Are DXA/aBMD and QCT/FEA Stiffness and Strength Estimates Sensitive to Sex and Age?

Dual X-ray absorptiometry (DXA) measures areal bone mineral density (aBMD) by simplifying a complex 3D bone structure to a 2D projection and is not equally effective for explaining fracture strength in women and men. Unlike DXA, subject-specific quantitative computed tomography-based finite element analysis (QCT/FEA) estimates fracture strength using 3D bone mineral distribution and geometry. By using experimentally-measured femoral stiffness and strength from a one hundred sample cadaveric cohort that included variations in sex and age, we wanted to determine if QCT/FEA estimates were able to better predict the experimental variations than DXA/aBMD. For each femur, DXA/aBMD was assessed and a QCT/FEA model was developed to estimate femoral stiffness and strength. Then, the femur was mechanically tested to fracture in a sideways fall on the hip position to measure stiffness and strength. DXA/aBMD and QCT/FEA estimates were compared for their sensitivity to sex and age with multivariate statistical analyses. When comparing the measured data with DXA/aBMD predictions, both age and sex were significant (p ≤ 0.0398) for both femoral stiffness and strength. However, QCT/FEA predictions of stiffness and strength showed sex was insignificant (p ≥ 0.23). Age was still significant (p ≤ 0.0072). These results indicate that QCT/FEA, unlike DXA/aBMD, accounted for bone differences due to sex.     

Nicotinamide phosphoribosyl-transferase/visfatin: A missing link between overweight/obesity and postmenopausal breast cancer? Potential preventive and therapeutic perspectives and challenges

Worldwide breast cancer (BC) constitutes a significant public health concern. Excess body weight is associated with postmenopausal BC (PBC) risk. Recent studies have shown that the constellation of obesity, insulin resistance and serum adipokine levels are associated with the risk and prognosis of PBC. Nicotinamide phosphoribosyl-transferase (Nampt), also known as visfatin and pre-B-cell-colony-enhancing factor, found in the visceral fat, represents a novel pleiotropic adipokine acting as a cytokine, a growth factor and an enzyme. It plays an important role in a variety of metabolic and stress responses as well as in the cellular energy metabolism, particularly NAD biosynthesis. Nampt exhibits proliferative, anti-apoptotic, pro-inflammatory and pro-angiogenic properties. Nampt’s insulin-mimetic function remains a controversial issue.     

Association of -308G/A and -238G/A polymorphisms of TNF-α and osteosarcoma risk

Objective: As a proinflammatory cytokine, TNF-α is associated with increased risk of osteosarcoma (OS). Our study aimed to explore the association of TNF-α polymorphisms and OS susceptibility in the Han Chinese population. Methods: 80 OS patients and 99 healthy people, matched on the age and sex, participated in the study. Genotyping was conducted by the method of polymerase chain reaction-restricted fragment length polymorphisms (PCR-RFLP). Then logistic regression was used to evaluate the effects of TNF-α polymorphisms (-308G/A and -238G/A) on the pathology of OS. Results: The frequency of AA genotype in -308G/A locus in the cases was significantly higher than that of the healthy group (20.0% vs. 6.1%). Patients with OS were more likely to possess AA genotype of -308G/A locus (OR=4.00, 95% CI=1.41-11.38). For the patients with A allele, the risk for OS increased 0.62 fold (OR=1.62, 95% CI=1.04-2.50). There was no remarkable relationship of -238G/A polymorphisms and OS susceptibility. In addition, we found that patients with G-A and A-A haplotypes was much higher in the cases than that of control group (68.0% and 25.0%, 53.0% and 38.9%, respectively). A-G haplotype appeared to increase the risk for OS (OR=1.93, 95% CI=1.13-2.94). Conclusion: The AA genotype of -308G/A locus of TNF-α gene was a risk factor for OS, however there was no correlation between -238G/A of TNF-α and OS.     

The interplay of HER2/HER3/PI3K and EGFR/HER2/PLC-γ1 signalling in breast cancer cell migration and dissemination

HER2 signalling by heterodimerisation with EGFR and HER3 in breast cancer is associated with worst outcome of the afflicted patients, which is attributed not only to the aggressiveness of such tumours but also to therapy resistance. Thus, in the present study we investigated the role of EGFR, HER2 and HER3 lateral signalling in cell migration by applying the MDA-MB-468-HER2 (MDA-HER2) breast cancer cell line, representing a valid model system. Knockdown of HER3 expression by siRNA resulted in decreased phosphorylated AKT (pAKT) levels, abrogated epidermal growth factor (EGF)-mediated PLC-γ1 activation and a diminished EGF-induced migratory activity, depicting the interplay of EGF receptor (EGFR)/HER2/PLC-γ1 and HER2/HER3/PI3K signalling in mediating the migration of EGFR/HER2/HER3-expressing breast cancer cells. Since therapy failure usually arises from metastatic cells, we further investigated whether HER3 signalling was active in established breast cancer disseminated tumour cell (DTC) lines as well as in primary DTCs derived from breast cancer patients. EGF treatment of DTC lines resulted solely in increased pAKT S473 levels, whereas in MDA-HER2 cells both pAKT S473 and pAKT T308 levels were increased upon EGF stimulation. Moreover, despite active HER3 molecules, as indicated by pTyr1222 staining, about 90% of analysed breast cancer patient DTCs exhibited very low or even no detectable pAKT S473 levels, suggesting that these cells might have fallen into dormancy. In summary, our data indicate the important role in EGFR, HER2 and HER3 lateral signalling in breast cancer cell migration. Moreover, our data further show that primary tumour cells and DTCs can vary in their HER activation status, which is important to know in the context of cancer therapy.     

Rearrangement/hypermutation/gene conversion: when,where and why?

Diversification strategies for immunoglobulins vary widely in different species. Here, Jean-Claude Weill and Claude-Agnès Reynaud argue that V(D)J recombination arose as a means for achieving allelic exclusion rather than diversity, and postulate that the choice of a diversification strategy is selected along with a specific site of B-cell differentiation. They propose that somatic mutation and gene conversion represent analogous molecular strategies occurring in specific chromatin accessibility contexts.     

Subgroups A1 and A2: Qualitative and/or Quantitative Distinctions?

In this editorial that was published in Immunological Communications, Special Issue on Immunohematology, volume 9, number 2, 1980, the authors unintentionally overlooked an important paper, which provides strong independent support for the interpretation of a structural, hence, qualitative, difference between subgroups A₁ and A₂. It is as follows:     

Pharmacokinetics,Efficacy, and Safety of Darunavir/Ritonavir 800/100 mg Once-Daily in Treatment-Naïve and -Experienced Patients

Abstract

Darunavir is a new protease inhibitor (PI) with in vitro activity against wild-type and PI-resistant HIV; it is used with the pharmacokinetic booster ritonavir. The currently approved dose of darunavir/ritonavir is 600/100 mg twice-daily, licensed for treatment-experienced patients. However, during the clinical development of darunavir, a range of once-daily and twice-daily doses of darunavir/ritonavir were evaluated. The relatively long terminal elimination plasma half-life of darunavir (15 hours) supports once-daily dosing. In treatment-naïve patients, the ARTEMIS trial has shown high rates of HIV RNA suppression for darunavir-ritonavir at the 800/100 mg once-daily dose (84% with HIV RNA <50 copies/mL at Week 48) versus a control arm of lopinavir/ritonavir (78% with HIV RNA <50 copies/mL). In a population pharmacokinetic substudy, darunavir 24-hour minimum plasma concentration levels remained above the predefined EC₅₀ of 55 ng/mL for all 335 patients evaluated in the ARTEMIS trial. Once-daily darunavir/ritonavir has also been evaluated in treatment-experienced patients in the TMC114-C207 proof-of-principle trial and the POWER 1 and 2 trials. For the overall POWER trial population, with significant baseline resistance to PIs, the rates of HIV RNA suppression <50 copies/mL at Week 24 for darunavir/ritonavir 800/100 mg once-daily were lower than for the 600/100 mg twice-daily dosage (31% vs. 47%, respectively). However, for patients with no genotypic darunavir resistance-associated mutations at baseline, rates of HIV RNA suppression were 62% and 67% for the 800/100 mg once-daily and 600/100 mg twice-daily doses. The current evidence from clinical trials of darunavir/ritonavir supports the efficacy of the 800/100 mg once-daily dose for treatment-naïve patients and further evaluation for treatment-experienced patients with no genotypic resistance to darunavir.     

ApoE ε2/ε3/ε4 polymorphism,ApoC-III/ApoE ratio and metabolic syndrome

Triglyceride-rich lipoproteins contain both apolipoproteins E (ApoE) and C-III (ApoC-III), which show opposite functional properties. The relationships between the ApoE (ε2/ε3/ε4) gene polymorphism and ApoC-III/ApoE ratio has never been investigated. A large population (n=552) of cardiovascular patients, without diabetes and/or lipid-lowering therapy, with or without metabolic syndrome (MetSyn), was genotyped for ε2/ε3/ε4 polymorphism and their ApoCIII/ApoE ratio was evaluated. A second group of patients (n=76) with peripheral artery disease was also genotyped and their ApoC-III/ApoE ratios were measured in HDL and non-HDL fractions. Subjects with E2 had higher and E4 carriers lower TG,ApoE and ApoC-III levels, respectively. The ApoCIII/ ApoE ratio showed an opposite trend, gradually increasing from E2/E2 to E4/E4 subjects. MetSyn patients also had an elevated ApoC-III/ApoE ratio and E4 carriers were more frequent in MetSyn patients (OR 2.08 with a 95%CI 1.22–3.5). The distribution of ApoC-III/ApoE ratio was confirmed also in the second group, with lower values in E2/E3 and higher in E3/E4 subjects. Similar results were obtained for the concentrations measured in non-HDL fractions, but not in the HDL fractions. ApoE ε2/ε/ε4 gene polymorphism is a determinant of the relative proportion of apolipoprotein C-III to E. Carriers of the unfavourable E4 allele present the highest ApoCIII/ApoE ratio and are twofold more frequent among individuals affected by MetSyn. These authors contributed equally to the work     

Hospital pharmacists’ knowledge about and attitude toward HIV/AIDS and patients living with HIV/AIDS in Kedah,Malaysia

Introduction

The current study aims to explore the knowledge, attitude, and perception of hospital pharmacists towards HIV/AIDS and patients living with HIV/AIDS (PLWHA) in the state of Kedah, Malaysia.

Material and methods

This was a cross-sectional study conducted among the hospital pharmacists in three government hospitals in Kedah, using a self-administered 43-item questionnaire. Data analysis was done using non-parametric and multinomial regression.

Results

A total of 75 respondents participated in this study, resulting in a response rate of 60.8%. The majority were found to be well aware of the causes of HIV/AIDS. However, about 34 (45.3%) believed erroneously that HIV/AIDS cannot be transmitted through tattooing or body piercing. Nearly 25 (33.3%) of the respondents believed that preventing the use of intravenous drugs may not be effective to prevent HIV/AIDS and endorsed social isolation as a measure to prevent HIV/AIDS. The majority (66.6%) had negative attitudes and about 20% held extremely negative attitudes. Findings from regression modelling revealed that hospital (–2 log likelihood = 215.182, χ² = 18.060, Df = 8, p = 0.021) and gender (–2 log likelihood = 213.643, χ² = 16.521, Df = 8, p = 0.035) were more likely to affect the attitudes of respondents.

Conclusions

Overall, more than one third of the respondents were found to have negative attitudes towards PLWHA. Gender, job experience, and hospitals with more HIV/AIDS patient visits were the main factors affecting attitudes.     

CTLA-4 +49 A/G and −318 C/T polymorphisms and susceptibility to multiple sclerosis: a meta-analysis

Objective: The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 A/G, and ?318?C/T polymorphisms confer susceptibility to multiple sclerosis (MS).

Methods: A meta-analysis of the associations between the CTLA-4 +49?A/G and ?318?C/T polymorphisms and MS.

Results: A total of 23 separate comparisons from 19 studies of the CTLA-4 +49 A/G polymorphism and 10 comparisons (8 studies) of the CTLA-4 ?318?C/T polymorphism were considered. Meta-analysis showed no association between MS and the CTLA-4 +49G allele in the analysis of all study subjects (OR?=?1.026, 95% CI?=?0.967–1.089, p?=?0.395). Stratification by ethnicity indicated no association between the CTLA-4 +49G allele and MS in Caucasians, Asians, or Arabs. Meta-analysis showed no association between RA and the CTLA-4 ?318C allele in all study subjects (OR?=?0.909, 95% CI?=?0.704–1.175, p?=?0.467). In addition, meta-analysis stratified by ethnicity revealed no association between MS and the CTLA-4 ?318 C/T polymorphism in Caucasian, Asian, or Arab populations.

Conclusions: This meta-analysis of published studies did not find an association between the CTLA-4 +49?A/G and ?318?C/T polymorphisms and susceptibility to MS in Caucasian, Asian, and Arab populations.     

Antimicrobial binding and growth kinetics in BacT/ALERT® FA Plus and BACTEC® Aerobic/F Plus blood culture media

The capacity of absorbent beads in BacT/ALERT® FA Plus and BACTEC® Aerobic/F Plus blood culture bottles to bind and neutralize antibiotics was compared. Binding was established using reverse-phase HPLC, and inactivation was based on the recovery of susceptible test stains from simulated blood cultures. The FA Plus medium demonstrated more rapid and better overall binding kinetics for each drug tested, resulting in significantly better overall recovery rates. Differences in time to detection favored the FA Plus medium for three drug/organism combinations and Aerobic/F Plus for two.     

Structural and spectroscopic characterization of a series of potassium- and/or sodium-substituted β-tricalcium phosphate

In this paper, we report X-ray diffraction investigations as well as Raman and solid-state (31)P and (23)Na magic angle spinning nuclear magnetic resonance (NMR) characterization of three series of calcium orthophosphates. The general formulae of the studied compounds are Ca(10.5-x/2)M(x)(PO(4))(7), where M=K or Na and x=0, 0.25, 0.50, 0.75, 1.0; and Ca(10)K(x)Na(1-x)(PO(4))(7), where x=0, 0.25, 0.5, 0.75, 1.0. These calcium orthophosphates are found to be isostructural with β-tricalcium phosphate (β-TCP, Ca(3)(PO(4))(2)) with the substitution of some calcium sites by potassium and/or sodium cations. The unit cell parameters vary continuously with the level of substitution, a characteristic of these solid solutions. The Raman spectra show the different vibrational bands of the phosphate groups PO(4), while the NMR chemical shifts are sensitive to the non-equivalent phosphorus and sodium ions present in these substituted samples. As both Raman and NMR spectroscopies are local probes, they offer tools to distinguish between these different phosphorus and phosphate groups, according to their structural site and local environment, especially the type of cation substituent. A convenient decomposition of the Raman and NMR spectra into Gaussian-Lorentzian components leads us to propose an assignment of the main observed bands of these substituted β-TCPs.     

Histamine release “in vivo” and “in vitro” induced by hypnotics in normal and atopic patients

The in vitro test of histamine release induced in the leukocytes of atopic subjects selected according to specific criteria would seem to be much more accurate to study the histamine releasing characteristics of intravenous agents than the in vivo study in patients who have to be anaesthetised. Moreover, different concentrations of the test drug may be used, and thus the threshold for histamine release may be compared. It is the test which we recommend for investigating new drugs. However, it is lengthy and expensive; it can therefore not be recommended as a routine preoperative investigation.