Hepatitis Delta Virus Reporting Requirements in the United States and Territories: A Systematic Review.

Hepatitis D virus (HDV) is a rare coinfection with hepatitis B virus. Currently, HDV is not a nationally notifiable disease in the United States. Only 55% of states and territories require HDV reporting, and most lack defined case definitions. Standardization of reporting requirements is crucial for monitoring HDV epidemiology.

Protective effects of phenelzine administration on synaptic and non-synaptic cortical mitochondrial function and lipid peroxidation-mediated oxidative damage following TBI in young adult male rats.

Traumatic brain injury (TBI) results in mitochondrial dysfunction and induction of lipid peroxidation (LP). Lipid peroxidation-derived neurotoxic aldehydes such as 4-HNE and acrolein bind to mitochondrial proteins, inducing additional oxidative damage and further exacerbating mitochondrial dysfunction and LP. Mitochondria are heterogeneous, consisting of both synaptic and non-synaptic populations, with synaptic mitochondria being more vulnerable to injury-dependent consequences. The goal of these studies was to explore the hypothesis that interrupting secondary oxidative damage following TBI using phenelzine (PZ), an aldehyde scavenger, would preferentially protect synaptic mitochondria against LP-mediated damage in a dose- and time-dependent manner. Male Sprague-Dawley rats received a severe (2.2 mm) controlled cortical impact (CCI)-TBI. PZ (3-30 mg/kg) was administered subcutaneously (subQ) at different times post-injury. We found PZ treatment preserves both synaptic and non-synaptic mitochondrial bioenergetics at 24 h and that this protection is partially maintained out to 72 h post-injury using various dosing regimens. The results from these studies indicate that the therapeutic window for the first dose of PZ is likely within the first hour after injury, and the window for administration of the second dose seems to fall between 12 and 24 h. Administration of PZ was able to significantly improve mitochondrial respiration compared to vehicle-treated animals across various states of respiration for both the non-synaptic and synaptic mitochondria. The synaptic mitochondria appear to respond more robustly to PZ treatment than the non-synaptic, and further experimentation will need to be done to further understand these effects in the context of TBI.

Pharmacological inhibition of lipid peroxidative damage by the 21-aminosteroid U-74389G improves cortical mitochondrial function following traumatic brain injury in young adult male rats.

The 21-aminosteroid ("lazaroid") U-74389G (U74), an inhibitor of lipid peroxidation (LP), was used to protect mitochondrial function following TBI in young adult male rats. The animals received a severe (2.2 mm) controlled cortical impact-TBI. U74 was administered intravenous at 15 min and 2 h post injury (hpi) followed by intraperitoneal dose at 8 hpi at the following doses (mg/kg): 0.3 (IV) + 1 (IP), 1 + 3, 3 + 10, 10 + 30. Total cortical mitochondria were isolated at 72 hpi and respiratory rates were measured. Mitochondrial 4-HNE and acrolein were evaluated as indicators of LP-mediated oxidative damage. At 72 h post-TBI injured animals had significantly lower mitochondrial respiration rates compared to sham. Administration of U74 at the 1 mg/kg dosing paradigm significantly improved mitochondrial respiration rates for States II, III, V(II) and RCR compared to vehicle-treated animals. At 72 h post-TBI injured animals administration of U74 also reduced reactive aldehydes levels compared to vehicle-treated animals. The aim of this study was to explore the hypothesis that interrupting secondary oxidative damage via acute pharmacological inhibition of LP by U74 following a CCI-TBI would provide mitochondrial neuroprotective effects in a dose-dependent manner. We found acute administration of U74 to injured rats resulted in improved mitochondrial function and lowered the levels of reactive aldehydes in the mitochondria. These results establish not only the most effective dose of U74 treatment to attenuate LP-mediated oxidative damage, but also set the foundation for further studies to explore additional neuroprotective effects following TBI.

Newer pharmacological approaches for antioxidant neuroprotection in traumatic brain injury.

Reactive oxygen species-induced oxidative damage remains an extensively validated secondary injury mechanism in traumatic brain injury (TBI) as demonstrated by the efficacy of various pharmacological antioxidants agents in decreasing post-traumatic free radical-induced lipid peroxidation (LP) and protein oxidative damage in preclinical TBI models. Based upon strong preclinical efficacy results, two antioxidant agents, the superoxide radical scavenger polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) and the 21-aminosteroid LP inhibitor tirilazad, which inhibits lipid peroxidation, (LP) were evaluated in large phase III trials in moderately- and severely-injured TBI patients. Both failed to improve 6 month survival and neurological recovery. However, in the case of tirilazad, a post hoc analysis revealed that the drug significantly improved survival of male TBI patients who exhibited traumatic subarachnoid hemorrhage (tSAH) that occurs in half of severe TBIs. In addition to reviewing the clinical trial results with PEG-SOD and tirilazad, newer antioxidant approaches which appear to improve neuroprotective efficacy and provide a longer therapeutic window in rodent TBI models will be presented. The first approach involves pharmacological enhancement of the multi-mechanistic Nrf2-antioxidant response element (ARE) pathway. The second involves scavenging of the neurotoxic LP-derived carbonyl compounds 4-hydroxynonenal (4-HNE) and acrolein which are highly damaging to neural protein and stimulate additional free radical generation. A third approach combines mechanistically complimentary antioxidants to interrupt post-TBI oxidative neurodegeneration at multiple points in the secondary injury cascade. These newer strategies appear to decrease variability in the neuroprotective effect which should improve the feasibility of achieving successful translation of antioxidant therapy to TBI patients.

Effects of Phenelzine Administration on Mitochondrial Function, Calcium Handling, and Cytoskeletal Degradation after Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) results in the production of peroxynitrite (PN), leading to oxidative damage of lipids and protein. PN-mediated lipid peroxidation (LP) results in production of reactive aldehydes 4-hydroxynonenal (4-HNE) and acrolein. The goal of these studies was to explore the hypothesis that interrupting secondary oxidative damage following a TBI via phenelzine (PZ), analdehyde scavenger, would protect against LP-mediated mitochondrial and neuronal damage. Male Sprague-Dawley rats received a severe (2.2 mm) controlled cortical impact (CCI)-TBI. PZ was administered subcutaneously (s.c.) at 15 min (10 mg/kg) and 12 h (5 mg/kg) post-injury and for the therapeutic window/delay study, PZ was administered at 1 h (10 mg/kg) and 24 h (5 mg/kg). Mitochondrial and cellular protein samples were obtained at 24 and 72 h post-injury (hpi). Administration of PZ significantly improved mitochondrial respiration at 24 and 72 h compared with vehicle-treated animals. These results demonstrate that PZ administration preserves mitochondrial bioenergetics at 24 h and that this protection is maintained out to 72 hpi. Additionally, delaying the administration still elicited significant protective effects. PZ administration also improved mitochondrial Ca2+ buffering (CB) capacity and mitochondrial membrane potential parameters compared with vehicle-treated animals at 24 h. Although PZ treatment attenuated aldehyde accumulation post-injury, the effects were insignificant. The amount of α-spectrin breakdown in cortical tissue was reduced by PZ administration at 24 h, but not at 72 hpi compared with vehicle-treated animals. In conclusion, these results indicate that acute PZ treatment successfully attenuates LP-mediated oxidative damage eliciting multiple neuroprotective effects following TBI.

Synaptic Mitochondria are More Susceptible to Traumatic Brain Injury-induced Oxidative Damage and Respiratory Dysfunction than Non-synaptic Mitochondria.

Traumatic brain injury (TBI) results in mitochondrial dysfunction and induction of lipid peroxidation (LP). Lipid peroxidation-derived neurotoxic aldehydes such as 4-HNE and acrolein bind to mitochondrial proteins, inducing additional oxidative damage and further exacerbating mitochondrial dysfunction and LP. Mitochondria are heterogeneous, consisting of both synaptic and non-synaptic populations. Synaptic mitochondria are reported to be more vulnerable to injury; however, this is the first study to characterize the temporal profile of synaptic and non-synaptic mitochondria following TBI, including investigation of respiratory dysfunction and oxidative damage to mitochondrial proteins between 3 and 120 h following injury. These results indicate that synaptic mitochondria are indeed the more vulnerable population, showing both more rapid and severe impairments than non-synaptic mitochondria. By 24 h, synaptic respiration is significantly impaired compared to synaptic sham, whereas non-synaptic respiration does not decline significantly until 48 h. Decreases in respiration are associated with increases in oxidative damage to synaptic and non-synaptic mitochondrial proteins at 48 h and 72 h, respectively. These results indicate that the therapeutic window for mitochondria-targeted pharmacological neuroprotectants to prevent respiratory dysfunction is shorter for the more vulnerable synaptic mitochondria than for the non-synaptic population.

Time courses of post-injury mitochondrial oxidative damage and respiratory dysfunction and neuronal cytoskeletal degradation in a rat model of focal traumatic brain injury.

Traumatic brain injury (TBI) results in rapid reactive oxygen species (ROS) production and oxidative damage to essential brain cellular components leading to neuronal dysfunction and cell death. It is increasingly appreciated that a major player in TBI-induced oxidative damage is the reactive nitrogen species (RNS) peroxynitrite (PN) which is produced in large part in injured brain mitochondria. Once formed, PN decomposes into highly reactive free radicals that trigger membrane lipid peroxidation (LP) of polyunsaturated fatty acids (e.g. arachidonic acid) and protein nitration (3-nitrotyrosine, 3-NT) in mitochondria and other cellular membranes causing various functional impairments to mitochondrial oxidative phosphorylation and calcium (Ca2+) buffering capacity. The LP also results in the formation of neurotoxic reactive aldehyde byproducts including 4-hydroxynonenal (4-HNE) and propenal (acrolein) which exacerbates ROS/RNS production and oxidative protein damage in the injured brain. Ultimately, this results in intracellular Ca2+ overload that activates proteolytic degradation of α-spectrin, a neuronal cytoskeletal protein. Therefore, the aim of this study was to establish the temporal evolution of mitochondrial dysfunction, oxidative damage and cytoskeletal degradation in the brain following a severe controlled cortical impact (CCI) TBI in young male adult rats. In mitochondria isolated from an 8 mm diameter cortical punch including the 5 mm wide impact site and their respiratory function studied ex vivo, we observed an initial decrease in complex I and II mitochondrial bioenergetics within 3 h (h). For complex I bioenergetics, this partially recovered by 12-16 h, whereas for complex II respiration the recovery was complete by 12 h. During the first 24 h, there was no evidence of an injury-induced increase in LP or protein nitration in mitochondrial or cellular homogenates. However, beginning at 24 h, there was a gradual secondary decline in complex I and II respiration that peaked at 72 h. post-TBI that coincided with progressive peroxidation of mitochondrial and cellular lipids, protein nitration and protein modification by 4-HNE and acrolein. The oxidative damage and respiratory failure paralleled an increase in Ca2+-induced proteolytic degradation of the neuronal cytoskeletal protein α-spectrin indicating a failure of intracellular Ca2+ homeostasis. These findings of a surprisingly delayed peak in secondary injury, suggest that the therapeutic window and needed treatment duration for certain antioxidant treatment strategies following CCI-TBI in rodents may be longer than previously believed.

Synaptic Mitochondria Sustain More Damage than Non-Synaptic Mitochondria after Traumatic Brain Injury and Are Protected by Cyclosporine A.

Currently, there are no Food and Drug Administration (FDA)-approved pharmacotherapies for the treatment of those with traumatic brain injury (TBI). As central mediators of the secondary injury cascade, mitochondria are promising therapeutic targets for prevention of cellular death and dysfunction after TBI. One of the most promising and extensively studied mitochondrial targeted TBI therapies is inhibition of the mitochondrial permeability transition pore (mPTP) by the FDA-approved drug, cyclosporine A (CsA). A number of studies have evaluated the effects of CsA on total brain mitochondria after TBI; however, no study has investigated the effects of CsA on isolated synaptic and non-synaptic mitochondria. Synaptic mitochondria are considered essential for proper neurotransmission and synaptic plasticity, and their dysfunction has been implicated in neurodegeneration. Synaptic and non-synaptic mitochondria have heterogeneous characteristics, but their heterogeneity can be masked in total mitochondrial (synaptic and non-synaptic) preparations. Therefore, it is essential that mitochondria targeted pharmacotherapies, such as CsA, be evaluated in both populations. This is the first study to examine the effects of CsA on isolated synaptic and non-synaptic mitochondria after experimental TBI. We conclude that synaptic mitochondria sustain more damage than non-synaptic mitochondria 24 h after severe controlled cortical impact injury (CCI), and that intraperitoneal administration of CsA (20 mg/kg) 15 min after injury improves synaptic and non-synaptic respiration, with a significant improvement being seen in the more severely impaired synaptic population. As such, CsA remains a promising neuroprotective candidate for the treatment of those with TBI.

Phenelzine Protects Brain Mitochondrial Function In Vitro and In Vivo following Traumatic Brain Injury by Scavenging the Reactive Carbonyls 4-Hydroxynonenal and Acrolein Leading to Cortical Histological Neuroprotection.

Lipid peroxidation (LP) is a key contributor to the pathophysiology of traumatic brain injury (TBI). Traditional antioxidant therapies are intended to scavenge the free radicals responsible for either initiation or propagation of LP. A more recently explored approach involves scavenging the terminal LP breakdown products that are highly reactive and neurotoxic carbonyl compounds, 4-hydroxynonenal (4-HNE) and acrolein (ACR), to prevent their covalent modification and rendering of cellular proteins nonfunctional leading to loss of ionic homeostasis, mitochondrial failure, and subsequent neuronal death. Phenelzine (PZ) is a U.S. Food and Drug Administration-approved monoamine oxidase (MAO) inhibitor (MAO-I) used for treatment of refractory depression that possesses a hydrazine functional group recently discovered by other investigators to scavenge reactive carbonyls. We hypothesized that PZ will protect mitochondrial function and reduce markers of oxidative damage by scavenging LP-derived aldehydes. In a first set of in vitro studies, we found that exogenous application of 4-HNE or ACR significantly reduced respiratory function and increased markers of oxidative damage (p < 0.05) in isolated noninjured rat brain cortical mitochondria, whereas PZ pre-treatment significantly prevented mitochondrial dysfunction and oxidative modification of mitochondrial proteins in a concentration-related manner (p < 0.05). This effect was not shared by a structurally similar MAO-I, pargyline, which lacks the hydrazine group, confirming that the mitochondrial protective effects of PZ were related to its carbonyl scavenging and not to MAO inhibition. In subsequent in vivo studies, we documented that PZ treatment begun at 15 min after controlled cortical impact TBI significantly attenuated 72-h post-injury mitochondrial respiratory dysfunction. The cortical mitochondrial respiratory protection occurred together with a significant increase in cortical tissue sparing.

Anatomical and functional outcomes following a precise, graded, dorsal laceration spinal cord injury in C57BL/6 mice.

To study the pathophysiology of spinal cord injury (SCI), we used the LISA-Vibraknife to generate a precise and reproducible dorsal laceration SCI in the mouse. The surgical procedure involved a T9 laminectomy, dural resection, and a spinal cord laceration to a precisely controlled depth. Four dorsal hemisection injuries with lesion depths of 0.5, 0.8, 1.1, and 1.4 mm, as well as normal, sham (laminectomy and dural removal only), and transection controls were examined. Assessments including the Basso Mouse Scale (BMS), footprint analysis, beam walk, toe spread reflex, Hargreaves' test, and transcranial magnetic motor-evoked potential (tcMMEP) analysis were performed to assess motor, sensorimotor, and sensory function. These outcome measures demonstrated significant increases in functional deficits as the depth of the lesion increased, and significant behavioral recovery was observed in the groups over time. Quantitative histological examination showed significant differences between the injury groups and insignificant lesion depth variance within each of the groups. Statistically significant differences were additionally found in the amount of ventral spared tissue at the lesion site between the injury groups. This novel, graded, reproducible laceration SCI model can be used in future studies to look more closely at underlying mechanisms that lead to functional deficits following SCI, as well as to determine the efficacy of therapeutic intervention strategies in the injury and recovery processes following SCI.