Elucidation of the role of the complex in hydride transfer reaction between methylene blue and 1-benzyl-1,4-dihydronictinamide by effect of γ-cyclodextrin

The kinetics of the hydride transfer reaction between Methylene Blue (MB+) and&#12288;1-benzyl-1,4-dihydronicotinamide (BNAH) were studied in 10 % ethanol-90 % water mixed solvents containing &#946;- and &#947;-cyclodextrins (&#946;-CD and &#947;-CD). The pseudo-first order rate constant shows kinetic saturation at high initial concentration of BNAH. This indicates the formation of a complex between MB+ and BNAH. The reaction was suppressed by addition of &#946;-CD, but enhanced by addition of &#947;-CD. MB+ and BNAH were separately accommodated within the &#946;-CD cavity and the cavity walls may protect the activity site of the reactants. On the other hand, in the MB+-BNAH-&#947;-CD system, the inclusion of the complex between MB+ and BNAH with &#947;-CD occurred. This effect of &#947;-CD can distinguish between the productive and non-productive nature of the complex.</p

Can a total knee arthroplasty be both rotationally unconstrained and anteroposteriorly stabilised? A pulsed fluoroscopic investigation

Objectives: Throughout the 20th Century, it has been postulated that the knee moves on the basis of a four-bar link mechanism composed of the cruciate ligaments, the femur and the tibia. As a consequence, the femur has been thought to roll back with flexion, and total knee arthroplasty (TKA) prostheses have been designed on this basis. Recent work, however, has proposed that at a position of between 0° and 120° the medial femoral condyle does not move anteroposteriorly whereas the lateral femoral condyle tends, but is not obliged, to roll back - a combination of movements which equates to tibial internal/femoral external rotation with flexion. The aim of this paper was to assess if the articular geometry of the GMK Sphere TKA could recreate the natural knee movements in situ/in vivo. Methods: The pattern of knee movement was studied in 15 patients (six male: nine female; one male with bilateral TKAs) with 16 GMK Sphere implants, at a mean age of 66 years (53 to 76) with a mean BMI of 30 kg/m2 (20 to 35). The motions of all 16 knees were observed using pulsed fluoroscopy during a number of weight-bearing and non-weight-bearing static and dynamic activities. Results: During maximally flexed kneeling and lunging activities, the mean tibial internal rotation was 8° (standard deviation (SD) 6). At a mean 112° flexion (SD 16) during lunging, the medial and lateral condyles were a mean of 2 mm (SD 3) and 8 mm (SD 4) posterior to a transverse line passing through the centre of the medial tibial concavity. With a mean flexion of 117° (SD 14) during kneeling, the medial and lateral condyles were a mean of 1 mm (SD 4) anterior and 6 mm (SD 4) posterior to the same line. During dynamic stair and pivoting activities, there was a mean anteroposterior translation of 0 mm to 2 mm of the medial femoral condyle. Backward lateral condylar translation occurred and was linearly related to tibial rotation. Conclusion: The GMK Sphere TKA in our study group shows movements similar in pattern, although reduced in magnitude, to those in recent reports relating to normal knees during several activities. Specifically, little or no translation of the medial femoral condyle was observed during flexion, but there was posterior roll-back of the lateral femoral condyle, equating to tibiofemoral rotation. We conclude that the GMK Sphere is anteroposteriorly stable medially and permits rotation about the medial compartment

Proinflammatory Phenotype and Increased Caveolin-1 in Alveolar Macrophages with Silenced CFTR mRNA

The inflammatory milieu in the respiratory tract in cystic fibrosis (CF) has been linked to the defective expression of the cystic transmembrane regulator (CFTR) in epithelial cells. Alveolar macrophages (AM), important contibutors to inflammatory responses in the lung, also express CFTR. The present study analyzes the phenotype of human AM with silenced CFTR. Expression of CFTR mRNA and the immature form of the CFTR protein decreased 100-fold and 5.2-fold, respectively, in AM transfected with a CFTR specific siRNA (CFTR-siRNA) compared to controls. Reduction of CFTR expression in AM resulted in increased secretion of IL-8, increased phosphorylation of NF-κB, a positive regulator of IL-8 expression, and decreased expression of IκB-α, the inhibitory protein of NF-κB activation. AM with silenced CFTR expression also showed increased apoptosis. We hypothesized that caveolin-1 (Cav1), a membrane protein that is co-localized with CFTR in lipid rafts and that is related to inflammation and apoptosis in macrophages, may be affected by decreased CFTR expression. Messenger RNA and protein levels of Cav1 were increased in AM with silenced CFTR. Expression and transcriptional activity of sterol regulatory element binding protein (SREBP), a negative transcriptional regulator of Cav1, was decreased in AM with silenced CFTR, but total and free cholesterol mass did not change. These findings indicate that silencing of CFTR in human AM results in an inflammatory phenotype and apoptosis, which is associated to SREBP-mediated regulation of Cav1

Tumor surveillance by circulating microRNAs: a hypothesis

A growing body of experimental evidence supports the diagnostic relevance of circulating microRNAs in various diseases including cancer. The biological relevance of circulating microRNAs is, however, largely unknown, particularly in healthy individuals. Here, we propose a hypothesis based on the relative abundance of microRNAs with predominant tumor suppressor activity in the blood of healthy individuals. According to our hypothesis, certain sets of circulating microRNAs might function as a tumor surveillance mechanism exerting continuous inhibition on tumor formation. The microRNA-mediated tumor surveillance might complement cancer immune surveillance

Insulin Promotes Glycogen Storage and Cell Proliferation in Primary Human Astrocytes

In the human brain, there are at least as many astrocytes as neurons. Astrocytes are known to modulate neuronal function in several ways. Thus, they may also contribute to cerebral insulin actions. Therefore, we examined whether primary human astrocytes are insulin-responsive and whether their metabolic functions are affected by the hormone.Commercially available Normal Human Astrocytes were grown in the recommended medium. Major players in the insulin signaling pathway were detected by real-time RT-PCR and Western blotting. Phosphorylation events were detected by phospho-specific antibodies. Glucose uptake and glycogen synthesis were assessed using radio-labeled glucose. Glycogen content was assessed by histochemistry. Lactate levels were measured enzymatically. Cell proliferation was assessed by WST-1 assay.We detected expression of key proteins for insulin signaling, such as insulin receptor β-subunit, insulin receptor substrat-1, Akt/protein kinase B and glycogen synthase kinase 3, in human astrocytes. Akt was phosphorylated and PI-3 kinase activity increased following insulin stimulation in a dose-dependent manner. Neither increased glucose uptake nor lactate secretion after insulin stimulation could be evidenced in this cell type. However, we found increased insulin-dependent glucose incorporation into glycogen. Furthermore, cell numbers increased dose-dependently upon insulin treatment.This study demonstrated that human astrocytes are insulin-responsive at the molecular level. We identified glycogen synthesis and cell proliferation as biological responses of insulin signaling in these brain cells. Hence, this cell type may contribute to the effects of insulin in the human brain

Genetic factors associated with intestinal metaplasia in a high risk Singapore-Chinese population: a cohort study

BMC Gastroenterology97

Common genetic variability in ESR1 and EGF in relation to endometrial cancer risk and survival

We investigated common genetic variation in the entire ESR1 and EGF genes in relation to endometrial cancer risk, myometrial invasion and endometrial cancer survival. We genotyped a dense set of single-nucleotide polymorphisms (SNPs) in both genes and selected haplotype tagging SNPs (tagSNPs). The tagSNPs were genotyped in 713 Swedish endometrial cancer cases and 1567 population controls and the results incorporated into logistic regression and Cox proportional hazards models. We found five adjacent tagSNPs covering a region of 15 kb at the 5′ end of ESR1 that decreased the endometrial cancer risk. The ESR1 variants did not, however, seem to affect myometrial invasion or endometrial cancer survival. For the EGF gene, no association emerged between common genetic variants and endometrial cancer risk or myometrial invasion, but we found a five-tagSNP region that covered 51 kb at the 5′ end of the gene where all five tagSNPs seemed to decrease the risk of dying from endometrial cancer. One of the five tagSNPs in this region was in strong linkage disequilibrium (LD) with the untranslated A61G (rs4444903) EGF variant, earlier shown to be associated with risk for other forms of cancer

Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions.</p> <p>Methods</p> <p>We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers) provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662.</p> <p>Results</p> <p>We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662.</p> <p>Conclusion</p> <p>The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation. However, the results in AT1-deficient mice show that blockage of AT1, unrelated to the pharmacological properties of AT1 blockers, also protects against dopaminergic cell death and neuroinflammation. Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.</p

End-stage extension of the knee and its influence on tibial tuberosity-trochlear groove distance (TTTG) in asymptomatic volunteers

PURPOSE: Increased tibial tuberosity-trochlear groove distance (TTTG) is one potential correcting parameter in patients suffering from lateral patellar instability. It was hypothesized that end-stage extension of the knee might influence the TTTG distance on MR images. METHODS: Transverse T1-weighted MR images of the knee were acquired at full extension, 15° and 30° flexion of the knee in 30 asymptomatic volunteers. MRI parameters: slice thickness: 3 mm, matrix: 256 × 384, FOV: 150 × 150 mm. Two observers independently measured the TTTG at all positions. RESULTS: Mean TTTG for observer 1 was 15.1 ± 3.2 mm at full extension, 10.0 ± 3.5 mm at 15° flexion and 8.1 ± 3.4 mm at 30° flexion. Mean TTTG for observer 2: 14.8 ± 3.3 mm at full extension, 9.4 ± 3.0 mm at 15° flexion, 8.6 ± 3.4 mm at 30° flexion. Mean values were significantly different (p < 0.001) between full extension and 15° as well as 30° flexion for both observers. Mean values were significantly different (p < 0.001) between 15° and 30° for observer 1, but not for observer 2 (n.s.). Interobserver agreement was very good (intraclass correlation coefficient: 0.87-0.88; p < 0.001). CONCLUSIONS: The TTTG increases significantly at the end-stage extension of the knee. Therefore, the comparability of published TTTG values measured on radiographs, CT and MRI at various flexion/extension angles of the knee are limited. LEVEL OF EVIDENCE: Development of diagnostic criteria in a consecutive series of patients and a universally applied 'gold' standard, Level II