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.

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.

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.

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.

Phase I study of infusional paclitaxel in combination with the P-glycoprotein antagonist PSC 833.

PURPOSE: PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion. PATIENTS AND METHODS: Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion. Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833. RESULTS: In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (C(pss)) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received a paclitaxel dose of 35 mg/m(2)/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non-small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma. CONCLUSION: PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent. This in turn will facilitate dosing to achieve comparable CPss and AUCs.

Sandostatin LAR in acromegalic patients: long-term treatment.

We have evaluated the long term effects and safety of Sandostatin LAR, a long acting formulation of octreotide, during 18 subsequent injections given every fourth week to 14 octreotide-sensitive acromegalic patients. The dosages (20, 30, or 40 mg) were adjusted according to GH response, side-effects, or symptom relief and assessed on day 28 after each injection. We found a stable and consistent suppression of GH and insulin-like growth factor (IGF-I) during the entire study period. Daily mean GH levels were suppressed below 2 micrograms/L in 9, to between 2-5 micrograms/L in 3, and to between 5-10 micrograms/L in 2 patients. The corresponding IGF-I values were suppressed to below 500 micrograms/L in 9 patients and to between 500-1000 micrograms/L in the remaining 5 patients. Increasing the dosage of Sandostatin LAR from 20 to 30 mg had no obvious additional effect on GH suppression, but provided a further decrease in IGF-I levels. Forty milligrams of the drug had no additional effect on GH or IGF-I compared to 30 mg. Acromegalic signs and symptoms improved during treatment. Although the fluctuations of daily mean octreotide levels were high, dosage increments caused an increase in the average serum concentration in the individual patient. Pituitary tumor size reduction was seen in all previously untreated patients (n = 4). We found only minor changes in glucose metabolism (oral glucose tolerance test and hemoglobin A1C) during treatment, but no biologically relevant changes in thyroid function (TSH, T3, and free T4). One patient developed asymptomatic gallstones, and another acquired vitamin B12 deficiency during treatment. The drug is well tolerated during long term treatment. Sandostatin LAR may well be the future medical treatment of choice for acromegalic patients.

Omnipaque vs. Hexabrix in intravenous DSA of the carotid arteries: randomized double-blind crossover study.

A randomized double-blind crossover study using Omnipaque 350 mg l/ml (iohexol) and Hexabrix 320 mg l/ml (ioxaglate) in 53 patients undergoing intravenous digital subtraction angiography of the carotid arteries revealed no significant differences in image quality. Some differences were found in subjective side effects that favored Omnipaque. Nausea was reported in four patients after injection of Hexabrix, and a metallic taste was significantly more frequent (p less than 0.01) with this contrast medium. The patients' preference for Omnipaque was also statistically significant (p less than 0.01). It was concluded that both contrast media are suitable for intravenous digital subtraction angiography.

Visual hallucinations in a case of reversible hypertension-induced brain oedema.

Visual hallucinations are commonly associated with seizures, drug effects, psychiatric disorders, or visual loss as 'release' phenomena. We report the case of a previously healthy 65-year-old woman, who was admitted to hospital with intermittent headache episodes accompanied by complex visual hallucinations. During these episodes the patient's blood pressure was 220/120 mmHg. In between symptomatic episodes she had no complaints and felt healthy. The neurological and ophthalmological examinations were normal but cerebral magnetic resonance imaging (MRI) showed multiple white matter abnormalities in the parieto-occipital regions. Rapid reversal of the symptoms and imaging abnormalities occurred concurrently with lowering of blood pressure. The history and the findings were similar to those recently described in the clinicoradiological 'posterior leukoencephalopathy' syndrome. Different pathogenic mechanisms are discussed. Copyright 1998 Lippincott Williams & Wilkins

Hydrocephalus in an achondroplastic child treated by venous decompression at the jugular foramen. Case report.

A 10-month-old child with achondroplasia with progressive head enlargement, ventriculomegaly, and wide subarachnoid spaces over the hemispheres was referred for evaluation. A steady-state lumbar infusion test revealed increased cerebrospinal fluid (CSF) outflow resistance (14 mm Hg/ml/min), and intra-arterial digital subtraction angiography (DSA) demonstrated bilateral venous outflow obstruction due to stenosis of the jugular foramen. Surgical decompression by opening the right jugular foramen relieved the clinical signs of intracranial hypertension. During the following year, the patient's head enlargement was moderate with relative normalization of size. Repeat DSA demonstrated improved venous runoff on the right side, and a steady-state lumbar infusion test demonstrated reduced CSF outflow resistance (10 mm Hg/ml/min). Venous decompression is causal therapy and may prove to be preferable to shunting in children with hydrocephalus and bilateral stenosis of the jugular foramen.

Assessment of intracranial hemodynamics in carotid artery disease by transcranial Doppler ultrasound.

Noninvasive transcranial Doppler recordings were correlated to the angiographic findings in 77 patients with carotid artery disease. Stenoses reducing the luminal area of the internal carotid artery by 75% or more also reduced the pulsatility transmission index (PTI) of the ipsilateral middle cerebral artery (MCA). The PTI is the pulsatility index of the artery under study expressed as a percent of the pulsatility index of another intracranial artery with presumed unimpeded inflow in the same individual. For stenoses in the 75% to 89% category. PTI reduction was significantly greater in patients with bilateral carotid stenosis, indicating an impaired potential for collateral flow in these patients. The PTI reduction probably reflects both the pressure drop across the stenosis and the cerebral autoregulatory response. Two criteria proved useful in demonstrating collateral MCA supply through the circle of Willis. On the recipient side, retrograde flow in the proximal anterior cerebral artery was demonstrated in 29 of the 31 patients when this flow pattern was disclosed angiographically. In 26 of these patients, the anterior cerebral artery on the supplying side also had clearly increased flow velocity. Increased flow velocities in the proximal posterior cerebral artery were present in 26 of the 30 vessels that were acting as a collateral channel to the ipsilateral MCA.

Pulsed Doppler techniques for measuring instantaneous maximum and mean flow velocities in carotid arteries.

A 5 MHz pulsed Doppler instrument measuring instantaneous maximum and mean flow velocities is presented. The maximum velocity estimator is based on the principle of frequency variable filtering controlled by a feedback loop to follow the velocity spectrum envelope. Findings by Doppler and bilateral selective carotid arteriography in 216 patients were compared. Extracranial carotid stenoses were identified by the finding of a vessel segment with locally increased flow velocity. Peak Velocity Ratio (PVR) was calculated from maximum velocities measured in the stenosis and in more distal Internal Carotid Artery (ICA) segments. Using PVR, ICA stenoses greater than 20% were detected with sensitivity 96%, specificity 94%, positive accuracy 94% and negative accuracy 96%. Total ICA occlusions were identified with sensitivity 97% and specificity 99%.

Childhood autism: the need for physical investigations.

In this paper the results of an extensive medical investigation of 25 children with childhood autism are presented and compared with those found in a group of non-autistic individuals matched for sex, age and intellectual level, all referred for developmental deviancy of unknown etiology. The examination included a psychiatric assessment and a neurological examination in addition to neurophysiological, chromosomal, metabolic and neuroimaging evaluation. In the clinical examination macrocephaly was found only among the autistic individuals, while the frequency of pathological cerebral CT and clinical parameters such as tendon reflexes and mobility problems was significantly greater in the control group. All the other pathological findings were found to occur with the same frequency in the two groups. Except for research purposes this study did not lend support to those who argue for extensive medical examinations for all children with autism. Based on the present findings, ordinary procedures for assessment of developmentally delayed children should be followed. This should include a systematic clinical neuropaediatric examination, an assessment of vision and hearing and a chromosome study, including that for fragile X.

Intravenous digital subtraction angiography of the precerebral and cerebral arteries in patients with TIA. A comparison with conventional angiography.

A study of the diagnostic utility of both intravenous digital subtraction angiography (IV-DSA) and conventional angiography of precerebral and cerebral arteries is presented. The series comprised 60 patients with TIA, who underwent the two procedures with a mean interval of 16 days. Conventional angiography was generally superior to IV-DSA, and this was particularly marked in the siphons and cerebral arteries. Only the excellent IV-DSA examinations obtained in a few patients with TIA could be accepted as final pre-operative procedures. Accurate imaging of the lesions and collateral flow pattern usually required intra-arterial injections, and intra-arterial DSA is now usually preferred.

Failure to confirm neurotoxic impairment using cerebral magnetic resonance imaging on solvent-exposed workers.

OBJECTIVES: The study aimed at assessing signs of nervous system impairment by cerebral magnetic resonance imaging (MRI) among workers with a history of long-term exposure to mixtures of organic solvents. METHODS: Thirty-six workers (mean age 44.1 years) with at least 10 (mean 23.9) years of occupational exposure to solvents and pair-matched referents with no former solvent exposure went through a blind, random-order investigation of cerebral MRI, performed with a 1.5-tesla scanner. RESULTS: Linear measurements of the MRI tomograms showed a slight tendency toward wider ventricles and broader cortical sulci in the reference group. Visual evaluation of the MRI by 2 experienced neuroradiologists showed no significant difference between the groups; however, there was substantial interobserver variability. CONCLUSIONS: The MRI findings of this study do not support the hypothesis that long-term low-level occupational exposure to organic solvents results in the development of brain atrophy, or specific MRI signal changes in the region of the basal ganglia and thalami.

Implementing the staff educator component of the oncology clinical nurse specialist role.

This article provides a brief overview of cancer nursing education, the oncology clinical nurse specialist's (OCNS's) responsibilities as staff educator, the current literature on OCNS teaching strategies, and how to choose a teaching method. A variety of creative teaching methods that facilitate effective and creative staff education are described.

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.