[The syndrome of inappropriate diuretic hormone secretion (SIADH) ending lethal during the use of paliperidon and lamotrigine]. / Het syndroom van inadequate secretie van het antidiuretisch hormoon (SIADH) met letale afloop tijdens gebruik van paliperidon en lamotrigine.

Hyponatremia, as a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), is well known with the use of nearly all antipsychotics and mood stabilizers. The first symptoms are atypical and are not always mentioned by the patient. However, not recognising the syndrome in due time can be lethal. We describe a 35-year-old woman who died due to lack of recognition of SIADH. The patient, who had a bipolar disorder and was for a long time on a paliperidone depot, developed complaints of nausea, vomiting and thirst after lamotrigine was prescribed. A few days after increasing the dose, she died; no evidence was found of suicide. The SIADH was probably triggered by the use of lamotrigine and paliperidone. Paying sufficient attention to the symptoms that may cause this syndrome, as well as their early recognition, could save lives.

[Pimavanserin: a new treatment for the Parkinson's disease psychosis]. / Pimavanserine: een nieuwe behandeling voor psychose bij de ziekte van Parkinson.

BACKGROUND: Clozapine is an effective drug for treating psychosis in Parkinson's disease (PDP) and is registered as such in the Netherlands. However, clozapine can have adverse effects, including agranulocytosis. The new drug pimavanserin was recently registered in the United States for the treatment of PDP.
AIM: To review the literature on pimavanserin and discuss the position it currently occupies in the Netherlands as a potential treatment for PDP.
METHOD: Systematic search of the literature.
RESULTS: We found reports on four randomised controlled trials (RCTs), one review and six articles about the pharmacokinetics and pharmacodynamics of pimavanserin. Pimavanserin is an effective treatment for PDP, and, like clozapine, it has very few negative effects on motor skills. However, all of the RCTs were funded by the manufacturer of pimavanserin and the trials were conducted in a very selective patient population. This means that results cannot be generalised. Long-term results are not yet available. In earlier trials clozapine was shown to have a greater and faster antipsychotic effect. Many clinicians and psychiatrists have a great deal of experience with this drug. Another important point is that no-one has yet conducted a trial comparing clozapine and pimavanserin.
CONCLUSION: Given that the current second drug of choice, namely quetiapine, has not been found to be effective for PDP, we are of the opinion that - if pimavanserin is registered in the Netherlands - pimavanserin could be used when the current drug of choice, clozapine, is not completely effective or is poorly tolerated. For patients who have cognitive impairments in addition to psychosis, we advise testing the patient's reaction to a cholinesterase inhibitor before starting the patient on a course of antipsychotics.

Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity.

In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function.

The fate of glycerol entering the rumen of dairy cows and sheep.

This study investigated the fate of glycerol entering the rumen, in particular whether glycerol could be absorbed across the rumen epithelium. Three non-lactating rumen-fistulated cows were used to calculate the overall disappearance rate of glycerol in vivo and evaluate the rate of ruminal glycerol absorption. Rumen epithelial tissues isolated from sheep were used to characterise glycerol transport properties. The rate of rumen microbial degradation of glycerol was then studied in an in vitro system under anaerobic and thermo-regulated conditions. The results showed that glycerol can be absorbed from the rumen in significant amounts. The fractional rate of absorption of glycerol was not affected by variations in glycerol concentration in the buffer solution in the in vivo study. The glycerol absorption apparently occurred largely by passive diffusion and was probably not facilitated by carriers. Glycerol also disappeared via microbial digestion and outflow from the rumen through the omasal orifice.

Effects of age and zinc supplementation on transport properties in the jejunum of piglets.

Zinc is effective in the prevention and treatment of post-weaning diarrhoea and in promoting piglet growth. Its effects on the absorption of nutrients and the secretory capacity of the intestinal epithelium are controversial. We investigated the effects of age, dietary pharmacological zinc supplementation and acute zinc exposure in vitro on small-intestinal transport properties of weaned piglets. We further examined whether the effect of zinc on secretory responses depended on the pathway by which chloride secretion is activated. A total of 96 piglets were weaned at 26 days of age and allocated to diets containing three different levels of zinc oxide (50, 150 and 2500 ppm). At the age of 32, 39, 46 and 53 days, piglets were killed, and isolated epithelia from the mid-jejunum were used for intestinal transport studies in conventional Ussing chambers, with 23 µm ZnSO4 being added to the serosal side for testing acute effects. Absorptive transport was stimulated by mucosal addition of d-glucose or l-glutamine. Secretion was activated by serosal addition of prostaglandin E2 , carbachol or by mucosal application of Escherichia coli heat-stable enterotoxin (Stp ). Jejunal transport properties showed significant age-dependent alterations (p < 0.03). Both absorptive and secretory responses were highest in the youngest piglets (32 d). The dietary zinc supplementation had no significant influence on jejunal absorptive and secretory responses. However, the pre-treatment of epithelia with ZnSO4 in vitro led to a small but significant decrease in both absorptive and secretory capacities (p < 0.05), with an exception for carbachol (p = 0.07). The results showed that, in piglets, chronic supplementation with zinc did not sustainably influence the jejunal transport properties in the post-weaning phase. Because transport properties are influenced by the addition of zinc in vitro, we suggest that possible epithelial effects of zinc depend on the acute presence of this ion.

Paludiculture can support biodiversity conservation in rewetted fen peatlands.

Paludiculture, the productive use of wet or rewetted peatlands, offers an option for continued land use by farmers after rewetting formerly drained peatlands, while reducing the greenhouse gas emissions from peat soils. Biodiversity conservation may benefit, but research on how biodiversity responds to paludiculture is scarce. We conducted a multi-taxon study investigating vegetation, breeding bird and arthropod diversity at six rewetted fen sites dominated by Carex or Typha species. Sites were either unharvested, low- or high-intensity managed, and were located in Mecklenburg-Vorpommern in northeastern Germany. Biodiversity was estimated across the range of Hill numbers using the iNEXT package, and species were checked for Red List status. Here we show that paludiculture sites can provide biodiversity value even while not reflecting historic fen conditions; managed sites had high plant diversity, as well as Red Listed arthropods and breeding birds. Our study demonstrates that paludiculture has the potential to provide valuable habitat for species even while productive management of the land continues.

Receptor for advanced glycation end products (RAGE) polymorphisms are associated with systemic lupus erythematosus and disease severity in lupus nephritis.

OBJECTIVE: Interaction of advanced glycation end products (AGEs) with their receptors (RAGE) plays an important role in inflammation in auto-immune diseases. Several functional polymorphisms of RAGE have been described. In this study we analysed the role of RAGE polymorphisms in disease susceptibility for systemic lupus erythematosus (SLE). In addition, we investigated whether these polymorphisms in SLE are associated with serum levels of soluble RAGE (sRAGE), renal involvement (lupus nephritis (LN)) and its outcome. METHODS: For this cross-sectional study DNA samples of 97 SLE patients, 114 LN patients and 429 healthy controls (HC) were genotyped for four RAGE polymorphisms: -429 T/C, -374 T/A, 2184 A/G and Gly82Ser. Differences in genotype frequencies and allele frequencies were tested between patients and HCs. In SLE patients, sRAGE was measured by enzyme-linked immunosorbent assay (ELISA). In addition, association of genotypes with sRAGE and disease severity in LN was analysed. RESULTS: The C allele of -429 T/C, the T allele of -374 T/A and the G allele of 2184 A/G were significantly more prevalent in SLE and LN compared with HC. In LN, the C allele of RAGE -429 T/C, the A allele of -374 T/A and the G allele of RAGE 2184 A/G polymorphism were significantly associated with more proteinuria and worse renal function during the first two years of treatment. No association of genotype with sRAGE was found. CONCLUSION: RAGE polymorphisms are associated with susceptibility to SLE and LN. In addition, some of these polymorphisms are likely to be associated with disease severity and initial response to treatment in LN.

Caprine CSN1S1 haplotype effect on gene expression and milk composition measured by Fourier transform infrared spectroscopy.

The Norwegian dairy goat population has a high frequency of a CSN1S1 (alphaS1-casein) haplotype with negative effects on protein and fat content. It is characterized by a single point deletion in exon 12 of CSN1S1, leading to a truncated protein and hence a low content of alphaS1-casein in the milk. This haplotype together with another haplotype with a deletion in exon 9 are called "weak" haplotypes. "Strong" haplotypes, on the other hand, have positive effects on important milk production traits. We show that expression of CSN1S1 in the mammary gland of lactating goats is significantly lower in animals with 2 weak haplotypes. Moreover, the effects of defective alleles were not detected in animals having 1 strong and 1 weak haplotype. Expression levels of other genes in the casein cluster were not affected by the CSN1S1 haplotypes investigated. Milk samples from goats with 2 weak haplotypes could be distinguished from the other milk samples using Fourier transform infrared (FTIR) spectroscopy and partial least squares discriminant analysis (PLS-DA). The PLS-DA components were related to spectra of pure caseins and whey proteins, hence FTIR has a potential for identifying milk samples with low alphaS1-casein content and different protein composition. The results indicate that FTIR-based measurements can be incorporated into breeding plans, or for selection of milk samples with high casein content, which in turn may improve cheese-making properties of the milk.

[An infant with facial skin lesions]. / Een zuigeling met huidafwijkingen in het gelaat.

A 42 year old woman was diagnosed with SLE, ANA and anti-SSA antibodies were positive. Her daughter had cutaneous lesions typical of neonatal lupus erythematosus. Children with NLE can also develop cardiac conducting disturbances. These are associated with significant morbidity and mortality, therefore, monitoring is required in patients with anti-SSA antibodies.

[Rheumatoid arthritis: more than a joint disease]. / Reumatoïde artritis: meer dan een gewrichtsziekte.

Rheumatoid arthritis (RA), one of the most common autoimmune disorders, mostly manifests itself as polyarthritis. However, extra-articular organ manifestations can also occur, even though their incidence has decreased substantially due to effective treatment with disease-modifying anti-rheumatic drugs. In this article we describe three patient cases of extra-articular manifestations in RA in the absence of prominent arthritis. The diversity of symptoms in RA can be of interest to different medical specialties who will occasionally encounter them in daily practice.

Analysis of C1q polymorphisms suggests association with systemic lupus erythematosus, serum C1q and CH50 levels and disease severity.

BACKGROUND: Several findings link systemic lupus erythematosus (SLE) with C1q, the first molecule of the classical complement pathway. Polymorphisms of the C1qA gene are associated with low serum C1q levels in patients with cutaneous LE, but C1q polymorphisms have not been studied in patients with systemic lupus. OBJECTIVE: To determine whether polymorphisms of the C1q genes are associated with SLE, disease phenotypes, serum C1q and CH50 levels. METHODS: DNA for genetic analysis was obtained from 103 Caucasian patients with SLE and their family members. Five tag single nucleotide polymorphisms (tag SNPs) served as unique markers for underlying SNPs in the genes of the C1q protein. The pedigree disequilibrium test (PDT) was applied to trios to determine association of markers with SLE, SLE phenotypes, low serum C1q and low CH50. Single SNP association and haplotype analysis was also performed. RESULTS: The PDT revealed a significant association of the tag SNP rs631090 (covering the C1qB gene) with SLE (p = 0.02). Rs631090 was moderately associated with low serum C1q levels (p = 0.06). In addition, the tag SNPs rs292001 and rs294183 were associated with more severe SLE (Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) damage index score>0; p = 0.007 and p = 0.02, respectively). Haplotype analysis and single SNP association analysis showed no significant associations, but additional analyses revealed that marker rs587585 is associated with low serum C1q and CH50 levels. CONCLUSIONS: C1q polymorphisms are associated with SLE, serum C1q and CH50 levels in a stable founder population of patients with SLE. Although the studied population was small and allele frequencies were low, this is the first study to suggest an association of C1q polymorphisms with SLE.

Long-term clopidogrel administration following severe coronary injury reduces proliferation and inflammation via inhibition of nuclear factor-kappaB and activator protein 1 activation in pigs.

BACKGROUND: The optimal duration of clopidogrel treatment following percutaneous coronary intervention (PCI) and the patient population that would benefit most are still unknown. In a porcine coronary injury model, we tested two different durations of clopidogrel treatment on severely or moderately injured arteries and examined the arterial response to injury. To understand the molecular mechanism, we also investigated the effects on transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1). MATERIALS AND METHODS: In 24 cross-bred pigs, one coronary artery was only moderately injured by percutaneous transluminal coronary angioplasty (PTCA) and one coronary artery was severely injured by PTCA and subsequent beta-irradiation (Brachy group). Animals received 325 mg aspirin daily for 3 months and 75 mg clopidogrel daily for either 28 days [short-term (ST) clopidogrel group] or 3 months [long-term (LT) clopidogrel group]. RESULTS: After 3 months, the number of proliferating cells per cross-section differed significantly between ST and LT in both injury groups (PTCA(ST) 90.2 +/- 10.3 vs. PTCA(LT )19.2 +/- 4.7, P < 0.05; Brachy(ST) 35.8 +/- 8.4 vs. Brachy(LT) 7.5 +/- 2.0, P < 0.05). Similar results were seen for inflammatory cells (CD3(+) cells): PTCA(ST) 23.5 +/- 3.55 vs. PTCA(LT )4.67 +/- 0.92, P < 0.05; Brachy(ST) 83.17 +/- 11.17 vs. Brachy(LT) 20 +/- 4.82, P < 0.05). Long-term administration also reduced the activity of NF-kappaB and AP-1 by 62-64% and 42-58%, respectively. However, the effects of different durations of clopidogrel administration on artery dimensions were not statistically significant. CONCLUSIONS: Regarding inflammation and transcription factor activity at the PCI site, long-term clopidogrel administration is superior to short-term administration, especially in severely injured arteries. Transferring our results to the human situation, patients with more severely diseased arteries may benefit from a prolonged clopidogrel medication after PCI.

Arsenic in potable desert groundwater: an analysis problem.

An accuracy investigation, initiated because of conflicting analytical data on the arsenic content for some 24 drinkinig water locations in the Mojave Desert, revealed that interference with the evolution of arsine in the American Public Health Association silver diethyldithiocarbamate method caused either color enhancement or arsine suppression. For certain types of natural waters this method is unreliable.

An extensive screen of the HLA region reveals an independent association of HLA class I and class II with susceptibility for systemic lupus erythematosus.

OBJECTIVES: The association of systemic lupus erythematosus (SLE) with the human leucocyte antigen (HLA) region is well known. In this study, we analysed the involvement of the HLA region in susceptibility for SLE in a stable founder, Caucasian population of SLE patients. METHODS: We performed an extensive screen of the entire HLA region on 103 SLE patients and family-based controls. Both single locus association analysis and haplotype sharing analysis were performed. The Additional Disease Locus Test (ADLT) was applied to examine the nature of the observed associations and to distinguish true causal associations from associations due to linkage disequilibrium (LD). RESULTS: Significant associations were observed at markers in the HLA class I, class II, and class III regions using both haplotype sharing and single locus methods. The haplotype sharing methods revealed the most significant difference at marker D6S1666 in the HLA class II region (p(HSS) = 0.00037, p(CROSS) = 1.7 x 10(-5)). The most significant result for single locus association was shown at marker D6S265 in the HLA class I region (p = 0.00019). The ADLT demonstrated that these markers represent independent associations. CONCLUSION: HLA class I, class II, and class III are associated with SLE, but only class I and class II contribute independently to increased risk of SLE.

Reducing inter-replicate variation in fourier transform infrared spectroscopy by extended multiplicative signal correction.

Fourier transform infrared (FT-IR) spectroscopy is a powerful tool for characterizing biological tissues and organisms, but it is plagued by replicate variation of various sources. Here, a method for estimating and correcting unwanted replicate variation in multivariate measurement signals, based on extended multiplicative signal correction (EMSC), is presented. Systematic patterns of unwanted methodological variations are estimated from replicate spectra, modeled by a linear subspace model, and implemented into EMSC. The method is applied to FT-IR spectra of two different sets of microorganisms (different double gene knockout strains of Saccharomyces cerevisiae and different species of Listeria) and compared to other preprocessing methods used in FT-IR absorption spectroscopy of microorganisms. The EMSC replicate correction turns out to perform best among the compared methods.

Front propagation in a one-dimensional autocatalytic reaction-subdiffusion system.

We study numerically the autocatalytic irreversible reaction A+B-->2A on a one-dimensional lattice for the case of subdiffusive reactants performing symmetric continuous-time random walks with the power-law waiting time density function psi(t) proportional, t(-1-alpha) with 0

Development of co-continuous morphology in blends of thermoplastic starch and low-density polyethylene.

This study focuses on the morphology development in blends of thermoplastic starch (TPS) with Low Density Polyethylene (LDPE) in the 40 to 80 TPS wt% concentration range. The effect of glycerol and water content on TPS rheology and the subsequent morphology development after blending with LDPE of various viscosity levels was investigated. The TPS/LDPE viscosity ratio was modified either by increasing the TPS plasticization or by proper selection of the LDPE grade. Particular attention was given to the effect of TPS humidity on viscosity and therefore humidity levels were carefully measured by Karl Fisher titration prior to rheometry. It was found that the viscosity of the TPS was highly dependent on the plasticizer level and that the flow activation energy of TPS was around 3 times higher than that of LDPE. Different types of blend morphologies were achieved from dispersed to co-continuous. It was found that the co-continuous structure appeared at higher TPS concentration when increasing the TPS/LDPE viscosity ratio.

The selective alpha7 nicotinic acetylcholine receptor agonist A-582941 activates immediate early genes in limbic regions of the forebrain: Differential effects in the juvenile and adult rat.

Due to the cognitive-enhancing properties of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists, they have attracted interest for the treatment of cognitive disturbances in schizophrenia. Schizophrenia typically presents in late adolescence or early adulthood. It is therefore important to study whether alpha7 nAChR stimulation activates brain regions involved in cognition in juvenile as well as adult individuals. Here, we compared the effects of the novel and selective alpha7 nAChR agonist 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) in the juvenile and adult rat forebrain using two markers, activity-regulated cytoskeleton-associated protein (Arc) and c-Fos, to map neuronal activity. Acute administration of A-582941 (1, 3, 10 mg/kg) induced a dose-dependent increase in Arc mRNA expression in the medial prefrontal cortex (mPFC) and the ventral/lateral orbitofrontal (VO/LO) cortex of juvenile, but not adult rats. This effect was mitigated by the alpha7 nAChR antagonist methyllycaconitine. A-582941 also increased c-Fos mRNA expression in the mPFC of juvenile, but not adult rats. Furthermore, A-582941 increased the number of Arc and c-Fos immunopositive cells in the mPFC, VO/LO, and shell of the nucleus accumbens, in both juvenile and adult rats. The A-582941-induced c-Fos protein expression was significantly greater in the mPFC and VO/LO of juvenile compared with adult rats. These data indicate that A-582941-induced alpha7 nAChR stimulation activates brain regions critically involved in working memory and attention. Furthermore, this effect is more pronounced in juvenile than adult rats, indicating that the juvenile forebrain is more responsive to alpha7 nAChR stimulation. This observation may be relevant in the treatment of juvenile-onset schizophrenia.

Estimating and correcting mie scattering in synchrotron-based microscopic fourier transform infrared spectra by extended multiplicative signal correction.

We present an approach for estimating and correcting Mie scattering occurring in infrared spectra of single cells, at diffraction limited probe size, as in synchrotron based microscopy. The Mie scattering is modeled by extended multiplicative signal correction (EMSC) and subtracted from the vibrational absorption. Because the Mie scattering depends non-linearly on alpha, the product of the radius and the refractive index of the medium/sphere causing it, a new method was developed for estimating the Mie scattering by EMSC for unknown radius and refractive index of the Mie scatterer. The theoretically expected Mie contributions for a range of different alpha values were computed according to the formulae developed by Van de Hulst (1957). The many simulated spectra were then summarized by a six-dimensional subspace model by principal component analysis (PCA). This subspace model was used in EMSC to estimate and correct for Mie scattering, as well as other additive and multiplicative interference effects. The approach was applied to a set of Fourier transform infrared (FT-IR) absorbance spectra measured for individual lung cancer cells in order to remove unwanted interferences and to estimate ranges of important alpha values for each spectrum. The results indicate that several cell components may contribute to the Mie scattering.