Clinical usage of ischemic tolerance-where are its limits?

Ischemic tolerance is a robust internal defense mechanism of all living organisms. The effectiveness of this mechanism has been repeatedly demonstrated in experiments, but a comprehensive review of the clinical applicability of this phenomenon in practice has not yet been published. The results in clinical practice sound ambiguous and unconvincing in comparison with the results of experimental studies. Also, in many localities, the effect of ischemic tolerance was not clinically proven. For the reasons mentioned, the authors analyze the possible causes of the mentioned discrepancies and provide a comprehensive insight into the possible relevant clinical use of this phenomenon in practice for different groups of patients.

Combined Radiocarpal Dislocation and Forearm Joint Injuries: A Proposed Modification of the Locker-Based Classification System.

The comprehensive locker-based classification system brought revolutionary insight into the treatment of often misdiagnosed forearm joint injuries. The authors of the classification scheme subsequently described a combination of simple elbow dislocations and forearm joint injuries (two- and three-locker injuries), but to date, no review of the literature on combined radiocarpal dislocation and forearm joint injuries has been undertaken. The combination of radiocarpal dislocation and forearm joint injury is a rare traumatic pattern, usually related to high-energy trauma. The aim of this study was to confirm the possible occurrence of a forearm joint injury and radiocarpal dislocation. We performed a systematic review of the existing literature, including case reports, to find combinations of radiocarpal dislocation and forearm joint injury. Only one case report was found. Based on the results of our search and the literature review, we recommend modifying the comprehensive locker-based classification system by adding injury patterns of combined forearm joint and neighboring joint injuries.

Ischemic Tolerance-A Way to Reduce the Extent of Ischemia-Reperfusion Damage.

Individual tissues have significantly different resistance to ischemia-reperfusion damage. There is still no adequate treatment for the consequences of ischemia-reperfusion damage. By utilizing ischemic tolerance, it is possible to achieve a significant reduction in the extent of the cell damage due to ischemia-reperfusion injury. Since ischemia-reperfusion damage usually occurs unexpectedly, the use of preconditioning is extremely limited. In contrast, postconditioning has wider possibilities for use in practice. In both cases, the activation of ischemic tolerance can also be achieved by the application of sublethal stress on a remote organ. Despite very encouraging and successful results in animal experiments, the clinical results have been disappointing so far. To avoid the factors that prevent the activation of ischemic tolerance, the solution has been to use blood plasma containing tolerance effectors. This plasma is taken from healthy donors in which, after exposure to two sublethal stresses within 48 h, effectors of ischemic tolerance occur in the plasma. Application of this activated plasma to recipient animals after the end of lethal ischemia prevents cell death and significantly reduces the consequences of ischemia-reperfusion damage. Until there is a clear chemical identification of the end products of ischemic tolerance, the simplest way of enhancing ischemic tolerance will be the preparation of activated plasma from young healthy donors with the possibility of its immediate use in recipients during the initial treatment.

Area of the plateau depression and higher age predict post-operative subsidence in split-depression lateral tibial fracture.

INTRODUCTION: The aim of this study was to determine factors that affect post-operative subsidence in split-depression lateral plateau tibial fracture (OTA/AO 41B3.1) which was treated with raft construct through a locking plate. PATIENTS AND METHODS: The retrospective study evaluated all split-depression lateral plateau tibial fracture cases treated with raft construct through a locking plate between 01/2015 and 04/2020 with a minimum of 12-month follow-up. Data on the patients' age, sex, time from injury to surgery, type of plate, and use of subchondral bone defect filler were retrieved from the hospital database. The measurements of total plateau area (TPA), depressed lateral plateau area (DPA), and maximal plateau depression (MPD) were performed on the patients' pre-operative CT scans. The percentage of DPA to TPA (%DPA) was calculated. Post-operative radiographs were used for the evaluation of plateau subsidence. A subsidence greater than 2 mm was considered a failure. RESULTS: There were 41 consecutive cases of split-depression lateral plateau tibial fracture in the reviewed period. Five cases were excluded, three of them were lost to follow up, 1 patient had no pre-operative CT scan and 1 had a history of cancer. A failure was identified in 11 (31%) cases. Patients in the failure group were older (61.0 vs 50.7 years, p = 0.01), and had a higher incidence of fractures extending into intercondylar eminence (100% vs 56%, p = 0.02). Multiple logistic regression identified DPA (OR = 3.6; 95%CI 1.4-9.5, p < 0.01) and age (OR = 1.2; 95% CI 1.0-1.4, p = 0.02) as predictive factors for plateau subsidence. DPA cut-off value for predicting subsidence greater than 2 mm was 5.8 cm2 [Area Under the ROC Curve 0.89 (95% CI 0.74-0.97), sensitivity 91%, specificity 80%, p < 0.01)]. CONCLUSION: Age and depressed lateral plateau area (DPA) in split-depression lateral plateau tibial fracture treated with raft construct through a locking plate are risk factors for post-operative subsidence greater than 2 mm.

A new comprehensive Classification Scheme for ECU Tendon Problems at the Wrist.

Based on a systematic review of the literature, description of previous classification schemes and new anatomical knowledge, a new comprehensive classification scheme for ECU tendon problems at the wrist is described.

Reversed Z-effect and Z-effect phenomena in femoral neck fracture treated with a dynamic locking plate fixation: Case report.

The aim of this case report is to present an unusual mechanism of failure of a dynamic locking plate (DLP), previously reported in dual lag screw proximal femoral nails. A 78-year-old female patient experienced a displaced right femoral neck fracture (FNF) which was managed with DLP. At the postoperative sixth-week appointment, her hip radiographs showed that two of three telescoping screws had slid within the telescrew barrel, and one screw was fully extended and cutting through the femoral head. At the third-month checkup, radiographs revealed an unhealed FNF and 12 mm sliding on all three telescoping screws. At the final 11th-month follow-up, two screws were completely collapsed and the previously nonpenetrating screw was partially extended and cutting through the femoral head. Femoral neck shortening and femoral neck nonunion were noticed as well. In conclusion, the postoperative course of the case supports the hypothesis of a specific pattern of DLP failure resembling reversed Z- and Z-effects found in dual lag screw proximal femoral nails.

Remote ischemic postconditioning as well as blood plasma from double-conditioned donor ameliorate reperfusion syndrome in skeletal muscle.

The aim of this study was to verify the possibility of preparation and effectiveness of the use of blood plasma containing an effector of ischemic tolerance activated by applying two sublethal stresses to a donor. As sublethal stresses, two periods of 20-minute hindlimb ischemia were used with a two-day interval between them. Active plasma was isolated six hours after the second hindlimb ischemia. The effectiveness of active plasma as well as remote postconditioning was tested after three hours of tourniquet-induced ischemia on the gastrocnemius muscle. The wet/dry ratio of gastrocnemius muscle (degree of tissue oedema), nitroblue tetrazolium reduction (tissue necrosis), and CatWalk test (hind limb functionality) were evaluated 24 h after the end of ischemia. Three hours of ischemia increased muscle oedema and necrosis in comparison to control by 26.72% (p < 0.001) and 41.58% (p < 0.001) respectively. Remote ischemic postconditioning as well as injection of conditioned blood plasma significantly prevented these changes, even when they were applied one or three hours after the end of ischemia. Equally effective double-conditioned plasma appears to have better prospects in life-threatening situations such as stroke and myocardial infarction.

Factors influencing femoral neck fracture healing after internal fixation with dynamic locking plate.

INTRODUCTION: The purpose of this study was to determine factors that affect the early failure of femoral neck fracture healing after internal fixation with a dynamic locking plate implant. PATIENTS AND METHODS: Retrospective analysis of all cases of femoral neck fracture (FNF) primarily treated with dynamic locking plate implant from 04/2014 to 04/2017 with a minimum of 6 month follow-up. For the purpose of the study age, sex and time from admission to surgery were retrieved from the hospital medical database. Patient's pre- and postoperative hip radiographs were reviewed by the authors. Radiographically detected fracture healing failure (non-union and screw cut-out) was recorded. RESULTS: For the period of the study, there were 77 consecutive FNF (76 patients) treated with the dynamic locking plate implant. Eight (10%) patients were lost to follow-up, 13 (17%) patients died within 6 months after surgery. Healing failure was identified in 23 (41%) of remaining 56 cases. Three of four (75% failure rate) failures were observed in cases with fair-quality reduction and two of two (100% failure rate) failures were noticed in the case of none telescoping screw located within subchondral bone. Multiple logistic regression showed an increased risk of fracture failure in cases with at least one completely collapsed telescoping screw (OR = 73.2; 95% CI 9.4-568.5, p < 0.01), while telescoping screws' location around centre of the femoral head reduces the risk of failure (OR = 14.7; 95% CI 1.6-135.1, p = 0.02). CONCLUSION: In our group of patients, fracture healing failure of the FNF treated with dynamic locking plate reached 41%. This high failure rate was associated with poor fracture reduction, not subchondrally and centrally placed telescoping screws and in the case of complete collapse on at least one of the telescoping screws.

Postconditioning Effectively Prevents Trimethyltin Induced Neuronal Damage in the Rat Brain.

Trimethyltin (TMT) is a toxic substance formerly used as a catalyst in the production of organic substances, as well as in industry and agriculture. TMT poisoning has caused death or severe injury in many dozens of people. The toxicity of TMT is mediated by dose dependent selective damage to the limbic system in humans and other animals, specifically the degeneration of CA1 neurons in the hippocampus. The typical symptoms include memory loss and decreased learning ability. Using knowledge gained in previous studies of global ischaemia, we used delayed postconditioning after TMT intoxication (8 mg/kg i.p.), consisting of applying a stressor (BR, bradykinin 150 µg/kg i.p.) 24 or 48 hours after the injection of TMT. We found that BR had preventive effects on neurodegenerative changes as well as learning and memory deficits induced by TMT intoxication.

Delayed remote ischemic postconditioning protects against transient cerebral ischemia/reperfusion as well as kainate-induced injury in rats.

To test the appropriateness of using delayed remote ischemic postconditioning against damage caused to the hippocampus by ischemia or apoptosis inducing intoxication, we chose 10-min normothermic ischemia induced by four-vessel occlusion or kainate injection (8 mg/kg i.p.) in rats. Ischemia alone caused the number of degenerated CA1 neurons after 7 days lasting reperfusion to be significantly (p<0.001) increased by 72.77%. Delayed remote ischemic postconditioning lasting 20 min was able to prevent massive increase in the neurodegeneration. The group with 10 min of ischemia and postconditioning after 2 days of reperfusion had only 15.87% increase in the number of apoptotic neurons. Seven days after kainic acid injection the number of surviving neurons was 42.8% (p<0.001), but the portion of surviving pyramidal cells in the postconditioning group is more than 98%. Our data show that remote postconditioning, performed with 20 min of tourniquet ischemia applied to the hind limb, is a simple method able to effectively stop the onset of neurodegeneration and prevent occurrence of massive muscle cell necrosis, even when used 2 days after the end of the adverse event. Surviving neurons retained a substantial part of their learning and memory ability.

An effective combination of two different methods of postconditioning.

Ischemic tolerance based on the synthesis of protective proteins acquires its full strength by repeated exposure to stress, and "the end effector of tolerance" may paradoxically be activated by the second or lethal stress, particularly in the case of preconditioning. That happens when an additional nonspecific stressor is applied either before (preconditioning) or after (postconditioning) the period of lethal ischemia. A combination of antioxidants with pre or postconditioning prevents the acquisition of tolerance, and in the case of more severe attacks repeated stress can lead to accumulation of damage. Our attempt to weaken ischemic injury to hippocampal CA1 with antioxidants applied after lethal stress, i.e. before delayed postconditioning, was ineffective. We then tried using rapid postconditioning consisting of 30-s reperfusion alternating with 15-s ischemia repeated three times and applied immediately at the end of lethal ischemia as a tool decreasing post-ischemic production of reactive oxygen species, and combining that with delayed postconditioning consisting of an i.p. injection of Bradykinin 2 days after lethal ischemia. This approach once more confirmed the efficacy of both rapid as well as delayed postconditioning but, more importantly, it demonstrated the possibility of effectively combining these two procedures. Our findings further confirm that in cases of delayed neuronal death, which is practically pathologically-induced apoptosis, there exists a 2-day-wide therapeutic window that can be effectively exploited.

Obturator artery injury after hip fracture surgery.

We present the case of a 55-year-old woman who sustained a left femoral neck fracture which was managed by insertion of a dynamic hip screw. Six hours after surgery, distension appeared in the left lower quadrant of her abdomen associated with a decline in haemoglobin concentration and clinical signs of ongoing bleeding. Computed tomography showed a left retroperitoneal mass without concomitant extravasation of contrast material. Exploratory laparotomy revealed a damaged left obturator artery with a large haematoma in its vicinity. After arterial ligation and retroperitoneal space decompression her postoperative course was uneventful. Reviewing intraoperative C arm images a 0.8 cm protrusion of the threaded guide wire was identified as the cause of obturator artery damage.

Postconditioning and anticonditioning: possibilities to interfere to evoked apoptosis.

The aim of this study was to validate the ability of postconditioning, used 2 days after kainate intoxication, to protect selectively vulnerable hippocampal CA1 neurons against delayed neuronal death. Kainic acid (8 mg/kg, i.p.) was used to induce neurodegeneration of pyramidal CA1 neurons in rat hippocampus. Fluoro Jade B, the specific marker of neurodegeneration, and NeuN, a specific neuronal marker were used for visualization of changes 7 days after intoxication without and with delayed postconditioning (norepinephrine, 3.1 mumol/kg i.p., 2 days after kainate administration) and anticonditioning (Extract of Ginkgo biloba, 40 mg/kg p.o used simultaneously with kainate). Morris water maze was used on 6th and 7th day after kainate to test learning and memory capabilities of animals. Our results confirm that postconditioning if used at right time and with optimal intensity is able to prevent delayed neuronal death initiated not only by ischemia but kainate intoxication, too. The protective effect of repeated stress-postconditioning was suppressed if extract of Ginkgo biloba (EGb 761, 40 mg/kg p.o.) has been administered together with kainic acid. It seems that combination of lethal stress and antioxidant treatment blocks the activation of endogenous protecting mechanism known as ischemic tolerance, aggravates neurodegeneration and, after repeated stress is able to cause cumulative damage. This observation could be very valuable in situation when the aim of treatment is elimination of unwanted cell population from the organism.

Delayed postconditionig initiates additive mechanism necessary for survival of selectively vulnerable neurons after transient ischemia in rat brain.

1. The aim of this study was to validate the role of postconditioning, used 2 days after lethal ischemia, for protection of selectively vulnerable brain neurons against delayed neuronal death. 2. Eight, 10, or 15 min of transient forebrain ischemia in rat (four-vessel occlusion model) was used as initial lethal ischemia. Fluoro Jade B, the marker of neurodegeneration, and NeuN, a specific neuronal marker were used for visualization of changes 7 or 28 days after ischemia without and with delayed postconditioning. 3. Our results confirm that postconditioning if used at right time and with optimal intensity can prevent process of delayed neuronal death. At least three techniques, known as preconditioners, can be used as postconditioning: short ischemia, 3-nitropropionic acid and norepinephrine. A cardinal role for the prevention of death in selectively vulnerable neurons comprises synthesis of proteins during the first 5 h after postconditioning. Ten minutes of ischemia alone is lethal for 70% of pyramidal CA1 neurons in hippocampus. Injection of inhibitor of protein synthesis (Cycloheximide), if administered simultaneously with postconditioning, suppressed beneficial effect of postconditioning and resulted in 50% of CA1 neurons succumbing to neurodegeneration. Although, when Cycloheximide was injected 5 h after postconditioning, this treatment resulted in survival of 90% of CA1 neurons. 4. Though postconditioning significantly protects hippocampal CA1 neurons up to 10 min of ischemia, its efficacy at 15 min ischemia is exhausted. However, protective impact of postconditioning in less-sensitive neuronal populations (cortex and striatum) is very good after such a damaging insult like 15 min ischemia. This statement also means that up to 15 min of ischemia, postconditioning does not induce cumulation of injuries produced by the first and the second stress.

Evidence for a role of second pathophysiological stress in prevention of delayed neuronal death in the hippocampal CA1 region.

In ischemic tolerance experiment, when we applied 5-min ischemia 2 days before 30-min ischemia, we achieved a remarkable (95.8%) survival of CA1 neurons. However, when we applied 5-min ischemia itself, without following lethal ischemia, we found out 45.8% degeneration of neurons in the CA1. This means that salvage of 40% CA1 neurons from postischemic degeneration was initiated by the second pathophysiological stress. These findings encouraged us to hypothesize that the second pathophysiological stress used 48 h after lethal ischemia can be efficient in prevention of delayed neuronal death. Our results demonstrate that whereas 8 min of lethal ischemia destroys 49.9% of CAI neurons, 10 min of ischemia destroys 71.6% of CA1 neurons, three different techniques of the second pathophysiological stress are able to protect against both: CA1 damage as well as spatial learning/memory dysfunction. Bolus of norepinephrine (3.1 micromol/kg i.p.) used two days after 8 min ischemia saved 94.2%, 6 min ischemia applied 2 days after 10 min ischemia rescued 89.9%, and an injection of 3-nitropropionic acid (20 mg/kg i.p.) applied two days after 10 min ischemia protected 77.5% of CA1 neurons. Thus, the second pathophysiological stress, if applied at a suitable time after lethal ischemia, represents a significant therapeutic window to opportunity for salvaging neurons in the hippocampal CA1 region against delayed neuronal death.

Ischaemic preconditioning in the rat brain: effect on the activity of several initiation factors, Akt and extracellular signal-regulated protein kinase phosphorylation, and GRP78 and GADD34 expression.

Translational repression induced during reperfusion of the ischaemic brain is significantly attenuated by ischaemic preconditioning. The present work was undertaken to identify the components of the translational machinery involved and to determine whether translational attenuation selectively modifies protein expression patterns during reperfusion. Wistar rats were preconditioned by 5-min sublethal ischaemia and 2 days later, 30-min lethal ischaemia was induced. Several parameters were studied after lethal ischaemia and reperfusion in rats with and without acquired ischaemic tolerance (IT). The phosphorylation pattern of the alpha subunit of eukaryotic initiation factor 2 (eIF2) in rats with IT was exactly the same as in rats without IT, reaching a peak after 30 min reperfusion and returning to control values within 4 h in both the cortex and hippocampus. The levels of phosphorylated eIF4E-binding protein after lethal ischaemia and eIF4E at 30 min reperfusion were higher in rats with IT, notably in the hippocampus. eIF4G levels diminished slightly after ischaemia and reperfusion, paralleling calpain-mediated alpha-spectrin proteolysis in rats with and without IT, but they did not show any further decrease after 30 min reperfusion in rats with IT. The phosphorylated levels of eIF4G, phosphatidylinositol 3-kinase-protein B (Akt) and extracellular signal-regulated kinases (ERKs) were very low after lethal ischaemia and increased following reperfusion. Ischaemic preconditioning did not modify the observed changes in eIF4G phosphorylation. All these results support that translation attenuation may occur through multiple targets. The levels of the glucose-regulated protein (78 kDa) remained unchanged in rats with and without IT. Conversely, our data establish a novel finding that ischaemia induces strong translation of growth arrest and DNA damage protein 34 (GADD34) after 4 h of reperfusion. GADD34 protein was slightly up-regulated after preconditioning, besides, as in rats without IT, GADD34 levels underwent a further clear-cut increase during reperfusion, this time as earlier as 30 min and coincident with translation attenuation.

Role of protein synthesis in the ischemic tolerance acquisition induced by transient forebrain ischemia in the rat.

Although ischemic preconditioning of the heart and brain is a well-documented neuroprotective phenomenon, the mechanism underlying the increased resistance to severe ischemia induced by a preceding mild ischemic exposure remains unclear. In this study we have determined the effect of ischemic preconditioning on ischemia/reperfusion-associated translation inhibition in the neocortex and hippocampus of the rat. We studied the effect of the duration on the sublethal ischemic episode (3, 4, 5 or 8 min), as well as the amount of time elapsed between sublethal and lethal ischemia on the cell death 7 days after the last ischemic episode. In addition, the rate of protein synthesis in vitro and expression of the 72-kD heat shock protein (hsp) were determined under the different experimental conditions. Our results suggest that two different mechanisms are essential for the acquisition of ischemic tolerance, at least in the CA1 sector of hippocampus. The first mechanism implies a highly significant reduction in translation inhibition after lethal ischemia, especially at an early time of reperfusion, in both vulnerable and nonvulnerable neurons. For the acquisition of full tolerance, a second mechanism, highly dependent on the time interval between preconditioning (sublethal ischemia) and lethal ischemia, is absolutely necessary; this second mechanism involves synthesis of protective proteins, which prevent the delayed death of vulnerable neurons.