carcinoma

The aim of this study was to assess the expression pattern and prognostic value of the high affinity glucose transporters GLUT-1, 3, 4, 8 and 9, SGLT-1 and of hexokinases (HK) I, II and III in squamous cell carcinoma of the tonsil and mobile tongue (TTSCC) by means of immunohistochemistry. Seventy-one consecutive patients suffering from TTSCC were included. The intensity and amount of positive tumour cells in the immunoreaction (histology score (H-score)) for GLUT-1, 3, 4, 8 and 9 as well as for HK-I, II and III were assessed independently by two experienced observers, blinded to the clinical results. H-scores as well as clinical variables were related to patient outcome. Median follow-up time was 49 months (range 1-123 months). Mean H-scores for GLUT expression in decreasing order of magnitude were respectively 10.99 for GLUT-1 (sd 3.9), 5.7 for GLUT-8 (sd 4.0), 5.4 for GLUT-3 (sd 3.7), 1.0 for GLUT-4 (sd 2.0), 1.1 (sd 1.3) for SGLT-1, and 0.4 for GLUT-9 (sd 0.6); GLUT-1 > GLUT-8 = GLUT-3 > GLUT-4 = GLUT-9 = SGLT-1 (with > meaning significantly (p<0.05 on ANOVA + posthoc Bonferroni correction) higher than and =, meaning not significantly different from). Mean H-scores for hexokinase expression were respectively 5.8 for HK-I (sd 3.5), 4.6 for HK-II (sd 3.0) and 2.0 for HK-III (sd 2.0); HK-I > HK-II > HK-III. Finally high H-scores for GLUT-4 were favourably related to disease-free and overall survival on multivariate analysis. To conclude, TTSCC expresses a wide variety of glucose transporter systems and hexokinase enzymes with the "housekeeping" GLUT-1 and HK-I being the most intensely expressed. GLUT-4 over-expression appears to confer a favourable prognosis in squamous cell carcinoma of the tonsil and mobile tongue. Additional studies confirming this finding in larger cohorts of patients are mandatory.     

Paranormal healing and hypertension

A prospective randomised trial was carried out to see whether paranormal healing by laying on of hands might reduce blood pressure in essential hypertension and whether such an effect might be due to a paranormal, psychological, or placebo factor. Patients were randomised to three treatment groups: paranormal healing by laying on of hands (n=40), paranormal healing at a distance (n=37), and no paranormal healing (controls; n=38). Healing at a distance and no paranormal healing were investigated double blind. Systolic and diastolic blood pressures were significantly reduced in all three groups at week 15 (mean reduction (95% confidence interval) 17·1 (14·0 to 20·2)/8·3 (6·6 to 10·0) mm Hg). Only the successive reductions in diastolic blood pressures among the groups from week to week were significantly different. Each week diastolic pressure was consistently lower (average 1·9 mm Hg) after healing at a distance compared with control, but on paired comparison these differences were not significant. Probably week to week variations among the groups accounted for any differences noted.In this study no treatment was consistently better than another and the data cannot therefore be taken as evidence of a paranormal effect on blood pressure. Probably the fall in blood pressure in all three groups either was caused by the psychosocial approach or was a placebo effect of the trial itself.     

Follow up study of 70 patients with renal artery stenosis treated by percutaneous transluminal dilatation.

Between April 1978 and April 1981, 70 patients with hypertension and renal artery stenosis were treated by percutaneous transluminal arterial dilatation. Selection of the patients was based solely on arteriographic criteria. Arteriography after dilatation showed considerable widening of the stenosed area in all patients. In 65 patients the effect of treatment on the blood pressure was assessed during follow up periods of one to four years. In 14 of these patients the hypertension was cured, in 29 it was improved, and in 22 there was no change. Patients with fibromuscular lesions benefited distinctly more than did those with atheromatous stenosis, only one of the 21 patients with fibromuscular lesions showing no change as compared with 21 of the 44 patients with atheromatous lesions. The only serious complication encountered was microcholesterol emboli, which developed in two patients with severe atheromatous lesions of the aorta. In the atheromatous group age and overall renal function had no influence on the blood pressure response. In the subgroup of patients with a unilateral lesion the renal vein renin ratios and asymmetrical curves obtained by renography had only a very limited predictive value. In experienced hands percutaneous transluminal arterial dilatation is relatively safe, and this study suggests that it should be attempted in all patients with renal artery stenosis. Only in patients with severe atheromatosis of the aorta should the risk associated with the catheterisation be weighed against the 50% or so chance of benefit from the procedure.     

Reduction of blood pressure,plasma cholesterol,and atherosclerosis by elevated endothelial nitric oxide

In the vascular system, nitric oxide is generated by endothelial NO synthase (eNOS). NO has pleiotropic effects, most of which are believed to be atheroprotective. Therefore, it has been argued that patients suffering from cardiovascular disease could benefit from an increase in eNOS activity. However, increased NO production can cause oxidative damage, cell toxicity, and apoptosis and hence could be atherogenic rather than beneficial. To study the in vivo effects of increased eNOS activity, we created transgenic mice overexpressing human eNOS. Aortic blood pressure was approximately 20 mm Hg lower in the transgenic mice compared with control mice because of lower systemic vascular resistance. The effects of eNOS overexpression on diet-induced atherosclerosis were studied in apolipoprotein E-deficient mice. Elevation of eNOS activity decreased blood pressure ( approximately 20 mm Hg) and plasma levels of cholesterol ( approximately 17%), resulting in a reduction in atherosclerotic lesions by 40%. We conclude that an increase in eNOS activity is beneficial and provides protection against atherosclerosis.     

Identification of ribosomal proteins specific to higher eukaryotic organisms

This report describes the identification of a novel protein named PS1D (Genbank accession number ), which is composed of an S1-like RNA-binding domain, a (cysteine)x3-(histidine) CCCH-zinc finger, and a very basic carboxyl domain. PS1D is expressed as two isoforms, probably resulting from the alternative splicing of mRNA. The long PS1D isoform differs from the short one by the presence of 48 additional amino acids at its amino-terminal extremity. Analysis of PS1D subcellular distribution by cell fractionation reveals that this protein belongs to the core of the eukaryotic 60S ribosomal subunit. Interestingly, PS1D protein is a highly conserved protein among mammalians as murine, human, and simian PS1D homologues share more than 95% identity. In contrast, no homologous protein is found in lower eukaryotes such as yeast and Caenorhabditis elegans. These observations indicate that PS1D is the first eukaryotic ribosomal protein that is specific to higher eukaryotes.     

First record of Synidotea laevidorsalis (Miers, 1881) (Crustacea: Isopoda) in Europe (Gironde estuary,France)

This note reports on the presence of a well established population of the isopod Synidotea laevidorsalis (Miers) in the Gironde estuary (southwestern France). This species is new for the European fauna. S. laevidorsalis is a nonendemic cool-temperate to subtropical, shallow-water species which was probably introduced into the study area from Asia. In the salinity range of 1 to 10 g 1^-1 of the Gironde the species constitutes an important component of the brackish-water hyperbenthic community. The population was already present in 1975 when it was misidentified as the native species Idotea emarginata (Fabricius).     

Isolation of a dimethylsulfide-utilizingHyphomicrobium species and its application in biofiltration of polluted air

The methylotrophic bacteriumHyphomicrobium VS was enriched and isolated, using activated sewage sludge as inoculum in mineral medium containing dimethylsulfide (DMS) at a low concentration to prevent toxicity. DMS concentrations above 1 mM proved to be growth inhibiting.Hyphomicrobium VS could use DMS, dimethylsulfoxide (DMSO), methanol, formaldehyde, formate, and methylated amines as carbon and energy source. Carbon was assimilated via the serine pathway. DMS-grown cells respired sulfide, thiosulfate, methanethiol, dimethyldisulfide and dimethyltrisulfide.To testHyphomicrobium VS for application in biofiltration of air polluted with volatile sulfur compounds two laboratory scale trickling biofilters with polyurethane and lava stone as carrier material were started up by inoculation with this bacterium. Both methanol- and DMS-grown cells could be used. Only a short adaptation period was needed. Short term experiments showed that high concentrations of DMS (1–2 µmol 1^–1) were removed very efficiently by the biofilters at space velocities up to 100 h^–1.Abbreviations VSC volatile sulfur compounds - DMS dimethylsulfide - DMDS dimethyldisulfide - DMTS dimethyltrisulfide - MT methanethiol - DMSO dimethylsulfoxide     

Deactivation of endothelium and reduction in angiogenesis in psoriatic skin and synovium by low dose infliximab therapy in combination with stable methotrexate therapy: a prospective single-centre study

Psoriasis and psoriatic arthritis are inflammatory diseases that respond well to anti-tumour necrosis factor-α therapy. To evaluate the effects of anti-tumour necrosis factor-α treatment on expression of adhesion molecules and angiogenesis in psoriatic lesional skin and synovial tissue, we performed a prospective single-centre study with infliximab therapy combined with stable methotrexate therapy. Eleven patients with both active psoriasis and psoriatic arthritis received infusions of infliximab (3 mg/kg) at baseline, and at weeks 2, 6, 14 and 22 in an open-label study. In addition, patients continued to receive stable methotrexate therapy in dosages ranging from 5 to 20 mg/week. Clinical assessments, including Psoriasis Area and Severity Index (PASI) and Disease Activity Score (DAS), were performed at baseline and every 2 weeks afterward. In addition, skin biopsies from a target psoriatic plaque and synovial tissue biopsies from a target joint were taken before treatment and at week 4. Immunohistochemical analysis was performed to detect the number of blood vessels, the expression of adhesion molecules and the presence of vascular growth factors. Stained sections were evaluated by digital image analysis. At week 16, the mean PASI was reduced from 12.3 ± 2.4 at baseline to 1.8 ± 0.4 (P ≤ 0.02). The mean DAS was reduced from 6.0 ± 0.5 to 3.6 ± 0.6 (P ≤ 0.02). We found some fluctuations in DAS response as compared with the change in PASI, with the latter exhibiting a steady decrease over time. After 4 weeks the cell infiltrate was reduced in both skin and synovium. There was a significant reduction in the number of blood vessels in dermis and synovium at week 4. A significant reduction in the expression of α_vβ₃ integrin, a marker of neovascularization, was also found in both skin and synovium at week 4. In addition, a significant reduction in the expression of adhesion molecules was observed in both skin and synovium at week 4. We also observed a trend toward reduced expression of vascular endothelial growth factor in both skin and synovium. In conclusion, low-dose infliximab treatment leads to decreased neoangiogenesis and deactivation of the endothelium, resulting in decreased cell infiltration and clinical improvement in psoriasis and psoriatic arthritis.