SENS-U: continuous home monitoring of natural nocturnal bladder filling in children with nocturnal enuresis - a feasibility study.

INTRODUCTION: Enuresis is a common problem in children. One treatment option is a wetting alarm that provides an alarm when incontinence occurs. A drawback of this approach is that the child is still awakened by wet sheets. Recently, a wearable, wireless ultrasonic bladder sensor became available, the SENS-U, which has the potential to prevent the enuretic event by waking up the child before the bladder is full. In this first feasibility study, the aim is to perform a night-time, home-based evaluation of the SENS-U in children with monosymptomatic nocturnal enuresis (MNE). PATIENTS AND METHODS: In this study, children (6-12 years) with MNE were included for a one-night monitoring session. During the night, the SENS-U continuously (i.e. every 30 s) estimated the filling status [notifications were deactivated]. In addition, urine volume was collected in a measurement cup (or diaper weight). The total measured natural nocturnal bladder filling (NNBF) cycles was analyzed by descriptive statistics. Before and after the measurement, sleep behavior was assessed by a selection of the Children's Sleep Habits Questionnaire. RESULTS: Fifteen patients (boys/girls: 13/2) [mean age: 8.6 ± 1.5 years] have been enrolled. One patient was excluded due to inadequate sensor-to-skin contact. For 14 children, 18 NNBF cycles were recorded (voiding diary) of which three patients (21%) had more than one NNBF cycle. The SENS-U was able to successfully detect 83% of the NNBF cycles. The three missed NNBF cycles had a voided volume ≤30 ml, which was at the lower limit of the sensor's detection range. The SENS-U had no effect on sleeping behavior. CONCLUSION: The SENS-U was able to monitor the natural nocturnal bladder filling successfully in children with monosymptomatic nocturnal enuresis at home, without disturbing their sleep. Future research focuses on investigating the usability of the SENS-U for both diagnostic - and treatment purposes.

[Heterogeneity of delirium cannot be captured by a simple diagnostic instrument]. / Heterogeniteit van delirium is niet te vangen met simpel screeningsinstrument.

The latest criteria for delirium (DSM-5) still encompass a very heterogeneous group of patients, as both risk factors and causes differ greatly between patients. This makes it unlikely that a single biomarker (e.g. an EEG signal) can be a valid and reliable diagnostic tool in clinical practice. Researchers should be very aware of this heterogeneity, as striving for uniform biomarkers would otherwise result in a considerable waste of research effort. In clinical practice, the delineation of delirium syndrome from dementia and coma using these DSM-5 criteria remains challenging. We state that patient outcomes can probably be improved most by interprofessional, personalised management and the monitoring of vulnerable patients during their individual disease trajectories.

Pharmacokinetics and safety results from the Phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease.

OBJECTIVES: A two-part (Phase 1B/3), sequential, open-label, multicentre study evaluated the pharmacokinetics (PK) and safety of intravenous (iv) posaconazole given as antifungal prophylaxis to neutropenic patients with AML or myelodysplastic syndrome (MDS) or to recipients at risk of invasive fungal disease (IFD) after allogeneic HSCT. METHODS: Patients (N = 237) received 300 mg of posaconazole iv twice daily on day 1, followed by 300 mg of posaconazole iv once daily for 4-28 days. After at least 5 days, patients were randomly assigned to receive posaconazole oral suspension, 400 mg twice daily or 200 mg three times daily, to complete a 28 day treatment course. Primary PK parameters were steady-state average concentration over the dosing interval (Cavg) and posaconazole trough levels (Cmin). RESULTS: Mean posaconazole Cmin was 1320 ng/mL (day 6) and 1297 ng/mL (day 8); steady-state Cmin was 1090 ng/mL (day 10). Mean steady-state posaconazole Cavg was 1500 ng/mL (day 10 or 14) and was similar in HSCT recipients (1560 ng/mL) and AML/MDS patients (1470 ng/mL). The most commonly reported treatment-related adverse events were diarrhoea (8%), nausea (5%) and rash (5%). IFD was reported in 3/237 patients (1%; 2 proven, 1 probable). CONCLUSIONS: Intravenous posaconazole at 300 mg was well tolerated, resulted in adequate steady-state systemic exposure and was associated with a low incidence of IFD in this population at high risk. TRIAL REGISTRY AND NUMBER: ClinicalTrials.gov, NCT01075984.

The impact of age on changes in quality of life among breast cancer survivors treated with breast-conserving surgery and radiotherapy.

BACKGROUND: The purpose of the study was to determine the impact of young age on health-related quality of life (HRQoL) by comparing HRQoL of younger and older breast cancer patients, corrected for confounding, and of young patients and a general Dutch population. METHODS: The population consisted of breast cancer survivors (stage 0-III) after breast-conserving surgery and radiotherapy. Health-related quality of life was prospectively assessed using the EORTC QLQ-C30 and QLQ-BR23 questionnaires. The association between age (⩽50; 51-70; ⩾70 years) and HRQoL over time was analysed with mixed modelling. The clinical relevance of differences between/within age groups was estimated with Cohen's D and consensus-based guidelines. The HRQoL data from the young patient cohort were compared with Dutch reference data at 3 years after radiotherapy. RESULTS: A total of 1420 patients completed 3200 questionnaires. Median follow-up was 34 (range 6-70) months. Median age was 59 (range 28-85) years. Compared with older subjects, young women reported worse HRQoL in the first year after radiotherapy, but clinical relevance was limited. Three years after radiotherapy, HRQoL values in the younger group were equal to those in the reference population. Pain and fatigue after radiotherapy improved, with medium clinical relevance. CONCLUSIONS: Three years after radiotherapy for breast cancer, young age was not a risk factor for decreased HRQoL.

Metabolism and excretion of asenapine in healthy male subjects.

The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of [(14)C]-asenapine to healthy male volunteers. Mean total excretion on the basis of the percent recovery of the total radioactive dose was ∼90%, with ∼50% appearing in urine and ∼40% excreted in feces; asenapine itself was detected only in feces. Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.

The interaction between cerebrovascular disease and neuroticism in late-life depression: a cross-sectional study.

OBJECTIVE: Vascular disease and neuroticism are both risk factors for late-life depression. In this study we examined the interaction between vascular disease and neuroticism as determinants of clinically relevant depressive symptoms (CRDS) in late-life. METHODS: Multivariate logistic regression in a survey of 1396 population-dwelling people aged ≥70 years. CRDS were defined as scoring ≥16 on the CES-D. Vascular disease was categorised into four levels: none, ≥2 vascular risk factors, cardiac disease or stroke. RESULTS: Neuroticism was strongly associated with CRDS in women (OR: 1.6, 95% CI: 1.4-1.8). In men vascular disease interacted negatively but significantly with neuroticism (cardiac disease by neuroticism: OR: 0.8, 95% CI: 0.6-0.9; stroke by neuroticism: OR: 0.8, 95% CI: 0.6-0.96) when predicting CRDS. CONCLUSIONS: In men vascular disease attenuates the predictive value of neuroticism in CRDS, which might be mediated by apathy caused by cerebrovascular disease.

Methodological issues in geriatric research.

There are important differences between performing research in geriatric medicine and in other fields of medicine. Geriatric research requires specific preconditions in all phases of conducting research due to the heterogeneity among geriatric patients and the high prevalence of multi-morbidity, often resulting in impaired physical, psychological and social performances. This paper discusses issues important for successful recruitment and selection of subjects, the informed consent procedure and selection of appropriate research designs and research instruments in geriatric research. The recommendations given are based on a review of relevant literature and own research experiences in the 'Nijmegen geriatric research programme on Brain Failure'.

Pharmacokinetic parameters of tibolone and metabolites in plasma, urine, feces, and bile from ovariectomized cynomolgus monkeys after a single dose or multiple doses of tibolone.

Levels of nonsulfated and sulfated tibolone metabolites were determined in plasma, urine, and feces from six ovariectomized, mature female cynomolgus monkeys after a single dose and multiple p.o. doses (including bile) of tibolone using validated gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry assays. In plasma, the predominant nonsulfated metabolite after single and multiple dosing was the estrogenic 3alpha-hydroxytibolone; levels of the estrogenic 3beta-hydroxytibolone were 10-fold lower and of progestagenic/androgenic Delta(4)-tibolone, 5-fold lower. Tibolone was undetectable. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone; levels of 3betaS,17betaS-tibolone were about 2-fold lower, and monosulfated 3-hydroxymetabolites were about 10-fold lower. After multiple doses, areas under the curve of nonsulfated metabolites were lower (2-fold), and those of sulfated metabolites were 25% higher. In plasma, >95% metabolites were disulfated. In urine, levels of all the metabolites after single and multiple doses were low. After a single dose, high levels of 3beta-hydroxytibolone and the 3-monosulfated metabolites (3betaS,17betaOH-tibolone and 3alphaS,17betaOH-tibolone) were found in feces. After multiple dosing, 3alpha-hydroxytibolone increased, and the ratio of 3alpha/3beta-hydroxytibolone became about 1. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone. Levels of all the metabolites in feces were higher after multiple doses than after a single dose. Levels of nonsulfated and 3-monosulfated metabolites were higher in feces than in plasma. Bile contained very high metabolite levels, except monosulfates. This may contribute to the metabolite content of the feces after multiple doses. 3beta-Hydroxytibolone and 3alphaS,17betaS-tibolone predominated. In conclusion, tibolone had different metabolite patterns in plasma, urine, feces, and bile in monkeys. The bile contributed to the metabolite pattern in feces after multiple doses. The major excretion route was in feces.

Selective tissue distribution of tibolone metabolites in mature ovariectomized female cynomolgus monkeys after multiple doses of tibolone.

Tibolone is a selective tissue estrogenic activity regulator (STEAR). In postmenopausal women, it acts as an estrogen on brain, vagina, and bone, but not on endometrium and breast. Despite ample supporting in vitro data for tissue-selective actions, confirmative tissue levels of tibolone metabolites are not available. Therefore, we analyzed tibolone and metabolites in plasma and tissues from six ovariectomized cynomolgus monkeys that received tibolone (0.5 mg/kg/day by gavage) for 36 days and were necropsied at 1, 1.25, 2.25, 4, 6, and 24 h after the final dose. The plasma and tissue levels of active, nonsulfated (tibolone, 3alpha-hydroxytibolone, 3beta-hydroxytibolone, and Delta(4)-tibolone), monosulfated (3alpha-sulfate,17beta-hydroxytibolone and 3beta-sulfate,17beta-hydroxytibolone), and disulfated (3alpha,17beta-disulfated-tibolone and 3beta,17betaS-disulfated-tibolone) metabolites were measured by validated gas chromatography with mass spectrometry and liquid chromatography with tandem mass spectrometry. Detection limits were 0.1 to 0.5 ng/ml (plasma) and 0.5 to 2 ng/g (tissues). In brain tissues, estrogenic 3alpha-hydroxytibolone was predominant with 3 to 8 times higher levels than in plasma; levels of sulfated metabolites were low. In vaginal tissues, major nonsulfated metabolites were 3alpha-hydroxytibolone and the androgenic/progestagenic Delta(4)-tibolone; disulfated metabolites were predominant. Remarkably high levels of monosulfated metabolites were found in the proximal vagina. In endometrium, myometrium, and mammary glands, levels of 3-hydroxymetabolites were low and those of sulfated metabolites were high (about 98% disulfated). Delta(4)-Tibolone/3-hydroxytibolone ratios were 2 to 3 in endometrium, about equal in breast and proximal vagina, and 0.1 in plasma and brain. It is concluded that tibolone metabolites show a unique tissue-specific distribution pattern explaining the tissue effects in monkeys and the clinical effects in postmenopausal women.

Regulation of developmental rate and germ cell proliferation in Caenorhabditis elegans by the p53 gene network.

Caenorhabditis elegans CEP-1 activates germline apoptosis in response to genotoxic stress, similar to its mammalian counterpart, tumor suppressor p53. In mammals, there are three p53 family members (p53, p63, and p73) that activate and repress many distinct and overlapping sets of genes, revealing a complex transcriptional regulatory network. Because CEP-1 is the sole p53 family member in C. elegans, analysis of this network is greatly simplified in this organism. We found that CEP-1 functions during normal development in the absence of stress to repress many (331) genes and activate only a few (28) genes. In response to genotoxic stress, 1394 genes are activated and 942 are repressed, many of which contain p53-binding sites. Comparison of the CEP-1 transcriptional network with transcriptional targets of the human p53 family reveals considerable overlap between CEP-1-regulated genes and homologues regulated by human p63 and p53, suggesting a composite p53/p63 action for CEP-1. We found that phg-1, the C. elegans Gas1 (growth arrest-specific 1) homologue, is activated by CEP-1 and is a negative regulator of cell proliferation in the germline in response to genotoxic stress. Further, we find that CEP-1 and PHG-1 mediate the decreased developmental rate and embryonic viability of mutations in the clk-2/TEL2 gene, which regulates lifespan and checkpoint responses.

[Efficacy and adverse reactions of antipsychotics for neuropsychiatric symptoms in dementia: a systematic review]. / Werkzaamheid en bijwerkingen van antipsychotica voor neuropsychiatrische symptomen bij dementie; een systematische.

OBJECTIVE: To assess the efficacy and adverse reactions of typical and atypical antipsychotics in the treatment of neuropsychiatric symptoms in dementia, and to examine the evidence for the cerebrovascular events warning for atypical antipsychotics. DESIGN: Systematic review. METHOD: Using Medline, Cinahl, PsyclNFO, Embase and the Cochrane central register of controlled trials (1980-2005), double-blind randomized controlled trials with intention-to-treat analysis were selected, which evaluated efficacy and adverse reactions of antipsychotics in the treatment of neuropsychiatric symptoms in dementia. The studies underwent a standardised validity assessment. RESULTS: After screening 950 studies, 14 studies on the effect of haloperidol, risperidone, olanzapine, quetiapine, tiapride, loxapine and perphenazine were selected. In 7 out of 10 studies, haloperidol, risperidone and olanzapine appeared to be more effective than placebo in the treatment of aggression and psychosis. Direct comparison between typical and atypical antipsychotics revealed no statistically significant difference. The most common adverse reactions were extrapyramidal symptoms and somnolence. These adverse reactions were less frequent with low-dose risperidone than with haloperidol or olanzapine, but risperidone and olanzapine were found to be associated with a higher risk of cerebrovascular events in two studies. CONCLUSION: The efficacy of typical and atypical antipsychotics is comparable, but only low-dose risperidone seems to be associated with fewer (extrapyramidal) side effects. The adverse reactions are inadequately described in the published data and consequently the warning of an increased risk of mortality could not be confirmed.

Frail elderly patients with dementia go too fast.

The reason why patients with dementia fall more often and sustain more fractures than patients without dementia remains unclear. Therefore, the relationship between dementia and gait velocity as a marker for mobility and falls in a cohort of frail elderly (mean age of 77.3 years) inpatients was assessed. Patients with dementia were expected to walk slower than patients without dementia. A trend was indeed observed: absolute gait velocity of 0.59 m/s in patients with dementia (n = 63) versus 0.65 m/s in patients without dementia (n = 62; p = 0.19). After adjustment for parkinsonism and walking aids, however, patients with dementia walked 0.44 m/s faster than patients without dementia (p = 0.02). Probable explanations are frontal lobe disinhibition and lack of insight, causing patients with dementia to walk relatively too fast in the context of their frailty. Therefore, the high risk of falls in dementia may be partially explained by the loss of control of gait velocity.

The old lady who liked liquorice: hypertension due to chronic intoxication in a memory-impaired patient.

The authors report an 85-year-old patient admitted because of cognitive impairment. During examination hypertension and hypokalaemia were found. After some time it was discovered that the patient was eating too much liquorice. The case demonstrates that liquorice intoxication should be considered as a cause of hypertension in old age. Furthermore the case demonstrates that missing an intoxication is a pitfall for medical history taking of patients with cognitive impairment.

[A patient with lessened sensitivity to acenocoumarol during a period of enteral feeding]. / Een patiënt met verminderde gevoeligheid voor acenocoumarol tijdens gebruik van sondevoeding.

A 69-year-old man was operated on for a subdural haematoma which had developed during the use of acenocoumarol. Directly after the operation the patient was started on enteral feeding. The acenocoumarol was restarted at a later stage. The dose of acenocoumarol needed for an appropriate level of blood-dilution was twice as high during the period of enteral feeding than it had been preoperatively. After the transition from enteral feeding to oral feeding it was possible to lower the dose of acenocoumarol. The need for a higher dose was probably due to enhanced binding of the proteins in the enteral feeding. The patient was admitted to a nursing home. The combination of acenocoumarol and enteral feeding occurs frequently in patients being rehabilitated. It is important to monitor the blood-dilution when starting and stopping enteral feeding.

Systematic review of quantitative clinical gait analysis in patients with dementia.

INTRODUCTION: Diminished mobility often accompanies dementia and has a great impact on independence and quality of life. New treatment strategies for dementia are emerging, but the effects on gait remains to be studied objectively. In this review we address the general effects of dementia on gait as revealed by quantitative gait analysis. METHODS: A systematic literature search with the (MESH) terms: 'dementia' and 'gait disorders' in Medline, CC, Psychlit and CinaHL between 1980-2002. Main inclusion criteria: controlled studies; patients with dementia; quantitative gait data. RESULTS: Seven publications met the inclusion criteria. All compared gait in Alzheimer's Disease (AD) with healthy elderly controls; one also assessed gait in Vascular Dementia (VaD). The methodology used was inconsistent and often had many shortcomings. However, there were several consistent findings: walking velocity decreased in dementia compared to healthy controls and decreased further with progressing severity of dementia. VaD was associated with a significant decrease in walking velocity compared to AD subjects. Dementia was associated with a shortened step length, an increased double support time and step to step variability. DISCUSSION: Gait in dementia is hardly analyzed in a well-designed manner. Despite this, the literature suggests that quantitative gait analysis can be sufficiently reliable and responsive to measure decline in walking velocity between subjects with and without dementia. More research is required to assess, both on an individual and a group level, how the minimal clinically relevant changes in gait in elderly demented patients should be defined and what would be the most responsive method to measure these changes.

Photosynthesis of Blueberry Leaves as Affected by Septoria Leaf Spot and Abiotic Leaf Damage.

Leaf spots caused by fungal pathogens or abiotic factors can be prevalent on southern blueberries after harvest during the summer and fall, yet little is known about how they affect physiological processes that determine yield potential for the following year. In this study, we measured CO2 assimilation and leaf conductance on field-grown blueberry plants affected by Septoria leaf spot (caused by Septoria albopunctata) or by edema-like abiotic leaf blotching. Net assimilation rate (NAR) on healthy leaves varied between 6.9 and 12.4 µmol m-2 s-1 across cultivars and measurement dates. Infection by S. albopunctata had a significant negative effect on photosynthesis, with NAR decreasing exponentially as disease severity increased (R2 ≥0.726, P < 0.0001). NAR was reduced by approximately one-half at 20% disease severity, and values approached zero for leaves with >50% necrotic leaf area. There was a positive, linear correlation between NAR and leaf conductance (R2 ≥ 0.622, P < 0.0001), suggesting that the disease may have reduced photosynthesis via decreased CO2 diffusion into affected leaves. Estimates of virtual lesion size associated with infection by S. albopunctata ranged from 2.8 to 3.1, indicating that the leaf area in which photosynthesis was impaired was about three times as large as the area covered by necrosis. For leaves afflicted by edema-like damage, there also was a significant negative relationship between NAR and affected leaf area, but the scatter about the regression was more pronounced than in the NAR-disease severity relationships for S. albopunctata (R2 = 0.548, P < 0.0001). No significant correlation was observed between leaf conductance and affected area on these leaves (P = 0.145), and the virtual lesion size associated with abiotic damage was significantly smaller than that caused by S. albopunctata. Adequate carbohydrate supply during the fall is critical for optimal flower bud set in blueberry; therefore, these results document the potential for marked yield losses due to biotic and abiotic leaf spots.