Early risk factors for miscarriage: a prospective cohort study in pregnant women

Many pregnancies are lost during early gestation, but clinicians still lack tools to recognize risk factors for miscarriage. Thus, the identification of risk factors for miscarriage during the first trimester in women with no obvious risk for a pregnancy loss was the aim of this prospective cohort trial. A total of 1098 women between gestation weeks 4 and 12 in whom no apparent signs of a threatened pregnancy could be diagnosed were recruited. Demographic, anamnestic, psychometric and biological data were documented at recruitment and pregnancy outcomes were registered subsequently. Among the cases with sufficiently available data, 809 successfully progressing pregnancies and 55 subsequent miscarriages were reported. In this cohort, risk of miscarriage was significantly increased in women at higher age (>33 years), lower body mass index (< or =20 kg/ m(2)) and lower serum progesterone concentrations (< or =12 ng/ml) prior to the onset of the miscarriage. Women with subsequent miscarriage also perceived higher levels of stress/demands (supported by higher concentrations of corticotrophin-releasing hormone) and revealed reduced concentrations of progesterone-induced blocking factor. These risk factors were even more pronounced in the subcohort of women (n = 335) recruited between gestation weeks 4 and 7. The identification of these risk factors and development of an interaction model of these factors, as introduced in this article, will help clinicians to recognize pregnant women who require extra monitoring and who might benefit from therapeutic interventions such as progestogen supplementation, especially during the first weeks of pregnancy, to prevent a miscarriage.     

Distinct glutaminyl cyclase expression in Edinger–Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Aβ pathology in Alzheimer’s disease

Glutaminyl cyclase (QC) was discovered recently as the enzyme catalyzing the pyroglutamate (pGlu or pE) modification of N-terminally truncated Alzheimer’s disease (AD) Aβ peptides in vivo. This modification confers resistance to proteolysis, rapid aggregation and neurotoxicity and can be prevented by QC inhibitors in vitro and in vivo, as shown in transgenic animal models. However, in mouse brain QC is only expressed by a relatively low proportion of neurons in most neocortical and hippocampal subregions. Here, we demonstrate that QC is highly abundant in subcortical brain nuclei severely affected in AD. In particular, QC is expressed by virtually all urocortin-1-positive, but not by cholinergic neurons of the Edinger–Westphal nucleus, by noradrenergic locus coeruleus and by cholinergic nucleus basalis magnocellularis neurons in mouse brain. In human brain, QC is expressed by both, urocortin-1 and cholinergic Edinger–Westphal neurons and by locus coeruleus and nucleus basalis Meynert neurons. In brains from AD patients, these neuronal populations displayed intraneuronal pE-Aβ immunoreactivity and morphological signs of degeneration as well as extracellular pE-Aβ deposits. Adjacent AD brain structures lacking QC expression and brains from control subjects were devoid of such aggregates. This is the first demonstration of QC expression and pE-Aβ formation in subcortical brain regions affected in AD. Our results may explain the high vulnerability of defined subcortical neuronal populations and their central target areas in AD as a consequence of QC expression and pE-Aβ formation.     

Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition.

Animal studies have shown that blockade of central mineralocorticoid receptors (MR) has anxiolytic effects and impairs several aspects of cognitive function. No study to date assessed the effects of MR blockade on anxiety and cognitive function in humans. In the present study, 16 healthy young men were treated either with placebo or with 300 mg spironolactone, a MR-antagonist, at 1100, 1330, and 1630 hours in a balanced cross-over design with the two study conditions being 1 week apart. At 1500 hours, the panic symptoms provoking compound cholecystokinin-tetrapeptide (CCK-4) was administered i.v. on both occasions and panic symptoms were assessed. We measured plasma ACTH and cortisol between 1300 and 1900 hours and assessed cognitive function between 1800 and 1900 hours. CCK-4 elicited panic symptoms and increased ACTH and cortisol secretion in both conditions. Intensity of panic symptoms after CCK-4 was not different between spironolactone and placebo. Spironolactone significantly impaired selective attention and delayed recall of visuospatial memory, and diminished set shifting/mental flexibility on a trend level. Pretreatment with spironolactone led to higher baseline cortisol levels compared to placebo whereas no differences in stimulated cortisol, baseline ACTH, and stimulated ACTH emerged. Blockade of MR with spironolactone increases baseline cortisol secretion and impairs cognitive function but has no effect on experimentally induced panic symptoms in humans, for the study design and dosage of spironolactone used. The domains of cognitive function that are impaired after blockade of MR in men, that is, selective attention, visuospatial memory, and mental flexibility/set shifting appear to be remarkably similar to those described in animal studies.     

Evaluation of beneficial and adverse effects of glucocorticoids on a newly developed full-thickness skin model.

Glucocorticoids (GCs) are highly effective compounds widely used in the treatment of inflammatory diseases; however, they offer distinct adverse effects such as skin thinning in response to long-term topical treatment. Nevertheless it is difficult to deduce the safety of a newly synthesized compound from its structural formula. Efficient assay systems that measure beneficial and adverse effects are needed. In the present study the applicability of a three-dimensional full-thickness skin model (FTSM) is tested to display GC-induced effects regarding anti-inflammation and atrophy. It is shown that topical application of a commercial GC ointment suppresses the ultraviolet (UV)B induced induction of interleukin (IL)-6 and IL-8. Addition of purified betamethasone-17-valerate, prednicarbate and clobetasol-17-propionate to the culture medium for 14 days caused a reduction in the number of epidermal cell-layers corresponding to the atrophic risk found in vivo. Similarly, repeated topical application of five GC creams induced epidermal thinning. Evidence is given that the inhibitory effect on keratinocyte proliferation contributes to this effect. Furthermore, dermal thinning was monitored by measuring type I collagen synthesis; a decreased collagen synthesis similar to the in vivo situation is shown. The present study demonstrates the versatility of this FTSM in the validation of effectiveness and safety of GCs.     

Induction of apoptosis of CD4+ T cells by immunomodulatory therapy of multiple sclerosis with glatiramer acetate

Glatiramer acetate (GA), a mixture of synthetic polypeptides, has beneficial effects on the clinical course and the MRI-defined disease activity of patients with multiple sclerosis (MS). In MS, evidence has been provided that the apoptosis of disease-relevant T cells is dysregulated. In this study, we investigated the effect of GA on T cell apoptosis, T cell activation, and cytokine profile of lymphocytes derived from 19 relapsing-remitting MS patients during the first year of GA therapy. Analysis of blood samples obtained every 6 weeks showed an increase in apoptotic T helper cells after 30 weeks of therapy. This effect remained until the end of the study and was accompanied by an increase in activated T cells and interleukin-4-producing lymphocytes. Thus, in addition to the established effect of GA on the cytokine network, GA-mediated immunomodulation might involve the apoptotic elimination of T helper cells.     

Optical coherence tomography in contact dermatitis and psoriasis

Optical coherence tomography (OCT) is a new noninvasive imaging technique. In this study, it was used for the investigation of contact dermatitis and psoriasis. In these common inflammatory skin diseases the value of OCT for quantification and monitoring of the changes in comparison with other bioengineering methods was evaluated. Repeated measurements were performed in healthy volunteers after experimental induction of irritant contact dermatitis and in patients with psoriasis. In the OCT images, the thickness of the epidermis and the signal attenuation coefficient in the upper dermis were evaluated. The changes were compared with measurements of transepidermal water loss, hydration, skin colour and surface roughness, and with high-frequency ultrasound measurements. In irritant dermatitis and psoriasis, thickening of the epidermis was detected and could be monitored over time. The light scattering in the upper dermis was lower than in healthy skin. This was interpreted to be due to the inflammation and oedema, leading to a less-dense arrangement of the collagen fibres. The changes in the OCT images did not significantly correlate with the changes shown by the other methods. OCT is an interesting tool for investigation of inflammatory skin diseases. It is a simple method for determination of epidermal thickness and therefore provides, in addition to other methods, information on the severity of the disease and on treatment effects.     

Effects of the novel antiepileptic drug levetiracetam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy

PURPOSE: Animal models in which seizures are elicited by chemical or electrical means are commonly used for identification and preclinical testing of novel antiepileptic drugs (AEDs). Such models have been successful in discovering all the new AEDs. However, despite the high efficacy of AEDs against elicited seizures in rodent models, a significant proportion of epilepsy patients with spontaneous recurrent seizures is resistant to these drugs. It is not known whether drug testing in rodent models with spontaneous recurrent seizures would yield a more predictive result with respect to AED efficacy in the clinic. This led us to test one of the novel AEDs, levetiracetam (LEV), in a rat model of temporal lobe epilepsy (TLE) with spontaneous recurrent seizures. METHODS: Wistar rats were subjected to pilocarpine-induced status epilepticus and recorded for spontaneous recurrent seizures in the months after pilocarpine treatment. A group of rats with frequent spontaneous seizures was used for the drug trial with LEV. The experimental protocol for drug testing in these rats was as follows. For 2 weeks, rats received subcutaneous implantation of osmotic minipumps filled with saline (predrug control period), followed by a 2-week period with implantation of LEV-filled minipumps (drug period), after which pumps were replaced by drug-free pumps for 2 weeks (postdrug control period). The LEV concentration in the pumps during the drug period was adjusted to give daily doses resulting in the maximal plasma concentration range determined previously in patients with TLE during prolonged treatment with LEV. During the 6 weeks of the experiment in epileptic rats, seizures were recorded by video monitoring. RESULTS: Average seizure frequency during the pre- and postdrug control period in a group of eight epileptic rats was 21 and 25 seizures. This was reduced to an average seizure frequency of 8 seizures during the 2 weeks of treatment with LEV. However, the individual response of rats to LEV varied markedly from complete seizure control to no effect at all, although plasma drug levels were within the therapeutic range in all rats. When seizure frequency was separately calculated for the first and second week of treatment, the significant anticonvulsant effect determined in the first week was partially diminished in the second week, suggesting that tolerance may have developed in some of the rats. CONCLUSIONS: The data demonstrate that interesting results can be obtained by drug testing in epileptic rats, giving a more realistic prediction of clinical efficacy than results from drug testing in animal models with elicited seizures. Thus, although drug trials in rats with spontaneous recurrent seizures are laborious and time-consuming, such trials should be added to the preclinical characterization of novel AEDs.