Comparison of the effects of D-003, a mixture of high-molecular-weight aliphatic acids from sugarcane wax, and pravastatin on bones and osteoclast apoptosis of ovariectomized rats

The mevalonate pathway is relevant in bone cells. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme of this route, stimulating osteoblast differentiation and activity. Pravastatin increases bone formation markers in postmenopausal women and bone density in diabetics. D-003 is a mixture of high-molecular-weight acids purified from sugarcane wax which inhibits cholesterol biosynthesis through HMG-CoA reductase regulation, preventing bone loss in osteoporosis induced with ovariectomy and prednisolone in rats. We investigated the effects of D-003 (50 mg/kg) and pravastatin (20 mg/kg) orally administered for 12 weeks to ovariectomized rats. Female rats were randomized in four groups (10 rats/group): two control groups treated with the vehicle, one false-operated (sham) and another ovariectomized (positive control), while two other groups received D-003 or pravastatin. Bone resorption and formation was studied through histomorphometry and apoptosis through immunohistochemistry. D-003 and pravastatin significantly (p < 0.001) prevented the changes of trabecular bone versus ovariectomized rats and (p < 0.001) the increase of the surface and number of osteoclasts versus ovariectomized controls. D-003 and pravastatin, however, did not modify osteoblast surfaces, a bone formation marker D-003 and pravastatin increased osteoclast apoptosis and reduced (p < 0.05) osteoblast and osteocyte apoptosis versus ovariectomized controls; D-003 was more effective (p < 0.05) than pravastatin. In conclusion, D-003 (50 mg/kg) orally administered for 12 weeks prevented bone loss and bone resorption in ovariectomized rats, increasing osteoclast apoptosis. The preventive effects of D-003 on bone loss and resorption in ovariectomized rats are comparable to those of pravastatin. Both drugs inhibited osteoblast apoptosis but failed to change osteoblast surface. The effects of D-003 on bone cell apoptosis were greater than those of pravastatin. Therefore, D-003 could be used to prevent or treat bone loss in postmenopausal women, but further animal studies and clinical trials are required to confirm the clinical relevance of this potential effect.     

Effects of D-003, a mixture of long-chain aliphatic primary acids, fluvastatin and the combined therapy of D-003 plus fluvastatin on the lipid profile of normocholesterolemic rabbits

D-003 is a mixture of long-chain aliphatic primary acids isolated from sugar cane wax with cholesterol-lowering effects proven in animals and healthy human volunteers. D-003 reduced serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in rabbits, while it increased high-density lipoprotein cholesterol (HDL-C) and did not affect triglycerides. D-003 inhibits cholesterol synthesis by regulating, instead of directly inhibiting, hydroxamethylglutaryl-CoA (HMGCoA) reductase activity. Although the ways in which D-003 and statins inhibit cholesterol biosynthesis are not identical, the strong competitive inhibition of cholesterol biosynthesis induced by statins suggests that an enhanced decrease of LDL-C and TC caused by the combined therapy D-003 plus statins is not expected. Nevertheless, taking into account the differential effects of D-003 and statins in HDL-C and triglycerides in rabbits, potential benefits of such combined therapy on other lipid variables cannot been discarded. Fluvastatin is a statin that inhibits competitively HMGCoA reductase, like other members of this class. This study was undertaken to compare the cholesterol-lowering effects of D-003, fluvastatin and the combined therapy of D-003 plus fluvastatin in normocholesterolemic rabbits. Animals were randomly distributed into four groups of eight. One control group received the vehicle, two groups were treated with D-003 or fluvastatin at 5 mg/kg/day each, and the fourth group received the combined therapy of both drugs at 5 mg/kg/day each. Treatments were orally administered for 30 days. Body weight, food consumption and overall animal behavior were recorded to detect any warning sign resulting from combined therapy. After treatment, it was found that both D-003 and fluvastatin had significantly lowered LDL-C - D-003 by 81.5% (p < 0.01) and fluvastatin by 61.4% (p < 0.05). Combined therapy reduced LDL-C values (75.9%). Final values and percent changes reached in all groups were different from the control (p < 0.01). The reductions of TC were consistent with LDL-C decreases, so that D-003, fluvastatin and combined therapy significantly lowered TC by 48.4% (p < 0.01), 39.7% (p < 0.05) and 45.3%, respectively, values being different from those of the control (p < 0.01). The responses of LDL-C and TC to combined therapy were statistically similar, but less pronounced than those reached by D-003 alone. D-003 and combined therapy, but not fluvastatin alone, increased HDL-C (+21.5% and + 19.0%, respectively), these changes being significant versus the control (p < 0.05). In turn, fluvastatin and combined therapy, but not D-003 alone, lowered triglycerides (13.6% and 13.0%, respectively, p < 0.05 versus control). The effects of combined therapy on HDL-C were similar to those of D-003 alone, and the effects of combined therapy on triglycerides were similar to those of fluvastatin alone. The only advantage of combined therapy appears to be that it shows better effects on HDL-C than those of fluvastatin alone and better effects on triglycerides than D-003 alone. No significant changes in lipid profile were observed in the control group. All groups showed similar food consumption and body weight gain, health status being unaffected by the treatments. It is concluded that D-003 and fluvastatin at 5 mg/kg/day administered orally for 30 days to normocholesterolemic rabbits lowered LDL-C and TC, D-003 being more effective in increasing HDL-C and fluvastatin in lowering triglycerides. Combined therapy did not improve the response of LDL-C and TC with respect to monotherapies, but induced better responses of HDL-C and triglycerides than fluvastatin alone had on HDL-C or D-003 alone had on triglycerides.     

Systems Medicine: from molecular features and models to the clinic in COPD

Background and hypothesis

Chronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression. Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns. We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways. We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice.

Objective and method

Our overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach. To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario. We used muscle dysfunction and co-morbidity as test cases for this framework.

Results

In the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models. This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions. In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations. We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model. In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice.

Conclusions

The results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models. Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them.

     

XPS analysis of poly[(3-hydroxybutyric acid)-co-(3-hydroxyvaleric acid)] film surfaces exposed to an allylamine low-pressure plasma

Homogeneous and stable layers were deposited through allylamine plasma polymerization (75 W, 100 Pa, 15 min) onto poly[(3-hydroxybutyric acid)-co-(3-hydroxyvaleric acid)] (91 : 9 wt.-%) (P(HB-co-9%HV)) film surfaces, XPS analysis using take-off angles of 20° and 70° and performed 10 days and 20 days after plasma treatment gives information on the composition (in atom%) of the modified surface: C, 62.74; N, 19.60; O, 17.65. The unexpected oxygen percentage is weaker if argon plasma pretreatment (25 W, 40 Pa, 5 min) is applied. Then, a succinct mechanism is proposed. The study of changes in element ratios and binding energy values shows that the majority of incorporated functional groups seem to be amide and imine groups.     

Clasificación de cesáreas por Grupos de Robson en dos periodos comparativos en el Hospital de Manacor

Objective

To identify groups of women with changes in cesarean rates in two different periods.

Subjects and methods

Deliveries in the Manacor Hospital in 2000-2001 and 2005-2006, were analyzed through a retrospective review of clinical records and were grouped using Robsońs classification.

Results

The cesarean rate increased from 14 to 18.6% with a statistically significant increase among women with a single cephalic pregnancy at term who underwent labor induction or elective cesarean section. These two groups were the major contributors to the cesarean rate at our hospital.

Conclusion

A trend towards an increase in the rates of cesarean section was found during the study period. Robson's Classification allowed us to identify the groups of women contributing to this increase.     

Inicio de un síndrome de Guillain-Barré durante la gestación

We present the case of a pregnant woman who developed severe Guillain-Barré syndrome in the third trimester and who required admission to the intensive care unit of the referral hospital for suspected disease progression. No clinical improvement was observed. Because the onset of diaphragm paralysis was suspected and the fetus was in the podalic position, emergency cesarean was performed. Given the rarity of onset of Guillain-Barré syndrome in pregnancy, we review this entity to improve knowledge of maternal and fetal management.     

The usefulness of growth hormone treatment for psychological status in young adult survivors of childhood leukaemia: an open-label study

Background  

To reduce the risk of brain damage children with acute lymphoblastic leukaemia (ALL) are nowadays mainly treated with intrathecal chemotherapy (ITC) instead of central nervous system (CNS) radiation therapy (CRT) to prevent CNS relapse. However, chemotherapy may also lead to cognitive deficits. As growth hormone deficiency (GHD) or impaired growth hormone secretion are frequently found in ALL patients treated with cranial radiation therapy and/or chemotherapy, we hypothesized that GH therapy may reduce cognitive deficits in these patients.     

新生期大白鼠皮下注射谷氨酸单钠对成年后下丘脑α-促黑素细胞激素神经元免疫反应性的影响

本文用免疫组化方法研究了新生期大白鼠注射谷氨酸单钠(MSG)对成年后下丘脑α-促黑素细胞激素(α-MSH)免疫反应神经元的影响,结果显示MSG处理以后下丘脑弓状核区α-MSII免疫反应神经元减少甚至完全消失,但不影响下丘脑背外侧区的α-MSH神经元群。文中还讨论了这两群α-MSH神经元的生理作用。