Search

Purpose Misconceptions regarding activity and toxicity of therapeutic interventions are common among cancer patients. There is little knowledge about the factors that contribute to a more realistic perception by patients. Methods This pilot study was designed as a prospective questionnaire survey and included 101 therapy-naïve patients treated at the Division of Oncology, Medical University of Vienna. After obtaining written informed consent, patients’ expectations about treatment aims, side effects and the satisfaction with their oncologic consultation were interrogated before the first treatment cycle by questionnaires. Results Of 101 patients, 53 (53%) were female and 67/101 (66%) were treated with curative attempt in an adjuvant or neo-adjuvant setting. The most common diagnoses were lung cancer (31%) and breast cancer (30%). Although 92% of patients were satisfied with the information given by their oncologist, palliative patients were more likely to declare that not everything was explained in an intelligible manner (p = 0.01). Patients with a first language other than German stated more often that their physician did not listen carefully enough (p = 0.02). Of 30 patients, 26 (87%) receiving chemotherapy with palliative intent believed that their disease was curable. Concerning adverse events, female patients anticipated more frequently hair loss (p = 0.003) and changes in taste (p = 0.001) compared to men. Patients under curative treatment were more likely to expect weight loss (p = 0.02) and lack of appetite (p = 0.01) compared to patients with palliative treatment intent. Conclusion In conclusion, cancer patients were satisfied with the patient-doctor communication. This prospective study aggregated patients’ concerns on side effects and the perception of therapeutic goals in therapy-naïve patients. Of note, the majority of patients treated in the palliative setting expected their treatment to cure the disease.

Recruiting and retaining medical, nursing, and allied health professionals in rural and remote areas is a worldwide challenge, compromising continuity of care and population health outcomes in these locations. Specifically, pharmacists play an essential and accessible frontline healthcare role, and are often the first point of contact for health concerns. Despite several incentives, there remains a maldistribution and undersupply of pharmacists in rural and remote areas across many parts of the world. Although current systematic reviews have focussed on factors affecting pharmacists' retention generally, literature specifically focused on rural pharmacist workforce in a global context remains limited. The aim of this systematic review is to identify factors associated with recruitment and retention of the pharmacist workforce in rural and remote settings. Better understanding of these contributors will inform more effective interventional strategies to resolve pharmacist workforce shortages.A systematic search of primary studies was conducted in online databases, including Medline, Embase, CINAHL, Scopus, Web of Science and PsycINFO, and by hand-searching of reference lists. Eligible studies were identified based on predefined inclusion/exclusion criteria and methodological quality criteria, utilising the Critical Appraisal Skills Programme (CASP) and Good Reporting of A Mixed Methods Study (GRAMMS) checklists.The final review included 13 studies, with quantitative, qualitative, or mixed methods research design. Study-specific factors associated with recruitment and retention of pharmacists in rural practice were identified and grouped into five main themes: geographic and family-related, economic and resources, scope of practice or skills development, the practice environment, and community and practice support factors.The results provide critical insights into the complexities of rural recruitment and retention of pharmacists and confirms the need for flexible yet multifaceted responses to overcoming rural pharmacist workforce challenges. Overall, the results provide an opportunity for rural communities and health services to better identify key strengths and challenges unique to the rural and remote pharmacist workforce that may be augmented to guide more focussed recruitment and retention endeavours.

Background Recruiting and retaining medical, nursing, and allied health professionals in rural and remote areas is a worldwide challenge, compromising continuity of care and population health outcomes in these locations. Specifically, pharmacists play an essential and accessible frontline healthcare role, and are often the first point of contact for health concerns. Despite several incentives, there remains a maldistribution and undersupply of pharmacists in rural and remote areas across many parts of the world. Although current systematic reviews have focussed on factors affecting pharmacists’ retention generally, literature specifically focused on rural pharmacist workforce in a global context remains limited. The aim of this systematic review is to identify factors associated with recruitment and retention of the pharmacist workforce in rural and remote settings. Better understanding of these contributors will inform more effective interventional strategies to resolve pharmacist workforce shortages. Methods A systematic search of primary studies was conducted in online databases, including Medline, Embase, CINAHL, Scopus, Web of Science and PsycINFO, and by hand-searching of reference lists. Eligible studies were identified based on predefined inclusion/exclusion criteria and methodological quality criteria, utilising the Critical Appraisal Skills Programme (CASP) and Good Reporting of A Mixed Methods Study (GRAMMS) checklists. Results The final review included 13 studies, with quantitative, qualitative, or mixed methods research design. Study-specific factors associated with recruitment and retention of pharmacists in rural practice were identified and grouped into five main themes: geographic and family-related, economic and resources, scope of practice or skills development, the practice environment, and community and practice support factors. Conclusions The results provide critical insights into the complexities of rural recruitment and retention of pharmacists and confirms the need for flexible yet multifaceted responses to overcoming rural pharmacist workforce challenges. Overall, the results provide an opportunity for rural communities and health services to better identify key strengths and challenges unique to the rural and remote pharmacist workforce that may be augmented to guide more focussed recruitment and retention endeavours.

Objective To describe the effect of rural placements and rural background on pharmacy students’ intention to practice rurally. Methods This cross-sectional study invited 250 pharmacy students to participate in the mixed-methods survey. Pharmacy students were invited to participate at the National Australian Pharmacy Student Association (NAPSA) annual congress held in Bendigo, Victoria in January 2014. This study aimed to investigate the pharmacy students’ intention to pursue a rural career. Results A total of 156 participants responded to the survey. Participants were mostly female (68%), and were aged under 30 years with the majority aged 20–24 years (116, 74%). A third of the respondents were (32%) identified with having a rural background, and about half of all the participants (53%) had undertaken a clinical placement. Students who came from a rural background were more likely to work in rural areas than urban after graduation (p Conclusion This study shows that rural exposure (rural background or rural placement) can positively affect students’ intentions to participate in the rural workforce regardless of their background. Students have a desire to understand rural health and are likely to consider a rural career.

Background Pharmacists are highly accessible health care professionals and have regular interactions with consumers that suffer acute mental illness. Though pharmacists are trained in psychopharmacology, they lack formal mental health intervention skills. A solution to address this gap is to up-skill pharmacists in mental health first aid (MHFA). Objectives The purpose of this study was to establish the mental health first aid training needs for Australian rural pharmacists in the community setting. In addition, barriers to pharmacists providing MHFA support were ascertained. Methods This study was conducted in two parts. First, semi-structured interviews were conducted with eight rural community pharmacists to ascertain enablers and barriers to MHFA training. Second, an online survey was conducted to assess the attitudes of pharmacists to MHFA and their training requirements. Data from the interviews were thematically analyzed. Results Six major themes were identified including evolving role of the pharmacist, importance of relationships, complexity of mental health, need for training in MHFA, low confidence and barriers to assisting in acute mental illness. Pharmacists were accepting of the need for MHFA, but expressed concern over their lack of training, time and resources. The survey results also supported these findings. Conclusions Pharmacists supported MHFA training, but expressed difficulties in balancing professional and business responsibilities. Given that pharmacists are accessible and regularly exposed to mental health, MHFA training should be a core component of pharmacists’ training and their primary health care role. Further research is needed to evaluate the benefits of such training in terms of the consumers’ mental health outcomes.

BACKGROUND: Current treatment modalities for cancer have been successful in achieving improved survivorship; however, they come with a number of long‐term adverse effects. Accidental falls are a common and clinically significant adverse event in people living with and beyond cancer and rates are higher than in the rest of the population. OBJECTIVES: To assess the effects of prescribed or provided exercise for reducing accidental falls, and falls risk factors of strength, flexibility and balance, in people living with and beyond cancer. SEARCH METHODS: We searched the following electronic databases from inception to 10 July 2018, with no restrictions: CENTRAL, MEDLINE, Embase, and seven other databases. We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) for ongoing trials, and reference lists of reviews and retrieved articles for additional studies. SELECTION CRITERIA: We included all randomised controlled trials investigating exercise interventions versus no treatment, usual care or non‐exercise interventions on falls incidence or falls risk factors in adults living with and beyond cancer (18 years of age or older at diagnosis). We excluded cross‐over studies and studies in acute or inpatient hospice care. DATA COLLECTION AND ANALYSIS: At least two review authors independently completed data extraction for included papers. We used Covidence software to manage screening, data collection and extraction. We assessed evidence using GRADE and presented results in a 'Summary of findings' table. MAIN RESULTS: Eleven studies (835 participants) compared exercise to usual care. No studies compared exercise with no treatment or non‐exercise interventions. The quality of the evidence was very low for the primary outcome rates of falls, and very low to low for the secondary outcomes. We downgraded the evidence due to study limitations (risk of bias), and issues of imprecision due to small sample sizes, inconsistency and indirectness. All studies were at high risk of bias for blinding of participants and personnel due to inability to blind participants to an exercise intervention. Risk of bias was generally low or unclear for other categories. There was generally little information on the important outcomes comparing exercise to usual care. Rates of falls and number of fallers: one study (223 participants) measured accidental falls, but reported neither the rate of falls or the number of fallers; there was no difference in the number of falls between exercise and usual care (very low‐quality evidence). Strength: 10 studies (813 participants) reported on strength outcomes. Two analyses favoured exercise over usual care: quadriceps strength (2 studies, 72 participants; mean difference (MD) 8.99 kg, 95% confidence interval (CI) 1.29 to 16.70; low‐quality evidence), and leg press (4 studies, 388 participants; MD 21.1 kg, 95% CI 8.47 to 33.74; low‐quality evidence). In one analysis of the Sit‐to‐Stand Test, there was no difference between exercise and usual care (4 studies, 214 participants; standardised mean difference (SMD) –0.45, 95% CI –1.05 to 0.14; very low‐quality evidence). Flexibility: one study (21 participants) reported on flexibility for Sit‐and‐Reach Distance (MD 2.05 cm, 95% CI 0.59 to 3.51; very low‐quality evidence). Balance: five studies (350 participants) measured three different balance outcomes. Two analyses favoured exercise over usual care: postural balance (4 studies, 127 participants; standardised mean difference (SMD) 0.44, 95% CI 0.08 to 0.79; very low‐quality evidence), and Backward Walk Test (2 studies, 280 participants; SMD –0.24, 95% CI –0.48 to –0.01; low‐quality evidence). There was no difference between exercise and usual care for the Timed Up‐and‐Go Test (1 study, 15 participants; MD –0.35 seconds, 95% CI –1.47 to 0.77; low‐quality evidence). Number of people sustaining a fall‐related fracture: the quality of the evidence for exercise reducing fall‐related fractures was very low. Adverse events: a single study (223 participants) noted some temporary muscle soreness on initiation of exercise or when there was an increase in the weight lifted. As no occurrence data were reported, we could not assess this variable further. No studies reported musculoskeletal injury. Analysis indicated that there was very low‐quality evidence that exercise did not increase fatigue. AUTHORS' CONCLUSIONS: There is a paucity of evidence for exercise training to reduce fall rates in people living with and beyond cancer. Exercise training may improve strength, flexibility and balance for people in this population, but the evidence is very low quality.

Objective: To examine rural pharmacists’ perspectives on their roles in oral health in rural communities and collaborations with dental practitioners. Design: A qualitative research study using face-toface, semistructured interviews. Interview data were thematically analysed with the assistance of Nvivo 10. Setting: Eleven rural communities across rural Tasmania. Participants: Twenty community pharmacists. Results: Five major themes emerged: (i) barriers for patients to access dental services; (ii) oral health presentations to rural pharmacies; (iii) roles of pharmacists in oral health care (subthemes: advice; health promotion; and referrals); (iv) collaborations with dental practitioners; and (v) oral health education and training. Conclusion: This study suggests that rural community pharmacists had advisory and referral roles in oral health and acknowledged that they could play a greater role in oral health promotion. It was suggested that oral health could be incorporated into existing pharmacy health promotion and surveillance activities. There was a lack of collaboration between pharmacists and dentists or dental services and limited oral health education and training provided to pharmacists. Stronger collaboration between pharmacists and dental practitioners and better oral health training for pharmacists may enhance their role in promoting oral health within rural communities.

Poly(N-isopropylacrylamide) (PNIPAAm) hydrogel films with incorporated graphene oxide (GO) were developed and tested as light-stimulated actuators. GO dispersions were synthesized via Hummers method and characterized toward their optical properties and photothermal energy conversion. The hydrogels were prepared by means of photopolymerization. In addition, the influence of GO within the hydrogel network on the lower critical solution temperature (LCST) was investigated by differential scanning calorimetry (DSC). The optical absorbance and the response to illumination were determined as a function of GO concentration for thin hydrogel films. A proof of principle for the stimulation with light was performed.

Background P-glycoprotein (P-gp), an efflux transporter of the blood–brain barrier, limits the access of multiple xenobiotics to the central nervous system (CNS). Thus drug-dependent inhibition, induction or genetic variation of P-gp impacts drug therapy. Methods We investigated atypical antipsychotics and their interaction with P-gp. Amisulpride, clozapine, N-desmethylclozapine, olanzapine, and quetiapine were assessed in vitro on their inhibitory potential and in vivo on their disposition in mouse serum and brain, and behaviourally on the RotaRod test. In vivo wildtype (WT) and mdr1a/1b double knockout mice (mdr1a/1b (−/−, −/−); KO) were investigated. Results In rhodamine 123 efflux assay drugs inhibitory potency to P-gp could be ranked quetiapine > N-desmethylclozapine > clozapine > olanzapine. When treating WT and KO mice i.p. and assessing brain and serum levels by HPLC analysis, P-gp expression has the highest but a rather short effect on the distribution of amisulpride, whereas the others ranked N-desmethylclozapine > olanzapine > quetiapine > clozapine; contrasted by in vivo behavioral changes at various time points. Here quetiapine > clozapine > olanzapine impacts behavior most when P-gp is lacking. Present results indicate the relevance of P-gp expression for CNS-drug therapy. Conclusions Combination of in vitro, and in vivo methods highlights that inhibitory potency did not reflect P-gp related drug disposition. But, when drugs were ranked for inhibitory potency, this order is reflected in pharmacodynamic changes or vice versa. Pharmacodynamic effects otherwise were at most correlated to drug brain levels, which however, were present only to a limited extent (by positron emission tomography) accessible in humans.

A preliminary initial enzyme-linked immunosorbent assay (LUCIO ® -Direct ELISA kit) and a preliminary DRI ® enzyme immunoassay were evaluated for drug detection in head hair with respect to lowered cutoff values recommended in Germany for the control of abstinence in cases of re-granting of drivers' licences. Following drug classes were included: cannabinoids, opiates, cocaine like substances, amphetamine, methamphetamine (and methylenedioxyamphetamines), methadone, and benzodiazepines. 759 analyses were performed using LUCIO ® -Direct ELISA kits and 936 analyses using DRI ® enzyme immunoassay tests. Sample size for each drug group and immunoassay test reached from 74 to 178. The LUCIO ® -Direct ELISA kit revealed a sensitivity of 91% for amphetamine up to 98% for methadone (methamphetamine 92%, cocaine 94%, opiates 94%, benzodiazepines 96%) and values of specificity of 72% for methadone up to 89% for amphetamine and benzodiazepines. The test was not useful for a preliminary screening for tetrahydrocannabinol (sensitivity of 65%) in consideration of a suggested cutoff of 0.02ng/mg. The DRI ® enzyme immunoassay test was only useful for morphine and cocaine testing at low recommended new cutoff values (0.1ng/mg) revealing sensitivities of 94% and 99%, respectively.

Quaternary ammonium compounds pose an analytical challenge. Mebezonium, a muscle-relaxing agent contained in veterinary euthanasia solution T61, was analyzed in body fluids, organs, and injection sites of a veterinarian by liquid chromatography-tandem mass spectrometry (LC-MS-MS) method. Additionally, embutramide and tetracaine, which are two other active ingredients contained in T61, methadone, xylazine, and analgesics were detected by LC-MS-MS and high-performance liquid chromatography-ultraviolet detection methods. For detection of mebezonium a solid-phase extraction (SPE) combined with ion-pairing reagent heptafluorobutyric acid was developed. Separation was achieved on Phenomenex Synergi Hydro RP C 18 column combined with ammonium formate buffer and acetonitrile (pH 3.5). To enrich other drugs, liquid-liquid extraction procedures were used. Most of these drugs were separated on a Restek Allure PFP Propyl column using the mentioned mobile phase. Mebezonium and embutramide were detected in femoral vein serum in concentrations of 10.9 and 2.0 mg/L, respectively. The concentration of xylazine and methadone in serum was 2.0 and 0.4 mg/L, respectively. The LC-MS-MS method with SPE combined with an ion-pairing reagent allowed the quantitation of mebezonium. Methadone was detected in toxic concentrations and was, in combination with xylazine and T61, considered to be the cause of death.

Background P-glycoprotein (P-gp), an efflux transporter localized in the blood–brain barrier, limits the access of multiple xenobiotics to the central nervous system (CNS). For the new antipsychotic aripiprazole and its active metabolite dehydroaripiprazole differences in disposition in blood and brain were investigated after acute and sub-chronic administration in a P-gp knockout mouse model. Methods Serum and brain concentrations of both drugs were measured at several time points 1–24 h after i.p. injection of 10 mg/kg aripiprazole and after 11 days of sub-chronic administration in several tissues. Moreover, the expression of P-gp was determined by Western blot analysis after sub-chronic administration of the drug. Results In both wild type and abcb1ab (−/−) mice concentration of aripiprazole in brain were up to 9 fold higher than in serum. For dehydroaripiprazole the mean brain to serum ratios were below two. Brain to serum concentrations of both substances were significantly higher after acute and sub-chronic administration in connection to the expression of P-gp indicated by higher levels in abcb1ab (−/−) mice especially for dehydroaripiprazole. Sub-chronic aripiprazole treatment in WT animals had no effect on P-gp expression in the blood–brain barrier. Conclusions Aripiprazole and, even more pronounced its active metabolite dehydroaripiprazole could be identified as substrates of P-gp. The efflux transporter P-gp must therefore be considered as a relevant factor that contributes to wanted or unwanted clinical effects in patients treated with aripiprazole.

The case of a 13-month-old boy with a diagnosis of unclear unconsciousness is reported on. As the physical examination did not lead to any explanation of his condition, the administration of drugs in the context of Munchausen syndrome by proxy was suspected. Complex forensic-toxicological analyses using HPLC/UV, LC/MS/MS, and GC/MS identified ambroxol and clobutinol, two drugs that are indicated for acute respiratory diseases. No other central active compounds were detected. The accusation of intentional bodily injury raised against the parents could be rebutted, since the boy's unconsciousness could be explained with a rare but harmful side effect of the antitussive clobutinol.

PURPOSE: The purpose of this study was to compare the diagnostic accuracy of whole-body MRI (WB-MRI) and bone scintigraphy (BS) for the screening of bone metastases for the first time in a large and homogeneous patient collective with breast cancer in a systematic and controlled study. MATERIALS AND METHOD: 213 breast cancer patients were evaluated for bone metastases under randomized, double-blinded and prospective conditions at two hospitals. All participants were examined by WB-MRI and BS over an average period of four days. The examinations were performed separately at two different locations. The WB-MRI protocol included T 1-TSE and STIR sequences. WB-MRI and BS were reviewed independently by experienced radiologists and nuclear medicine specialists in a consensus reading. RESULTS: In 66 % of cases bone metastases were excluded by both procedures, and bone metastases were detected concordantly in 2 % of cases. In 7 % of cases there were discrepant results: in 7 cases BS was false-positive when WB-MRI was negative. In 5 / 7 cases BS was negative when WB-MRI identified bone metastases. In 89 % of cases BS was uncertain when WB-MRI was true-negative. In 17 % of cases WB-MRI showed important (non-) tumor-associated findings. The sensitivity, specificity, positive and negative predictive value and diagnostic accuracy for WB-MRI were 90 %, 94 %, 82 %, 98 % and 99 % and for BS those were 40 %, 81 %, 36 %, 91 % and 93 %. CONCLUSION: It could be demonstrated that WB-MRI is superior to BS for detecting bone metastases in breast cancer patients. These results should be considered for the next version of the S 3 guideline “Diagnosis, Therapy and Follow-Up of Breast Cancer”.

Aripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D(2)/D(3)) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D(2)/D(3) antagonist [(18)F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia.Sixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [(18)F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole.Mean dopamine D(2)/D(3) receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (E(max)) values close to saturation. The values for serum concentration predicted to provide 50% of E(max) (EC(50)) were in the range of 5-10 ng/ml in all brain regions. The D(2)/D(3) receptors were completely saturated when serum aripiprazole concentration exceeded 100-150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142).Because of its high affinity for D(2)/D(3) receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D(2)/D(3) receptors must remain nearly saturated for as long as 1 week after the last dose.

Efflux transporters, like P-glycoprotein (P-gp), may limit the access of drugs to the brain via the blood-brain barrier. The antipsychotic drug risperidone and its active metabolite 9-hydroxyrisperidone (paliperidone) are substrates of P-gp. Motor behavior of P-gp deficient mice (mdr1a/1b (-/-, -/-)) and wild type animals on a rotarod after acute doses of risperidone or haloperidol, a nonsubstrate of P-gp, were analysed aiming to show that P-gp substrate properties of an antipsychotic drug have functional consequences. Behavioral tests revealed dose-dependent effects of 0.3-3 mg/kg risperidone in wild type animals 0.5-12 h after i.p. injection of the drug. In knockout mice the 0.3 mg/kg dose of risperidone was as effective as the 3 mg/kg dose in wild type mice. A dose of 0.3 mg/kg haloperidol, however, exhibited similar pharmacodynamic effects in both genotypes. Brain concentrations of risperidone plus 9-hydroxyrisperidone were 10-fold higher in knockout than in wild type animals whereas brain concentrations of haloperidol did not differ between the two genotypes. P-gp-dependent brain distribution kinetics and behavioral effects of risperidone give evidence that the expression of P-gp has an impact on psychotropic drug actions when treating patients with drugs that are substrates of P-gp.

An automated high performance liquid chromatography with column-switching and ultraviolet detection was developed for the analysis of risperidone and 9-hydroxyrisperidone. The method needs minimum sample preparation and is useful for the detection down to a limit of 1 ng mL−1. Sample clean-up of serum was carried out on a CN 20 μm SPE-column using 8% (v/v) acetonitrile in water. Chromatographic separation was performed on ODS Hypersil C18 material with 38% (v/v) acetonitrile and 0.4% (v/v) TEMED in water. Application of the method to the analysis of serum samples confirmed its suitability for therapeutic drug monitoring of risperidone and 9-hydroxyrisperidone.

Aripiprazole, a novel antipsychotic drug, is metabolized by CYP3A4 and CYP2D6 forming mainly its active metabolite dehydroaripiprazole. In this study, aripiprazole and dehydroaripiprazole serum levels of psychiatric patients were measured and related to dose, comedication, and clinical effects including therapeutic and side effects. Patients were treated with mean doses of 20 +/- 8 mg/day of aripiprazole (median 15 mg, range 7.5-60 mg). Serum levels correlated significantly with the dose (r = 0.419; P0.01), with a mean value of aripiprazole of 214 +/- 140 ng/ml. Mean concentrations of the active metabolite dehydroaripiprazole amounted to 40% of the parent compound. Comedication with CYP3A4 and CYP2D6 inducers or inhibitors changed serum levels up to 51%. Improvement was best in patients with a serum level between 150 and 300 ng/ml. No or only mild side effects were detected in patients, with aripiprazole plasma concentrations between 110 and 249 ng/ml. A total of 32% of the patients who received no other antipsychotic drug besides aripiprazole reported side effects; tension being the most frequent one. Since serum levels of aripiprazole and dehydroaripiprazole were highly variable between individuals, and distinct ranges were associated with good therapeutic response and minimal side effects, it seems likely that therapeutic drug monitoring can be helpful to improve the antipsychotic drug therapy.

Aripiprazole is a novel atypical antipsychotic drug for the treatment of schizophrenia and schizoaffective disorders (1)(2)(3). The drug is metabolized by the cytochrome P450 isoenzymes 3A4 and 2D6 (4). Because of high interindividual variability in the expression of these enzymes, the aripiprazole concentration varies among healthy individuals after administration of the drug (5). In patients, insufficient response or side effects, such as somnolence, akathisia, or nausea, may result from too low or too high drug concentrations. Therapeutic drug monitoring (TDM), which is established practice for many antipsychotic drugs (6)(7), may be helpful for patients treated with aripiprazole. We measured aripiprazole by HPLC with column-switching and ultraviolet detection, based on a previously reported method for TDM of the antidepressant reboxetine (8). Pure drug was not available; we therefore incubated tablets containing 15 mg of aripiprazole base (Abilify®; Bristol-Myers Squibb/Otsuka Pharmaceuticals) for several days in the dark at room temperature in 15 mL per tablet of methanol (LiChrosolve; Merck) or ultrapure water adjusted to pH 2 with 0.1 mol/L HCl. Before chromatographic analysis, suspensions were shaken and cleared by centrifugation (3000 g for 5 min). Maximum solution was attained within the first 24 h. Because the mean drug concentrations in samples diluted to concentrations of 100, 200, or 500 μg/L differed little (2.7%; range, −7% to 10%) between methanol and water solutions, complete solution by methanol was assumed. Methanolic solutions were used for the preparation of calibrator samples with 6 concentrations between 50 and 500 μg/L and quality-control samples containing 50, 250, or 400 μg/L, prepared by supplementing drug-free plasma with aripiprazole. Perphenazine base from Sigma was used as internal standard in a final concentration of 0.0615 g/L. Blood for serum preparation was collected from 27 schizophrenic patients who had been treated with aripiprazole. The …

BACKGROUND: During human pregnancy, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays an important role in protecting the fetus from high maternal glucocorticoid concentrations by converting cortisol to inactive cortisone. Furthermore, 11beta-HSD2 is indirectly involved in the regulation of the prostaglandin inactivating enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH), because cortisol reduces the gene expression and enzyme activity of PGDH in human placental cells. OBJECTIVE: To examine developmental changes in placental 11beta-HSD2 and PGDH gene expression during the 2nd and 3rd trimesters of human pregnancies. METHODS: In placental tissue taken from 20 healthy women with normal pregnancy and 20 placentas of 17 mothers giving birth to premature babies, 11beta-HSD2 and PGDH mRNA expression was determined using quantitative real-time PCR. RESULTS: Placental mRNA expression of 11beta-HSD2 and PGDH increased significantly with gestational age (r=0.55, P=0.0002 and r=0.42, P=0.007). In addition, there was a significant correlation between the two enzymes (r=0.58, P

The objective of the present study was to examine the impact of preeclampsia on the relation of leptin and neuropeptide Y (NPY) gene expression in human placenta. A second goal was to monitor the change of leptin messenger RNA (mRNA) with increasing gestational age. Placental tissue was obtained from 17 premature deliveries, 18 term deliveries, and 10 mothers with preeclampsia. Gene expression of leptin, NPY, and two housekeeping genes (b-actin and glyceraldehyde-3-phosphate dehydrogenase was quantified using real-time PCR. The leptin/b-actin mRNA ratio was significantly higher in specimens of patients with preeclampsia than in those of gestational agematched controls (0.63 6 0.23 vs. 0.09 6 0.04 relative U (RU); P 5 0.03). NPY/b-actin mRNA was significantly reduced in the preeclampsia group (0.003 6 0.001 vs. 0.026 6 0.008 RU in controls; P 5 0.01). The NPY/leptin ratio was 0.11 6 0.09 for preeclamptic placenta samples and 1.7 6 0.6 RU for the controls (P 5 0.02). The leptin/b-actin ratio was significantly lower in placenta from premature deliveries than in term deliveries (0.02 6 0.004 vs. 0.12 6 0.05 RU; P 5 0.01). Similar results were obtained for normalization to glyceraldehyde3-phosphate dehydrogenase mRNA. Our data suggest an increase of placental leptin production with gestational age. In patients with preeclampsia, elevated leptin expression goes along with suppressed NPY expression. This resembles hypothalamic regulation. (J Clin Endocrinol Metab 84: 2755‐2758, 1999)

A petrological and geochemical study of an area of approximately 750 km2 has been carried out on representative lithological units of the extensive Sierra Norte-Ambargasta batholith (SNAB), in the Sierra Norte-Ambargasta range of the easternmost Sierras Pampeanas system of central Argentina. This batholith has intruded a dominantly metasedimentary basement of Precambrian age, which is mainly composed of quartzofeldsphatic-biotite or sericite-chlorite schists, and minor quartz-arenites of local distribution. The most primitive rocks of the magmatic sequence are diorite to tonalite microgranular enclaves (ME), which are included in the granodiorite-monzogranite (GM) basement. A large differentiated dacite-rhyolite (DR) stock intruded the earlier granitoids. All of these units were later intruded by highly evolved subalkaline granitoids (HESG) composed of miarolitic monzogranites, granite porphyries and large aplite dykes, which emplacement was controlled by old regional structural corridors. Geochemical parameters show that these granitoids series were derived from crystal fractionation of calc-alkaline magmas of metaluminous to weakly peraluminous composition. Discriminatory diagrams for tectonomagmatic settings, and the petrological and geochemical signature of the studied lithologies indicate that most granitoids of the intrusive sequence are the result of I-Type calc-alkaline magmatism. These granitoids are typical representatives of a precollisional volcanic arc environment, spatially related to an active continental margin. A significant chemical gap along the fractional crystallization trend separates the most evolved silica-rich granitoids from the less evolved units. This gap is attributed to the absence of representative magmatism of the syncollisional stage within the orogenic cycle. Silica and K-feldspar rich-rocks of the HESG-group are the result of intrusions that occured after the main magmatic activity, in a late-to post-orogenic tectonic setting. The occurrence of molybdenum, copper and other base-metal sulfides, associated with alteration assemblages that are common in porphyry systems, are in line with I-Type dacitic-rhyolitic magmatism in a volcanic arc geotectonic regime. Barren quartz-seriate greisen alteration is characteristic of the late-stage evolution of miarolitic monzogranites of the HESG-group. Radiometric ages for the SNAB granitoids suggest Upper Precambrian to Lower Paleozoic magmatic activity. Calc-alkaline arc magmatic activity of this age in the Sierra Norte of Cordoba, the easternmost block of the Oriental Sierras Pampeanas, raises the important question whether to assign the main magmatic activity of this region to the Pampean or to the Famatinian orogenic cycles. Our data suggest that the main igneous basement of the Sierra Norte-Ambargasta batholith consist of precollisional granitoids related to an orogenic cycle that most likely overlaps the G1 magmatic cycle of the Pampean orogen.

Introduction Aripiprazole, an atypical antipsychotic drug with mixed antagonism and agonism on dopamine D2 and serotonin receptors, is a substrate of the efflux transporter P-glycoprotein (P-gp). Here we tested the pharmacodynamic consequences of these properties in a P-gp deficient mouse model by studying the effects of aripiprazole and of ziprasidone on motor coordination. Methods The motor behaviour of wild-type (WT) and P-gp deficient [abcb1ab(-/-)] mice was investigated on a RotaRod. Mice received acute injections of either aripirazole or ziprasidone. For comparison, the dopamine receptor antagonist haloperidol and serotonin receptor ligands buspirone and ketanserin were also applied. Results Pharmacokinetic analyses revealed P-gp activity for aripiprazole and ziprasidone. This was indicated by 3.1- and 1.9-fold higher ratios of brain to plasma concentrations of drugs in knock-out to WT animals. Acute doses of ariprazole or ziprasidone impaired motor behaviour on the RotaRod. Effects were similar after injection of haloperidol, whereas the serotonin receptor ligands buspirone and ketanserin enhanced RotaRod performance. Genotype dependent differences of motor performance were found for aripiprazole but not for ziprasidone. Discussion Evidence was given that P-gp substrate properties have pharmacodynamic consequences for aripiprazole but not for ziprasidone and thus affect dopamine receptor related motor behaviour.

Purpose and Background In the UK, family-centred care (FCC) is espoused as being firmly embedded within the approach to care delivery when working with children and families (Smith and Coleman, 2010). Whilst the Royal College of Nursing (2009) advocates family involvement in pain care, research suggests parents and children are not actively involved in care decisions. The study explored the extent to which parents/main carers are involved and partners in their child’s pain care and the factors that influence parental involvement. The “Family-Centred Care continuum” was the conceptual framework used to examine parental involvement. Methods A qualitative ethnographical approach was adopted. Data were collected using non-participant observation and follow up interviews with a purposive sample of nurses, parents and children on the children’s wards of a district general hospital. Framework approach underpinned data analysis. Results Partnership between nurses and parents was not overtly evident in relation to pain care. Involvement appeared to be “unspoken”, with neither party (nurse or parent) being clear about the extent to which parents can be, or are involved in care. Few examples of explicit negotiation related to pain care were observed. However, parents attempted to be involved and act as advocates for their child, particularly when pain care was perceived as sub-optimal. Parents used a number of strategies to be advocates for their child whether supported by nurses or not, including; being determined to be involved by persistence; speaking up for their child; having or gaining knowledge about their child’s care and knowing their child. Nurse’s actions either promoted involvement and parent advocacy or hindered it. Providing information, planning care with parents, valuing parent contributions and supporting parent choices were facilitating factors. Hindering factors were identified as; making decisions without involving parents; lack of communication and variations in understanding of the principles and subsequent implementation of FCC. Conclusions and implications Nurses require knowledge and confidence to implement collaboration with parents, by empowering parents and overtly negotiating roles. Further research is necessary to identify how nurses can support parents to be partners in care.

Numerous death cases due to suffocation in a toxic or oxygen deficient gas atmosphere have been described in the literature, but unfortunately especially cases involving inert gases like helium are often presented without detailed toxicological findings. Observations on two suicides are reported, one by helium and the other by argon inhalation. During autopsies gas samples from the lungs were collected directly into headspace vials by a procedure ensuring minimal loss and dilution. Qualitative gas analyses were performed using headspace gas chromatography-mass spectrometry (HS-GC/MS). For carrier gas the commonly used helium was replaced by hydrogen. Qualitative positive results were obtained in the argon case, but the case involving helium revealed negative findings. The use of HS-GC/MS enables in principle to detect inert gases like argon or helium. However, a number of factors may later influence the results as, e.g. a longer period of time between death and sampling or pre-analytical artefacts during sampling of such highly volatile substances. In absence of analytical data supporting helium exposure, the causes of death in the actual cases were found to be asphyxia and in both cases the manner was suicide.

An interrelation between consumption of illegal drugs and committing an indictable offence has been repeatedly discussed in literature. In a retrospective study serum concentrations of illegal and legal drugs as well as data originating from police reports and examinations by physicians taking blood from individuals being suspected to be under the influence of drugs were evaluated. Results from 4816 cases were available. Property offences were the most frequent type (36%) as well as consumption of cannabinoids (55%). Psychophysiological conditions of consumers were compared with according serum concentrations. Close correlations between stimulating drugs and violence associated crime could not be found. Stimulated as well as sedated behaviour occurring following the consumption of various drugs might be the reason for no clear correlation between types of offence and consumed illegal or legal drugs in this study.

In der vorliegenden Untersuchung sollten 50 Probandenfalle (25 Manner und 25 Frauen) mittels Elektromyographie, Sonographie und Gesichtsphotographie hinsichtlich ihrer Masseterktivitat, Masseter-ausmase und Gesichtsmorphologie untersucht werden, um eventuelle Zusammenhange festzustellen. Die Untersuchung ergab folgende Resultate: Die Masseteraktivitat und die Masseterausmase zeigten eine grose inter- und intraindividuelle Variabilitat. Mannliche und weibliche Probanden unterschieden sich zum Teil erheblich voneinander. Die Zusammenhange zwischen der Masseteraktivitat, den Masseterausmasen und der Gesichtsmorphologie waren nur schwach ausgepragt, zeigten sich jedoch deutlicher bei weiblichen als bei mannlichen Probanden: Frauen mit schmaleren Gesichtern und groserem Mandibularbasiswinkel hatten kleinere Masseterdicken, und Frauen mit einem kleineren anterioren Gesichtshohenindex zeigten geringere Masseteraktivitat und kleinere Masseterbreiten in relaxiertem Zustand.

PURPOSE: This study was designed to examine the relationships between maternal perceptions of an acutely ill child, nurse caregivers and contextual factors in a pediatric critical care unit. METHODS: Subjects were mothers of 20 children who had had their first bone marrow transplant and the primary nurse of each child. The study was conducted on a bone marrow transplant unit. Variables included the acuity of the child, maternal satisfaction with nursing care, maternal vigilance as measured by the time spent at the child's bedside, nurses' attitudes toward family involvement with care, nursing experience and bone marrow transplant unit variables (census, unit acuity and staffing deficit). RESULTS: Positive associations were observed between the child's acuity and maternal satisfaction with nursing care, and between maternal vigilance and staffing deficit. There was an inverse relationship between maternal vigilance and length of nursing experience of the primary nurse and between positive attitudes of nurses toward family participation and years of nursing experience. CONCLUSION: These results show the complex nature of parental perceptions and involvement in the hospitalized child's care. They suggest that maternal attitudes about caregiving are associated with the child's acuity and that maternal vigilance is related to nursing and environmental factors, principally critical care experience of the primary nurse.

Due to sensitive limits of detection of chromatographic methods and low limit values regarding the screening of drugs under the terms of impairment in safe driving (§ 24a StVG, Street Traffic Law in Germany), preliminary immunoassay (IA) tests should be able to detect also low concentrations of legal and illegal drugs in serum in forensic cases. False-negatives should be avoided, the rate of false-positive samples should be low due to cost and time. An optimization of IA cutoff values and a validation of the assay is required for each laboratory. In a retrospective study results for serum samples containing amphetamine, methylenedioxy derivatives, cannabinoids, benzodiazepines, cocaine (metabolites), methadone and opiates obtained with CEDIA drugs of abuse reagents on a Hitachi 912 autoanalyzer were compared with quantitative results of chromatographic methods (gas or liquid chromatography coupled with mass spectrometry (GC/MS or LC/MS)). Firstly sensitivity, specificity, positive and negative predictive values and overall misclassification rates were evaluated by contingency tables and compared to ROC-analyses and Youden-Indices. Secondly ideal cutoffs were statistically calculated on the basis of sensitivity and specificity as decisive statistical criteria with focus on a high sensitivity (low rates of false-negatives), i.e. using the Youden-Index. Immunoassay (IA) and confirmatory results were available for 3014 blood samples. Sensitivity was 90% or more for nearly all analytes: amphetamines (IA cutoff 9.5 ng/ml), methylenedioxy derivatives (IA cutoff 5.5 ng/ml), cannabinoids (IA cutoff 14.5 ng/ml), benzodiazepines (IA cutoff >0 ng/ml). Test of opiates showed a sensitivity of 86% for a IA cutoff value of >0 ng/ml. Values for specificity ranged between 33% (methadone, IA cutoff 10 ng/ml) and 90% (cocaine, IA cutoff 20 ng/ml). Lower cutoff values as recommended by ROC analyses were chosen for most tests to decrease the rate of false-negatives. Analyses enabled the definition of cutoff values with good values for sensitivity. Small rates of false-positives can be accepted in forensic cases.

In 2009 cutoff values of assessment criteria to testify abstinence control in order to estimate driving ability were standardized in Germany. The cutoff values are lower than required in existing guidelines like SAMHSA and there is critical discussion about detection of low concentrations by using immunoassay, especially concerning amphetamines in urine (50 ng/ml). In this study Direct ELISA kits were tested for their applicability to identify the absence of amphetamines, cannabinoids, opiates, cocaine, methadone and benzodiazepines in urine. Results were confirmed by LC/MS or GC/MS analyses. Sensitivity, specificity, predictive values (positive as well as negative) and overall misclassification rates were evaluated by contingency tables and were compared to ROC-analyses. Sensitivity results as well as specificity results were satisfying showing sensitivity values higher than 96% for each analyte. The amphetamine test we used showed sensitivity and specificity of 100% and 88%, respectively, even if amphetamine tests usually react with high cross-reactivity. Our study results include high discrimination at required cutoff values between positives and negatives for each drug group and demonstrate that immunological tests complying with requirements of current decreased urine cutoff values for assessment of driving ability do exist.

An uncommon suicide by oral ingestion of potassium cyanide salts and contemporaneous inhalation of hydrogen cyanide is presented. A 48-year-old tradesman was found dead sitting in his car. A penetrating odor of bitter almonds was noticed when opening the doors. A camping stove and a cooking pot containing large amounts of dark blue crystals were found in the footwell of the car. White powder adhered to his fingers and to the area around the mouth. Furthermore bottles containing potassium ferrocyanide and different kinds of acid and leach were found in the car together with internet information about, e.g. potassium ferrocyanide and potassium cyanide. At autopsy hemorrhages and erosions of the mucosa of the respiratory tract, esophagus and stomach were found. Concentrations of cyanide were 0.2mg/l in stomach contents, 0.96mg/kg in brain tissue, 2.79mg/kg in lungs, and 5.3mg/l in blood. The white and toxic powder potassium cyanide was formed by heating of the yellow crystals of potassium ferrocyanide on the camping stove. This powder was probably ingested orally. Addition of acid converted the salt into the highly toxic gas hydrogen cyanide. Oxidation with atmospheric oxygen built the dark blue ferrous compound Prussian blue. This case report of a person who was not familiar with chemicals demonstrates the acquisition of professional information via the internet, enabling a suicide with a complex procedure.

Extrapyramidal motoric symptoms are casual side effects under antipsychotic medication. New generation antipsychotics are expected to have a reduced risk due to different receptor affinities. Here, haloperidol and the new generation antipsychotics, risperidone, amisulpride, and aripiprazole, were examined with both catalepsy test and rotarod performance test to screen for their usability in mice. Mice treated with haloperidol, risperidone, and aripiprazole showed dose and time-dependent impairment. Amisulpride-treated mice showed no signs of catalepsy. Catalepsy test and rotarod performance test were useful methods to detect side effects of both generation antipsychotics. Catalepsy test provided more specificity whereas the rotarod test provided higher degree of sensitivity to motor impairment including catalepsy.

The purpose of this study was to compare the diagnostic accuracy of whole-body MRI (WB-MRI) and bone scintigraphy (BS) for the screening of bone metastases for the first time in a large and homogeneous patient collective with breast cancer in a systematic and controlled study.213 breast cancer patients were evaluated for bone metastases under randomized, double-blinded and prospective conditions at two hospitals. All participants were examined by WB-MRI and BS over an average period of four days. The examinations were performed separately at two different locations. The WB-MRI protocol included T 1-TSE and STIR sequences. WB-MRI and BS were reviewed independently by experienced radiologists and nuclear medicine specialists in a consensus reading.In 66 % of cases bone metastases were excluded by both procedures, and bone metastases were detected concordantly in 2 % of cases. In 7 % of cases there were discrepant results: in 7 cases BS was false-positive when WB-MRI was negative. In 5 / 7 cases BS was negative when WB-MRI identified bone metastases. In 89 % of cases BS was uncertain when WB-MRI was true-negative. In 17 % of cases WB-MRI showed important (non-) tumor-associated findings. The sensitivity, specificity, positive and negative predictive value and diagnostic accuracy for WB-MRI were 90 %, 94 %, 82 %, 98 % and 99 % and for BS those were 40 %, 81 %, 36 %, 91 % and 93 %.It could be demonstrated that WB-MRI is superior to BS for detecting bone metastases in breast cancer patients. These results should be considered for the next version of the S 3 guideline "Diagnosis, Therapy and Follow-Up of Breast Cancer".

The authors report on two cases of suspected Munchausen by proxy syndrome. In a 3-year-old boy, clinical toxicological analyses produced suspicious clues that an antidepressant had been administered, which could not be verified by forensic toxicological investigations. In a 13-month-old boy, the mother was also suspected of having poisoned the child. Initial clinical toxicological examinations failed to explain the observed symptoms (unclear unconsciousness, narrowed pupils). While in the first case, the incorrect interpretation of findings by a laboratory without forensic experience resulted in suspicions against the mother, the cause for the observed symptoms in the second case could be proved by complex analyses not performed before and the suspicion that the clinical picture had been intentionally brought about could be cleared up (use of an antitussive containing clobutinol). The two reports show that especially in cases with a potential forensic background, adequately qualified forensic laboratories with a broad spectrum of analytical methods should be involved.

Cellular interactions as they occur in the stem cell niche or in context with leukocyte activation are effective mechanisms for the regulation of cellular states in vivo. The analysis of the underlying principles is of high clinical interest. Unfortunately, conventional applications used for addressing the related questions often pool biological data of cellular subpopulations or provide only end point analyses of signal transduction processes. This leads to blurred data or ignores important information from the dynamics of cellular behaviour, respectively. Here, we present a novel microfluidic platform for the initiation and analysis of cellular interactions on a single-cell level. We used the system to stimulate single T cells with anti-CD3/anti-CD28-presenting microbeads and analyzed the cytosolic calcium signal simultaneously. T cell activation was examined 16 - 24 h after stimulus presentation and was correlated with the previously recorded calcium signal. A significant difference between the calcium patterns of activated and non-activated cells was detected. This shows that the dynamics of a cellular response can provide useful information about the specific physiological state of a cell. The described technique accounts for this finding and could help to diversify our view of intercellular communication.

The condition of the fallopian tubes was assessed in 100 fertile women on whom a caesarean section had been performed and in 100 infertile women who had undergone a diagnostic laparascopy. The 100 infertile women revealed both peritubal adhesions (20% vs 2%) and fimbrial agglutinations (4% vs 0%) in a significantly higher number of cases. When the diagnostic procedure was extended to include the salpingoscopy of 20 women with periampullary and peritubal adhesions, 10% of them were found to be suffering from damage of the endosalphinx. In patients with fimbrial agglutination, the same diagnostic procedure revealed mucosal damage in 40% of the cases. The rate of damage to the endosalpinx may help to explain the relatively high rate of ectopic pregnancies (15%) following microsurgical fimbrioplasty. Thus, in cases where the patient is suffering from peritubal adhesions and fimbrial agglutinations, salpinogoscopy can be of use in deciding whether microsurgery is indicated. In those cases, where there is evidence of damage to the endosalpinx, in-vitro fertilization with intrauterine embryo transfer must be considered as the preferential method.

Multi Drug Resistance (MDR) carriers in the Blood-Brain-Barrier (BBB) protect the brain from pharmacological tissue damage. Of all of the MDR xenobiotic efflux pumps highly expressed in the BBB p-glycoprotein (p-gp, MDR1) handles the largest fraction of commonly prescribed drugs. We investigated the role of p-gp on metabolic (pharmacokinetic) and behavioral (pharmacodynamic) effects of aripiprazole (ari) in a p-gp k.o. mouse model (mdr1a/b -/-). Wild type and transgenic mice were acutely treated (i.p.) with either aripiprazole or its active metabolite dehydroaripiprazole (d-ari), or saline. Blood serum and brain tissue levels were measured 1,3,6,9, and 24h after injection. Behavioral changes were analysed on a rotarod and in the radial water maze learning task 0.5h after treatment. Kinetic investigation revealed significant differences (p

Leiomyomatosis peritonealis disseminata (LPD) is a rare disease characterised by the presence of multiple smooth muscle tumour nodules throughout the peritoneal cavity. Approximately 50 cases of LPD have been reported to date in the world literature. There is a very high association with excess exogenous and endogenous female gonadal steroids, specifically oestrogen and progesterone. LPD has been described almost only in premenopausal women and is mostly asymptomatic. Four cases of malignant transformation of this disease have been reported. We report a case of a patient with prolonged exposure to oral contraceptives, operated because of hypermenorrhea and 'myoma in statu nascendi'. A metastasing myomatous tumour was suspected during the operation. LPD was diagnosed by intraoperative histological examination. Abdominal hysterectomy was performed. Five months later a second laparotomy had to be done because of an ovarian endometriosis tumour of about 10 cm size. A bilateral salpingo-oophorectomy and omentectomy were performed.