Paclitaxel and cyclosporine A show supra-additive antiproliferative effects on smooth muscle cells by activation of protein kinase C

We intended to establish a pharmacologic concept of synergistic antiproliferative effects on smooth muscle cells (SMC) by using paclitaxel and cyclosporine A at clinically applicable doses. Coronary SMC were incubated with paclitaxel and cyclosporine A at concentrations of 10 – 20 nmol/L and 83 – 415 nmol/L, respectively. Antiproliferative effects were assessed by cell counts, [³H]thymidine incorporation and cell cycle analysis. In addition, apoptosis was studied by cytoplasmic histone-associated DNA fragments and in vitro protein kinase C activity (PKC) was determined by immunoassay. We found paclitaxel and cyclosporine A to exert a highly supra-additive antiproliferative effect on SMC with significant reductions of cell counts (p < 0.01) and [³H]thymidine incorporation (p < 0.05). SMC were found to be arrested at the G2/M transition. This antiproliferative effect was observed in the absence of DNA fragmentation above values obtained for single compound treatment, which had virtually no impact on cell proliferation. DNA fragmentation started to increase at a drug combination comprising paclitaxel at the higher dose of 20 nmol/L. Under the treatment with both paclitaxel and cyclosporine A, PKC activity showed a 1.8-fold increase (p < 0.05) compared with untreated controls. In conclusion, PKC mediates supra-additive antiproliferative effects of paclitaxel and cyclosporine A on SMC. The data demonstrate a highly efficient pharmacologic concept for the inhibition of SMC proliferation. Further studies are needed to test this concept under in vivo conditions for the prevention of restenosis or transplant vasculopathy by systemic application of cyclosporine A – when already applied for immunosuppressive purposes – and local delivery of paclitaxel. Received: 28 August 2001, Returned for revision: 25 September 2001, Revision received: 20 November 2001, Accepted: 4 December 2001     

Postnatal confirmation of prenatally diagnosed trisomy 20 mosaicism in a patient with linear and whorled nevoid hypermelanosis

Linear and whorled nevoid hypermelanosis (LWNH) is characterized by hyperpigmented reticulate macules in a Blaschko linear arrangement without atrophy or preceding inflammation. Underlying chromosomal mosaicism was often assumed, but has been verified in only a few published cases. We report a 7-year-old boy with LWNH associated with congenital ventricular septal defect and psychomotor retardation. Prenatal chromosomal analysis of amniocytes revealed trisomy 20 mosaicism, which was not confirmed in peripheral blood lymphocytes after birth. Histologic sections of skin biopsy specimens taken at age 6 years showed hyperpigmentation of the basal epidermal layer with prominent melanocytes and isolated melanophages in the upper dermis. Cytogenetic analysis of cultured skin fibroblasts revealed an extra chromosome 20 in 5 of the 30 metaphases studied (17%). Mosaic trisomy 20 is one of the most common autosomal mosaicisms identified in amniocytes and is, as a rule, compatible with normal pregnancy outcome. In postnatal analysis of peripheral blood lymphocytes, an extra chromosome 20 could never be detected. However, when confirmed in skin fibroblasts, trisomy 20 mosaicism may be associated with systemic anomalies. The present case shows for the first time an association of LWNH with trisomy 20 mosaicism and emphasizes the importance of analyzing skin fibroblasts in cases of prenatally diagnosed trisomy 20.     

Successful Treatment with Atomoxetine of an Adolescent Boy with Attention Deficit/Hyperactivity Disorder,Extreme Obesity,and Reduced Melanocortin 4 Receptor Function

ObjectiveRecent case reports suggest a link between reduced melanocortinergic tone and both obesity and attention deficit / hyperactivity disorder (ADHD). We present the case of a 13-year-old, male, obese MC4R mutation carrier with ADHD.Case ReportThe boy carries a heterozygous mutation in the melanocortin 4 receptor gene (MC4R; Met281Val), that leads to a reduced receptor function. Dominant mutations of this type represent major gene effects for obesity. He participated in a lifestyle intervention program for obesity and received treatment with the selective norepinephrine re-uptake inhibitor atomoxetine for 31 months. The boy markedly reduced his BMI from 47.2 to 29.6 kg/m².ConclusionAtomoxetine proved to efficiently reduce weight in a severely obese MC4R mutation carrier with ADHD. We briefly discuss possible mechanisms for our observation, including evidence for the functional connectivity between melanocortinergic, dopaminergic, and norepinephrinergic brain circuitries.Key Words: Pharmacogenetics, Brain-derived neurotrophic factor, Weight loss, Appetite control, Methylphenidate     

Mapping Different Intra-Hemispheric Parietal-Motor Networks Using Twin Coil TMS

BackgroundAccumulating evidence suggests anatomical and functional differences in connectivity between the anterior and posterior parts of the inferior-parietal lobule (IPL) and the frontal motor areas.Objective/HypothesisThis study investigates whether different intra-hemispheric parietal-motor interactions can be observed along the anterior–posterior axis of the IPL in the resting human brain.MethodsWe use a twin coil transcranial magnetic stimulation technique to test intra-hemispheric interactions between three points adjacent to the intra-parietal sulcus (anterior, central, posterior) and the ipsilateral primary motor cortex (M1) at rest in both hemispheres.ResultsWe found that stimulation of the anterior IPL resulted in an inhibition of the ipsilateral M1 in both hemispheres. Stimulation of the central and posterior IPL resulted in a facilitatory effect on ipsilateral M1 in the left but not for the right hemisphere. Additionally we show that there is considerable inter-subject variability concerning the optimal parietal facilitatory and inhibitory position.ConclusionsThe IPL has distinct inhibitory and facilitatory connections to the ipsilateral M1. Whereas inhibitory connections are observed in both hemispheres, facilitatory connections are asymmetric. These parietal-motor networks may represent the basis for the functional differences between these regions in reaching and grasping tasks and mirror the functional asymmetry observed in the motor system. From a practical point of view, we note that the inter-subject variability means that future TMS studies of the parietal area might consider a hot-spot localization similar to the procedures commonly used for M1.     

Hyperkinetic seizures in patients with temporal lobe epilepsy: clinical features and outcome after temporal lobe resection

Purpose: Temporal lobe epilepsy (TLE) is usually associated with automatisms. Hyperkinetic seizures are supposed to be unusual. Because we witnessed several patients with TLE and ictal hyperkinetic symptoms, we retrospectively assessed the number, clinical findings, and seizure outcome in such patients who had undergone temporal lobe resection. Methods: We reviewed medical history, video–electroencephalography (EEG) recording and neuroimaging of adult patients who underwent epilepsy surgery for TLE at the Kork Epilepsy Center over the last 20 years with a minimum postoperative follow‐up of 12 months. Key Findings: Among 294 patients who were resected exclusively in the temporal region, we identified 17 (6%) who presented with hyperkinetic semiology such as violent vocalization, complex movements of the proximal segments of the limbs, rotation of the trunk, pelvic thrusting, or early tonic or dystonic posturing. Most of the patients had a preceding aura. Ictal EEG activity was located in the corresponding temporal region, usually with a wide distribution over temporal electrodes with fast spread to unilateral frontal electrodes and to the contralateral side. Neuroimaging revealed extended lesions in the temporal lobe involving mesial and neocortical structures. Most of the patients underwent classical anterior temporal lobe resection including amygdalo‐hippocampectomy. Fourteen patients (82%) became completely seizure‐free (Engel class Ia). Histopathology showed mainly focal cortical dysplasia plus hippocampal sclerosis. Significance: Hyperkinetic seizure semiology may occasionally occur in patients with TLE and is, therefore, no contradiction to the hypothesis of TLE if scalp EEG patterns and neuroimaging findings correspond. The postoperative seizure outcome is favorable in such patients and not different from outcome data in classical TLE.     

The Role of Comorbid Mood Disorders in Cognitive Behavioral Therapy for Childhood Social Anxiety

Background

Children with a social anxiety disorder have worse treatment outcomes after Cognitive Behavior Therapy (CBT) than children with other anxiety disorders. Anxiety disorders and mood disorders are strongly related and especially social anxiety is related to high comorbidity rates with mood disorders. The aim of the study was to investigate how comorbid mood disorders are related to treatment outcomes after CBT and whether this can explain the worse outcomes for childhood social anxiety.

Methods

Participants were 152 referred clinically children (7–18 years) with either a social anxiety disorder (n?=?52) or another anxiety disorder (n?=?100) of whom 24.3% (n?=?37) had a comorbid mood disorder. Child anxiety, internalizing symptoms, and quality of life were measured pre-treatment, post-treatment, 3 months and 1 year after treatment, using child and both parents’ report.

Results

Children with a primary social anxiety disorder more often had a comorbid mood disorder than children with another primary anxiety disorder. Children with a mood disorder had more severe anxiety problems before treatment. Comorbid mood disorders were related to greater anxiety reductions after treatment. The worse outcomes for children with a primary social anxiety disorder remained after controlling for comorbid mood disorders.

Conclusions

Findings stress the importance of future studies examining why the presence of a comorbid mood disorder is associated with greater anxiety reductions, and other factors that explain the worse treatment outcomes found for childhood social anxiety disorder.

     

Influences of smoking and caffeine consumption on trigeminal pain processing

Background

Many human and animal studies have shown the influence of nicotine and caffeine on pain perception and processing. This study aims to investigate whether smoking or caffeine consumption influences trigeminal pain processing.

Methods

Sixty healthy subjects were investigated using simultaneous recordings of the nociceptive blink reflex (nBR) and pain related evoked potentials (PREP) following nociceptive electrical stimulation on both sides of the forehead (V1). Thirty subjects were investigated before and after smoking a cigarette, as well as before and after taking a tablet of 400 mg caffeine.

Results

After smoking PREP showed decreased N2 and P2 latencies indicating central facilitation at supraspinal (thalamic or cortical) level. PREP amplitudes were not changed. NBR showed a decreased area under the curve (AUC) indicating central inhibition at brainstem level. After caffeine intake no significant changes were observed comparing nBR and PREP results before consumption.

Conclusions

Smoking influences trigeminal pain processing on supraspinal and brainstem level. In the investigated setting, caffeine consumption does not significantly alter trigeminal pain processing. This observation might help in the further understanding of the pathophysiology of pain disorders that are associated with excessive smoking habits such as cluster headache. Previous smoking has to be taken into account when performing electrophysiological studies to avoid bias of study results.