Preexisting musculoskeletal burden and its development under letrozole treatment in early breast cancer patients.

One of the most common adverse events (AEs) occurring during treatment with aromatase inhibitors (AIs) is musculoskeletal pain. The aim of our study was to analyze the influence of preexisting muscle/limb pain and joint pain on the development of AI-induced musculoskeletal AEs. Women eligible for upfront adjuvant endocrine therapy with letrozole were included in the PreFace study, a multicenter phase IV trial. During the first treatment year, they were asked to record musculoskeletal AEs monthly by answering questions regarding pain symptoms and rating the pain intensity on a numeric rating scale from 0 (no pain) to 10 (very strong pain). Pain values were compared using nonparametric statistical tests. Overall, 1,416 patients were evaluable. The average pain value over all time points in women with preexisting muscle/limb pain was 4.3 (median 4.3); in those without preexisting pain, it was 2.0 (median 1.7). In patients without preexisting muscle/limb pain, pain levels increased relatively strongly within the first 6 months (mean increase +0.9, p < 0.00001) in comparison with those with preexisting pain (mean increase +0.3, p < 0.001), resulting in a statistically significant difference (p < 0.00001) between the two groups. The development of joint pain was similar in the two groups. Women without preexisting muscle/limb pain or joint pain have the greatest increase in pain after the start of adjuvant AI therapy. Women with preexisting pain have significantly higher pain values. The main increase in pain values takes place during the first 6 months of treatment.

Association between breast cancer risk factors and molecular type in postmenopausal patients with hormone receptor-positive early breast cancer.

PURPOSE: Evidence shows that genetic and non-genetic risk factors for breast cancer (BC) differ relative to the molecular subtype. This analysis aimed to investigate associations between epidemiological risk factors and immunohistochemical subtypes in a cohort of postmenopausal, hormone receptor-positive BC patients. METHODS: The prospective, single-arm, multicenter phase IV PreFace study (Evaluation of Predictive Factors Regarding the Effectivity of Aromatase Inhibitor Therapy) included 3529 postmenopausal patients with hormone receptor-positive early BC. Data on their epidemiological risk factors were obtained from patients' diaries and their medical histories. Data on estrogen receptor, progesterone receptor, and HER2 receptor status were obtained from pathology reports. Patients with incomplete information were excluded. Data were analyzed using conditional inference regression analysis, analysis of variance, and the chi-squared test. RESULTS: In a cohort of 3392 patients, the strongest association with the molecular subtypes of BC was found for hormone replacement therapy (HRT) before diagnosis of early BC. The analysis showed that patients who took HRT at diagnosis had luminal A-like BC more often (83.7%) than those who had never taken HRT or had stopped taking it (75.5%). Luminal B-like BC and HER2-positive BC were diagnosed more often in women who had never taken HRT or had stopped taking it (13.3% and 11.2%, respectively) than in women who were taking HRT at diagnosis of BC (8.3% and 8.0%, respectively). CONCLUSIONS: This analysis shows an association between HRT and the distribution of molecular subtypes of BC. However, no associations between other factors (e.g., age at diagnosis, body mass index, smoking status, age at menopause, number of deliveries, age at first delivery, breastfeeding history, or family history) were noted.

Quantitative SERS analysis of azorubine (E 122) in sweet drinks.

Considering both the potential effects on human health and the need for knowledge of food composition, quantitative detection of synthetic dyes in foodstuffs and beverages is an important issue. For the first time, we report a fast quantitative analysis of the food and drink colorant azorubine (E 122) in different types of beverages using surface-enhanced Raman scattering (SERS) without any sample preparation. Seven commercially available sweet drinks (including two negative controls) with high levels of complexity (sugar/artificial sweetener, ethanol content, etc.) were tested. Highly uniform Au "film over nanospheres" (FON) substrates together with use of Raman signal from silicon support as internal intensity standard enabled us to quantitatively determine the concentration of azorubine in each drink. SERS spectral analysis provided sufficient sensitivity (0.5-500 mg L(-1)) and determined azorubine concentration closely correlated with those obtained by a standard HPLC technique. The analysis was direct without the need for any pretreatment of the drinks or Au surface. Our SERS approach is a simple and rapid (35 min) prescan method, which can be easily implemented for a field application and for preliminary testing of food samples.

Directional Water Wicking on a Metal Surface Patterned by Microchannels.

This work focuses on the simulation and experimental study of directional wicking of water on a surface structured by open microchannels. Stainless steel was chosen as the material for the structure motivated by industrial applications as fuel cells. Inspired by nature and literature, we designed a fin type structure. Using Selective Laser Melting (SLM) the fin type structure was manufactured additively with a resolution down to about 30 µm. The geometry was manufactured with three different scalings and both the experiments and the simulation show that the efficiency of the water transport depends on dimensionless numbers such as Reynolds and Capillary numbers. Full 3D numerical simulations of the multiphase Navier-Stokes equations using Volume of Fluid (VOF) and Lattice-Boltzmann (LBM) methods reproduce qualitatively the experimental results and provide new insight into the details of dynamics at small space and time scales. The influence of the static contact angle on the directional wicking was also studied. The simulation enabled estimation of the contact angle threshold beyond which transport vanishes in addition to the optimal contact angle for transport.

Hydrogel-based piezoresistive pH sensors: investigations using FT-IR attenuated total reflection spectroscopic imaging.

The strong swelling ability of the pH-responsive poly(acrylic acid)/poly(vinyl alcohol) (PAA/PVA) hydrogel makes the development of a new type of sensor possible, which combines piezoresistive-responsive elements as mechanoelectrical transducers and the phase transition behavior of hydrogels as a chemomechanical transducer. The sensor consists of a pH-responsive PAA/PVA hydrogel and a standard pressure sensor chip. However, a time-dependent sensor output voltage mirrors only the physical swelling process of the hydrogel but not the corresponding chemical reactions. Therefore, an investigation of the swelling behavior of this hydrogel is essential for the optimization of sensor design. In this work, Fourier transform infrared (FT-IR) spectroscopic imaging was used to study the swelling of the hydrogel under in situ conditions. In particular, laterally and time-resolved FT-IR images were obtained in the attenuated total reflection mode and the entire data set of more than 80,000 FT-IR spectra was evaluated by principal component analysis (PCA). The first and third principal components (PCs) indicate the swelling process. Molecular changes within the carboxyl groups were observed in the second and fourth PC and identified as key processes for the swelling behavior. It was found that time-dependent molecular changes are similar to the electrical sensor output signal. The results of the FT-IR spectroscopic images render an improved chemical sensor possible and demonstrate that in situ FT-IR imaging is a powerful method for the characterization of molecular processes within chemical-sensitive materials.

The CYP3A4*1B allele increases risk for small cell lung cancer: effect of gender and smoking dose.

CYP3A isozymes are involved in tobacco carcinogen- and steroid-metabolism, and are expressed in human lung tissue showing interindividual variation in expression and activity. The CYP3A4*1B allele has been associated with a two-fold higher promoter activity and with high-grade prostate cancers. The very frequent intron 3 polymorphism in the CYP3A5 gene (CYP3A5*3) results in decreased CYP3A5 protein levels. A case-control study was conducted in 801 Caucasian lung cancer patients that included 330 adenocarcinomas, 260 squamous cell carcinomas, 171 small cell lung cancers (SCLC) and 432 Caucasian hospital-based controls. CYP3A-genotyping was performed by capillary polymerase chain reaction followed by fluorescence-based melting curve analysis. A significantly increased SCLC risk for CYP3A4*1B allele carriers [odds ratio (OR) 2.25, 95% confidence interval (CI) 1.11-4.55, P=0.02] was found. After dividing cases and controls by gender, an increased lung cancer risk for CYP3A4*1B carriers (OR 3.04, 95% CI 0.94-9.90, P=0.06) for women but not for men (OR 1.00, 95% CI 0.56-1.81) was revealed. Heavier smoking men (> or =20 pack-years) with the CYP3A4*1B allele had a significant OR for lung cancer of 3.42 (95% CI 1.65-7.14, P=0.001) compared to *1A/*1A carriers with lower tobacco exposure (<20 pack-years). For women, the respective OR was 8.00 (95% CI 2.12-30.30, P=0.005). Genotype frequencies were generally in Hardy-Weinberg equilibrium, except for CYP3A5 where a greater than expected number of CYP3A5*1 homozygotes was observed among cases (P=0.006). In addition, we observed linkage disequilibrium of CYP3A4 and CYP3A5 (P<0.00001), but a non-significantly increased lung cancer risk was only found for homozygous CYP3A5*1 allele carriers (OR 5.24, 95% CI 0.85-102.28, P=0.14) but not for heterozygotes. To confirm our observation that the CYP3A4*1B allele increases SCLC risk and modifies the smoking-related lung cancer risk in a gender-specific manner, further studies, including CYP3A haplotype analysis, will be necessary.

Association between the risk for lung adenocarcinoma and a (-4) G-to-A polymorphism in the XPA gene.

Polymorphisms of genes coding for DNA repair can affect lung cancer risk. A common single nucleotide (-4) G-to-A polymorphism was identified previously in the 5' untranslated region of the XPA gene. In a case-control study in European Caucasians, the influence of this polymorphism on primary lung cancer risk overall and according to histologic subtypes was investigated. Four hundred sixty-three lung cancer cases (including 204 adenocarcinoma and 212 squamous cell carcinoma) and 460 tumor-free hospital controls were investigated using PCR amplification and melting point analysis of sequence-specific hybridization probes. Odds ratios (OR) were calculated by multiple logistic regression analysis adjusting for age, gender, smoking habits, and occupational exposure and showed a slightly enhanced risk for all lung cancer cases as well as for squamous cell carcinoma and adenocarcinoma cases. Gene-environment interactions were analyzed with respect to smoking and occupational exposure. A nearly 3-fold increased risk for adenocarcinoma associated with the XPA AA genotype was observed for occupationally exposed individuals (OR, 2.95; 95% confidence interval, 1.42-6.14) and for heavy smokers (OR, 2.52; 95% confidence interval, 1.17-5.42). No genotype-dependent increase in OR was found for nonexposed individuals or those smoking <20 pack-years. The significant effect of the XPA polymorphism in heavy smokers and occupationally exposed individuals suggests an important gene-environment interaction for the XPA gene. The underlying mechanisms as to why AA homozygotes are predisposed to lung adenocarcinoma and which specific carcinogens are involved remains to be determined.

Genotype relationships in the CYP3A locus in Caucasians.

Genetic polymorphisms of the human CYP3A family affect clinical drug efficacy and may modify cancer risk. CYP3A genes show high sequence similarity that had previously lead to misallocation of CYP3A polymorphisms. Recent studies indicated a high degree of or even complete linkage for certain CYP3A alleles. Reliable LightCycler-based genotyping methods were developed and their degree of linkage in a large Caucasian population (n = 1210) investigated. Strong linkage disequilibrium was confirmed between CYP3A4, CYP3A5, and CYP3AP1 (each at P < 10(-5)). Contrary to some previous results claiming complete linkage between the phenotypically relevant CYP3A5*1 and a variant in a pseudogene promoter region CYP3AP1*1 we found among 428 controls (15 of 66) and 782 lung cancer cases (25 of 115) approximately 22% of CYP3AP1*1 carriers to be homozygous for CYP3A5*3 We conclude that contrary to previous assumptions, the CYP3AP1 genotype is not a reliable predictor for CYP3A5 activity.

Smart hydrogel based microsensing platform for continuous glucose monitoring.

In this paper, we present preliminary results showing the response of glucose-sensitive hydrogels, confined in micro-pressure sensors, to the changes in environmental glucose concentration. The glucose concentrations were incrementally varied between 20 and 0mM in 0.15M PBS solution at 7.4 pH and bovine serum at 7.4 pH at room temperature and response of the sensor was recorded. The micro sensors demonstrate a response time of 10 minutes in both PBS and serum. Tissue response after 55 days of subcutaneous implantation of a EtO sterilized sensor in mice is presented. The preliminary analysis of the surrounding tissue shows inflammation which is believed not to interfere with the sensor performance.

In-vitro investigations of a pH- and ionic-strength-responsive polyelectrolytic hydrogel using a piezoresistive microsensor.

Environmental responsive or smart hydrogels show a volume phase transition due to changes of external stimuli such as pH or ionic strength of an ambient solution. Thus, they are able to convert reversibly chemical energy into mechanical energy and therefore they are suitable as sensitive material for integration in biochemical microsensors and MEMS devices. In this work, micro-fabricated silicon pressure sensor chips with integrated piezoresistors were used as transducers for the conversion of mechanical work into an appropriate electrical output signal due to the deflection of a thin silicon bending plate. Within this work two different sensor designs have been studied. The biocompatible poly(hydroxypropyl methacrylate-N,N-dimethylaminoethyl methacrylate-tetra-ethyleneglycol dimethacrylate) (HPMA-DMA-TEGDMA) was used as an environmental sensitive element in piezoresistive biochemical sensors. This polyelectrolytic hydrogel shows a very sharp volume phase transition at pH values below about 7.4 which is in the range of the physiological pH. The sensor's characteristic response was measured in-vitro for changes in pH of PBS buffer solution at fixed ionic strength. The experimental data was applied to the Hill equation and the sensor sensitivity as a function of pH was calculated out of it. The time-dependent sensor response was measured for small changes in pH, whereas different time constants have been observed. The same sensor principal was used for sensing of ionic strength. The time-dependent electrical sensor signal of both sensors was measured for variations in ionic strength at fixed pH value using PBS buffer solution. Both sensor types showed an asymmetric swelling behavior between the swelling and the deswelling cycle as well as different time constants, which was attributed to the different nature of mechanical hydrogel-confinement inside the sensor.

[Pelargonium sidoides-extract (EPs 7630): registration confirms efficacy and safety]. / Pelargonium sidoides-Extrakt (EPs 7630): Zulassung bestätigt Wirksamkeit und Verträglichkeit.

For centuries the roots of Pelargonium sidoides DC have been used in South African ethno-medicine for the treatment of respiratory diseases. In Germany, a medicinal product containing a special extract of this substance is among the group of self-medication products most widely bought at chemist's shops. In December 2005, the Federal Institute for Drugs and Medical Devices (BfArM, Bonn) approved a new license for its use as a drug. The following review focuses on the current pharmacological, toxicological and clinical data covering the efficacy and innocuousness of this drug when administered for the treatment of acute bronchitis.

Ginkgo extract or cholinesterase inhibitors in patients with dementia: what clinical trials and guidelines fail to consider.

Dementia of Alzheimer's type (DAT), together with vascular dementia, is the most important indication for Ginkgo biloba extract (EGb). The therapeutic efficacy of this extract is founded on neuroprotective, metabolic and rheological effects. In addition to these mechanisms--which also form the basis of the activity of the older synthetic nootropics--the hypothesis that DAT is due to a "cholinergic deficit" at central synapses has led, over the last decade, to the development of a new group of drugs for this indication, the cholinesterase (ChE) inhibitors. Thus nowadays, EGb is competing, on the synthetic side, with the ChE inhibitors tacrine, donepezil, rivastigmine and galantamine. No direct comparative trials have been undertaken, but long-term studies lasting 24-56 weeks to demonstrate efficacy have been carried out with both groups of substances in accordance with current EU guidelines. To date, only one psychometric scale has gained general acceptance as the primary criterion of efficacy, namely the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), whose scores range from 0 to 70 (the lower the better). The initial scores of patients in the trials were between 20 and 30; the improvements after 6 months treatment (less those seen with placebo) were about 2 points under Ginkgo extract and 2 to 4 points with the ChE inhibitors. However, the relatively small differences are called into question by the occurrence of drug-specific side effects with the ChE inhibitors. Unlike the treatment with EGb, up to 90% of the patients given the ChE inhibitors developed nausea and vomiting, so there is a suspicion that methodological reasons in the sense of an "unblinding" of the treatment groups caused the apparent superiority in the intensity of the effect. In addition, the benefits of treatment were rapidly reversed after ending administration of ChE inhibitors, which did not occur to the same extent with EGb. Adverse drug reactions are more than 10 times more common with the ChE inhibitors and the treatment costs about five times higher than with EGb. Given the limited therapeutic options for DAT, treatment with EGb still appears to be the method of choice compared to the ChE inhibitors.

Clinical trials with hypericum extracts in patients with depression--results, comparisons, conclusions for therapy with antidepressant drugs.

By the spring of 2002, results from 34 controlled, double-blind trials of Hypericum extracts in some 3000 patients, predominantly with mild to moderate forms of depression, had been published. An overview is given of the studies conducted since 1990. In the majority of them, the efficacy criterion (primary endpoint) was the score and/or response rate on the Hamilton Rating Scale of Depression (HAMD). In ten studies, based on extracts prepared with 50% or 60% ethanol in water (V/V), the dosages ranged from 300 mg to 1050 mg of extract per day. Five of the ten studies were placebo-controlled and in all five cases, the Hypericum extract was shown to be significantly superior. Results with Hypericum were as good or even better than with imipramine or fluoxetine. In the period since 1990, a total of twelve controlled trials have been published with one particular extract prepared with 80% methanol in water (V/V), of which six were placebo-controlled, two compared Hypericum with imipramine and one each with maprotiline, amitriptyline, sertraline or light therapy. Dosages ranged from 450-1200 mg extract per day. Statistical analysis of the total Hamilton scores showed significant differences between Hypericum extract and placebo in four of the six placebo-controlled studies and a trend in favour of the active treatment in the other two. Of the five comparative trials against four different synthetic antidepressants, amitriptyline was significantly superior to Hypericum after six weeks of therapy, whilst there were no significant differences in treatment outcome between Hypericum and the other synthetics in the remaining four studies. The results of the trials conducted to date show no major differences in efficacy of the alcoholic extracts. Taking all the results into account, it can be assumed that the threshold dose for efficacy against individual symptoms and complaints that occur in the course of the depressive illness could be about 300 mg of extract per day. In the medically supervised treatment of mild to moderate depression, doses of approximately 500-1000 mg of extract per day of these preparations of St. John's Wort are of comparable efficacy to synthetic antidepressants in their normally prescribed dosages.

Pharmacokinetic herb-drug interactions: are preventive screenings necessary and appropriate?

Pharmacokinetic interactions often occur as a result of activity changes of drug-metabolizing and transporting proteins, especially cytochrome P450 (CYP) isoenzymes and P-glycoprotein (P-gp). The activity of these enzymes and drug transporters can be enhanced or inhibited by synthetic drugs as well as by natural products. Since the number of herb-drug interactions has increased in recent years, systematic in vitro screenings and more clinical studies to identify such interactions were proposed for herbal medicinal products. However, previous results regarding this issue are not only contradictory but also of less predictability. One reason for the discrepancies could be the lack of validation of the recommended in vitro tests. Furthermore, it has to be considered that pharmacokinetic drug interactions are not only mediated by herbal medicines but also by several foods, beverages and life-style products. Since herbal medicines are considered to have a broad therapeutic range, a preventive risk assessment for pharmacokinetic drug interactions should first be realized for synthetic drugs with a narrow therapeutic index. Efforts to identify all possible interactions will lead to limitless investigations and to inconsistent decisions.