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.

     

Hormonal and metabolic responses to nesting activities in the green turtle, Chelonia mydas

We examined the association between green turtle nesting activities and plasma profiles of hormones that are widely implicated in aspects of heightened metabolism and energy regulation; epinephrine (EPI), norepinephrine (NE) and corticosterone. In conjunction, we examined plasma profiles of glucose and lactate to infer metabolic processes associated with green turtle nesting behaviour. Finally, because these hormones are also involved in mediating behaviour and physiology associated with stressful situations, we examined the effect of a stressor encountered during nesting, physical disturbance, on hormone levels. Plasma profiles of epinephrine, norepinephrine and corticosterone were not significantly altered across different stages of nesting. Plasma glucose and lactate both exhibited significant increases related to nesting activity; glucose increased dramatically during the emergence stage of nesting before stabilizing, and lactate levels continued to increase throughout the nesting process. There was no significant association between plasma hormones and glucose. For female turtles that abandoned nesting activities due to competition for nest space, there was no significant difference in plasma levels of epinephrine, norepinephrine and corticosterone compared to females that persisted with nesting activities. Overall, while distinct metabolic changes took place in nesting females, there was little association in profiles of hormones typically considered important for regulating heightened metabolism and nesting activity. This disassociation could arise because hormonal action may be altered in breeding female green turtles to facilitate reproductive processes.     

Effects of human activities on Komodo dragons in Komodo National Park

Understanding how threatened wildlife can coexist with humans over the long term is a central issue in conservation and wildlife management. Komodo National Park in Eastern Indonesia, harbors the largest extant populations of the endemic Komodo dragon (Varanus komodoensis). Consistent with global trends, this species is expected to be increasingly exposed to human activities and in particular growing ecotourism activities. Here we comprehensively evaluated how human activities affected individual and population level attributes of Komodo dragons. We compared Komodo dragons phenotypic (behaviour, body size, and body condition) and demographic (age structure, sex ratio, survival, and density) responses to variation in human activities across national park. Komodo dragons were found to exhibit pronounced responses to high human activity level relative to sites with low and negligible human activities. Komodo dragons exposed to ecotourism exhibited significantly less wariness, larger body mass, better body condition, and higher survival. These results are entirely consistent with ecotourism activities that provided Komodo dragons with long-term and substantial nutritional subsidies as a consequence of feeding and human food refuse. However, we also noted the potential negative consequences of altered behaviour and adult-biased populations in ecotourism areas which may influence demographic processes through intraspecific competition or predation. To address this issue, we recommend that three management strategies to be implemented in future include: (1) removal of human-mediated nutritional subsidies, (2) alternative ecotourism, and (3) spatial regulation of ecotourism. Furthermore, we advocate the development of approaches to achieve a socio–ecological sustainability that benefits both people and wildlife conservation.     

Maximum body size among insular Komodo dragon populations covaries with large prey density

This study documents variation in maximum body size of Komodo dragons ( Varanus komodoensis ) among the four extant island populations in Komodo National Park and compares an indirect measure of deer density, the major prey item for large dragons, to differences in maximum body size among islands. The largest 15% of dragons from the large islands of Komodo and Rinca were significantly longer and heavier than the largest 15% of dragons on the small islands of Gili Motang and Nusa Kode. There was a 33% difference in snout vent length (SVL) between dragons found on Komodo and those found on Gili Motang, with mass varying by more than four-fold. Density of deer pellet groups between islands ranged from 5.86±0.75 groups per transect on Gili Motang to 20.73±1.02 groups per transect on Komodo Island. Maximal dragon SVL and mass was highly positively correlated with this index of deer density. Low prey density on the two small islands could constrain body size via energetic constraints. At present we can not deduce if insular body size variation has arisen through genotypic or phenotypic mechanisms.     

Further Experience with Azathioprine in Rheumatoid Arthritis

Azathioprine has been shown to reduce the steroid requirements of patients with severe rheumatoid arthritis. Twenty-seven patients treated with azathioprine have now been followed up for 30 months. At the end of this period only 10 were still taking the drug. Maximum steroid reduction occurred within the first 12 months of treatment. Some steroid-sparing effect seemed to persist after the drug was stopped. There was no evidence that azathioprine prevented radiological deterioration. No deaths occurred and toxic effects always reversed on stopping the drug.     

Genetic Deletion of Mst1 Alters T Cell Function and Protects against Autoimmunity

Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4⁺ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1^−/− B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1^−/− CD4⁺ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4⁺ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.