Tonic stimulation of the pharyngeal mucosa causes pain and a reversible increase of inflammatory mediators.

OBJECTIVE AND DESIGN: To develop a model of the inflammatory component of non-infectious sore throat using tonic stimulation and quantification of inflammatory mediators in pharyngeal lavage fluid. MATERIAL OR SUBJECTS: Forty-five healthy volunteers. TREATMENT: Cold dry air. METHOD: Tonic stimulation of the pharynx was achieved using a constant stream of cold dry air to the back of the throat. Following optimization of stimulation conditions (phase 1), pharyngeal pain, irritation, and swallowing discomfort were assessed using visual analog scales, and the concentration of inflammatory markers were measured in pharyngeal lavage fluid (phase 2). RESULTS: Optimum conditions for tonic pharyngeal stimulation were cold dry air at 12 °C, relative humidity 20 %, at a flow rate of 12 L/min for 15 min. Analysis of pharyngeal lavage fluid collected 5 min after stimulation showed significant increases in prostaglandin E2 (P = 0.018), thromboxane B2 (P < 0.001), and substance P (P < 0.001), but no increase in peptidoleukotriene. When the stimulus was removed, the level of inflammatory markers in pharyngeal lavage fluid returned to baseline by 30 min post-stimulation. These objective measures mirrored subjective pain ratings. CONCLUSIONS: Tonic stimulation of the pharyngeal mucosa with cold dry air causes pain and an increase of inflammatory mediators which are reversible.

A longitudinal systems biology analysis of lactulose withdrawal in hepatic encephalopathy.

The pathogenesis of hepatic encephalopathy(HE) is unclear. However gut flora changes, inflammation and neuro-glial injury have been implicated. The aim was to evaluate factors that were associated with HE recurrence after lactulose withdrawal by analyzing the clinical phenotype, stool microbiome and systemic metabolome longitudinally. HE patients on a standard diet who were adherent on lactulose underwent characterization of their phenotype [cognition, inflammatory cytokines, in-vivo brain MR spectroscopy(MRS)], gut microbiome (stool Multitag Pyrosequencing) and metabolome (urine/serum ex-vivo MRS) analysis while on lactulose and on days 2, 14 and 30 post-withdrawal. Patients whose HE recurred post-withdrawal were compared to those without recurrence. We included seven men (53 ± 8 years) who were adherent on lactulose after a precipitated HE episode were included. HE recurred in three men 32 ± 6 days post-withdrawal. In-vivo brain MRS showed increased glutamine+glutamate (Glx) and decreased myoinositol with a reduction in stool Faecalibacterium spp., post-withdrawal. HE recurrence was predicted by poor baseline inhibitory control and block design performance and was associated with a shift of choline metabolism from tri-methylamine oxide formation towards the development of di-methylglycine, glycine and creatinine. This was accompanied by a mixed effect on the immune response (suppressed IL-10 and Th1/Th2/Th17 response). The correlation network showed Prevotella to be linked to improved cognition and decreased inflammation in patients without HE recurrence. We conclude that lactulose withdrawal results in worsening cognition, mixed inflammatory response effect, lowered stool Faecalibacterium and increase in MR-measurable brain Glx. HE recurrence post-lactulose withdrawal can be predicted by baseline cognitive performance and is accompanied by disrupted choline metabolism.

Pilot multimodal twin imaging study of generalized anxiety disorder.

BACKGROUND: Generalized anxiety disorder (GAD) is a common chronic condition that is relatively understudied compared to other psychiatric syndromes. Neuroimaging studies have begun to implicate particular neural structures and circuitry in its pathophysiology; however, no genetically informative research has examined the potential sources of reported brain differences. METHODS: We acquired spectroscopic, volumetric, and diffusion tensor magnetic resonance imaging data from a pilot study of 34 female subjects selected from monozygotic twin pairs based upon their affection status for GAD, and examined brain regions previously implicated in fear and anxiety for their relationship with affection status and genetic risk. RESULTS: Lifetime GAD associated with increased creatine levels in the amygdala, smaller left hippocampal volume, and lower fractional anisotropy in the uncinate fasciculus which connects amygdala and frontal cortex. In addition, GAD genetic risk predicted increases in myo-inositol in the amygdala and, possibly, glutamate/glutamine/GABA alterations in the hippocampus. The association of lifetime GAD with smaller hippocampal volume was independent of major depression and might represent a common genetic risk marker for internalizing disorders. CONCLUSIONS: These preliminary data suggest that GAD and its genetic risk factors are likely correlated with volumetric and spectroscopic changes in fear-related limbic structures and their connections with the frontal cortex.

Assessment of mitochondrial impairment and cerebral blood flow in severe brain injured patients.

BACKGROUND: We believe that in traumatic brain injury (TBI), the reduction of N-acetyl aspartate (NAA) occurs in the presence of adequate cerebral blood flow (CBF) which would lend support to the concept of mitochondrial impairment. The objective of this study was to test this hypothesis in severely injured patients (GCS 8 or less) by obtaining simultaneous measures of CBF and NAA. METHODS: Fourteen patients were studied of which six patients presented as diffuse injury at admission CT, while focal lesions were present in eight patients. CBF using stable xenon method was measured at the same time that NAA was measured by magnetic resonance proton spectroscopy (1HMRS) in the MR suite. Additionally, diffusion weighted imaging (DWI) and maps of the apparent diffusion coefficient (ADC) were assessed. FINDINGS: In diffuse injury, NAA/Cr reduction occurred uniformly throughout the brain where the values of CBF in all patients were well above ischemic threshold. In focal injury, we observed ischemic CBF values in the core of the lesions. However, in areas other than the core, CBF was above ischemic levels and NAA/Cr levels were decreased. CONCLUSIONS: Considering the direct link between energy metabolism and NAA synthesis in the mitochondria, this study showed that in the absence of an ischemic insult, reductions in NAA concentration reflects mitochondrial dysfunction.

Impact of continuous low level heatwrap therapy in acute low back pain patients: subjective and objective measurements.

OBJECTIVES: Muscular pain is usually associated with increased muscle tension resulting in a vicious tension-pain-cycle, leading to increased alertness and stress. However, this has not been broadly evaluated using objective methods, for example, looking at neurophysiologic changes. The focus of this study was, therefore, to combine objective [spontaneous electroencephalogram (EEG) as a surrogate of alertness and stress] with subjective parameters (self-assessed pain affected variables) to investigate the effect of continuous low-level heat therapy in low back pain (LBP)-patients. METHODS: This investigation was a randomized, active controlled, parallel-designed study. Thirty patients were randomly assigned to one of 2 groups: the control group, in which patients were provided with oral analgesics (nonsteroidal anti-inflammatory drug) and instructed to use it if needed, and the treatment group, in which patients in addition to oral analgesics as rescue medication were provided with a heatwrap therapy. The objective parameters were assessed by measuring the power of frequency bands in the spontaneous EEG. The subjective parameters (sleep pattern, well-being, pain intensity, etc.) were assessed by a Pain, Sleep, and Stress Questionnaire. RESULTS: In the EEG-recordings, the heatwrap therapy group showed decreased power in Beta-1 and Beta-2 frequency bands compared with the control group, indicating a reduction in arousal. Also, in comparison to the control group, the heatwrap therapy group reported significantly reduced LBP, everyday situations being less stressful, a better night's sleep, and a decreased number of daytime naps. DISCUSSION: In addition to classic psychophysical assessment of pain-related parameters and sleep quality, performance in daily life, we were able to obtain objective measures (EEG) that suggest an acute therapeutic relaxation on the basis of the central nervous system effects accompanying the reported significant pain relief. We believe that this was due to a reduced nociceptive information load in LBP-patients after the use of the heatwrap therapy.

In vitro and in vivo imaging studies of a new endohedral metallofullerene nanoparticle.

PURPOSE: To evaluate the effectiveness of a functionalized trimetallic nitride endohedral metallofullerene nanoparticle as a magnetic resonance (MR) imaging proton relaxation agent and to follow its distribution for in vitro agarose gel infusions and in vivo infusions in rat brain. MATERIALS AND METHODS: The animal study was approved by the animal care and use committee. Gd(3)N@C(80) was functionalized with poly(ethylene glycol) units, and the carbon cage was hydroxylated to provide improved water solubility and biodistribution. Relaxation rate measurements (R1 = 1/T1 and R2 = 1/T2) of water solutions of this contrast agent were conducted at 0.35-, 2.4-, and 9.4-T MR imaging. Images of contrast agent distributions were produced following infusions in six agarose gel samples at 2.4 T and from direct brain infusions into normal and tumor-bearing rat brain at 2.4 T. The relaxivity of a control functionalized lutetium agent, Lu(3)N@C(80), was also determined. RESULTS: Water hydrogen MR imaging relaxivity (r1) for this metallofullerene nanoparticle was markedly higher than that for commercial agents (eg, gadodiamide); r1 values of 102, 143, and 32 L . mmol(-1) . sec(-1) were measured at 0.35, 2.4, and 9.4 T, respectively. In studies of in vitro agarose gel infusion, the use of functionalized Gd(3)N@C(80) at concentrations an order of magnitude lower resulted in equivalent visualization in comparison with commercial agents. Comparable contrast enhancement was obtained with direct infusions of 0.013 mmol/L of Gd(3)N@C(80) and 0.50 mmol/L of gadodiamide in live normal rat brain. Elapsed-time studies demonstrated lower diffusion rates for Gd(3)N@C(80) relative to gadodiamide in live normal rat brain tissue. Functionalized metallofullerenes directly infused into a tumor-bearing brain provided an improved tumor delineation in comparison with the intravenously injected conventional Gd(3+) chelate. A control lutetium functionalized Lu(3)N@C(80) nanoparticle exhibited very low MR imaging relaxivity. CONCLUSION: The new functionalized trimetallic nitride endohedral metallofullerene species Gd(3)N@C(80)[DiPEG5000(OH)(x)] is an effective proton relaxation agent, as demonstrated with in vitro relaxivity and MR imaging studies, in infusion experiments with agarose gel and in vivo rat brain studies simulating clinical conditions of direct intraparenchymal drug delivery for the treatment of brain tumors.