Total Tissue Loss Research Articles

Poly(ADP-Ribose) Polymerase Inhibitor PJ34 Reduces Brain Damage after Stroke in the Neonatal Mouse Brain.

The poly(ADP-ribose) polymerase inhibitor PJ34 has recently been reported to increase cerebral blood flow, via the endothelial NO synthase, in the naive mouse brain throughout life. We addressed here the benefits of PJ34 after neonatal ischemia on hemodynamics and components of the neurovascular unit including the blood-brain barrier (BBB), microglia, and astrocytes. Nine-day-old mice were subjected to permanent MCA occlusion (pMCAo), and treated with either PBS or PJ34 (10 mg/kg). Mean blood-flow velocities (mBFV) were measured in both internal carotid arteries (ICA) and basilar trunk (BT) using Doppler-ultrasonography. BBB opening was assessed through somatostatin-receptor type-2 internalization and immunohistochemistry at 24 and 48 h. Lesion areas were measured 8 days after ischemia. In PBS-treated mice, pMCAo involved a drop in mBFV in the left ICA (p < 0.001 vs. basal), whereas mBFV remained stable in both right ICA and BT. PJ34 prevented this drop in the left ICA (NS vs. basal) and increased mBFV in the right ICA (p = 0.0038 vs. basal). No modification was observed in the BT. In contrast to PBS, BBB disruption extent and astrocyte demise were reduced in PJ34 mice only in the rostral brain at 48 h and 8 days post-pMCAo, respectively. Accordingly, 8 days after pMCAo, affected areas were reduced in the rostral brain (Bregma +0.86 and +0.14 mm), whereas total tissue loss was not reduced after PJ34 (4.0 ± 3.1%) vs. PBS (5.8 ± 3.4%). These results show that PJ34 reduced BBB permeability, astrocyte demise, and tissue loss (particularly in the rostral territories), suggesting that collateral supply mainly proceeds from the anterior ICA’s branches in the ischemic neonatal mouse brain.

Impacts of parrotfish predation on a major reef-building coral: quantifying healing rates and thresholds of coral recovery

Parrotfishes are important Caribbean herbivores that are believed to indirectly benefit corals by grazing algae; yet, some species also feed on live coral, which may have direct negative impacts on coral growth and survivorship. Caribbean parrotfishes prey upon multiple coral species but have particularly high rates of predation on Orbicella annularis, a major framework building coral and an endangered species. While some researchers have suggested that parrotfishes may have significant long-term impacts on heavily targeted species such as O. annularis, the patterns of coral recovery from parrotfish predation scars remain poorly understood. To address this knowledge gap, we tracked the fate of parrotfish bite scars on O. annularis colonies across two Caribbean islands for up to 2 months. We evaluated differences in coral healing between islands in response to a number of variables including the initial scar surface area, scar abundance per coral colony, colony surface area, and water depth. We used these data to develop a predictive model of O. annularis tissue loss from recent parrotfish bite scars. We then applied this model to surveys of the distribution of bite scars at a point in time to estimate long-term tissue loss of O. annularis colonies from a standing stock of bite scars. Our findings suggest that the initial scar surface area is one of the most important predictors of coral tissue loss. The data also indicate that there are thresholds in patterns of coral tissue regeneration: we observed that small scars (≤ 1.25 cm2) often fully heal, while larger scars (≥ 8.2 cm2) had minimal tissue regeneration. The vast majority of observed scars (~ 87%) were 1.25 cm2 or less, and our model predicted that O. annularis colonies would regenerate nearly all the corresponding scar area. In contrast, while scars greater than or equal to 8.2 cm2 were infrequent (~ 6% of all observed scars), our model predicted that these larger scars would account for over 96% of the total tissue loss for grazed colonies. Overall, our results suggest that the immediate negative impacts of parrotfish predation on coral tissue loss appear to be driven primarily by a few exceptionally large bite scars. While further work is needed to understand the long-term impacts of corallivory and quantify the net impacts of parrotfish herbivory and corallivory on Caribbean coral reefs, this study is an important step in addressing factors that impact the recovery of a heavily targeted and ecologically important Caribbean coral from parrotfish predation.

Early Mobilization in Lower Extremity Frostbite Injury: Preliminary Experience at a Single Burn Center.

Cold exposure that leads to frostbite puts patients at high risk for extremity amputations. Recent treatment advances, such as thrombolytic administration, have decreased amputation rates. However, little is known about patient outcomes with early mobilization of affected limbs. A retrospective review of 41 patients admitted for lower extremity frostbite was performed at an urban hospital burn unit. All patients received the institution's standard frostbite treatment protocol. The study group was allowed to bear weight within 72 hours, while the control group was immobilized beyond this time frame. No significant differences were found between groups when comparing total tissue loss, complications, or hospital length of stay. Previous treatment of frostbite at our institution involved strict avoidance of weight bearing to the affected extremity due to concern for repeat trauma and associated complications. Our findings show that patients who ambulated sooner had comparable outcomes to those immobilized for longer time periods. Larger studies would be useful to determine a standard time to mobilization in frostbite treatment protocols.

Injuries caused by fragmenting rifle ammunition

IntroductionAlthough penetrating injuries are encountered on a regular basis in high volume trauma centres, most civilian trauma teams will be unfamiliar with the treatment of patients with injuries caused by fragmenting ammunition. The terrorist attacks in Norway on July 22, 2011 included a shooting spree causing 69 deaths and 60 injured. One of the weapons used was a semi-automatic rifle, calibre 5.56mm, with soft tip, short stop ammunition. The aim of the present study was to describe the characteristic injury patterns and lessons learned from the treatment of multiple patients admitted at the regional trauma centre with injuries from this type of ammunition. MethodsWe undertook an observational study of patients admitted at Oslo University Hospital, Ulleval after the shooting spree at Utoya on July 22, 2011. Data on demographics, injuries, injury severity, surgical procedures and outcome were collected prospectively. ResultsOf the 21 patients admitted after the shooting incident, 18 were identified with injuries caused by fragmenting ammunition and included in the study. Median age was 17 years (IQR 16, 19), median ISS 21 (IQR 12, 30) and 12 patients were female. They had been hit by a total of 38 projectiles, of which 32 were fragmenting bullets. Of the seven patients who sustained injuries to the head, neck and face, one patient required a craniotomy and one patient had a non-survivable head injury. Of the 11 patients with torso injuries, six of the eight patients with chest injuries had intra-thoracic injuries that could be treated with chest tubes only. One patient had cardiac tamponade, requiring thoracotomy. Six patients underwent laparotomy, four of them more than one. Of the 10 patients with extremity injuries, two had nerve injuries and six patients had fractures. Five amputations were performed within the first nine days.A total of 101 operations were required within the first four weeks. The majority of these were repeated soft tissue debridements due to progressive necrosis. ConclusionKnowledge about the specific challenges created by the progressive soft tissue necrosis caused by fragmenting ammunition should lead to planned, repeated debridements to reduce total tissue loss and complications.

Soft Tissue Alterations in Esthetic Postextraction Sites

Dimensional alterations of the facial soft and bone tissues following tooth extraction in the esthetic zone play an essential role to achieve successful outcomes in implant therapy. This prospective study is the first to investigate the interplay between the soft tissue dimensions and the underlying bone anatomy during an 8-wk healing period. The analysis is based on sequential 3-dimensional digital surface model superimpositions of the soft and bone tissues using digital impressions and cone beam computed tomography during an 8-wk healing period. Soft tissue thickness in thin and thick bone phenotypes at extraction was similar, averaging 0.7 mm and 0.8 mm, respectively. Interestingly, thin bone phenotypes revealed a 7-fold increase in soft tissue thickness after an 8-wk healing period, whereas in thick bone phenotypes, the soft tissue dimensions remained unchanged. The observed spontaneous soft tissue thickening in thin bone phenotypes resulted in a vertical soft tissue loss of only 1.6 mm, which concealed the underlying vertical bone resorption of 7.5 mm. Because of spontaneous soft tissue thickening, no significant differences were detected in the total tissue loss between thin and thick bone phenotypes at 2, 4, 6, and 8 wk. More than 51% of these dimensional alterations occurred within 2 wk of healing. Even though the observed spontaneous soft tissue thickening in thin bone phenotypes following tooth extraction conceals the pronounced underlying bone resorption pattern by masking the true bone deficiency, spontaneous soft tissue thickening offers advantages for subsequent bone regeneration and implant therapies in sites with high esthetic demand (Clinicaltrials.gov NCT02403700).

Thrombin Causes Neuronal Atrophy and Acute but not Chronic Cell Death.

Brain injury after intracerebral hemorrhage (ICH) arises from numerous contributors, of which some also play essential roles. Notably, thrombin production, needed to stop bleeding, also causes acute cell death and edema. In some rodent models of ICH, peri-hematoma neurons die over weeks. Hence we evaluated whether thrombin is responsible for this chronic degeneration. Functional impairments after ICH also result from sub-lethal damage to neurons, especially the loss of dendrites. Thus, we evaluated whether thrombin infusion alone, a reductionist model of ICH, causes similar injury. Adult rats had a modest intra-striatal infusion of thrombin (1 U) or saline followed by a behavioral test, to verify impairment, 7 days later. After this they were euthanized and tissue stained with Golgi-Cox solution to allow the assessment of dendritic morphology in striatal neurons. In a second experiment, rats survived 7 or 60 days after thrombin infusion in order to histologically determine lesion volume. Thrombin caused early cell death and considerable atrophy in surviving peri-lesion neurons, which had less than half of their usual numbers of branches. However, total tissue loss was comparable at 7 (24.1 mm3) and 60 days (25.6 mm3). Thrombin infusion causes early cell death and neuronal atrophy in nearby surviving striatal neurons but thrombin does not cause chronic tissue loss. Thus, the chronic degeneration found after ICH in rats is not simply and solely due to acute thrombin production. Nonetheless, thrombin is an important contributor to behavioral dysfunction because it causes cell death and substantial dendritic injury.

Lithium-Mediated Long-Term Neuroprotection in Neonatal Rat Hypoxia–Ischemia is Associated with Antiinflammatory Effects and Enhanced Proliferation and Survival of Neural Stem/Progenitor Cells

The aim of this study was to evaluate the long-term effects of lithium treatment on neonatal hypoxic-ischemic brain injury, inflammation, and neural stem/progenitor cell (NSPC) proliferation and survival. Nine-day-old male rats were subjected to unilateral hypoxia-ischemia (HI) and 2 mmol/kg lithium chloride was injected intraperitoneally immediately after the insult. Additional lithium injections, 1 mmol/kg, were administered at 24-hour intervals for 7 days. Animals were killed 6, 24, 72 hours, or 7 weeks after HI. Lithium reduced total tissue loss by 69%, from 89.4±14.6 mm(3) in controls (n=15) to 27.6±6.2 mm(3) in lithium-treated animals (n=14) 7 weeks after HI (P<0.001). Microglia activation was inhibited by lithium treatment, as judged by Iba-1 and galectin-3 immunostaining, and reduced interleukin-1β and CCL2 levels. Lithium increased progenitor, rather than stem cell, proliferation in both nonischemic and ischemic brains, as judged by 5-bromo-2-deoxyuridine labeling 24 and 72 hours as well as by phospho-histone H3 and brain lipid-binding protein labeling 7 weeks after HI. Lithium treatment also promoted survival of newborn NSPCs, without altering the relative levels of neuronal and astroglial differentiation. In summary, lithium conferred impressive, morphological long-term protection against neonatal HI, at least partly by inhibiting inflammation and promoting NSPC proliferation and survival.

Lithium reduces apoptosis and autophagy after neonatal hypoxia–ischemia

Lithium is used in the treatment of bipolar mood disorder. Reportedly, lithium can be neuroprotective in models of adult brain ischemia. The purpose of this study was to evaluate the effects of lithium in a model of neonatal hypoxic–ischemic brain injury. Nine-day-old male rats were subjected to unilateral hypoxia–ischemia (HI) and 2 mmol/kg lithium chloride was injected i.p. immediately after the insult. Additional lithium injections, 1 mmol/kg, were administered at 24-h intervals. Pups were killed 6, 24 or 72 h after HI. Lithium reduced the infarct volume from 24.7±2.9 to 13.8±3.3 mm3 (44.1%) and total tissue loss (degeneration + lack of growth) from 67.4±4.4 to 38.4±5.9 mm3 (43.1%) compared with vehicle at 72 h after HI. Injury was reduced in the cortex, hippocampus, thalamus and striatum. Lithium reduced the ischemia-induced dephosphorylation of glycogen synthase kinase-3β and extracellular signal-regulated kinase, the activation of calpain and caspase-3, the mitochondrial release of cytochrome c and apoptosis-inducing factor, as well as autophagy. We conclude that lithium could mitigate the brain injury after HI by inhibiting neuronal apoptosis. The lithium doses used were in the same range as those used in bipolar patients, suggesting that lithium might be safely used for the avoidance of neonatal brain injury.

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.

Long-Lasting Functional Disabilities in Middle-Aged Rats with Small Cerebral Infarcts

Recommendations from experts and recently established guidelines on how to improve the face and predictive validity of animal models of stroke have stressed the importance of using older animals and long-term behavioral-functional endpoints rather than relying almost exclusively on acute measures of infarct volume in young animals. The objective of the present study was to determine whether we could produce occlusions in older rats with an acceptable mortality rate and then detect reliable, long-lasting functional deficits. A reversible intraluminar suture middle cerebral artery occlusion (MCAO) procedure was used to produce small infarcts in middle-aged rats. This resulted in an acceptable mortality rate, and robust disabilities were detected in functional assays, although the degree of total tissue loss measured 90 d after MCAO was quite modest. Infarcted animals were functionally impaired relative to sham control animals even 90 d after the occlusions, and when animals were subgrouped based on amount of tissue loss, MCAO animals with only 4% tissue loss exhibited enduring neurological-behavioral impairments relative to sham-operated controls, and the functional impairments in the group with the largest infarcts (20% tissue loss) were more severe than the functional impairments in the rats with 4% tissue loss. These results suggest that this model, using reversible MCAO to produce small infarcts and long-lasting functional-behavioral deficits in older rats, may represent an advance in the relatively higher-throughput modeling of stroke and its recovery in rodents and may be useful in the development and characterization of future stroke therapies.

Corono-radicular reconstruction of pulpless teeth: A mechanical study using finite element analysis

Statement of Problem. Following endodontic therapy, teeth need to be protected, particularly in the cervical region, where the majority of fractures occur. The likelihood of a fracture depends on the condition of the crown and the type of reconstruction performed. Purpose. This simulation study was designed to compare the effect of different corono-radicular reconstruction methods on stress transmission to dental tissues. Material and Methods. The study software performed stress analysis of complex structures by finite element analysis. Seven 3-dimensional models were created, each representing a tooth embedded in a bony medium. The following parameters affecting corono-radicular restoration were studied: 2 levels of coronal destruction, core materials, post materials when present, and absence of post. The 2 levels of coronal tissue loss were (1) total tissue loss of the coronal dentin and (2) partial tissue loss of the coronal dentin with 2-mm surviving dentin walls. Teeth with 2 different levels of tissue loss (first study parameter) were reconstructed by 4 different techniques: nickel chromium (NiCr) cast post and core, NiCr post and composite core combination, carbon fiber post and composite core combination, and composite restoration without post. A NiCr crown covered each of the models and received a 30° oblique occlusal load at a constant intensity of 100 N. The software computed the stresses (local tensile stress inducing cracks and compressive stress) for each of the models, comparing maximum intensity observed, localization, and concentration. Results. Whatever the type of stress (tensile or compressive), the greatest stress was observed in the cervical region, regardless of the model. Only tensile stresses potentially responsible for fractures were compared. Cervical tensile stresses exceeded 230 Pa in the absence of a ferrule and were less than 140 Pa when a ferrule was present. In the absence of a ferrule, the NiCr composite/post combination generated greater cervical stress (254 Pa) than the cast post and core (235 Pa). Results with a ferrule showed 92 Pa for the NiCr composite/post combination and 90.5 Pa for the cast post and core. In the presence of a ferrule, the tensile stress intensities generated by the composite restoration with no root canal post (139 Pa) were 51% greater than those generated by the NiCr/composite combination and approximately 26% greater than those generated by the composite/carbon combination. Conclusion. Within the limitations of this study, it was confirmed that all simulated reconstructed teeth were more subject to stress in the cervical region. The absence of a cervical ferrule was found to be a determining negative factor, giving rise to considerably higher stress levels. When no ferrule was present, the NiCr post/composite combination generated greater cervical stress than cast post and cores. Nevertheless, the peripheral ferrule seemed to cancel the mechanical effect of the reconstruction material on the intensity of the stresses. With a ferrule, the choice of reconstruction material had no impact on the level of cervical stress. The root canal post, the purpose of which is to protect the cervical region, was also shown to be beneficial even with sufficient residual coronal dentin. In the presence of a root canal post, cervical stress levels were lower than when no root canal post was present. Moreover, the higher the elasticity modulus, the lower the stress levels. (J Prosthet Dent 2002;88:442-8.)

Graded hypotension and MCA occlusion duration: effect in transient focal ischemia.

The first 2 h of middle cerebral artery occlusion (MCAO) are likely critical in determining the final outcome in ischemic stroke. To study this early postischemic period, male Wistar rats (n = 161) were subjected to right MCAO with closely spaced step variations in both duration of MCAO and blood pressure (BP), using the intraluminal suture technique. Quantitative neuropathology was performed at 25 coronal planes of the brain after 1-week survival. Atrophy was measured as the difference between the two hemispheres and was added to cortical and striatal necrosis to obtain total tissue loss. Damage consistently increased monotonically with increasing duration of occlusion only when infarct size was expressed as percentage of the contralateral hemisphere, but not when expressed as mm3, because of variable tissue size. The results showed that already at 1 week, the quantity of tissue loss due to resorption and transsynaptic effects approached the quantity of geographically traceable necrosis in cortex and striatum. Minimum brain damage (5%) occurred after 60 min at a BP of 80 mm Hg, with almost no cortical necrosis. Damage was extremely sensitive to hypotension and MCAO duration. At a BP of 40 mm Hg, 60 min of MCAO produced 25% damage, accelerating every 20 min during the 2-h period studied. At BP 80 mm Hg, 120 min of MCAO produced the same damage as only 80 min of MCAO at BP 60 mm Hg. At 60-, 80-, 100-, and 120-min duration of MCAO, infarct size was significantly reduced with increasing BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropathological endpoints in experimental stroke pharmacotherapy: the importance of both early and late evaluation.

This study addresses the issue of endpoint selection in the evaluation of neuroprotective drugs in experimental focal ischaemia. Previous work with the permanent middle cerebral artery (MCA) occlusion model in the rat has demonstrated that the ischaemic lesion does not acquire its final appearance until at least 28 days after the ictus. Therefore, the effect of the NMDA receptor blocker MK-801 (dizocilpine maleate) was evaluated both early (3 days) and late (28 days) after MCA occlusion to determine if the previously reported protective effect of a single post-ischaemic dose of MK-801 found in acute experiments remained after 28 days. Mk-801 (0.5 mg/kg, i.v.) or isotonic saline was randomly given to rats 30 min after MCA occlusion. Infarct volume and volume of ipsilateral and contralateral hemispheres were estimated from camera lucida drawings of 8 defined coronal histological sections of the brain. As expected, a 40% (p < 0.05) reduction of infarct size was found in MK-801 treated rats after 3 days. In animals evaluated 28 days after MCA occlusion, no significant difference in infarct size, total tissue loss (infarct volume+ipsilateral hemisphere atrophy) or remaining non-infarcted tissue (contralateral hemisphere--total tissue loss) was seen between the MK-801 and placebo treated rats. The results suggest that the single dose treatment with MK-801 postponed the evolution of the infarct, which at 3 days after MCA occlusion is still in progress, possibly by ameliorating oedema formation. It remains to be shown if a multiple dose treatment with NMDA receptor antagonists improves the final neuropathological outcome after experimental stroke.(ABSTRACT TRUNCATED AT 250 WORDS)