Effectiveness of Thalamic Ventralis Oralis Anterior and Posterior Nuclei Deep Brain Stimulation for Posttraumatic Dystonia.

Herein we report that the ventralis oralis anterior and posterior (Voa/Vop) nuclei of the thalamus may be effective alternative targets for deep brain stimulation (DBS) to improve posttraumatic dystonia when the globus pallidus interna is traumatically damaged. This patient presented at age 35 years with a clinical diagnosis of posttraumatic cervical and bilateral upper limb acquired dystonia resulting from intracerebral and intraventricular hemorrhage after a motorcycle accident at age 19 years. Due to a right globus pallidus interna traumatic lesion, conventional DBS targeting of the inferior basal ganglia was not possible; thus, the alternative Voa/Vop nuclei target was implanted. The patient realized significant benefit and at last follow-up 3 years postoperatively continued to endorse marked benefit and improvement of dystonia symptoms with minimal adverse effects from bilateral DBS implantation in the alternative targets of the Voa/Vop nuclei of the thalamus.

The development of ultra-high field MRI guidance technology for neuronavigation.

OBJECTIVE: Magnetic resonance imaging at 7T offers improved image spatial and contrast resolution for visualization of small brain nuclei targeted in neuromodulation. However, greater image geometric distortion and a lack of compatible instrumentation preclude implementation. In this report, the authors detail the development of a stereotactic image localizer and accompanying imaging sequences designed to mitigate geometric distortion, enabling accurate image registration and surgical planning of basal ganglia nuclei. METHODS: Magnetization-prepared rapid acquisition with gradient echo (MPRAGE), fast gray matter acquisition T1 inversion recovery (FGATIR), T2-weighted, and T2*-weighted sequences were optimized for 7T in 9 human subjects to visualize basal ganglia nuclei, minimize image distortion, and maximize target contrast-to-noise and signal-to-noise ratios. Extracranial spatial distortions were mapped to develop a skull-contoured image localizer embedded with spherical silicone fiducials for improved MR image registration and target guidance. Surgical plan accuracy testing was initially performed in a custom-developed MRI phantom (n = 5 phantom studies) and finally in a human trial. RESULTS: MPRAGE and T2*-weighted sequences had the best measures among global measures of image quality (3.8/4, p < 0.0001; and 3.7/4, p = 0.0002, respectively). Among basal ganglia nuclei, FGATIR outperformed MPRAGE for globus pallidus externus (GPe) visualization (2.67/4 vs 1.78/4, p = 0.008), and FGATIR, T2-weighted imaging, and T2*-weighted imaging outperformed MPRAGE for substantia nigra visualization (1.44/4 vs 2.56/4, p = 0.04; vs 2.56/4, p = 0.04; vs 2.67/4, p = 0.003). Extracranial distortion was lower in the head's midregion compared with the base and apex ( 1.17-1.33 mm; MPRAGE and FGATIR, p < 0.0001; T2-weighted imaging, p > 0.05; and T2*-weighted imaging, p = 0.013). Fiducial placement on the localizer in low distortion areas improved image registration (fiducial registration error, 0.79-1.19 mm; p < 0.0001) and targeting accuracy (target registration error, 0.60-1.09 mm; p = 0.04). Custom surgical software and the refined image localizer enabled successful surgical planning in a human trial (fiducial registration error = 1.0 mm). CONCLUSIONS: A skull-contoured image localizer that accounts for image distortion is necessary to enable high-accuracy 7T imaging-guided targeting for surgical neuromodulation. These results may enable improved clinical efficacy for the treatment of neurological disease.

MELD-Na > 16 is associated with high peri-procedural and short-term mortality in patients with ruptured hepatocellular carcinoma treated with emergent transarterial embolization.

PURPOSE: To evaluate prognostic factors associated with peri-procedural (30 days) and short-term (90 days) mortality in the United States cohort of patients following emergent transarterial embolization for ruptured hepatocellular carcinoma. METHODS: Patients with ruptured hepatocellular carcinoma treated with emergent TAE between January 2001 and December 2019 were retrospectively identified (n = 24). Average age was 62 years (range, 23-78 year); 15 (62.5%) were men. Univariate and Cox proportional hazard modeling were used to determine independent predictors of overall survival (OS) following TAE. OS stratified by Model for End-Stage Liver Disease-Sodium score was assessed using Kaplan-Meier analysis. RESULTS: Twenty-one patients (88%) died during a mean clinical follow-up period of 328 ± 139 days. MELD-Na score (HR 1.22 per 1-unit increase; 95% CI 1.06-1.46; p = 0.005) and pre-rupture ECOG PS score (HR 8.1; 95% CI 1.28-51.2; p = 0.026) were independent predictors of decreased overall survival. There was no significant association between overall survival and presence of cardiovascular co-morbidities (p = 0.60), hemorrhagic shock on presentation (p = 0.16), portal vein thrombus (p = 0.08), vasopressor support required (p = 0.79), intubation required (p = 0.40), acute kidney injury (p = 0.58), and number of packed red blood cell transfusions (p = 0.22). The median OS was 64 days. Median OS was significantly greater in patients with a MELD-Na score ≤ 16 as compared to those with a MELD-Na score > 16 (166.5 days vs 9 days, p = 0.011). Cumulative OS rates in those with a MELD-Na score ≤ 16 at 30, 60, 90, and 360 days were 79%, 64%, 64%, and 25%, respectively, vs 33%, 33%, 11%, and 0%, respectively, in those with a MELD-Na score > 16. CONCLUSION: MELD-Na > 16 is associated with very high peri-procedural (67% at 30 days) and short-term (89% at 90 days) mortality in patients with ruptured HCC treated with emergent transarterial embolization. A better understanding of these prognostic factors may help guide treatment decisions and provide realistic expectations when counseling patients and their families.

Hypoxia-Associated Changes in Striatal Tonic Dopamine Release: Real-Time in vivo Measurements With a Novel Voltammetry Technique.

INTRODUCTION: Striatal tonic dopamine increases rapidly during global cerebral hypoxia. This phenomenon has previously been studied using microdialysis techniques which have relatively poor spatio-temporal resolution. In this study, we measured changes in tonic dopamine during hypoxia (death) in real time with high spatio-temporal resolution using novel multiple cyclic square wave voltammetry (MCSWV) and conventional fast scan cyclic voltammetry (FSCV) techniques. METHODS: MCSWV and FSCV were used to measure dopamine release at baseline and during hypoxia induced by euthanasia, with and without prior alpha-methyl-p-tyrosine (AMPT) treatment, in urethane anesthetized male Sprague-Dawley rats. RESULTS: Baseline tonic dopamine levels were found to be 274.1 ± 49.4 nM (n = 5; mean ± SEM). Following intracardiac urethane injection, the tonic levels increased to a peak concentration of 1753.8 ± 95.7 nM within 3.6 ± 0.6 min (n = 5), followed by a decline to 50.7 ± 21.5 nM (n = 4) at 20 min. AMPT pre-treatment significantly reduced this dopamine peak to 677.9 ± 185.7 nM (n = 3). FSCV showed a significantly higher (p = 0.0079) peak dopamine release of 6430.4 ± 1805.7 nM (n = 5) during euthanasia-induced cerebral hypoxia. CONCLUSION: MCSWV is a novel tool to study rapid changes in tonic dopamine release in vivo during hypoxia. We found a 6-fold increase in peak dopamine levels during hypoxia which was attenuated with AMPT pre-treatment. These changes are much lower compared to those found with microdialysis. This could be due to improved estimation of baseline tonic dopamine with MCSWV. Higher dopamine response measured with FSCV could be due to an increased oxidation current from electroactive interferents.

Bombesin prevents the atrophy of Peyer's patches and the dysfunction of M cells in rabbits receiving long-term parenteral nutrition.

BACKGROUND: Long-term parenteral nutrition (PN) induces atrophy of the gut-associated lymphoid tissue (GALT). We examined whether bombesin could ameliorate this atrophy of Peyer's patches and the down-regulation of particle transport by M cells, which was also observed in rabbits undergoing PN. METHODS: Adult female rabbits were randomized into 6 groups to receive chow ad libitum, chow + bombesin, PN, or PN + bombesin (20 microg/kg, subcutaneously every 8 hours) for 2 or 4 weeks. At the end of each nutrition period, a laparotomy was performed under anesthesia and a suspension of 1 x 10(10)/mL of 0.5-microm fluorescent microspheres was injected into the lumen of intestinal segments containing Peyer's patches and incubated for 2 hours. After the incubation, segments were harvested and prepared for light microscopy, immunohistochemistry, fluorescent microscopy, and electron microscopy. RESULTS: Long-term PN reduced the size of ileal Peyer's patches, the number of microspheres that was taken up into the follicle-associated epithelium of lymphoid nodules, and the area of Peyer's patch surface occupied by M cells. The number of intraepithelial lymphocytes within the follicle-associated epithelium near the perifollicular crypts of Peyer's patches was also reduced by long-term PN. These consequences were dramatically ameliorated by treatment with bombesin. No ultrastructural alteration of the M cells of Peyer's patches was found in the chow, the PN, or the PN + bombesin groups. CONCLUSIONS: Bombesin prevents PN-induced atrophy of GALT, reduction of M cell numbers, and decrease in particulate transport by M cells during long-term PN. Bombesin may modulate the genesis of and particulate transport by M cells through stimulation of lymphoid cells in Peyer's patch epithelium near perifollicular crypts, where M cells and other constituents of lymphoid follicle epithelium are generated, thereby preserving mucosal immunity.

Ocular defense mechanisms with special reference to the demonstration and functional morphology of the conjunctiva-associated lymphoid tissue in Japanese monkeys.

In order to define the histological components of ocular defense, the conjunctiva in Japanese monkeys was studied using a whole mount method, light microscopy, and electron microscopy. We investigated the distribution of the conjunctiva-associated lymphoid tissue (CALT) using stereoscopic observations of the conjunctiva immunostained with human leukocyte antigen (HLA)-DR antibody and /or stained with alcian-blue. The outer surface of the conjunctival fornix was lined by sheets of mucus secreting goblet cells, with small epithelial patches without goblet cells, scattered among them. The patches, termed CALT, consisted of flattened epithelial cells, intraepithelial lymphocytes and dendritic cells, and lymphoid follicles with a germinal center. The CALT in Japanese monkeys was fundamentally similar in structure to those found in other animal species. CALT patches ranged in size ranging from 200 microm to 300 microm in diameter. The number of patches varied from 20 to 40 in the superior eyelid and 10 to 20 in the inferior eyelid. Latex microspheres administrated as eye drops were selectively taken up first by flattened associated epithelial cells covering the surfaces of CALT patches and then by intraepithelial dendritic cells of the CALT. These morphological findings show that CALT patches in the eyelids of primates are focal sites for particulate uptake and contact with lymphoid constituents, indicating that they are inductive sites for the common mucosal immune system as well as important components in ocular defense.

Basis for the age-related decline in intestinal mucosal immunity.

The elderly are characterized by mucosal immunosenescence and high rates of morbidity and mortality associated with infectious diseases of the intestinal tract. Little is known about how the differentiation of immunoglobulin A (IgA) plasma cells in Peyer's patches (PPs) and their subsequent homing to the small intestinal lamina propria (LP) is affected by aging. Quantitative immunohistochemical analyses demonstrated a 2-fold increase in the number of IgA+ cells in the PPs, coupled with significant declines in the numbers of IgA+ and antibody-positive cells in the intestinal LP of senescent rats compared to young adult animals. These data suggest that aging diminishes the emigration of IgA immunoblasts from these lymphoid aggregates, as well as their migration to the intestinal LP. Flow cytometry and lymphocyte adoptive transfer studies showed 3- to 4-fold age-related declines in the homing of antibody-containing cells and mesenteric lymph node lymphocytes to the small intestines of rhesus macaques and rats, respectively. The number of peripheral blood IgA immunoblasts expressing the homing molecule alpha4beta7 declined 30% in senescent rats. This was accompanied by a > 17% decrease in the areal density of LP blood vessels staining positive for the cell adhesion molecule MAdCAM-1. Cumulatively, declines in expression of these homing molecules constitute a substantial age-related diminution of IgA immunoblast homing potential. In vitro antibody secretion by LP plasma cells, i.e. antibody secreted per antibody-positive cell, remains unchanged as a function of donor age. Intestinal mucosal immunosenescence is a consequence of reduced homing of IgA plasma cells to the intestinal LP as a result of declines in homing molecule expression.

Tacrolimus (FK506) and cyclosporine reduce the uptake and transport of particles into rabbit Peyer's patches.

Tacrolimus (FK) and cyclosporine (Cs) are potent immunosuppressants that effectively prevent the rejection of transplanted organs including liver and small intestine. Our study examined the effects of these immunosuppressants on Peyer's patches, which play an important role in mucosal immune response through uptake and transport of enteric microorganisms and macromolecules in the gut-associated lymphoid tissues. After administration of FK and Cs, we assessed changes in lymphoid follicle structure and quantified the uptake and transport of particles in the follicle associated epithelium (FAE) including M cells, using fluorescent latex microspheres in rabbit Peyer's patches. Rabbits, five in each group, received oral administration of FK (3.2 mg/kg), Cs (10 mg/kg), or phosphate-buffered saline daily for 7 days. After 2 days of withdrawal, rabbits were anesthetized, and received injections with 2 ml of the suspension of 0.5-microm fluorescent microspheres (1010/ml) into ligated intestinal segments containing Peyer's patches. After 2 hr of gentle agitation, segments were removed, rinsed, fixed with periodate-lysine-2% paraformaldehyde, frozen, and sections were stained with fluorescent phalloidin to label brush border actin filaments. The size of the lymphoid follicles in each group was measured under a light microscope. The number of microspheres in follicles was assessed in graphically defined areas of follicles from each group. In addition, immunohistochemical analysis of CD43 and MHC-II positive cells in FAE of lymphoid follicles of each group was performed. FK and Cs significantly reduced the height of lymphoid domes and the height and width of follicles, as compared to those of controls. In both FK and Cs groups, the numbers of microspheres that adhered, were taken up and were transported into lymphoid follicles were smaller than in controls, indicating that their movement rates into deep layers were markedly reduced. Furthermore, FK and Cs reduced the mean numbers of CD43 and MHC-II positive cells in FAE per unit area (mm2) as compared with controls. These findings suggest that FK and Cs may produce immunosuppressive effects, at least in part, through reduction of the uptake and transport of particles into Peyer's patches, and by reduction of the number of immunoreactive cells in FAE of Peyer's patches.