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.

     

Increased rainfall variability and reduced rainfall amount decreases soil CO2 flux in a grassland ecosystem

Predicted climate changes in the US Central Plains include altered precipitation regimes with increased occurrence of growing season droughts and higher frequencies of extreme rainfall events. Changes in the amounts and timing of rainfall events will likely affect ecosystem processes, including those that control C cycling and storage. Soil carbon dioxide (CO₂) flux is an important component of C cycling in terrestrial ecosystems, and is strongly influenced by climate. While many studies have assessed the influence of soil water content on soil CO₂ flux, few have included experimental manipulation of rainfall amounts in intact ecosystems, and we know of no studies that have explicitly addressed the influence of the timing of rainfall events. In order to determine the responses of soil CO₂ flux to altered rainfall timing and amounts, we manipulated rainfall inputs to plots of native tallgrass prairie (Konza Prairie, Kansas, USA) over four growing seasons (1998–2001). Specifically, we altered the amounts and/or timing of growing season rainfall in a factorial combination that included two levels of rainfall amount (100% or 70% of naturally occurring rainfall quantity) and two temporal patterns of rain events (ambient timing or a 50% increase in length of dry intervals between events). The size of individual rain events in the altered timing treatment was adjusted so that the quantity of total growing season rainfall in the ambient and altered timing treatments was the same (i.e. fewer, but larger rainfall events characterized the altered timing treatment). Seasonal mean soil CO₂ flux decreased by 8% under reduced rainfall amounts, by 13% under altered rainfall timing, and by 20% when both were combined (P<0.01). These changes in soil CO₂ flux were consistent with observed changes in plant productivity, which was also reduced by both reduced rainfall quantity and altered rainfall timing. Soil CO₂ flux was related to both soil temperature and soil water content in regression analyses; together they explained as much as 64% of the variability in CO₂ flux across dates under ambient rainfall timing, but only 38–48% of the variability under altered rainfall timing, suggesting that other factors (e.g. substrate availability, plant or microbial stress) may limit CO₂ flux under a climate regime that includes fewer, larger rainfall events. An analysis of the temperature sensitivity of soil CO₂ flux indicated that temperature had a reduced effect (lower correlation and lower Q₁₀ values) under the reduced quantity and altered timing treatments. Recognition that changes in the timing of rainfall events may be as, or more, important than changes in rainfall amount in affecting soil CO₂ flux and other components of the carbon cycle highlights the complex nature of ecosystem responses to climate change in North American grasslands.     

Rhodanile Blue; a Rapid and Selective Stain for Heinz Bodies

Equal volumes of heparinized or EDTA-treated blood and a 0.5% solution of rhodanile blue (E. Gurr, Michrome No. 1156) in 1% NaCl were mixed and allowed to stand for 2 rain. Thin smears were then prepared, air dried and examined under oil. Heinz bodies stained deep purple and contrasted well with the yellow-orange to blue-green cytoplasm. Durable mounts could be made by applying a cover glass with a resinous mediiun to the dry smear (D. P. X. was used). The reticular material in reticulocytes did not stain in 2 min but could be stained by allowing the stain to act 5 min.     

Enzyme activities and antibiotic susceptibility of colonial variants of Bacillus subtilis and Bacillus licheniformis

A nonmucoid colonial variant of a mucoid Bacillus subtilis strain produced less amylase activity and a transparent colonial variant of a B. licheniformis strain produced less protease activity compared with their parents. Antibiotic susceptibility patterns of the colonial variants differed, and increased resistance to beta-lactam antibiotics was correlated with increased production of extracellular beta-lactamase.     

Glutamic acid modification of vincristine toxicity

The principal limiting feature of the antitumor agent, vincristine, in the clinic has been neurotoxicity; there are no known agents which can routinely prevent or decrease this side effect. Glutamic acid in laboratory and clinical investigations in the early 1960s was found to antagonize vinblastine, another clinically useful vinca alkaloid. Glutamic acid 250 mg/kg/d i.p. was given to normal mice treated with repetitive doses of vincristine 1.5 mg/kg every other day. When glutamic acid was given both before and during vincristine administration, it produced a 49-79% increase in survival compared to control mice receiving vincristine only (p less than 0.01). Other schedules of glutamic acid administration were ineffective. Also, there appeared to be a delay in development of neurotoxic manifestations (toe-walking gait) but the results were not as consistent as the improvement in survival. Glutamic acid given to tumor-bearing mice (P-388 and P-1534 murine leukemia) did not inhibit the antitumor effect of vincristine-induced host toxicity in a schedule-dependent fashion without inhibition of the antitumor effect of vincristine.     

Tissue Turnover Rates and Isotopic Trophic Discrimination Factors in the Endothermic Teleost,Pacific Bluefin Tuna (Thunnus orientalis)

Stable isotope analysis (SIA) of highly migratory marine pelagic animals can improve understanding of their migratory patterns and trophic ecology. However, accurate interpretation of isotopic analyses relies on knowledge of isotope turnover rates and tissue-diet isotope discrimination factors. Laboratory-derived turnover rates and discrimination factors have been difficult to obtain due to the challenges of maintaining these species in captivity. We conducted a study to determine tissue- (white muscle and liver) and isotope- (nitrogen and carbon) specific turnover rates and trophic discrimination factors (TDFs) using archived tissues from captive Pacific bluefin tuna (PBFT), Thunnus orientalis, 1–2914 days after a diet shift in captivity. Half-life values for ¹⁵N turnover in white muscle and liver were 167 and 86 days, and for ¹³C were 255 and 162 days, respectively. TDFs for white muscle and liver were 1.9 and 1.1‰ for δ ¹⁵N and 1.8 and 1.2‰ for δ ¹³C, respectively. Our results demonstrate that turnover of ¹⁵N and ¹³C in bluefin tuna tissues is well described by a single compartment first-order kinetics model. We report variability in turnover rates between tissue types and their isotope dynamics, and hypothesize that metabolic processes play a large role in turnover of nitrogen and carbon in PBFT white muscle and liver tissues. ¹⁵N in white muscle tissue showed the most predictable change with diet over time, suggesting that white muscle δ ¹⁵N data may provide the most reliable inferences for diet and migration studies using stable isotopes in wild fish. These results allow more accurate interpretation of field data and dramatically improve our ability to use stable isotope data from wild tunas to better understand their migration patterns and trophic ecology.     

TDAG51 induces renal interstitial fibrosis through modulation of TGF-β receptor 1 in chronic kidney disease

Chronic kidney disease (CKD) is characterized by the gradual loss of renal function and is a major public health concern. Risk factors for CKD include hypertension and proteinuria, both of which are associated with endoplasmic reticulum (ER) stress. ER stress-induced TDAG51 protein expression is increased at an early time point in mice with CKD. Based on these findings, wild-type and TDAG51 knock-out (TDKO) mice were used in an angiotensin II/deoxycorticosterone acetate/salt model of CKD. Both wild-type and TDKO mice developed hypertension, increased proteinuria and albuminuria, glomerular injury, and tubular damage. However, TDKO mice were protected from apoptosis and renal interstitial fibrosis. Human proximal tubular cells were used to demonstrate that TDAG51 expression induces apoptosis through a CHOP-dependent mechanism. Further, a mouse model of intrinsic acute kidney injury demonstrated that CHOP is required for ER stress-mediated apoptosis. Renal fibroblasts were used to demonstrate that TGF-β induces collagen production through an IRE1-dependent mechanism; cells treated with a TGF-β receptor 1 inhibitor prevented XBP1 splicing, a downstream consequence of IRE1 activation. Interestingly, TDKO mice express significantly less TGF-β receptor 1, thus, preventing TGF-β-mediated XBP1 splicing. In conclusion, TDAG51 induces apoptosis in the kidney through a CHOP-dependent mechanism, while contributing to renal interstitial fibrosis through a TGF-β-IRE1-XBP1 pathway.Subject terms: Endoplasmic reticulum, Apoptosis, End-stage renal disease, Preclinical research, Chronic inflammation     

Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study

Introduction  

Improvement of rheumatoid arthritis (RA) during pregnancy has been causatively associated with increased galactosylation of immunoglobulin G (IgG) N-glycans. Since previous studies were small, did not include the postpartum flare and did not study sialylation, these issues were addressed in the present study.     

Multispectral fingerprinting for improved in vivo cell dynamics analysis

Background  

Tracing cell dynamics in the embryo becomes tremendously difficult when cell trajectories cross in space and time and tissue density obscure individual cell borders. Here, we used the chick neural crest (NC) as a model to test multicolor cell labeling and multispectral confocal imaging strategies to overcome these roadblocks.