Profiling of immune-related gene expression in children with familial hypercholesterolaemia.

BACKGROUND: Innate and adaptive immune responses are pivotal in atherosclerosis, but their association with early-stage atherosclerosis in humans is incompletely understood. In this regard, untreated children with familial hypercholesterolaemia may serve as a human model to investigate the effect of elevated low-density lipoprotein (LDL)-cholesterol. OBJECTIVES: We aimed to study the immunological and inflammatory pathways involved in early atherosclerosis by examining mRNA molecules in peripheral blood mononuclear cells (PBMCs) from children with FH. METHODS: We analysed the level of 587 immune-related mRNA molecules using state-of-the-art Nanostring technology in PBMCs from children with (n = 30) and without (n = 21) FH, and from FH children before and after statin therapy (n = 10). RESULTS: 176 genes (30%) were differentially expressed between the FH and healthy children at P < 0.05. Compared to healthy children, the dysregulated pathways in FH children included the following: T cells (18/19); B cells (5/6); tumour necrosis factor super family (TNFSF) (6/8); cell growth, proliferation and differentiation (5/7); interleukins (5/9); toll-like receptors (2/5); apoptosis (3/7) and antigen presentation (1/7), where the ratio denotes higher expressed genes to total number of genes. Statin therapy reversed expression of thirteen of these mRNAs in FH children. CONCLUSION: FH children display higher PBMC expression of immune-related genes mapped to several pathways, including T and B cells, and TNFSF than healthy children. Our results suggest that LDL-C plays an important role in modulating expression of different immune-related genes, and novel data on the involvement of these pathways in the early atherosclerosis may represent future therapeutic targets for prevention of atherosclerotic progression.

Genetic Variation/Evolution and Differential Host Responses Resulting from In-Patient Adaptation of Mycobacterium avium.

Members of the Mycobacterium avium complex (MAC) are characterized as nontuberculosis mycobacteria and are pathogenic mainly in immunocompromised individuals. MAC strains show a wide genetic variability, and there is growing evidence suggesting that genetic differences may contribute to a varied immune response that may impact the infection outcome. The current study aimed to characterize the genomic changes within M.avium isolates collected from single patients over time and test the host immune responses to these clinical isolates. Pulsed-field gel electrophoresis and whole-genome sequencing were performed on 40 MAC isolates isolated from 15 patients at the Department of Medical Microbiology at St. Olavs Hospital in Trondheim, Norway. Isolates from patients (patients 4, 9, and 13) for whom more than two isolates were available were selected for further analysis. These isolates exhibited extensive sequence variation in the form of single-nucleotide polymorphisms (SNPs), suggesting that M. avium accumulates mutations at higher rates during persistent infections than other mycobacteria. Infection of murine macrophages and mice with sequential isolates from patients showed a tendency toward increased persistence and the downregulation of inflammatory cytokines by host-adapted M. avium strains. The study revealed the rapid genetic evolution of M. avium in chronically infected patients, accompanied by changes in the virulence properties of the sequential mycobacterial isolates.

Case report: a troublesome ophthalmic artery aneurysm.

Objective and Importance When treating large unruptured ophthalmic artery (OA) aneurysms causing progressive blindness, surgical clipping is still the preferred method because aneurysm sac decompression may relieve optic nerve compression. However, endovascular treatment of OA aneurysms has made important progress with the introduction of stents. Although this development is welcomed, it also makes the choice of treatment strategy less straightforward than in the past, with the potential of missteps. Clinical Presentation A 56-year-old woman presented with a long history of progressive unilateral visual loss and magnetic resonance imaging showing a 20-mm left-sided OA aneurysm. Intervention Because of her long history of very poor visual acuity, we considered her left eye to be irredeemable and opted for endovascular therapy. The OA aneurysms was treated with stent and coils but continued to grow, threatening the contralateral eye. Because she failed internal carotid artery (ICA) balloon test occlusion, we performed a high-flow extracranial-intracranial bypass with proximal ICA occlusion in the neck. However, aneurysm growth continued due to persistent circulation through reversed blood flow in distal ICA down to the OA and the cavernous portion of the ICA. Due to progressive loss of her right eye vision, we surgically occluded the ICA proximal to the posterior communicating artery and excised the coiled, now giant, OA aneurysm. This improved her right eye vision, but her left eye was permanently blind. Conclusion This case report illustrates complications of the endovascular and surgical treatment of a large unruptured OA aneurysm.

Expression of perilipins in human skeletal muscle in vitro and in vivo in relation to diet, exercise and energy balance.

The perilipin proteins enclose intracellular lipid droplets. We describe the mRNA expression of the five perilipins in human skeletal muscle in relation to fatty acid supply, exercise and energy balance. We observed that all perilipins were expressed in skeletal muscle biopsies with the highest mRNA levels of perilipin 2, 4 and 5. Cultured myotubes predominantly expressed perilipin 2 and 3. In vitro, incubation of myotubes with fatty acids enhanced mRNA expression of perilipin 1, 2 and 4. In vivo, low fat diet increased mRNA levels of perilipin 3 and 4. Endurance training, but not strength training, enhanced the expression of perilipin 2 and 3. Perilipin 1 mRNA correlated positively with body fat mass, whereas none of the perilipins were associated with insulin sensitivity. In conclusion, all perilipins mRNAs were expressed in human skeletal muscle. Diet as well as endurance exercise modulated the expression of perilipins.

Metabolic switching of human skeletal muscle cells in vitro.

In this review we will focus on external factors that may modify energy metabolism in human skeletal muscle cells (myotubes) and the ability of the myotubes to switch between lipid and glucose oxidation. We describe the metabolic parameters suppressibility, adaptability and substrate-regulated flexibility, and show the influence of nutrients such as fatty acids and glucose (chronic hyperglycemia), and some pharmacological agents modifying nuclear receptors (PPAR and LXR), on these parameters in human myotubes. Possible cellular mechanisms for changes in these parameters will also be highlighted.

Metabolic switching of human myotubes is improved by n-3 fatty acids.

The aim of the present study was to examine whether pretreatment with different fatty acids, as well as the liver X receptor (LXR) agonist T0901317, could modify metabolic switching of human myotubes. The n-3 FA eicosapentaenoic acid (EPA) increased suppressibility, the ability of glucose to suppress FA oxidation. Substrate-regulated flexibility, the ability to increase FA oxidation when changing from a high glucose, low fatty acid condition ("fed") to a high fatty acid, low glucose ("fasted") condition, was increased by EPA and other n-3 FAs. Adaptability, the capacity to increase FA oxidation with increasing FA availability, was enhanced after pretreatment with EPA, linoleic acid (LA), and palmitic acid (PA). T0901317 counteracted the effect of EPA on suppressibility and adaptability, but it did not affect these parameters alone. EPA per se accumulated less, however, EPA, LA, oleic acid, and T0901317 treatment increased the number of lipid droplets (LD) in myotubes. LD volume and intensity, as well as mitochondrial mass, were independent of FA pretreatment. Microarray analysis showed that EPA regulated more genes than the other FAs and that specific pathways involved in carbohydrate metabolism were induced only by EPA. The present study suggests a favorable effect of n-3 FAs on skeletal muscle metabolic switching and glucose utilization.

The Hydrodynamic Effect of Bare Platinum Coils versus Hydrogel-Coated Platinum Coils.

SUMMARY: HydroCoils (HES) were designed to obtain a better initial aneurysm occlusion and increased durability of endovascular treatment. We compared the immediate hydrodynamic effects of HES versus bare platinum coils (Guglielmi detachable coils, GDC). Intra-aneurysmal pressure and flow were measured with a 0.014 inch guidewire mounted transducer in silicone aneurysms mounted onto a pulsatile flow phantom before and after consecutively coiling with GDC and HES. We evaluated flow using the thermodilution technique along with changes in steady pressure and sudden increases in pressure. We also considered the effect of the coils on the transmission of pressure from the parent artery to the dome of the aneurysm. Intra-aneurysmal pressure remained unchanged after maximal packing with either GDC or HES. Sudden increases in pressure were less attenuated within the aneurysm after coiling with HES. In spite of HES obtaining a much higher percentage filling volume in the aneurysms, GDC equivalently virtually abolished intra-aneurysmal flow apart from in one instance where there was significant persistent flow after coiling with GDC. The effects of HES in terms of pressure and flow attenuation within the aneurysm could hence not be proven superior to GDC.

Stochastic multiscale model for carbonate rocks.

A multiscale model for the diagenesis of carbonate rocks is proposed. It captures important pore scale characteristics of carbonate rocks: wide range of length scales in the pore diameters; large variability in the permeability; and strong dependence of the geometrical and transport parameters on the resolution. A pore scale microstructure of an oolithic dolostone with generic diagenetic features is successfully generated. The continuum representation of a reconstructed cubic sample of side length 2mm contains roughly 42 x 10{6} crystallites and pore diameters varying over many decades. Petrophysical parameters are computed on discretized samples of sizes up to 1000{3}. The model can be easily adapted to represent the multiscale microstructure of a wide variety of carbonate rocks.

Endovascular reperfusion therapy in acute ischaemic stroke.

OBJECTIVES: Endovascular reperfusion therapy in acute ischaemic stroke comprises a number of pharmacological and mechanical procedures. Mechanical embolectomy offers the promise of efficacious treatment for patients in whom pharmacological thrombolysis is contraindicated or might be ineffective. The purpose of this review is to outline endovascular reperfusion therapy in acute ischaemic stroke with focus on mechanical embolectomy. MATERIALS & METHODS: Data on endovascular reperfusion therapy were acquired through searches in MEDLINE 1990-2006 by cross referencing relevant key words. RESULTS: Mechanical embolectomy works well on large-volume proximal occlusions for which there was previously no effective treatment. Early safety trials are promising, efficacy in terms of recanalisation is substantial, and both safety and efficacy is expected to improve with further advances in technology. CONCLUSIONS: Intravenous thrombolysis with tPA revolutionised acute stroke treatment a decade ago. Endovascular reperfusion therapy now offers the promise of a second revolution, expanding the number of patients eligible and the time window open for specific stroke treatment.

Cerebral thrombotic microangiopathy and antiphospholipid antibodies in Aicardi-Goutieres syndrome--report of two sisters.

Cerebral thrombotic microangiopathy was found at autopsy in one of two sisters with Aicardi-Goutieres syndrome, whereas the other revealed increased serum levels of anticardiolipin IgG antibodies (measured only in the living sister); both typical features of systemic lupus erythematosus. These findings add support to the suggestion that Aicardi-Goutieres syndrome and systemic lupus erythematosus are closely related disorders in which dysregulated production of interferon-alpha might play a crucial role.

Emotional responses during unilateral amobarbital anesthesia: differential hemispheric contributions?

OBJECTIVES: To explore (1) effects of test and subject variables in determining euphoric and dysphoric responses during unilateral amobarbital anesthesia and (2) which cerebral areas contribute to the emotional responses. METHOD: Incidence of euphoric and dysphoric reactions during left- and right-sided amobarbital anesthesia of the internal carotid artery (ICA) and selective anesthesia of the middle cerebral (MCA) and the posterior cerebral (PCA) artery was recorded. The sample comprised 270 Norwegians (6-61 years), and a total of 562 injections were performed under conditions endeavoring to calm down the patients. RESULTS: The overall incidence of observed emotional responses during ICA anesthesia was 21.5%, euphoric reactions being about 10 times more frequent than dysphoric. The incidence of euphoric reactions, however, was not significantly higher under right- than under left-sided anesthesia, and dysphoric reactions were not more frequent under left- than under right-sided anesthesia. Indeed, 13 patients showed elevated mood under both right- and left-sided anesthesia. Anesthesia of the territories of ICA and MCA gave rise to similar results, while no cases of mood change were observed under selective PCA anesthesia. CONCLUSION: It is concluded that unilateral amobarbital anesthesia as such, irrespective of side, may trigger both euphoric and dysphoric responses. The relative frequency obtained is influenced importantly both by the emotional responsiveness of the subjects and the emotional climate of the test situation. Finally, it is suggested that brain regions supplied by the PCA contribute less to modulation of euphoric and dysphoric responses than those supplied by the MCA or the ICA.

Reduced neuropsychological test performance in asymptomatic carotid stenosis: The Tromsø Study.

OBJECTIVE: To assess the relationship between asymptomatic carotid stenosis, neuropsychological test performance, and silent MRI lesions. METHODS: Performance on several neuropsychological tests was compared in 189 subjects with ultrasound-assessed carotid stenosis and 201 control subjects without carotid stenosis, recruited from a population health study. Subjects with a previous history of stroke were excluded. The test battery included tests of attention, psychomotor speed, memory, language, speed of information processing, motor functioning, intelligence, and depression. Sagittal T1-weighted and axial and coronal T2-weighted spin echo MRI was performed, and presence of MRI lesions (white matter hyperintensities, lacunar and cortical infarcts) was recorded. RESULTS: Subjects with carotid stenosis had significantly lower levels of performance in tests of attention, psychomotor speed, memory, and motor functioning, independent of MRI lesions. There were no significant differences in tests of speed of information processing, word association, or depression. Cortical infarcts and white matter hyperintensities were equally distributed among persons with and without carotid stenosis. Lacunar infarcts were more frequent in the stenosis group (p = 0.03). CONCLUSIONS: Carotid stenosis was associated with poorer neuropsychological performance. This could not be explained by a higher proportion of silent MRI lesions in persons with asymptomatic carotid stenosis, making it less likely that the cognitive impairment was caused by silent emboli.

Brain cysts associated with mutation in the Aristaless related homeobox gene, ARX.

The novel Aristaless related homeobox gene, ARX, is widely expressed in the brain and is thought to play a key role in the regulation of brain development. Neurological phenotypes caused by ARX mutations have recently started to unfold. We describe a 72 year old man with X-linked mental retardation due to a 24 bp duplication mutation in exon 2 of the ARX gene. Cerebral MRI showed bilateral cystic-like cavities in both the cerebral and cerebellar hemispheres. No retraction or expansion in neighbouring parenchyma was observed, there was no history of acute neurological impairment, and no risk factors for cerebrovascular disease were found. The lesions appeared to be congenital and represented benign developmental cysts, possibly caused by the ARX mutation.

MR angiography in the follow-up of coiled cerebral aneurysms after treatment with Guglielmi detachable coils.

PURPOSE: Intra-arterial digital subtraction angiography (DSA) has been considered the gold standard examination in the follow-up of patients treated with Guglielmi detachable coils (GDCs). However, DSA is an invasive and expensive investigation and results in exposure to ionising radiation to both patient and operator. The aim of this study was to compare MR angiography (MRA) with DSA with regard to patency of the occlusion of aneurysms following GDC treatment. MATERIAL AND METHODS: We performed 75 MRA and DSA examinations on 51 patients treated with GDCs. The examinations were performed 3-36 months after embolisation and the interval between MRA and DSA was less than 1 week. Hard copies of both studies were interpreted retrospectively and independently for residual flow within the aneurysm, residual aneurysmal neck, and parent and branch vessel flow. RESULTS: Patency status of parent and branch vessel flow was correctly identified with MRA in all patients except 1. The sensitivity of MRA in revealing residual flow within the aneurysm was 97%. The specificity in ruling out residual flow within the aneurysm was 91%. CONCLUSION: MRA may replace DSA in the long-term follow-up of coiled cerebral aneurysms. The initial follow-up examination should, however, include both modalities.

A Phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (valspodar).

BACKGROUND: PSC 833 is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5-day continuous infusion. METHODS: Seventy-nine patients with advanced malignant disease were enrolled in the trial and treated with escalating doses of PSC 833. Pharmacokinetic interactions between PSC 833 and vinblastine were anticipated. Accordingly, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study. RESULTS: The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every 12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m(2) per day vinblastine as a continuous intravenous infusion (CIV) for 5 days; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formulation in combination with 0.6 mg/m(2) per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for the combination, constipation, fever. and neutropenia. Increased oral bioavailability and increased peak and trough concentrations were observed with the microemulsion formulation. Significant interpatient variability in pharmacokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the kidney, 3 patients had complete responses, and 1 patient had a partial response. CONCLUSIONS: PSC 833 in combination with vinblastine can be administered safely to patients provided the vinblastine dose is adjusted for pharmacokinetic interactions. The high interpatient variability is a significant confounding factor. Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable. Improved methods for predicting pharmacokinetic interactions should improve future studies.

Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report.

Depsipeptide, FR901228, has demonstrated potent in vitro and in vivo cytotoxic activity against murine and human tumor cell lines. In the laboratory, it has been shown to be a histone deacetylase (HDAC) inhibitor. In a phase I trial of depsipeptide conducted at the National Cancer Institute, 3 patients with cutaneous T-cell lymphoma had a partial response, and 1 patient with peripheral T-cell lymphoma, unspecified, had a complete response. Sézary cells isolated from patients after treatment had increased histone acetylation. These results suggest that inhibition of HDAC is a novel and potentially effective therapy for patients with T-cell lymphoma.

[Resection of malignant tumors involving the anterior cranial fossa]. / Reseksjon av maligne svulster med relasjon til fremre skallgrop.

BACKGROUND: The craniofacial approach has greatly facilitated resections of tumours involving the base of the anterior cranial fossa when compared to either the transcranial or transfacial approach alone. MATERIAL AND METHODS: This approach was used in 11 patients with malignant tumours localized to the ethmoid sinus, orbit and bone or soft tissue of the base of the anterior part of the skull. By combining a low frontal or frontolateral craniotomy with resection of the facial skull, en bloc resections were accomplished. A frontogaleal periostal flap or a muscle flap from the temporal muscle was used to replace resected bone and to seal the skull base. RESULTS: There were no peri- or postoperative deaths. One patient died due to local recurrence, one patient is alive with residual tumour six years after surgery, and one is reoperated due to local recurrence. In addition one patient developed recurrence of a previously treated tumour of the maxillary sinus. Two patients developed meningitis and one pneumocephalus postoperatively. One patient has partial loss of vision and two patients underwent dacryocystorhinostomy due to epiphora. INTERPRETATION: The planning and execution of this type of surgery requires close interaction in an interdisciplinary team, in particular between neurosurgeon and head and neck surgeon.

[Choice of neuroradiological methods in ophthalmology--the eye and the lacrimal apparatus]. / Valg av nevroradiologiske metoder i oftalmologi--øyeeplet og tåreveiene.

With improved imaging methods, the possibility of demonstrating pathological changes in the visual pathways has increased substantially. However, optimal evaluation of visual disorders requires familiarity with the anatomy and pathology of the visual pathways, and with the many advances in neuroimaging. The purpose of this article is to provide clinicians with a practical approach for selecting the most appropriate imaging modalities. Choice of technique is discussed with reference to anatomical regions rather than a complete list of diseases. Ophthalmoscopy reveals many intraocular abnormalities. Imaging studies help in cases where opaque media preclude a view of the fundus. In addition, imaging studies assist in confirming the extraocular extent of the lesion. The advantages and disadvantages of x-ray, computed tomography and magnetic resonance imaging are discussed and illustrated by examples.

[Choice of neuroradiological methods in ophthalmology--the optic nerve, muscles of the eye and orbit]. / Valg av nevroradiologiske metoder i oftalmologi--synsnerven, øyemusklene og orbita.

Optimal imaging of the orbital structures presents a challenge. Images of this region may be disturbed by ocular movements, and orbital fat may prevent visualisation of the optic nerve and retrobulbar lesions. In this article, we intend to provide practical guidelines for the evaluation of orbital abnormalities, on the basis of our own experiences and a study of selected literature. Computed tomography (CT) and magnetic resonance imaging (MRI) are both useful for the detection and characterisation of orbital abnormality. However, for diagnostic work-up of the optic nerves, contrast-enhanced, fat-suppressed MRI best demonstrates the pattern and severity of optic nerve abnormality and allows assessment of the intracranial part of the optic nerves and associated intracranial abnormality. In the case of bony involvement, spiral CT imaging is the modality of choice. It is quick, inexpensive and allows multiplanar reconstruction. Not uncommonly, CT as well as MRI may be needed to characterise an orbital lesion.

[Neuroradiological imaging of the 3rd, 4th and 6th cranial nerves]. / Nevroradiologisk fremstilling av 3., 4. og 6. hjernenerve.

The ocular motor cranial nerves (III, IV, VI) control the eye movements in a near association with the higher cortical areas. Clinically, the most common presentation of abnormal ocular motility is double vision. Identifying the cause of ocular nerve palsy can be difficult, and a large percentage of such cases still remains undiagnosed, even in a new era of neuroradiological techniques. Close co-operation between the clinician and the radiologist is necessary for the selection of the best imaging methods for the specific clinical problem, in order to set the aetiological and topological diagnosis. This article provides a practical review of advances in neuroimaging of the ocular motor nerves.