Can the PROPER intervention reduce psychotropic drug prescription in nursing home residents with dementia? Results of a cluster-randomized controlled trial.

OBJECTIVES: To evaluate the effect of the PROPER intervention in nursing home residents with dementia on the prevalence of psychotropic drug use and neuropsychiatric symptoms. DESIGN: A cluster-randomized controlled design with two parallel groups (intervention versus usual care) and assessments at 0, 6, 12, and 18 months. SETTING: Thirty-one dementia special care units within 13 long-term care organizations in the Netherlands. PARTICIPANTS: Three hundred eighty nursing home residents with dementia. INTERVENTION: The PROPER intervention consisted of a structured and repeated multidisciplinary medication review, supported by education and continuous evaluation. MEASUREMENTS: Prescriptions of antipsychotics, antidepressants, anxiolytics, and hypnotics, and occurrence of neuropsychiatric symptoms. RESULTS: The prescription of any type of psychotropic drugs increased in the intervention group, and decreased in the control group, with an estimated difference of 3.9 percentage points per 6 months (p = 0.01). Effects for the individual drug groups were minor (differences of 1.6 percentage points and below per 6 months) and not statistically significant. The occurrence of neuropsychiatric symptoms remained stable in both the intervention and control groups during the follow-up of 18 months. CONCLUSIONS: The PROPER intervention failed to demonstrate effectiveness in reducing the prevalence of psychotropic drugs. It may be interesting to enrich the intervention with components that address personal attitudes and communication between nursing home professionals, not only with respect to the prescription of psychotropic drugs, but also to neuropsychiatric symptoms.The study has been registered in The Netherlands Trial Register (NTR3569).

Gonadal function and pubertal development in patients with Silver-Russell syndrome.

STUDY QUESTION: Is gonadal function affected in males and females with Silver-Russell Syndrome (SRS)? SUMMARY ANSWER: Sertoli cell dysfunction is more common in males with SRS, with 11p15 LOM, but gonadal function seems to be unaffected in females with SRS. WHAT IS KNOWN ALREADY: Males with SRS have an increased risk for genital abnormalities such as cryptorchidism and hypospadias, which could be associated with reproductive problems in later life. In SRS females, an association has been described with Mayer-Rokitansky-Küster-Hauser syndrome, which might compromise their reproductive function. STUDY DESIGN, SIZE, DURATION: Longitudinal follow-up study, involving 154 subjects, over a time period of 20 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Thirty-one SRS patients (14 males) and 123 non-SRS patients born at same gestational age (SGA; 65 males). All received growth hormone and 27.3% received additional gonadotropin-releasing hormone analog treatment (GnRHa). MAIN RESULTS AND THE ROLE OF CHANCE: Mean age at onset of puberty was 11.5 years in SRS males versus 11.6 years in non-SRS males (P = 0.51), and 10.5 years in SRS females versus 10.7 years in non-SRS females (P = 0.50). Four of the 14 SRS males had a post-pubertal inhibin-B level below the fifth percentile compared to healthy controls, and two of them an FSH above the 95th percentile, indicating Sertoli cell dysfunction. One of them had a history of bilateral cryptorchidism and orchiopexy. All SRS females had AMH, LH and FSH levels within the reference range. Pubertal duration to Tanner stage five was similar in SRS and non-SRS. Pubertal height gain was better in SRS patients who additionally received GnRHa (P < 0.01). Mean age at menarche was 13.1 years in SRS versus 13.3 years in non-SRS (P = 0.62). One SRS female had primary amenorrhea due to Müllerian agenesis. LIMITATIONS, REASONS FOR CAUTION: As this is a rare syndrome, the SRS group had a small size. WIDER IMPLICATIONS OF THE FINDINGS: As gonadal function is not affected in females with SRS, it is likely that reproductive function is also not affected. Sertoli cell dysfunction in males with SRS could cause impaired reproductive function and should be assessed during pubertal development. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for the study. The authors have no conflicts of interest.

Efficacy of antipsychotics in dementia depended on the definition of patients and outcomes: a meta-epidemiological study.

OBJECTIVES: Postulating that efficacy of antipsychotics for agitation and psychosis in dementia is best estimated in trials among patients with these symptoms and with symptom-specific outcomes, we investigated whether clinically broader definitions affected the pooled efficacy. STUDY DESIGN AND SETTING: Trials were searched in multiple databases and categorized according to patient population (agitated, psychotic, and mixed) and outcome scale (agitation, psychosis, and generic). Standardized mean differences with 95% confidence intervals were calculated for conventional and atypical antipsychotics separately. RESULTS: Thirty trials met our inclusion criteria. Conventional antipsychotics might have a small effect in agitated patients on agitation scales (-0.44, -0.88, 0.01) and in psychotic patients on psychosis scales (-0.31, -0.61, -0.02). There was no effect on generic scales. Efficacy of atypical antipsychotics was not established in agitated patients on agitation scales (-0.15, -0.43, 0.13) and in psychotic patients on psychosis scales (-0.11, -0.20, -0.03) but was small in mixed patients on agitation scales (-0.29, -0.40, -0.18). CONCLUSION: Pooled efficacy of antipsychotics for agitation and psychosis in dementia is biased when based on trials that included patients without these target symptoms or on results measured with generic scales. This finding is important for reviewers and guideline developers who select trials for reviews.

[A toddler with a swelling of his penis]. / Een kleuter met een zwelling aan zijn penis.

A 4-year-old boy presented with a subcutaneous, yellowish swelling of 0.8 by 1.5 cm on his penis. We made the diagnosis of a smegma retention cyst. This cyst is the result of a physiologic phenomenon that originates from the separation of the foreskin.

Long-Term Results of GH Treatment in Silver-Russell Syndrome (SRS): Do They Benefit the Same as Non-SRS Short-SGA?

CONTEXT: Silver-Russell syndrome (SRS) is a genetically heterogeneous syndrome characterized by low birth weight, severe short stature, and variable dysmorphic features. GH treatment is a registered growth-promoting therapy for short children born small for gestational age, including SRS, but there are limited data on the GH response in SRS children and on differences in response among the (epi)genetic SRS subtypes (11p15 aberrations, maternal uniparental disomy of chromosome 7 [mUPD7], and idiopathic SRS). OBJECTIVES: To compare growth and adult height between GH-treated small for gestational age children with and without SRS (non-SRS), and to analyze the difference in GH response among SRS genotypes. DESIGN AND SETTING: A longitudinal study. PARTICIPANTS: Sixty-two SRS and 227 non-SRS subjects. INTERVENTION: All subjects received GH treatment (1 mg/m(2)/d). MAIN OUTCOME MEASURES: Adult height and total height gain. RESULTS: The SRS group consisted of 31 children with 11p15 aberrations, 11 children with mUPD7, and 20 children with idiopathic SRS. At the start of GH treatment, mean (SD) height standard deviation score [SDS] was significantly lower in SRS (-3.67 [1.0]) than in non-SRS (-2.92 [0.6]; P < .001). Adult height SDS was lower in SRS (-2.17 [0.8]) than in non-SRS (-1.65 [0.8]; P = .002), but the total height gain SDS was similar. There was a trend toward a greater height gain in mUPD7 than in 11p15 (P = .12). CONCLUSION: Children with SRS have a similar height gain during GH treatment as non-SRS subjects. All (epi)genetic SRS subtypes benefit from GH treatment, with a trend toward mUPD7 and idiopathic SRS having the greatest height gain.

Climbing fibers in spinocerebellar ataxia: A mechanism for the loss of motor control.

The spinocerebellar ataxias (SCAs) form an ever-growing group of neurodegenerative disorders causing dysfunction of the cerebellum and loss of motor control in patients. Currently, 41 different genetic causes have been identified, with each mutation affecting a different gene. Interestingly, these diverse genetic causes all disrupt cerebellar function and produce similar symptoms in patients. In order to understand the disease better, and define possible therapeutic targets for multiple SCAs, the field has been searching for common ground among the SCAs. In this review, we discuss the physiology of climbing fibers and the possibility that climbing fiber dysfunction is a point of convergence for at least a subset of SCAs.

Cerebellar ataxia and functional genomics: Identifying the routes to cerebellar neurodegeneration.

Cerebellar ataxias are progressive neurodegenerative disorders characterized by atrophy of the cerebellum leading to motor dysfunction, balance problems, and limb and gait ataxia. These include among others, the dominantly inherited spinocerebellar ataxias, recessive cerebellar ataxias such as Friedreich's ataxia, and X-linked cerebellar ataxias. Since all cerebellar ataxias display considerable overlap in their disease phenotypes, common pathological pathways must underlie the selective cerebellar neurodegeneration. Therefore, it is important to identify the molecular mechanisms and routes to neurodegeneration that cause cerebellar ataxia. In this review, we discuss the use of functional genomic approaches including whole-exome sequencing, genome-wide gene expression profiling, miRNA profiling, epigenetic profiling, and genetic modifier screens to reveal the underlying pathogenesis of various cerebellar ataxias. These approaches have resulted in the identification of many disease genes, modifier genes, and biomarkers correlating with specific stages of the disease. This article is part of a Special Issue entitled: From Genome to Function.

Enhanced basal lubrication and the contribution of the Greenland ice sheet to future sea-level rise.

We assess the effect of enhanced basal sliding on the flow and mass budget of the Greenland ice sheet, using a newly developed parameterization of the relation between meltwater runoff and ice flow. A wide range of observations suggest that water generated by melt at the surface of the ice sheet reaches its bed by both fracture and drainage through moulins. Once at the bed, this water is likely to affect lubrication, although current observations are insufficient to determine whether changes in subglacial hydraulics will limit the potential for the speedup of flow. An uncertainty analysis based on our best-fit parameterization admits both possibilities: continuously increasing or bounded lubrication. We apply the parameterization to four higher-order ice-sheet models in a series of experiments forced by changes in both lubrication and surface mass budget and determine the additional mass loss brought about by lubrication in comparison with experiments forced only by changes in surface mass balance. We use forcing from a regional climate model, itself forced by output from the European Centre Hamburg Model (ECHAM5) global climate model run under scenario A1B. Although changes in lubrication generate widespread effects on the flow and form of the ice sheet, they do not affect substantial net mass loss; increase in the ice sheet's contribution to sea-level rise from basal lubrication is projected by all models to be no more than 5% of the contribution from surface mass budget forcing alone.

Large and rapid melt-induced velocity changes in the ablation zone of the Greenland Ice Sheet.

Continuous Global Positioning System observations reveal rapid and large ice velocity fluctuations in the western ablation zone of the Greenland Ice Sheet. Within days, ice velocity reacts to increased meltwater production and increases by a factor of 4. Such a response is much stronger and much faster than previously reported. Over a longer period of 17 years, annual ice velocities have decreased slightly, which suggests that the englacial hydraulic system adjusts constantly to the variable meltwater input, which results in a more or less constant ice flux over the years. The positive-feedback mechanism between melt rate and ice velocity appears to be a seasonal process that may have only a limited effect on the response of the ice sheet to climate warming over the next decades.

Climacteric complaints in the community.

BACKGROUND: At the onset of the climacteric, healthy middle-aged women present with a variety of complaints, especially in general practice. In these first years of entering the menopause, vaginal blood loss alters from irregular periods to complete amenorrhoea. According to these different menstrual patterns, we can distinguish a pre-, peri- and postmenopausal phase. It could be useful to know whether specific climacteric complaints are related to these different phases. OBJECTIVE: The aim of this study was to investigate the relationship between climacteric complaints and the menstrual pattern during the menopausal transition in a population-based cross-sectional survey of healthy middle-aged women. METHODS: All women aged 47-54 years, living in the city of Eindhoven, were invited to participate in the Eindhoven Osteoporosis Study (EPOS); 6648 (78%) agreed to participate. All women completed a questionnaire concerning climacteric complaints. Climacteric status was defined by menstrual history. Odds ratios (ORs) were obtained for the relationship between climacteric status and climacteric complaints. Multiple logistic regression analysis was carried out, with climacteric status as the dependent variable. RESULTS: Of the 27 items in the questionnaire concerning climacteric complaints, seven were significantly different between all three climacteric phases (P: < 0.1). After multiple logistic regression analysis, comparing peri- and premenopause, only flushing (OR 5.9) was significantly different. Between post- and perimenopause, seven symptoms appeared to be different: three urogenital complaints [vaginal dryness (OR 1.6), vaginal discharge (OR 0.4) and pain during intercourse (OR 1.9)], three vasomotor symptoms [daytime sweating (OR 1.4), night-time sweating (OR 0.7) and flushing (OR 1.9)] and, finally, insomnia (OR 1.3). When comparing post- and premenopause, flushing (OR 13.4), insomnia (OR 2.1) and depressed mood (OR 0.6) were significantly different, in addition to three urogenital symptoms: vaginal dryness (OR 2.6), vaginal discharge (OR 0.3) and pain during intercourse (OR 2.1). CONCLUSION: The major findings of the study are that flushing is strongly associated with the transition from pre- to perimenopause, while urogenital complaints, daytime sweating and insomnia are more prominent in the transition from peri- to postmenopause.

Chemistry, pharmacology and pharmacokinetics of N,N',N" -triethylenethiophosphoramide (ThioTEPA).

N,N',N" -triethylenethiophosphoramide (thioTEPA) is a trifunctional alkylating agent with a broad spectrum of antitumour activity developed in the 1950s. The drug is now experiencing renewed interest as it appears to be one of the most effective anticancer drugs in high dose regimens. Despite many years of experience with thioTEPA, pharmacologic data are incomplete and controversy remains with respect to the dose-dependent pharmacokinetics of thioTEPA. In recent years greater insight has been obtained into the metabolism of thioTEPA, but there is still a gap between the total urinary excretion of thioTEPA and metabolites and the alkylating activity. In vivo and in vitro studies show that alkylation of DNA by thioTEPA can follow two pathways, but it remains unclear which pathway represents the precise mechanism of action. The currently available sensitive analytical methods for thioTEPA and its metabolites can be used to elucidate the many questions that still exist even so many years after its introduction. An overview is given of the chemistry, pharmacology, clinical use and toxicity of thioTEPA as well as its pharmacokinetics and analytical methods for thioTEPA and its metabolites.

Fasting gastric fluid and fecal polyamine concentrations in premature infants.

BACKGROUND: The role of milk polyamines in the development of the gastrointestinal tract of human infants is presently unknown. Polyamine concentrations are higher in human milk than in infant formulas. The aim of the present study was to gather data on luminal polyamines by measuring gastric fluid and fecal polyamine concentrations in premature infants during the postnatal period. We further compared gastric fluid polyamine concentrations with those reported for milk and looked for possible relationships between luminal polyamine concentrations, age, and growth rate. METHODS: High-performance liquid chromatography was used for the measurement of polyamine concentrations in both fecal and gastric fluid samples. RESULTS: Ninetieth centiles for gastric polyamines during the first week were 62, 28, 82, and 14 microM for putrescine, spermidine, spermine, and cadaverine, respectively. These values are higher than those reported for human milk and infant formulas. Polyamine concentrations were unrelated to either age or growth rate. Ninetieth centiles for fecal polyamines during the first week were 7668, 5176, 53, and 75 microM for cadaverine, putrescine, spermidine, and spermine, respectively. CONCLUSIONS: Fasting gastric fluid polyamine concentrations in premature infants are higher than those reported for either human milk or infant formulas. The high fecal cadaverine and putrescine concentrations are probably of bacterial origin.

Fecal polyamine concentration in children with and without nutrient malabsorption.

BACKGROUND: Fermentation products of malabsorbed nutrients are thought to be responsible for intestinal adaptation following small bowel resection in rats. It has been suggested that either short-chain fatty acids or polyamines (mainly putrescine and cadaverine) could be the fermentation products involved. There are no data available on fecal polyamine content in humans. The present study compared the fecal polyamine concentrations in children with and without malabsorption. METHODS: Sixteen (8 girls, 8 boys) malabsorption patients (cystic fibrosis: 13, short bowel syndrome: 2, biliary atresia: 1) with a mean age of 8 years were compared to 17 (9 girls, 8 boys) sick children without malabsorption (mean age 5.7 years). Three-day fecal collections were performed and analyzed for fat and polyamine concentrations. High-performance liquid chromatography (HPLC) was used for the measurement of polyamine concentrations. RESULTS: Mean and SEM for fecal fat excretion was 13.4 +/- 2.5 g/day and 1.5 +/- 0.3 g/day in the malabsorption and control group respectively. Median fecal cadaverine and putrescine concentrations were 3723 mumol.kg-1 feces and 4737 mumol.kg-1 feces for the malabsorption group and 114 mumol.kg-1 feces and 306 mumol.kg-1 feces for the control group (p < 0.007 and < 0.00001 respectively). No significant differences were found for fecal spermine and spermidine concentrations between the two groups. CONCLUSIONS: Children with malabsorption show very high fecal putrescine and cadaverine concentrations. Our results support the hypothesis that fecal polyamines could be important.