Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome.

ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369

Effect of neutralization of rat IL-6 bioactivity on collateral blood supply from retrograde flow via cortical anastomoses in the rat central nervous system

PubMedID: 12069291The purpose of this study was to determine whether neutralization of rat interleukin-6 (IL-6) bioactivity increases the collateral blood supply from retrograde flow via the major middle cerebral artery branches after experimental middle cerebral artery occlusion in the rat. Seventy rats were randomly allocated to four main groups: Group I (n = 10) consisted of normal controls; Group II (n = 20) underwent craniectomy only; Group III (n = 20) was subjected to middle cerebral artery occlusion; and Group IV (n = 20) underwent middle cerebral artery occlusion and treatment with anti-rat IL-6 antibody. Half of the rats from each of Groups II, III and IV were killed at 24 h and the other half at 72 h after craniectomy alone or occlusion. A single dose of antibody did not affect middle cerebral artery caliber, but administration of three doses resulted in a significant increase in the diameter of middle cerebral artery compared to the findings in the corresponding occlusion-only groups. The results suggest that neutralization of rat IL-6 bioactivity in long-term recovery increases the collateral blood supply from retrograde flow via cortical anastomoses after experimental arterial occlusion in the rat brain

Effect of thyrotropin releasing hormone on the cerebral artery after CO2 laser induced lesion

[No abstract available

The effects of trapidil on fibroblastic activity, schwann cell proliferation, and platelet-derived growth factor receptor levels in the experimental sciatic nerve injury

BACKGROUND: Trapidil, an antianginal drug with inhibitory effects on platelet-derived growth factor (PDGF), has been shown to reduce reactive fibrosis in models of central nervous system injury. Therefore, we evaluated trapidil's effects on fibroblast activity, Schwann cell proliferation, and PDGF receptor levels in rats after transection and anastomosis of the sciatic nerve. We also evaluated the effect of Schwann cell proliferation on regeneration of anastomosed sciatic nerves. METHODS: Wistar rats were randomly divided into 3 groups. Group 1 (N?10) was used to determine normal peripheral nerve morphology (via light and electron microscopy) and PDGF receptor levels. Group 2 (N?20) underwent sciatic nerve anastomosis after nerve transection to examine the influence of the surgical procedure on PDGF receptor levels and the microscopic findings. Group 3 (20 rats) received a single intraperitoneal dose of trapidil (40 mg/kg) immediately after the surgical procedure to investigate its effects on fibroblast activity, Schwann cell proliferation, and PDGF levels. RESULTS: PDGF-A and PDGF-B receptor levels were lower in group 3, the trapidil-treated group, than group 2 on all posttransection days examined. Ultrastructural analysis revealed that group 3 also had lower levels of fibroblast activity and Schwann cell proliferation than group 2. However, the peripheral nerve ultrastructure and degree of axonal regeneration were similar between groups 2 and 3 at 14 days posttransection. CONCLUSIONS: Trapidil treatment significantly decreased reactive fibrosis and PDGF receptor expression after peripheral nerve injury, and thus, may be useful therapeutically. These results also suggest that Schwann cells alone are not effective in promoting neurite formation. © 2008 by Lippincott Williams & Wilkins

The effect of thyrotropin releasing hormone on carbon dioxide laser induced lesion of the cerebral artery

PubMedID: 9090641Carbon dioxide laser which is used widely in neurosurgery has less traumatic effect on the tissue beside the lesion than other types of laser. There has been little study on the changes to the vascular tissue, following laser application. We performed a study on 4 groups of dogs; comprising craniectomy only, craniectomy and thyrotropin releasing hormone (TRH), craniectomy and laser, and craniectomy, laser and TRH. We applied CO2 laser on the angular artery of two groups of dogs. To one group we infused TRH for 15 days following the laser application and to the other group we did not. We investigated the ultrastructural and biochemical changes and the effect of TRH on the tissue 15 days following laser application. In our study, we observed an increase in superoxide dismutase activity and a decrease in ATP- ase activities in the degenerated tissue on which CO2 laser was applied. TRH partially prevented the vascular degeneration of CO2 laser but did not significantly change superoxide dismutase and Adenosine-5'-triphosphatase activities

Effect of naloxone after spinal cord injury in the rat: Inducible nitric oxide synthase expression, superoxide dismutase activity, and ultrastructural changes

Endorphins have been implicated in the pathophysiology of spinal cord injury (SCI). Although some possible mechanisms for the therapeutic actions of naloxone have been postulated, the exact mechanism of these favorable actions is not yet known with certainty. The benefit of naloxone in the recovery of neurologic function has generally been attributed to its action at the opiate receptors. The effect of naloxone on the inducible nitric oxide synthase (iNOS) immunoreactivity, superoxide dismutase (SOD) level, and ultrastructural findings were studied in rats at the early and late stages of SCI, produced with an aneurysm clip on the T2 to T7 segments. Seventy rats were randomly allocated to 4 groups. The animals in group 1 (10 rats) were killed to provide normal spinal cord tissue for testing. Group 2 (20 rats) underwent 6-segment laminectomy so that the effects of total laminectomy could be determined. Group 3 (20 rats) underwent 6-segment T2 to T7 laminectomy, and SCI was produced by extradural compression of the exposed cord. The same procedures were performed in the 20 rats in group 4, but these rats also received 1 (2 mg/kg) intraperitoneal injection of naloxone immediately after the injury, a second dose 24 hours after trauma, and a third dose 48 hours after trauma. Half of the animals from groups 3 and 4 were killed 2 hours after trauma, and the other half were killed 48 hours after trauma. The exposed cord segments were immediately removed and processed for analysis. The results showed that naloxone treatment reduces secondary structural changes in damaged rat spinal cord tissue by affecting iNOS and SOD activity

Effect of dexamethasone, barbiturate and hypothermy on edema induced by CO2 laser brain lesion in the dog: Light and electron microscopic study

PubMedID: 8738363Experiments were carried out to compare the effectiveness of dexamethasone, a barbiturate, and hypothermy on experimental cerebral edema caused by CO2 laser in dogs. Experimental brain lesions were created over the right frontal cortex of the dogs through the intact dura mater with CO2 laser energy (40 W impact, 0,5 second duration, for a total time of 4 seconds on a 12.5 mm surface). Animals were divided into four groups and treated with dexamethasone, a barbiturate, hypothermy, and a crystalloid (control group). The brains were examined 48 hours after injury. Histologically all brain lesions showed three distinct layers with a vaporized center bordered by a zone of coagulation necrosis surrounded by edema. The main finding in the surrounding coagulation and edematous layers was dilatation of the vessels. Hemorrhage was sometimes observed mainly in the edematous layer. The effect of these therapies on the laser lesion and the effectiveness of these therapies on surrounding cerebral edema were evaluated by both light and electron microscopy. The control group showed significantly greater edema than the dexamethasone group. There was only a minimal difference between the control group and the barbiturate group, and there was no significant difference in amount of edema between control group and the hypothermy group. There was less edema in the dexamethasone group than in the other ones. These data suggest that dexamethasone inhibits edema in CO2 laser lesions with the same efficacy as shown in the treatment of vasogenic edema

The effect of immediate decompression on the optic nerve in retrobulbar hematoma

PubMedID: 8875505We produced retrobulbar hematoma in both orbits of 10 pigs in order to assess the effects of blood elements and pressure created by the hematoma on the optic nerves. Ten other pigs were used as a control group. Following decompression in the right orbits, ocular movements, fundi, and intraocular pressure were evaluated for 6 weeks. At the end of the 6th week the optic nerves of 20 pigs were dissected bilaterally for measurements of ATP-ase activity and ultrastructural examination. The results of the ultrastructural examination of the optic nerves of the control group were normal. Optic nerves with decompressed retrobulbar hematoma showed minimal degeneration, whereas the nerves subjected to retrobulbar hematoma with no decompression showed significant degenerative changes. For all groups ATP-ase activities were measured and evaluated. Na+,K+ ATP-ase activities decreased, while Ca++, Mg++ ATP-ase activities increased with the extent of degeneration. Optic nerve damage can develop after trauma. Decompression procedures are not among the causes of optic nerve degeneration but retrobulbar hematoma can result in optic neuropathy caused by the compression from the hematoma and the direct effect of blood waste products on the optic nerve