Glioma-Induced Disruption of Resting-State Functional Connectivity and Amplitude of Low-Frequency Fluctuations in the Salience Network

BACKGROUND AND PURPOSE:Cognitive challenges are prevalent in survivors of glioma, but their neurobiology is incompletely understood. The purpose of this study was to investigate the effect of glioma presence and tumor characteristics on resting-state functional connectivity and amplitude of low-frequency fluctuations of the salience network, a key neural network associated with cognition.MATERIALS AND METHODS:Sixty-nine patients with glioma (mean age, 48.74 [SD, 14.32] years) who underwent resting-state fMRI were compared with 31 healthy controls (mean age, 49.68 [SD, 15.54] years). We identified 4 salience network ROIs: left/right dorsal anterior cingulate cortex and left/right anterior insula. Average salience network resting-state functional connectivity and amplitude of low-frequency fluctuations within the 4 salience network ROIs were computed.RESULTS:Patients with gliomas showed decreased overall salience network resting-state functional connectivity (P = .001) and increased amplitude of low-frequency fluctuations in all salience network ROIs (P < .01) except in the left dorsal anterior cingulate cortex. Compared with controls, patients with left-sided gliomas showed increased amplitude of low-frequency fluctuations in the right dorsal anterior cingulate cortex (P = .002) and right anterior insula (P < .001), and patients with right-sided gliomas showed increased amplitude of low-frequency fluctuations in the left anterior insula (P = .002). Anterior tumors were associated with decreased salience network resting-state functional connectivity (P < .001) and increased amplitude of low-frequency fluctuations in the right anterior insula, left anterior insula, and right dorsal anterior cingulate cortex. Patients with high-grade gliomas had decreased salience network resting-state functional connectivity compared with healthy controls (P < .05). The right anterior insula showed increased amplitude of low-frequency fluctuations in patients with grade II and IV gliomas compared with controls (P < .01).CONCLUSIONS:By demonstrating decreased resting-state functional connectivity and an increased amplitude of low-frequency fluctuations related to the salience network in patients with glioma, this study adds to our understanding of the neurobiology underpinning observable cognitive deficits in these patients. In addition to more conventional functional connectivity, amplitude of low-frequency fluctuations is a promising functional-imaging biomarker of tumor-induced vascular and neural pathology.

Detrimental effects of cancer on cognitive function and, consequently, on the quality of life are emerging as a key focus of cancer survivorship both in research and clinical practice.^1,2 Brain tumors have been shown to affect memory, processing, and attention in patients; however, their underlying neurobiology is incompletely understood.³ Using resting-state functional MR imaging (rsfMRI) to evaluate changes in cognitive resting-state networks may provide a better understanding of the pathology underlying the observable cognitive disruptions in gliomas, the most common primary brain tumor in adults.A “triple network model” of neurocognitive pathology has been proposed, which encompasses the default mode network, involved in mind wandering; the central executive network, involved in decision-making; and the salience network (SN), implicated in modulating activation of the default mode network and central executive network by detecting the presence of salient stimuli.^4-8 While previous rsfMRI research has largely focused on tumor-induced changes in the default mode network,^9,10 our study examined the less-studied SN, a network rooted in the anterior insula and the dorsal anterior cingulate cortex.⁶Prior studies evaluating gliomas and SN resting-state functional connectivity (RSFC) provided conflicting results in small patient samples: Maesawa et al¹⁰ found no significant differences in the SN in 12 patients, while Liu et al¹¹ more recently found decreased SN connectivity in 13 patients. Gliomas impact the integrity of the neurovascular unit to varying degrees, resulting in neurovascular uncoupling that has been reported to confound fMRI interpretations in patients with brain tumors.^12-14 Additionally, research has reported neuronal plasticity manifested by structural reorganization and functional remodeling of neural networks in patients with gliomas with possible alterations in clinically observable cognitive manifestations.^15-17 An rsfMRI metric, the amplitude of low-frequency fluctuations (ALFF), has recently shown promise as a biomarker for brain plasticity and hemodynamic characterization, including neurovascular uncoupling in patients with gliomas.^15-19The purpose of this study was to investigate the effect of glioma presence and tumor characteristics on overall RSFC and regional normalized ALFF within the SN in a large patient population. We hypothesized that there would be decreased average SN RSFC and altered ALFF in patients with gliomas compared with healthy controls. Recent studies have acknowledged that gliomas have variable effects on network integrity based on lesion location and proximity to network ROIs,^20-22 and unilateral gliomas can be associated with plasticity in both the ipsilateral and contralateral hemispheres.^11,17 Research also supports differences in resting-state network reorganization in aggressive high-grade gliomas compared with slower-growing low-grade gliomas.^20,23 Therefore, we also hypothesized that there would be differences in average SN RSFC and regional ALFF in patients based on the anterior-versus-posterior location, hemispheric side, and grade of glioma.     

Fabrication and design of transdermal fluconazole spray

The objective of the present study was to formulate fluconazole transdermal spray for obtaining modified drug transport using eutectic mixture, ethyl cellulose, polyethylene oxide and alcohol. The formulated products were characterized. The selection of the optimized batch was done considering the results of drug transport in the first hour, the time required for 90% drug transport, viscosity and spray angle of the formulations. The inclusion of eutectic mixture, consisting of equal parts of camphor and menthol, showed improved drug transport through rat skin. The optimized batch exhibited larger mean zone of inhibition (antifungal activity), efficient in vivo activity and short term stability.     

Association of catalytic iron with cardiovascular disease

The ability of iron to cycle reversibly between its ferrous and ferric oxidation states is essential for the biological functions of iron but may contribute to vascular injury through the generation of powerful oxidant species. We examined the association between chemical forms of iron that can participate in redox cycling, often referred to as "catalytic" or "labile" iron, and cardiovascular disease (CVD). In our cross-sectional study of 496 participants, 85 had CVD. Serum catalytic iron was measured using the bleomycin-detectable iron assay that detects biologically active iron. The odds of existing CVD for subjects in the upper third of catalytic iron were 10 times that of subjects with lower catalytic iron in unadjusted analyses. The association was decreased by 1/2 by age adjustment, but little additional attenuation occurred after adjusting for age, Framingham Risk Score, estimated glomerular filtration rate, hypertension status, high-density lipoprotein cholesterol, and systolic blood pressure, with the association remaining strong and significant (odds ratio 3.8, 95% confidence interval 1.4 to 10.1). In conclusion, we provide preliminary evidence for a strong detrimental association between high serum catalytic iron and CVD even after adjusting for several co-morbid conditions; however, broader prospective studies are needed to confirm these findings, which would support therapeutic trials to assess the beneficial effects of iron chelators on CVD.     

Fifteen years' experience of treating atherosclerotic renal artery stenosis by interventional nephrologists in India

Atherosclerotic renal artery stenosis (ARAS) is an important cause of kidney disease, accelerated hypertension (HTN), and its treatment is controversial. Our aim was to evaluate the outcomes, safety, and efficacy of percutaneous transluminal angioplasty (PTA) for ARAS. Retrospective analysis of ARAS was performed among 470 angiographies during 1995–2010. Patients with nonatherosclerotic RAS and renal transplant were excluded. We assessed preintervention and postintervention mean arterial pressure (MAP), antihypertensive medications, and renal function to classify as deteriorated (>10% increase in MAP/increase in drugs/>20% reduced GFR), improved (>10% reduced MAP/reduced drugs/>20% increased eGFR), or stabilized (<10% change in MAP/same antihypertensive drugs/<20% change in eGFR) at last follow‐up. A total of 220 subjects with mean age of 57.6 ± 10.4 years underwent PTA and/or stenting. The average follow‐up was 23.07 ± 21.2 months. Accelerated HTN, HTN onset >50 years, unexplained renal failure, and unilateral small kidney were the most common presentations. In all, 255 significant stenotic lesions in 220 patients (119 unilateral, 66 single functioning kidney, and 35 bilateral) were observed. In total, 255 PTA were performed, including 177 stenting. Technical success was seen in 220/243 (90.5%) subjects. Combined MAP and antihypertensive drugs improved in 154/220 (70%) patients. Renal function improved/stabilized in 175/220 (79.5%). Angioplasty and stenting are relatively safe and feasible tools for control of blood pressure (BP) in ARAS. Angioplasty produced improvement/stabilization of BP in 70%, and the renal function in 79.5% subjects.     

The dual effect of urinary macromolecules on the crystallization of calcium oxalate endogenous in urine

Summary The nucleation-promoting and growth-inhibiting activities of urinary macromolecules on the crystallization of calcium oxalate endogenous in urine of stoneformers and normal controls were studied by freezing the ultrafiltrate and retentate fractions of concentrated whole urine (pH 5.3, 1,250 mosmol/kg). Among the normal controls, macromolecules nominally of 10–20 kDa showed nucleation-promoting and growth-inhibiting activities; the 5–10 kDa population was incapable of such effects but did cooperate with molecules >10 kDa in enhancing the effect. In the case of stone-formers, molecules in the nominal ranges of 5–10 kDa and 10–20 kDa when considered separately were not active in the aspects studied but collectively could cooperate to produce pronounced effects. Application of the test to urine ultrafiltrate reconstituted with polyanionic macromolecules recovered from urine indicated that molecules from stoneformers were more powerful than those from normal controls in bringing about promotion of nucleation and inhibition of growth of crystals from urinary calcium oxalate.     

The Effect of Pressure-Induced Mechanical Stretch on Vascular Wall Differential Gene Expression

High blood pressure is responsible for the modulation of blood vessel morphology and function. Arterial hypertension is considered to play a significant role in atherosclerotic ischaemic heart disease, stroke and hypertensive nephropathy, whereas high venous pressure causes varicose vein formation and chronic venous insufficiency and contributes to vein bypass graft failure. Hypertension exerts differing injurious forces on the vessel wall, namely shear stress and circumferential stretch. Morphological and molecular changes in blood vessels ascribed to elevated pressure consist of endothelial damage, neointima formation, activation of inflammatory cascades, hypertrophy, migration and phenotypic changes in vascular smooth muscle cells, as well as extracellular matrix imbalances. Differential expression of genes encoding relevant factors including vascular endothelial growth factor, endothelin-1, interleukin-6, vascular cell adhesion molecule, intercellular adhesion molecule, matrix metalloproteinase-2 and -9 and plasminogen activator inhibitor-1 has been explored using ex vivo cellular or organ stretch models and in vivo experimental animal models. Identification of pertinent genes may unravel new therapeutic strategies to counter the effects of pressure-induced stretch on the vessel wall and hence minimise its notable complications.     

Ectopic adrenocortical tissue found at groin exploration in children: incidence in relation to diagnosis, age and sex

OBJECTIVE: To assess the incidence of ectopic adrenocortical tissue (EACT) in the groin in children, and examine the relationship between the incidence and the underlying diagnosis, age and sex. PATIENTS AND METHODS: From computer records, all groin explorations between 1988 and 2002 in patients < or = 15 years old were identified. Cases of EACT were identified from computer histology records, and the incidence in different groups compared. RESULTS: Of 935 groin explorations, EACT was identified in 25 (2.7%); there were no cases in girls. The incidence was 0.7% at inguinal herniotomy (IH), 4.1% at ligation of the patent processus vaginalis for communicating hydrocele (P = 0.03 vs IH), and 3.3% at exploration for undescended testes (P = 0.02 vs IH). In boys with undescended testes the incidence of EACT was similar in different age groups (0-7 years, 3.3%; 8-15 years 3.2%, P = 0.96). CONCLUSIONS: The overall incidence of EACT at groin exploration was 2.7%, with none detected in girls. There was no evidence of involution of EACT with increasing age. The incidence of EACT varied with the underlying diagnosis, but the reason for this is unknown.     

How to approach major surgery where patients refuse blood transfusion (including Jehovah's Witnesses)

Jehovah's Witnesses do not permit the use of allogeneic blood products. An increasing number of patients are refusing blood transfusion for non-religious reasons. In addition, blood stores are decreasing, and costs are increasing. Transfusion avoidance strategies are, therefore, desirable. Bloodless surgery refers to the co-ordinated peri-operative care of patients aiming to avoid blood transfusion, and improve patient outcomes. These principles are likely to gain popularity, and become standard practice for all patients. This review offers a practical approach to the surgical management of Jehovah's Witnesses, and an introduction to the principles of bloodless surgery that can be applied to the management of all patients.