Bringing Anatomical Information into Neuronal Network Models.

For constructing neuronal network models computational neuroscientists have access to wide-ranging anatomical data that nevertheless tend to cover only a fraction of the parameters to be determined. Finding and interpreting the most relevant data, estimating missing values, and combining the data and estimates from various sources into a coherent whole is a daunting task. With this chapter we aim to provide guidance to modelers by describing the main types of anatomical data that may be useful for informing neuronal network models. We further discuss aspects of the underlying experimental techniques relevant to the interpretation of the data, list particularly comprehensive data sets, and describe methods for filling in the gaps in the experimental data. Such methods of "predictive connectomics" estimate connectivity where the data are lacking based on statistical relationships with known quantities. Exploiting organizational principles that link the plethora of data in a unifying framework can be useful for informing computational models. Besides overarching principles, we touch upon the most prominent features of brain organization that are likely to influence predicted neuronal network dynamics, with a focus on the mammalian cerebral cortex. Given the still existing need for modelers to navigate a complex data landscape full of holes and stumbling blocks, it is vital that the field of neuroanatomy is moving toward increasingly systematic data collection, representation, and publication.

Sexual distress and associated factors among cervical cancer survivors: A cross-sectional multicenter observational study.

BACKGROUND: To assess whether sexual distress among cervical cancer (CC) survivors is associated with frequently reported vaginal sexual symptoms, other proposed biopsychosocial factors and whether worries about painful intercourse mediate the relation between vaginal sexual symptoms and sexual distress. METHODS: A cross-sectional study was conducted among 194 sexually active partnered CC survivors aged 25 to 69 years. Sexual distress, vaginal sexual symptoms, sexual pain worry, anxiety, depression, body image concerns, and relationship dissatisfaction and the sociodemographic variables age, time since treatment, and relationship duration were assessed by using validated self-administrated questionnaires. RESULTS: In total, 33% (n = 64) of the survivors scored above the cut-off score for sexual distress. Higher levels of sexual distress were shown to be associated with higher levels of vaginal sexual symptoms, sexual pain worry, relationship dissatisfaction, and body image concerns. Furthermore, the results showed that sexual pain worry partly mediated the association between vaginal sexual symptoms and sexual distress, when controlling for relationship dissatisfaction and body image concerns. CONCLUSIONS: Appropriate rehabilitation programs should be developed for CC survivors to prevent and reduce not only vaginal sexual symptoms but also sexual pain worry, relationship dissatisfaction, and body image concerns to reduce sexual distress.

A nurse-led sexual rehabilitation intervention after radiotherapy for gynecological cancer.

PURPOSE: Although vaginal dilator use after combined pelvic radiation therapy and brachytherapy (RT/BT) is recommended to prevent vaginal shortening and stenosis, women fail to use them and experience sexual problems. A nurse-led sexual rehabilitation intervention targeting sexual recovery and vaginal dilatation was developed. Its feasibility was investigated during a prospective, longitudinal, observational pilot study. METHODS: Four oncology nurses were specifically trained to conduct the intervention. Gynecologic cancer patients treated with RT/BT were assessed using (i) questionnaires on frequency of dilator use (monthly), sexual functioning, and sexual distress (at baseline and 1, 6, and 12 months) and psychological and relational distress (at 1, 6, and 12 months); (ii) semi-structured interviews (between 6 and 12 months); and (iii) consultation recordings (a random selection of 21 % of all consults). RESULTS: Twenty participants were 26-71 years old (mean = 40). Eight participants discontinued participation after 3 to 9 months. At 6 months after RT, 14 out of 16 (88 %), and at 12 months 9 out of 12 (75 %), participants dilated regularly, either by having sexual intercourse or by using dilators. Sexual functioning improved between 1 and 6 months after RT, with further improvement at 12 months. Most participants reported that the intervention was helpful and the nurses reported having sufficient expertise and counseling skills. CONCLUSIONS: According to the pilot results, the intervention was feasible and promising for sexual rehabilitation and regular dilator use after RT. Its (cost-)effectiveness will be investigated in a randomized controlled trial.

HPV-negative squamous cell carcinoma of the anal canal is unresponsive to standard treatment and frequently carries disruptive mutations in TP53.

BACKGROUND: Human papillomavirus (HPV), p16 expression, and TP53 mutations are known prognostic factors in head and neck squamous cell carcinoma, but their role in squamous cell carcinoma of the anal canal (SCCAC) is less well established. The objective of this study was to determine the prognostic significance of tumour HPV status, p16 and p53 expression, and mutations in TP53 in patients with SCCAC receiving (chemo)radiotherapy. METHODS: Human papillomavirus DNA was determined using an INNO-LiPA-based assay in tumour tissue of 107 patients with locally advanced SCCAC. Patients were treated with radiotherapy, with or without concurrent chemotherapy consisting of a fluoropyrimidine and mitomycin C. Expression of p16 and p53 was determined using immunohistochemistry. Exons 2-11 of TP53 in tumour tissue were sequenced. RESULTS: DNA of high-risk HPV types was detected in 93 out of 107 tumours (87%), all of which overexpressed p16 (HPV+/p16+). Of 14 HPV-negative (HPV-) tumours (13%), 10 (9%) were p16-negative (HPV-/p16-) and 4 (4%) overexpressed p16 (HPV-/p16+). Patients with HPV-/p16- disease had inferior 3-year locoregional control (LRC) (15%) compared with patients with HPV+/p16+ tumours (82%, P<0.001) and HPV-/p16+ tumours (75%, P=0.078). Similarly, 3-year overall survival (OS) was 35% (HPV-/p16-) vs 87% (HPV+/p16+, P<0.001) and 75% (HPV-/p16+, P=0.219). Disruptive mutations in TP53 were found in 80% of HPV-/p16- tumours vs 6% of HPV+/p16+ tumours (P<0.001). In multivariate analysis, HPV-/p16- status was an independent predictor of inferior LRC and OS. CONCLUSIONS: HPV- tumours are frequently TP53 mutated. HPV-/p16- status is a strong predictor for reduced LRC and OS, and alternative treatment strategies for patients with HPV-/p16- disease need to be explored.

Demonstration of a spaser-based nanolaser.

One of the most rapidly growing areas of physics and nanotechnology focuses on plasmonic effects on the nanometre scale, with possible applications ranging from sensing and biomedicine to imaging and information technology. However, the full development of nanoplasmonics is hindered by the lack of devices that can generate coherent plasmonic fields. It has been proposed that in the same way as a laser generates stimulated emission of coherent photons, a 'spaser' could generate stimulated emission of surface plasmons (oscillations of free electrons in metallic nanostructures) in resonating metallic nanostructures adjacent to a gain medium. But attempts to realize a spaser face the challenge of absorption loss in metal, which is particularly strong at optical frequencies. The suggestion to compensate loss by optical gain in localized and propagating surface plasmons has been implemented recently and even allowed the amplification of propagating surface plasmons in open paths. Still, these experiments and the reported enhancement of the stimulated emission of dye molecules in the presence of metallic nanoparticles lack the feedback mechanism present in a spaser. Here we show that 44-nm-diameter nanoparticles with a gold core and dye-doped silica shell allow us to completely overcome the loss of localized surface plasmons by gain and realize a spaser. And in accord with the notion that only surface plasmon resonances are capable of squeezing optical frequency oscillations into a nanoscopic cavity to enable a true nanolaser, we show that outcoupling of surface plasmon oscillations to photonic modes at a wavelength of 531 nm makes our system the smallest nanolaser reported to date-and to our knowledge the first operating at visible wavelengths. We anticipate that now it has been realized experimentally, the spaser will advance our fundamental understanding of nanoplasmonics and the development of practical applications.

Bridging between professionals in perinatal care: towards shared care in the Netherlands.

Relatively high perinatal mortality rates in the Netherlands have required a critical assessment of the national obstetric system. Policy evaluations emphasized the need for organizational improvement, in particular closer collaboration between community midwives and obstetric caregivers in hospitals. The leveled care system that is currently in place, in which professionals in midwifery and obstetrics work autonomously, does not fully meet the needs of pregnant women, especially women with an accumulation of non-medical risk factors. This article provides an overview of the advantages of greater interdisciplinary collaboration and the current policy developments in obstetric care in the Netherlands. In line with these developments we present a model for shared care embedded in local 'obstetric collaborations'. These collaborations are formed by obstetric caregivers of a single hospital and all surrounding community midwives. Through a broad literature search, practical elements from shared care approaches in other fields of medicine that would suit the Dutch obstetric system were selected. These elements, focusing on continuity of care, patient centeredness and interprofessional teamwork form a comprehensive model for a shared care approach. By means of this overview paper and the presented model, we add direction to the current policy debate on the development of obstetrics in the Netherlands. This model will be used as a starting point for the pilot-implementation of a shared care approach in the 'obstetric collaborations', using feedback from the field to further improve it.

Development and validation of a LC-MS/MS method for the in vitro analysis of 1-hydroxymidazolam in human liver microsomes: application for determining CYP3A4 inhibition in complex matrix mixtures.

Complementary and alternative medicines (CAM) can affect the pharmacokinetics of anticancer drugs by interacting with the metabolizing enzyme cytochrome P450 (CYP) 3A4. To evaluate changes in the activity of CYP3A4 in patients, levels of 1-hydroxymidazolam in plasma are often determined with liquid chromatography-quadrupole mass spectrometry (LC-MS/MS). However, validated LC-MS/MS methods to determine in vitro CYP3A4 inhibition in human liver microsomes are scarce and not optimized for evaluating CYP3A4 inhibition by CAM. The latter is necessary because CAM are often complex mixtures of numerous compounds that can interfere with the selective measurement of 1-hydroxymidazolam. Therefore, the aim was to validate and optimize an LC-MS/MS method for the adequate determination of CYP3A4 inhibition by CAM in human liver microsomes. After incubation of human liver microsomes with midazolam, liquid-liquid extraction with tert-butyl methyl ether was applied and dried samples were reconstituted in 50% methanol. These samples were injected onto a reversed-phase chromatography consisting of a Zorbax Extend-C18 column (2.1 × 150 mm, 5.0 µm particle size), connected to a triple quadrupole mass spectrometer with electrospray ionization. The described LC-MS/MS method was validated over linear range of 1.0-500 nm for 1-hydroxymidazolam. The results revealed good inter-assay accuracy (≥85% and ≤115%) and within-day and between-day precisions (coefficient of variation ≤ 4.43%). Furthermore, the applicability of this assay for the determination of CYP3A4 inhibition in complex matrix mixtures was successfully demonstrated in an in vitro experiment in which CYP3A4 inhibition by known CAM (ß-carotene, green tea, milk thistle and St. John's wort) was determined.

Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors.

AIMS: Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed pharmacological properties of empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors. METHODS: [(14)C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [(14)C]-mannose and [(14)C]-myo-inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with [(3)H]-labelled empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker diabetic fatty (ZDF) rats. RESULTS: Empagliflozin has an IC(50) of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approximately 1 h). Compared with other SGLT-2 inhibitors, empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high. CONCLUSIONS: Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes.

The impact of mobility on HIV control: a modelling study.

Mobility is associated with HIV due to more risky sexual behaviour of mobile groups such as travellers and migrants. Limited participation of such groups may reduce the effectiveness of HIV interventions disproportionally. The established STDSIM model, which simulates transmission and control of HIV and STD, was extended to simulate mobility patterns based on data from Tanzania. We explored the impact of non-participation of mobile groups (travellers and recent migrants) on the effectiveness of two interventions: condom promotion and health education aiming at partner reduction. If mobile groups do not participate, the effectiveness of both interventions could be reduced by 40%. The impact of targeting travellers with a combined HIV campaign is close to that of a general population intervention. In conclusion, it is important to account for possible non-participation of migrants and travellers. If non-participation is substantial, impact of interventions can be greatly improved by actively approaching these people.

Dose-response relationship between alcohol consumption before and during pregnancy and the risks of low birthweight, preterm birth and small for gestational age (SGA)-a systematic review and meta-analyses.

BACKGROUND: Descriptions of the effects of moderate alcohol consumption during pregnancy on adverse pregnancy outcomes have been inconsistent. OBJECTIVE: To review systematically and perform meta-analyses on the effect of maternal alcohol exposure on the risk of low birthweight, preterm birth and small for gestational age (SGA). SEARCH STRATEGY: Using Medical Subject Headings, a literature search of MEDLINE, EMBASE, CINAHL, CABS, WHOlist, SIGLE, ETOH, and Web of Science between 1 January 1980 and 1 August 2009 was performed followed by manual searches. SELECTION CRITERIA: Case-control or cohort studies were assessed for quality (STROBE), 36 available studies were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted the information on low birthweight, preterm birth and SGA using a standardised protocol. Meta-analyses on dose-response relationships were performed using linear as well as first-order and second-order fractional polynomial regressions to estimate best fitting curves to the data. MAIN RESULTS: Compared with abstainers, the overall dose-response relationships for low birthweight and SGA showed no effect up to 10 g pure alcohol/day (an average of about 1 drink/day) and preterm birth showed no effect up to 18 g pure alcohol/day (an average of 1.5 drinks/day); thereafter, the relationship showed a monotonically increasing risk for increasing maternal alcohol consumption. Moderate consumption during pre-pregnancy was associated with reduced risks for all outcomes. CONCLUSIONS: Dose-response relationship indicates that heavy alcohol consumption during pregnancy increases the risks of all three outcomes whereas light to moderate alcohol consumption shows no effect. Preventive measures during antenatal consultations should be initiated.

Explaining differences in birth outcomes in relation to maternal age: the Generation R Study.

OBJECTIVE: To examine the association between maternal age and birth outcomes, and to investigate the role of sociodemographic and lifestyle-related determinants. DESIGN: Population-based prospective cohort study from early pregnancy onwards. SETTING: Rotterdam, the Netherlands. POPULATION: A cohort of 8568 mothers and their children. METHODS: Maternal age was assessed at enrolment. Information about sociodemographic (height, weight, educational level, ethnicity, parity) and lifestyle-related determinants (alcohol consumption, smoking habits, folic acid supplement use, caffeine intake, daily energy intake) and birth outcomes was obtained from questionnaires and hospital records. Multivariate linear and logistic regression analyses were used. MAIN OUTCOMES MEASURES: Birthweight, preterm delivery, small-for-gestational-age, and large-for-gestational-age. RESULTS: As compared with mothers aged 30-34.9 years, no differences in risk of preterm delivery were found. Mothers younger than 20 years had the highest risk of delivering small-for-gestational-age babies(OR 1.6, 95% CI: 1.1-2.5); however, this increased risk disappeared after adjustment for sociodemographic and lifestyle-related determinants. Mothers older than 40 years had the highest risk of delivering large-for-gestational-age babies (OR 1.3, 95% CI: 0.8-2.4). The associations of maternal age with the risks of delivering large-for-gestational-age babies could not be explained by sociodemographic and lifestyle-related determinants. CONCLUSIONS: As compared with mothers aged 30-34.9 years, younger mothers have an increased risk of small-for-gestational-age babies, whereas older mothers have an increased risk of large-for-gestational-age babies. Sociodemographic and lifestyle-related determinants cannot fully explain these differences.

Colonic diverticulitis: a prospective analysis of diagnostic accuracy and clinical decision-making.

OBJECTIVE: To evaluate the diagnostic accuracy of clinical evaluation and cross-sectional imaging modalities such as ultrasound and computed tomography for patients with suspected colonic diverticulitis and to determine the value of these examinations in clinical decision-making. METHOD: A prospective analysis was conducted of 802 consecutive patients that presented with abdominal pain at the emergency department. Initial clinical diagnoses and management proposals were compared to the final diagnoses and therapeutic strategies for all patients. RESULTS: Fifty-seven patients were identified with colonic diverticulitis as the final diagnosis. The positive and negative predictive values for the clinical diagnosis of colonic diverticulitis were 0.65 and 0.98 respectively. Additional cross-sectional imaging had a positive and negative predictive value of respectively 0.95 and 0.99 or higher. These additional examinations led to a correct change of the initial clinical diagnosis in 37% of the patients, and a change in management in only 7%. CONCLUSION: The accuracy of the clinical diagnosis for colonic diverticulitis is low. Ultrasound and computed tomography have superior diagnostic accuracy but these examinations rarely change the initial management proposal.

A job-related fitness test for the Dutch police.

BACKGROUND: The variety of tasks that characterize police work highlights the importance of being in good physical condition. AIMS: To take a first step at standardizing the administration of a job-related test to assess a person's ability to perform the physical demands of the core tasks of police work. The principal research questions were: are test scores related to gender, age and function and are test scores related to body mass index (BMI) and the number of hours of physical exercise? METHODS: Data of 6999 police officers, geographically spread over all parts of The Netherlands, who completed a physical competence test over a 1 year period were analysed. RESULTS: Women performed the test significantly more slowly than men. The mean test score was also related to age; the older a person the longer it took to complete the test. A higher BMI was associated with less hours of body exercise a week and a slower test performance, both in women and men. CONCLUSIONS: The differences in individual test scores, based on gender and age, have implications for future strategy within the police force. From a viewpoint of 'same job, same standard' one has to accept that test-score differences may lead to the exclusion of certain staff. However, from a viewpoint of 'diversity as a business issue', one may have to accept that on average, both female and older police officers are physically less tailored to their jobs than their male and younger colleagues.

Feasibility of CT quantification of intratumoural 166Ho-microspheres.

BACKGROUND: Microspheres loaded with radioactive 166Ho (166Ho-MS) are novel particles for radioembolisation and intratumoural treatment. Because of the limited penetration of ß radiation, quantitative imaging of microsphere distribution is crucial for optimal intratumoural treatment. Computed tomography (CT) may provide high-resolution and fast imaging of the distribution of these microspheres, with lower costs and widespread availability in comparison with current standard single-photon emission tomography (SPECT) and magnetic resonance imaging. This phantom study investigated the feasibility of CT quantification of 166Ho-MS. METHODS: CT quantification was performed on a phantom with various concentrations of HoCl and Ho-MS to investigate the CT sensitivity and calibrate the CT recovery. 166Ho-MS were injected into ex vivo tissues, in VX-2 cancer-bearing rabbits, and in patients with head-neck cancer, to demonstrate sensitivity and clinical visibility. The amount of Ho-MS was determined by CT scanning, using a density-based threshold method and compared with a validated 166Ho SPECT quantification method. RESULTS: In the phantom, a near perfect linearity (least squares R2 > 0.99) between HU values and concentration of 166Ho was found. Ex vivo tissue experiments showed an excellent correlation (r = 0.99, p < 0.01) between the dose calibrator, SPECT, and CT imaging. CT recovery was on average 86.4% ex vivo, 76.0% in rabbits, and 99.1% in humans. CONCLUSION: This study showed that CT-based quantification of Ho microspheres is feasible and is a high-resolution alternative to SPECT-based determination of their local distribution.

Juvenile-adult habitat shift in permian fossil reptiles and amphibians.

Among extant large reptiles, juveniles often occupy different habitats from those of adults or subadults and thus avoid competition with and predation from the older animals; small juveniles often choose cryptic habitats because they are vulnerable to a wide variety of predators. Evidence from fossil humeri and femora of Early Permian reptiles collected from sediments of several distinct habitats indicate that similar shifts in habitat occurred. Juvenile Dimetrodon seem to have favored cryptic habitats around swamp and swampy lake margins; adults favored open habitats on the floodplains. Similar patterns of habitat shift seem to be present in the reptile Ophiacodon and the amphibian Eryops and may have been common in fossil tetrapods of the Permian-Triassic.

Maternal anthropometrics are associated with fetal size in different periods of pregnancy and at birth. The Generation R Study.

OBJECTIVE: We aimed to examine the associations of maternal anthropometrics with fetal weight measured in different periods of pregnancy and with birth outcomes. DESIGN: Population-based birth cohort study. SETTING: Data of pregnant women and their children in Rotterdam, the Netherlands. POPULATION: In 8541 mothers, height, prepregnancy body mass index (BMI) and gestational weight gain were available. METHODS: Fetal growth was measured by ultrasound in mid- and late pregnancy. Regression analyses were used to assess the impact of maternal anthropometrics on fetal weight and birth outcomes. MAIN OUTCOME MEASURES: Fetal weight and birth outcomes: weight (grams) and the risks of small (<5th percentile) and large (>95th percentile) size for gestational age at birth. RESULTS: Maternal BMI in pregnancy was positively associated with estimated fetal weight during pregnancy. The effect estimates increased with advancing gestational age. All maternal anthropometrics were positively associated with fetal size (P-values for trend <0.01). Mothers with both their prepregnancy BMI and gestational weight gain quartile in the lowest and highest quartiles showed the highest risks of having a small and large size for gestational age child at birth, respectively. The effect of prepregnancy BMI was strongly modified by gestational weight gain. CONCLUSIONS: Fetal growth is positively affected by maternal BMI during pregnancy. Maternal height, prepregnancy BMI and gestational weight gain are all associated with increased risks of small and large size for gestational age at birth in the offspring, with an increased effect when combined.

Population-level effect of HSV-2 therapy on the incidence of HIV in sub-Saharan Africa.

BACKGROUND: Herpes simplex virus type 2 (HSV-2) infection increases acquisition and transmission of HIV, but the results of trials measuring the impact of HSV-2 therapy on HIV genital shedding and HIV acquisition are mixed, and the potential impact of HSV-2 therapy on the incidence of HIV at the population level is unknown. METHODS: The effects of episodic and suppressive HSV-2 therapy were simulated using the individual-level model STDSIM fitted to data from Cotonou, Benin (relatively low HIV prevalence) and Kisumu, Kenya (high HIV prevalence). Clinician- and patient-initiated episodic therapy, started when symptomatic, were assumed to reduce ulcer duration. Suppressive therapy, given regardless of symptoms, was also assumed to reduce ulcer frequency and HSV-2 infectiousness. RESULTS: Clinician-initiated episodic therapy in the general population had almost no effect on the incidence of HIV. The impact of patient-initiated therapy was higher because of earlier treatment initiation, but still low (<5%) unless symptom recognition and treatment-seeking behaviour were very high. Suppressive therapy given to female sex workers (FSW) in Kisumu had little effect on population HIV incidence. In Cotonou, suppressive therapy in FSW with high coverage and long duration reduced population HIV incidence by >20% in the long term. Impact was increased in both cities by also treating a proportion of their clients. Long-term suppressive therapy with high coverage in the general population could reduce HIV incidence by more than 30%. CONCLUSIONS: These results show that HSV-2 therapy could potentially have a population-level impact on the incidence of HIV, especially in more concentrated epidemics. However, a substantial impact requires high coverage and long duration therapy, or very high symptom recognition and treatment-seeking behaviour.

Differences in hepatic cytochrome P450 activity correlate with the strain-specific biotransformation of medetomidine in AX/JU and IIIVO/JU inbred rabbits.

Medetomidine is an alpha(2)-adrenoceptor agonist with sedative and analgesic properties. Previously we demonstrated significant differences in the response to medetomidine between two inbred rabbit strains, denoted IIIVO/JU and AX/JU. The aim of the present study was twofold: first, to compare the hepatic CYP450 enzyme activities between these rabbit strains [n = 13(male male,7 female female)/strain]. To this end, liver microsomes were incubated with known fluorescent substrates for the major drug-metabolizing CYP450 isoforms. A comparison of the obtained results indicated significant gender differences as well as differences between the two rabbit inbred strains. Secondly, the biotransformation rate of medetomidine in liver microsomes of both rabbit strains was determined using liquid chromatography coupled to tandem mass spectrometry. The rate of hydroxymedetomidine and medetomidine carboxylic acid formation was found to be significantly higher in the AX/JU strain. Specific CYP2D and CYP2E inhibitors could decrease the formation of both metabolites. Significant correlations were found between the rate of biotransformation of medetomidine and the activities of CYP2D and CYP2E, as well as between CYP450 enzyme activities and the anaesthetic response to medetomidine.

Intratumoral injection of radioactive holmium ( 166 Ho) microspheres for treatment of oral squamous cell carcinoma in cats.

BACKGROUND & AIMS: A "microbrachytherapy" was developed as treatment option for inoperable tumours by direct intratumoral injection of radioactive holmium-166 ( 166 Ho) microspheres (MS). 166 Ho emits ß-radiation which potentially enables a high, ablative, radioactive-absorbed dose on the tumour tissue while sparing surrounding tissues. MATERIALS & METHODS: Safety and efficacy of 166 Ho microbrachytherapy were evaluated in a prospective cohort study of 13 cats with inoperable oral squamous cell carcinoma without evidence of distant metastasis. RESULTS: Local response rate was 55%, including complete response or partial response (downstaging) enabling subsequent marginal resection. Median survival time was 113 days overall, and 296 days for patients with local response. Side effects were minimal. Tumour volume was a significant predictor of response. DISCUSSION: Response rate may be further improved by optimizing the intratumoral spatial distribution of 166 Ho MS. CONCLUSION: 166 Ho microbrachytherapy has potential as a minimally invasive, single procedure radio-ablation treatment of unresectable tumours with minimal morbidity.

Primary retroperitoneal mucinous cystadenoma with sarcoma-like mural nodule : a case report and review of the literature.

Primary retroperitoneal cystadenomas are extremely rare. This is the first report in literature to describe a primary retroperitoneal cystadenoma with a sarcoma-like mural nodule. A 45-year-old woman complained of a left-sided abdominal mass. A computed tomography scan revealed a cystic mass with a mural nodule, which seemed to originate from the tail of the pancreas. At laparotomy the cyst was not adhered to the pancreas but localized retroperitoneally. Histologic examination showed a mucinous cystadenoma with only foci of borderline malignancy with a mural "sarcoma-like" nodule. In view of the surgical and histopathological findings, the mucinous cystadenoma was regarded as primary retroperitoneal. This case demonstrates that in the era of radiological preoperative refinement, pathological diagnosis remains of utmost importance, especially for rare cases.