Reduction In Tissue Loss Research Articles

Effectiveness of a Glyceryl Trinitrate (GTN) Patch in Preventing Amputation, Improving Pain Control and Reducing the Size of Tissue Loss for a Patient With Critical Limb-Threatening Ischaemia (CLTI).

Background Foot ulcer is a common complication of poorly controlled diabetes and peripheral vascular disease (PVD). The current standard of treatment for diabetic foot ulcers includes the management of underlying risk factors, wound debridement, use of antibiotics for infection, off-loading with cast, and revascularisation surgery. The glyceryl trinitrate (GTN) patch is currently off-licence in treating PVD or diabetic foot ulcers. This study aims to evaluate the effectiveness of the GTN patch in preventing amputation, improving pain control, and reducing the size of tissue loss (ulcer/gangrene) or localised ischaemic area. Method This is a pilot study of 30 patients who were started on the GTN patchfrom February 2020 to October 2021. Inclusion criteria were patients who have critical limb-threatening ischaemia (CLTI) and with no viable options or are at high risk for revascularisation, both endovascular and open surgery. Patients who were on a GTN patch for less than six weeks at the time of data collection or had unclear outcomes were excluded. The outcomes were retrospectively collected on prevention of amputation, improvement in pain control, and reduction in tissue loss (the size of ulcer/gangrene) or localised ischaemic area with the use of a GTN patch. The binomial test was used to compare the observed outcome of the GTN patch and the expected outcome, which was assumed to be 50% in this study. Results Ninety-three per cent (93%) of the patients who had GTN patches successfully avoided amputation (p<0.0001). Eighty-four per cent (84%) of patients reported better pain control (p=0.0022) and improvement in the size of ulcer/gangrene/localised ischaemic areas (p=0.0005). Conclusion The GTN patch is effective in preventing amputation, improving pain control, and reducing the size of ulcer/gangrene/localised ischaemic areas in patients who have end-stage CLTI and no viable options or who are at high risk for revascularisation surgery.

Abstract W P108: Pharmacological Evaluation of a BDNF Nano-Particle Formulation after Experimental Stroke

Backgrounds: Brain Derived Neurotrophic factor (BDNF) is a well-recognized neuro-protective and neuro-restorative protein of the neurotrophin family. Unfortunately, systemically administered native BDNF has minimal therapeutic effects due to poor blood brain barrier permeability and short half-life. Therefore, the aim of this study was to utilize a novel nano-particle formulation of BDNF for enhanced delivery to the brain in mice after middle cerebral artery occlusion (MCAO). Methods: Male C57BL/6J (8-10 weeks) mice were randomly assigned to saline or BDNF nano (Exp group 1, n=6/group) or saline vs. BDNF native vs. BDNF nano (Exp group 2, n=8/group) and subjected to 60min of MCAO. The mice in Exp. group 1 were treated twice with either saline or BDNF Nanoparticles (250μg/kg i.v) 3 and 24 hrs after the onset of MCAO. Exp group2 was also treated twice with saline vs. BDNF native vs. BDNF nano (250μg/kg i.v) but treatment was delayed until 12 hrs after MCAO with a second dose at 24 hrs. Mice were tested weekly on several behavioral tests and were sacrificed on day 15 and brains used for histological analysis. Results: Treatment with BDNF nanoparticles 3 hours after MCAo (Exp group 1) led to a significant (p&lt;0.0062) reduction in tissue loss (42.33±2.24 vs 31.02± 4.02) and earlier behavioral recovery. When we delayed treatment to 12 hrs after MCAO, neither native nor BDNF nanoparticles reduced tissue loss compared to saline. Neurological deficit scores were similar between groups. However, treatment with BDNF nanoparticles led to early improvements in memory/cognitive performance (Day 7) in the Novel Object Recognition Test (NORT) and reduced immobility (p&lt; 0.05, 155.2± 18.56 Saline vs 162.8± 15.55 BDNF native vs.117.0±25.44 in BDNF nano) in the tail suspension test suggestive of a reduced depressive phenotype in BDNF nano treated mice. Conclusions: This study reveals that BDNF nanoparticle formulation is neuroprotective when given within three hours of stroke, and enhances neuronal repair and behavioral recovery beyond that seen with native BDNF even in the absence of decreased infarct size when treatment is delayed.

Efficacy of Fluoride Compounds and Stannous Chloride as Erosion Inhibitors in Dentine

The aim of this study was to evaluate the anti-erosive effects of different fluoride compounds and one tin compound in the context of the complex pathohistology of dentine erosion, with particular emphasis on the role of the organic portion. Samples were subjected to two experiments including erosive acid attacks (0.05 molar citric acid, pH 2.3; 6 × 2 min/day) and applications (6 × 2 min/day) of the following test solutions: SnCl₂ (815 ppm Sn), NaF (250 ppm F), SnF₂ (250 ppm F, 809 ppm Sn), amine fluoride (AmF, 250 ppm F), AmF/NaF (250 ppm F), and AmF/SnF₂ (250 ppm F, 409 ppm Sn). The demineralised organic fraction was enzymatically removed either at the end of the experiment (experiment 1) or continuously throughout the experiment (experiment 2). Tissue loss was determined profilometrically after 10 experimental days. In experiment 1, the highest erosive tissue loss was found in the control group (erosion only); the AmF- and NaF-containing solutions reduced tissue loss by about 60%, reductions for SnCl₂, AmF/SnF₂, and SnF₂ were 52, 74 and 89%, respectively. In experiment 2, loss values generally were significantly higher, and the differences between the test solutions were much more distinct. Reduction of tissue loss was between 12 and 34% for the AmF- and NaF-containing preparations, and 11, 67 and 78% for SnCl₂, AmF/SnF₂, and SnF₂, respectively. Stannous fluoride-containing solutions revealed promising anti-erosive effects in dentine. The strikingly different outcomes in the two experiments suggest reconsidering current methodologies for investigating anti-erosive strategies in dentine.

Hypertonic saline attenuates tissue loss and astrocyte hypertrophy in a model of traumatic brain injury

Hypertonic saline is currently being used in the treatment of patients with post-traumatic cerebral edema and elevated intracranial pressure resulting from TBI. A limited number of studies show the cellular effects of hypertonic saline and no studies, to our knowledge, have investigated the effects on astrocytes. The role of astrocyte responses after traumatic brain injury remains unclear. There is evidence that reduced astrocyte proliferation is detrimental while increased hypertrophy and proliferation are signs of increased injury severity. Therefore, this study focused on the hypothesis that hypertonic saline-induced improvements in histological outcome are time dependent and may be associated with alterations in astrocyte hypertrophy after cortical contusion injury. Histopathological changes at 7 days after controlled cortical impact (CCI) injury were examined. Brain tissue loss determined using cresyl violet staining and astrocyte hypertrophy and proliferation were assessed using glial fibrillary acidic protein immunostaining in hypertonic saline and normal saline treated rats, and untreated, injured controls. Effects of the timing of hypertonic saline treatment administration on tissue loss were also examined. Plasma osmolarity and sodium levels were measured over 4 h and again at 24 h following hypertonic saline administration. Results show that hypertonic saline treatment reduced tissue loss that correlated with attenuated astrocyte hypertrophy characterized by reductions in astrocyte immunoreactivity without changes in the number of astrocytes after CCI injury. Delayed treatment of hypertonic saline resulted in the greatest reduction in tissue loss compared to all other treatments indicating that there is a therapeutic window for hypertonic saline use after traumatic brain injury.

Effect of stannous and fluoride concentration in a mouth rinse on erosive tissue loss in enamel in vitro

The aim of this in vitro study was to investigate the influence of stannous and fluoride ion concentrations in various experimental solutions on erosion progression in enamel. Human enamel specimens were subjected to a cyclic de- and remineralisation procedure for 10 days, with six demineralisation periods per day, of 5 min each. Erosive demineralisation was performed with 0.05 M citric acid (pH 2.3). Except in the control group, specimens were treated for 2 min with test solutions after the first and the sixth demineralisation. Test solutions were: 1500 mg/L F − groups: group 1: 2800 mg/L Sn 2+; group 2: 2100 mg/L Sn 2+; group 3: 1400 mg/L Sn 2+; group 4: 700 mg/L Sn 2+; 1000 mg/L F − groups: group 5: 2100 mg/L Sn 2+; group 6: 1400 mg/L Sn 2+. All preparations were adjusted to pH 4.5. Tissue loss was determined profilometrically after the last experimental day. As expected, the greatest tissue loss (μm, mean ± S.D.) was found in the control group (72.6 ± 11.5). All test solutions were able to reduce tissue loss significantly ( p ≤ 0.001). The reduction of tissue loss by test solutions depended on the ratio of the tin concentration to the fluoride concentration. Lowest values were obtained by the application of the solutions of group 1 (7.8 ± 2.5) and group 5 (7.6 ± 5.2). Solutions with high concentrations of tin and fluoride are very effective in reducing erosive tissue loss, and their efficacy increased with increasing ratios of tin to fluoride concentrations.

Dual Role of Intrauterine Immune Challenge on Neonatal and Adult Brain Vulnerability to Hypoxia-Ischemia

Epidemiologic evidence has underlined the impact of prenatal inflammation on the development of postnatal hypoxia-ischemia (HI) brain injury. To study to what extent prenatal inflammation affects CNS vulnerability later during development, C57BL/6 mice were subjected to intrauterine injection of lipopolysaccharide (LPS) at gestational day 15. At postnatal day (PND) 5, 9, and 70, the offspring were subjected to HI. It was found that, in neonatal mice, LPS-exposed brains showed markedly enhanced brain injury after HI, whereas in adult mice, LPS exposure resulted in a significant reduction in tissue loss after HI. Reduced myelin in subcortical white matter was noticed after HI in the LPS-exposed brains at PND14 and PND75. Increased activities of nuclear factor-kappaB and caspase-3 were obtained in fetal/neonatal brain after LPS administration. Conclusions were that 1) a prenatal low dose of LPS sensitized to HI-induced brain injury in neonates but confers protection in adulthood, 2) reduced myelination is seen after prenatal LPS exposure and HI in both neonatal and adult mice despite the fact that LPS reduced total tissue loss in adult mice; and 3) nuclear factor-kappaB and caspase-3 activation early after LPS exposure may play a role in the sensitization/protection (preconditioning) effects.

Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats.

Critical factors influencing the neuroprotective efficacy of postischemic hypothermia include depth, duration, and time of onset of cooling. In clinical practice, there is an unavoidable lag between the hypoxic-ischemic (HI) insult and the opportunity to initiate cooling. We hypothesized that early administration of a neuroprotective agent in combination with later-onset cooling could represent an effective therapeutic intervention after neonatal HI. We evaluated whether treatment with topiramate, a clinically available anticonvulsant, increased the efficacy of delayed post-HI hypothermia in a neonatal rat stroke model. Postnatal day 7 (P7) rats underwent right carotid artery ligation followed by 1.5 hours of exposure to 8% oxygen. Fifteen minutes post-HI, animals received injections of topiramate (30 mg/kg) or PBS. Cooling was initiated 3 hours later ("delayed hypothermia") in all animals (3 hours, in 27 degrees C incubator). Functional outcome (forepaw response to vibrissae stimulation) and pathology (morphometric lesion measurements) were evaluated at P15 and P35. Neither topiramate nor delayed hypothermia alone conferred protection in this protocol. Combined treatment with topiramate and delayed hypothermia improved both performance and pathological outcome in P15 and P35 rats compared with PBS-treated animals that underwent delayed hypothermia concurrently. At P15, functional measures were better in topiramate-treated animals (mean correct forepaw response 9.3/10 versus 4.8/10; P<0.001), and there was >50% reduction in tissue loss (P<0.001); trends were similar at P35. Our data provide the impetus for further evaluation of therapeutic approaches that combine drug therapy with delayed-onset cooling after neonatal HI brain injury.

Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells.

To better direct repair following spinal cord injury (SCI), we designed an implant modeled after the intact spinal cord consisting of a multicomponent polymer scaffold seeded with neural stem cells. Implantation of the scaffold-neural stem cells unit into an adult rat hemisection model of SCI promoted long-term improvement in function (persistent for 1 year in some animals) relative to a lesion-control group. At 70 days postinjury, animals implanted with scaffold-plus-cells exhibited coordinated, weight-bearing hindlimb stepping. Histology and immunocytochemical analysis suggested that this recovery might be attributable partly to a reduction in tissue loss from secondary injury processes as well as in diminished glial scarring. Tract tracing demonstrated corticospinal tract fibers passing through the injury epicenter to the caudal cord, a phenomenon not present in untreated groups. Together with evidence of enhanced local GAP-43 expression not seen in controls, these findings suggest a possible regeneration component. These results may suggest a new approach to SCI and, more broadly, may serve as a prototype for multidisciplinary strategies against complex neurological problems.

Relative susceptibility of deciduous and permanent dental hard tissues to erosion by a low pH fruit drink in vitro

Objectives: The objectives of this study were two-fold: (1) to determine (by surfometry) loss of deciduous and permanent enamel and dentine following 15 days' exposure to a single low pH orange drink; and (2) to determine (by surfometry) loss of deciduous and permanent enamel and dentine following exposure to the product 2 versus 4 times per day for 15 days. Methods: This in vitro study employed the validated methodology described by West and co-workers [Journal of Dentistry, 1998;26:329–335.] Results: In all four tissues, erosion was progressive over time, though this pattern was more linear in enamel than in dentine. In general, erosion of enamel was greater in the deciduous tissue, while erosion of dentine was greater in the permanent tissue. However, these differences were rarely of statistical significance. Increasing frequency of exposure resulted in a non-proportional increase in tissue loss. Conclusions: Differences in susceptibility of deciduous and permanent tissues to erosion by a low pH drink in vitro appear to exist, though these may not be of statistical significance. Care may be indicated in the delivery of dietary advice, since reduced frequency of exposure to a low pH drink does not appear to result in a proportional reduction in tissue loss.

Long-term effects of methylprednisolone following transection of adult rat spinal cord.

Clinically, high-dose treatment with the glucocorticosteroid, methylprednisolone (MP), within 8 h after spinal cord injury, has been shown to improve neurological recovery. The current standard of care is to administer MP as a bolus of 30 mg/kg followed by a 23-h infusion of 5.4 mg/kg/h to spinal cord injured patients. To better understand the role of MP in neuroprotection, we have studied how MP administration affects macrophage accumulation, tissue loss, and axonal dieback at 1, 2, 4 and 8 weeks after a complete transection of the eighth thoracic spinal cord in the adult rat. A 30 mg/kg dose of MP was administered intravenously at 5 min, and 2 and 4 h after injury. The number of ED1 (antibody against microglia/macrophages) -positive cells was quantified in a 500-micrometer-wide strip of tissue directly adjacent and parallel to the transection. At all time points, MP treatment led to a significant decrease in the number of ED1-positive cells in both rostral and caudal stumps. Over the 2-month post-transection period, the average MP-induced reduction in the number of ED1-positive cells was 82% in the rostral cord stump and 66% in the caudal stump. Using a computerized image analysis system, it was observed that MP treatment resulted in a significant reduction in tissue loss in both cord stumps at 2, 4 and 8 week post-injury. Over the 2-month post-lesion period, the average MP-induced reduction in tissue loss in the caudal cord stump was higher than that in the rostral stump; 48 versus 37%, respectively. Immunostaining for neurofilaments and growth-associated protein-43 (GAP-43) revealed the presence of numerous axons near and in the lesion site. Anterograde neuronal tracing with biotinylated dextran amine showed that, in MP-treated animals, dieback of vestibulospinal fibres, but not of corticospinal fibres, was significantly diminished at all time points studied. In addition, with MP administration, 1 and 2 weeks after injury, an increase in the number of vestibulospinal fibres was found at 1 and 2 mm from the transection, suggesting transient regenerative sprouting of these fibres. The results demonstrate that treatment with MP shortly after spinal cord transection in the adult rat led to a long-term reduction of ED1-positive cells and spinal tissue loss, reduced dieback of vestibulospinal fibres, and a transient sprouting of vestibulospinal fibres near the lesion at 1 and 2 weeks post-lesion. The possible relationships between the inflammatory changes, spinal tissue sparing, and axonal survival and sprouting are complex and need to be further explored.

Dose-dependent reduction of tissue loss and functional impairment after spinal cord trauma with the AMPA/kainate antagonist NBQX

Initial studies on the role of glutamate receptors in traumatic spinal cord injury (SCI) implicated the NMDA subclass of ionotropic glutamate receptors in contributing to functional deficits. Recently we obtained evidence suggesting that non-NMDA ionotropic receptors may participate in producing a portion of the behavioral impairment after SCI. To test this hypothesis we have conducted a dose-response experiment, focally injecting 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX; 1.5, 5, or 15 nmol), a highly selective antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors, or vehicle alone, into the injury site beginning at 15 min after a standardized contusive SCI. Behavioral tests of hindlimb reflex and coordinated sensorimotor function were performed 1 d after injury and weekly thereafter. At 4 weeks, spinal cord tissue was examined using quantitative histopathological and immunocytochemical techniques. We found a dose-dependent reduction in tissue loss at the thoracic injury site, with greater residual amounts of both gray matter and myelinated white matter. The maximum dose (15 nmol) significantly reduced the average length of the lesions and doubled the area of residual white matter at the epicenter. Serotonin immunoreactivity caudal to the lesion, used as a marker for descending motor control axons, was also increased in a dose-related manner and nearly tripled with the highest dose of NBQX as compared to controls. Most importantly, the reduced tissue loss in NBQX-treated groups was correlated with reduced functional deficits. There was a dose-dependent enhancement of speed and degree of recovery of both reflex and coordinated hindlimb motor activity, and reduction in the time required for establishing a reflex bladder. The long-term functional deficits at 4 weeks after SCI were reduced in a dose-related manner. Further, regression analyses demonstrated a significant correlation between the increase in amount of residual tissue and improvement in hindlimb function. Our results suggest that in this type of incomplete contusive SCI, a large and functionally important proportion of the tissue loss appears to be due to secondary injury mediated by local AMPA/kainate receptors.