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.     

Paroxysmal nocturnal haemoglobinuria phenotype cells and leucocyte subset telomere length in childhood acquired aplastic anaemia

The significance of paroxysmal nocturnal haemoglobinuria (PNH^pos) cells and leucocyte subset telomere lengths in paediatric aplastic anaemia (AA) is unknown. Among 22 children receiving immunosuppressive therapy (IST) for AA, 73% (16/22) were PNH^pos, of whom 94% achieved at least a partial response (PR) to IST; 11/16 (69%) achieved complete response (CR). Only 2/6 (33%) PNH^neg patients achieved PR. PNH^pos patients were less likely to fail IST compared to PNH^neg patients (odds ratio 0·033; 95% confidence interval 0·002–0·468; P = 0·012). Children with AA had short granulocyte (P = 7·8 × 10^?9), natural killer cell (P = 6·0 × 10^?4), naïve T lymphocyte (P = 0·002) and B lymphocyte (P = 0·005) telomeres compared to age‐matched normative data.     

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.     

Missed signs of autonomic dysreflexia in a tetraplegic patient after incorrect placement of urethral Foley catheter: a case report

Background

Autonomic dysreflexia is poorly recognised outside of spinal cord injury centres, and may result in adverse outcomes including mortality from delayed diagnosis and treatment. We present a spinal cord injury patient, who developed autonomic dysreflexia following incorrect placement of urethral Foley catheter. Health professionals failed to recognise signs and symptoms of autonomic dysreflexia as well as its significance in this tetraplegic patient.

Case presentation

A tetraplegic patient started sweating profusely following insertion of a Foley catheter per urethra. The catheter was draining urine; there was no bypassing, no bleeding per urethra, and no haematuria. Patient’s wife, who had been looking after her tetraplegic husband for more than forty years, told the health professionals that the catheter might have been placed incorrectly but her concerns were ignored. Ultrasound scan of urinary tract revealed no urinary calculi, no hydronephrosis. The balloon of Foley catheter was not seen in urinary bladder but this finding was not recognised by radiologist and spinal cord physician. Patient continued to sweat profusely; therefore, CT of pelvis was performed, but there was a delay of ten days. CT revealed the balloon of Foley catheter in the over-stretched prostate-membranous urethra; the tip of catheter was not located within the urinary bladder but was lying distal to bladder neck. Flexible cystoscopy was performed and Foley catheter was inserted into the bladder over a guide wire. The intensity of sweating decreased; noxious stimuli arising from traumatised urethra might take a long while to settle.

Conclusion

Inserting a catheter in a tetraplegic patient should be carried out by a senior health professional, who is familiar with spasm of bladder neck which occurs frequently in tetraplegic patients. Facilities for urgent CT scan should be available to check the position of Foley catheter in spinal cord injury patients when a patient manifests signs and symptoms of autonomic dysreflexia following insertion of a urethral catheter. When an isolated symptom such as flushing or sweating is noticed in a tetraplegic patient, doctors should seek out other signs/symptoms of autonomic dysreflexia.

     

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.     

Post-thaw aging affects activity of lactate dehydrogenase

Freeze-thawing is routinely used to study freezing-induced irreversible protein denaturation in the formulation characterization and development of lyophilized proteins. In most cases, the temperature profiles of the samples are not fully monitored during freeze-thawing and therefore, the sample thermal histories are largely unknown. The objective of this study was to develop experimental protocols for the study of isothermal protein degradation using a temperature-step apparatus. Freeze-thaw experiments were performed at a freezing rate of 10 degrees C/min and various thawing rates (0.5-3.3 degrees C/min) using a temperature-step apparatus. In our efforts to design validation studies, we encountered anomalies in the recovered enzyme activity data of an enzyme, lactate dehydrogenase at the end of freeze-thawing. The effect of thawing rate was studied to explain the variability in the data. In addition, post-thaw "aging" of freshly frozen and thawed samples was performed at 5 degrees C to reduce the variability in the recovered enzyme activity. Results from these experiments implicate the use of aging of dilute multimeric enzymes at the end of freeze-thawing to control the variability in enzyme assays.