Skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) by inhibiting activation of the IGF-I signaling pathways.

We showed that unloading markedly diminished the effects of IGF-I to activate its signaling pathways, and the disintegrin echistatin showed a similar block in osteoprogenitor cells. Furthermore, unloading decreased alphaVbeta3 integrin expression. These results show that skeletal unloading induces resistance to IGF-I by inhibiting activation of the IGF-I signaling pathways at least in part through downregulation of integrin signaling. INTRODUCTION: We have previously reported that skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) with respect to bone formation. However, the underlying mechanism remains unclear. The aim of this study was to clarify how skeletal unloading induces resistance to the effects of IGF-I administration in vivo and in vitro with respect to bone formation. MATERIALS AND METHODS: We first determined the response of bone to IGF-I administration in vivo during skeletal unloading. We then evaluated the response of osteoprogenitor cells isolated from unloaded bones to IGF-I treatment in vitro with respect to activation of the IGF-I signaling pathways. Finally we examined the potential role of integrins in mediating the responsiveness of osteoprogenitor cells to IGF-I. RESULTS: IGF-I administration in vivo significantly increased proliferation of osteoblasts. Unloading markedly decreased proliferation and blocked the ability of IGF-I to increase proliferation. On a cellular level, IGF-I treatment in vitro stimulated the activation of its receptor, Ras, ERK1/2 (p44/42 MAPK), and Akt in cultured osteoprogenitor cells from normally loaded bones, but these effects were markedly diminished in cells from unloaded bones. These results were not caused by altered phosphatase activity or changes in receptor binding to IGF-I. Inhibition of the Ras/MAPK pathway was more impacted by unloading than that of Akt. The disintegrin echistatin (an antagonist of the alphaVbeta3 integrin) blocked the ability of IGF-I to stimulate its receptor phosphorylation and osteoblast proliferation, similar to that seen in cells from unloaded bone. Furthermore, unloading significantly decreased the mRNA levels both of alphaV and beta3 integrin subunits in osteoprogenitor cells. CONCLUSION: These results indicate that skeletal unloading induces resistance to IGF-I by inhibiting the activation of IGF-I signaling pathways, at least in part, through downregulation of integrin signaling, resulting in decreased proliferation of osteoblasts and their precursors.     

The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.

BACKGROUND & AIMS: We conducted a systematic review and a meta-analysis to estimate the magnitude and determinants of association between diabetes and hepatocellular carcinoma (HCC). METHODS: MEDLINE searches were conducted for published full studies (between January 1966 and February 2005) that provided risk estimates and met criteria concerning the definition of exposure and outcomes. Two investigators independently performed standardized search and data abstraction. Unadjusted and adjusted odds ratios for individual outcomes were obtained or calculated for each study and were synthesized using a random-effects model. RESULTS: A total of 26 studies met our inclusion and exclusion criteria. Among 13 case-control studies, diabetes was associated significantly with HCC in 9 studies (pooled odds ratio, 2.5; 95% confidence interval, 1.8-3.5). Among 13 cohort studies, diabetes was associated significantly with HCC in 7 studies (pooled risk ratio, 2.5; 95% confidence interval, 1.9-3.2). The results were relatively consistent in different populations, different geographic locations, and a variety of control groups. The significant association between HCC and diabetes was independent of alcohol use or viral hepatitis in the 10 studies that examined these factors. Few studies adjusted for diet and obesity. CONCLUSIONS: Diabetes is associated with an increased risk for HCC. However, more research is required to examine issues related to the duration and treatment of diabetes, and confounding by diet and obesity.     

Non-invasive endotracheal delivery of paclitaxel-loaded alginate microparticles

Aerosolized chemotherapeutics leads to higher, localized and continuous concentrations of active agents in lung tissue with lower side effects for other organs. The present study was performed on jugular vein cannulated rats which endothracheally received 4 mg/kg of free paclitaxel powder (Free-PTX), paclitaxel-loaded alginate microparticles (PTX-ALG-MPs) and i.v. paclitaxel (Anzatax^®). Pharmacokinetic parameters for Free-PTX and PTX-ALG-MPs contain higher AUC, mean residence time (MRT),half-life and bioavailability, with lower elimination constant (k_e). Statistical analysis showed that the amount of paclitaxel per gram of lung tissue after 0.5, 6 and 24 h after administration of Free-PTX was lower than PTX-ALG-MPs. Lung tissue AUC for Free-PTX was lower than PTX-ALG-MPs. According to the obvious advantages obtained, such as dose lowering and increasing paclitaxel residence time and half-life. It should be noted that cell cytotoxicity test on normal airway cell lines was not examined in this study but due to previous reports on safety of inhaled paclitaxel, it can be suggested that pulmonary delivery of paclitaxel can be a useful non-invasive route of administration compared with i.v administration.     

Cervical myelopathy secondary to omovertebral bone in the pediatric patient with Sprengel deformity

Sprengel deformity is a congenital anomaly arising mainly in the shoulder girdle, associated with elevation of dysplastic scapula. skeletal anomalies, mainly Klippel-Feil syndrome, hemivertebrae, and omovertebral bone may be present along Sprengel anomaly. The omovertebral bone is an abnormal bone that originates from the superomedial edge of the scapula with different insertion points along the posterior cervical spine, seen in about third of the patients with Sprengel anomaly. While cosmetic to functional impairment is a common presentation to the omovertebral bone, cervical myelopathy is a rare presentation. Here, we described our experience, management and follow up of 13-year-old boy presented with cervical myelopathy secondary to the omovertebral bone.

Sprengel deformity is a complex anomaly of the shoulder girdle, associated with elevation of dysplastic scapula.1-4 Clinically, it is associated with disfigurement and limitation of shoulder movement. Other skeletal anomalies – mainly, Klippel–Feil syndrome, hemivertebrae, and omovertebral bone may be present.4 The omovertebral bone is an abnormal bone that originates from the superomedial edge of the scapula with different insertion points along the posterior cervical spine, seen in about a third of patients with Sprengel anomaly.2,5 The clinical presentation ranges from cosmetic to functional impairment, while cervical myelopathy is a rare presentation related to omovertebral bone. The management and follow up is less described in the literature contributed to its rare occurance.6 Here, the author described a 13-year- old boy diagnosed with Sprengel deformity presented with myelopathic manifestation, where cervical magnetic resonance imaging (MRI) showed signal cord changes secondary to compression by intraspinal extension of the omovertebral bone. The patient underwent uneventful resection of the abnormal bone, and spinal cord decompression.     

Antifungal efficiency of wild plants against human-opportunistic pathogens

BackgroundFungal infection with opportunistic fungi can cause a serious problem for immunocompromised persons such as organ-transplant recipients, cancer, and HIV/AIDS patients. Control of these organisms using natural products is an interesting strategy to avoid the use of heavy chemotherapy in patients.ObjectiveThis study aimed to use the extract of Forsskaolea tenacissima L. and Xanthium spinosum L. to suppress the growth of Candida albicans and Geotrichum candidum and to investigate their potential mode of action.Materials and methodsDifferent plant extracts were tested for their antifungal activity using disc diffusion method and their mode of action was explored using the scanning electron microscopy (SEM) and gas chromatography-mass spectrometry (GC-MS).ResultsThe results showed that chloroform extract of X. spinosum was the most effective against G. candidum, inhibiting its growth at very low concentration (38 μg/mL). Chloroform extract of F. tenacissima was the most effective against C. albicans, with a minimum inhibitory concentration of 39 μg/mL. SEM demonstrated the fungitoxicity of the plant extracts against both pathogens. C. albicans treated with plant extract were invaginated and ruptured and the treated mycelia of G. candidum were distorted and squashed. GC-MS analysis showed that the chloroform extract of both plants had 13 different compounds.ConclusionDue to these promising results, these extracts should be further investigated and tested on different strains of C. albicans and G. candidum towards validation of their efficacy as a natural drug.     

Intracerebral injection of low amounts of norharman induces moderate Parkinsonism-like behavioral symptoms in rat

β-Carbolines (BCs) are considered to be endogenous toxins and have been proposed as possible causative candidates inducing Parkinson's disease (PD). However, there is controversy about the effect and also effective dose of these compounds in the etiology of PD. This study was designed to further examine the effect of norharman (NH), a BC which in mammalian brain occurs at high levels in the substantia nigra, on the development of Parkinsonism-like behaviors in rats. A small amount (4μl) of NH solution at 2 or 200ng/ml was unilaterally injected into either striatum or substantia nigra (SN) by stereotaxic surgery. The development of Parkinsonism was assessed by three conventional behavioral tests, compared to the effects of unilateral 6-hydroxydopamine (6-OHDA) - induced lesions in the nigrostriatal pathway. An apomorphine-induced rotational test revealed no Parkinsonism-like behavior in the NH treated groups. However, rats that received the high concentration of NH into their SN showed significant biased swings in the elevated body swing test. In a rotarod test, NH treated groups showed relatively weak motor performance and their learning patterns were close to that of the 6-OHDA treated rats. Considering that the rotational test is only valid in animals with severe Parkinsonism, but time spent on the rotating rod correlates inversely with severity of Parkinsonism, our results indicate that a single exposure to low amounts of NH is effective in producing moderate Parkinsonism-like behavioral symptoms, possibly through a neurotoxic effect of this agent on the SN dopaminergic neurons.     

Prevalence and short-term mortality of acute-on-chronic liver failure: A national cohort study from the USA

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Effect of peptide length on the conjugation to the gold nanoparticle surface: a molecular dynamic study

Background

Gold nanoparticles now command a great deal of attention for medical applications. Despite the importance of nano-bio interfaces, interaction between peptides and proteins with gold surfaces is not still fully understood, especially in a molecular level.

Methods

In the present study computational simulation of adsorption of 20 amino acids, in three forms of mono-amino acid, homo di-peptide and homo tri-peptide, on the gold nanoparticles was performed by Gromacs using OPLSAA force field. The flexibility, stability, and size effect of the peptides on the gold nanoparticles were studied as well as the molecular structure of them.

Results

According to our results, adsorbed homo tri-peptides on the gold surface had more flexibility, more gyration, and the farthest distance from the GNP in comparison with homo di-peptides and mono-amino acids.

Conclusion

Our findings provide new insights into the precise control of interactions between amino acids anchored on the GNPs.