Importance of assessing biomarkers and physiological parameters of anemia-induced tissue hypoxia in the perioperative period

Abstract Anemia is associated with increased risk of Acute Kidney Injury (AKI), stroke and mortality in perioperative patients. We sought to understand the mechanism(s) by assessing the integrative physiological responses to anemia (kidney, brain), the degrees of anemia-induced tissue hypoxia, and associated biomarkers and physiological parameters. Experimental measurements demonstrate a linear relationship between blood Oxygen Content (CaO2) and renal microvascular PO2 (y = 0.30x + 6.9, r2= 0.75), demonstrating that renal hypoxia is proportional to the degree of anemia. This defines the kidney as a potential oxygen sensor during anemia. Further evidence of renal oxygen sensing is demonstrated by proportional increase in serum Erythropoietin (EPO) during anemia (y = 93.806*10−0.02, r2= 0.82). This data implicates systemic EPO levels as a biomarker of anemia-induced renal tissue hypoxia. By contrast, cerebral Oxygen Delivery (DO2) is defended by a profound proportional increase in Cerebral Blood Flow (CBF), minimizing tissue hypoxia in the brain, until more severe levels of anemia occur. We hypothesize that the kidney experiences profound early anemia-induced tissue hypoxia which contributes to adaptive mechanisms to preserve cerebral perfusion. At severe levels of anemia, renal hypoxia intensifies, and cerebral hypoxia occurs, possibly contributing to the mechanism(s) of AKI and stroke when adaptive mechanisms to preserve organ perfusion are overwhelmed. Clinical methods to detect renal tissue hypoxia (an early warning signal) and cerebral hypoxia (a later consequence of severe anemia) may inform clinical practice and support the assessment of clinical biomarkers (i.e., EPO) and physiological parameters (i.e., urinary PO2) of anemia-induced tissue hypoxia. This information may direct targeted treatment strategies to prevent adverse outcomes associated with anemia.

Neurophysiological and Clinical Correlates of Acute Posthypoxic Myoclonus.

SUMMARY: Prognostication following cardiorespiratory arrest relies on the neurological examination, which is supported by neuroimaging and neurophysiological testing. Acute posthypoxic myoclonus (PHM) is a clinical entity that has prognostic significance and historically has been considered an indicator of poor outcome, but this is not invariably the case. "Malignant" and more "benign" forms of acute PHM have been described and differentiating them is key in understanding their meaning in prognosis. Neurophysiological tests, electroencephalogram in particular, and clinical phenotyping are crucial in defining subtypes of acute PHM. This review describes the neurophysiological and phenotypic markers of malignant and benign forms of acute PHM, a clinical approach to evaluating acute PHM following cardiorespiratory arrest in determining prognosis, and gaps in our understanding of acute PHM that require further study.

[Response to perampanel in a patient with chronic post-hypoxic myoclonus]. / Respuesta a perampanel en un paciente con mioclono posthipóxico crónico.

INTRODUCTION: Chronic post-hypoxic myoclonus is a condition in which the predominant clinical picture is myoclonus following hypoxic brain damage, usually due to cardiorespiratory arrest. It is a condition that is usually treated with antiepileptic drugs, in most cases with a modest clinical response. CASE REPORT: We report the case of a patient who started with jerking movements, compatible with myoclonus in the four limbs and the face the day after recovering from a cardiorespiratory arrest. An electroencephalogram was performed during which the myoclonias were recorded with no electrical correlates. During admission, and in successive visits after discharge, different antiepileptic treatments were tried for the myoclonias, which were refractory and affected the patient's quality of life. Two years after onset, treatment with perampanel up to a dose of 4 mg was initiated and the patient reported a significant clinical improvement, as evidenced in the visits. CONCLUSIONS: Perampanel may be an effective alternative for the treatment of myoclonias in patients with chronic post-hypoxic myoclonus.

TITLE: Respuesta a perampanel en un paciente con mioclono posthipóxico crónico.Introducción. El mioclono posthipóxico crónico es un cuadro cuya clínica predominante son las mioclonías que acontecen tras un daño cerebral hipóxico, generalmente por parada cardiorrespiratoria. Es una entidad que se trata generalmente con fármacos antiepilépticos, con una modesta respuesta clínica en la mayoría de los casos. Caso clínico. Paciente que comienza con movimientos de sacudidas, compatibles con mioclonías de las cuatro extremidades y faciales al día siguiente de una parada cardiorrespiratoria recuperada. Se realizó un electroencefalograma durante el cual se registraron las mioclonías sin presentar correlato eléctrico. Durante el ingreso, y en sucesivas visitas tras el alta, se probaron diferentes tratamientos antiepilépticos para las mioclonías, que fueron refractarias y comportaron una afectación de la calidad de vida del paciente. Tras dos años de evolución, se inició tratamiento con perampanel hasta una dosis de 4 mg y el paciente refirió una mejoría clínica importante, evidenciada en consultas. Conclusiones. El perampanel puede suponer una alternativa eficaz para el tratamiento de las mioclonías en pacientes con mioclono posthipóxico crónico.

Recombinant Human Growth Hormone Activates Neuroprotective Growth Factors in Hypoxic Brain Injury in Neonatal Mice.

Perinatal hypoxia severely disrupts cerebral metabolic and maturational programs beyond apoptotic cell death. Antiapoptotic treatments such as erythropoietin are suggested to improve outcomes in hypoxic brain injury; however, the results are controversial. We analyzed the neuroprotective effects of recombinant human growth hormone (rhGH) on regenerative mechanisms in the hypoxic developing mouse brain in comparison to controls. Using an established model of neonatal acute hypoxia (8% O2, 6 hours), P7 mice were treated intraperitoneally with rhGH (4000 µg/kg) 0, 12, and 24 hours after hypoxic exposure. After a regeneration period of 48 hours, expression of hypoxia-inducible neurotrophic factors (erythropoietin [EPO], vascular endothelial growth factor A [VEGF-A], insulin-like growth factors 1 and 2 [IGF-1/-2], IGF binding proteins) and proinflammatory markers was analyzed. In vitro experiments were performed using primary mouse cortical neurons (E14, DIV6). rhGH increased neuronal gene expression of EPO, IGF-1, and VEGF (P < .05) in vitro and diminished apoptosis of hypoxic neurons in a dose-dependent manner. In the developing brain, rhGH treatment led to a notable reduction of apoptosis in the subventricular zone and hippocampus (P < .05), abolished hypoxia-induced downregulation of IGF-1/IGF-2 expression (P < .05), and led to a significant accumulation of endogenous EPO protein and anti-inflammatory effects through modulation of interleukin-1ß and tumor necrosis factor α signaling as well as upregulation of cerebral phosphorylated extracellularly regulated kinase 1/2 levels (ERK1/2). Indicating stabilizing effects on the blood-brain barrier (BBB), rhGH significantly modified cerebrovascular occludin expression. Thus, we conclude that rhGH mediates neuroprotective effects by the activation of endogenous neurotrophic growth factors and BBB stabilization. In addition, the modification of ERK1/2 pathways is involved in neuroprotective actions of rhGH. The present study adds further evidence that pharmacologic activation of neurotrophic growth factors may be a promising target for neonatal neuroprotection.

Increased Seizure Susceptibility for Rats Subject to Early Life Hypoxia Might Be Associated with Brain Dysfunction of NRG1-ErbB4 Signaling in Parvalbumin Interneurons.

Neuregulin 1 (NRG1)-induced activation of ErbB4 in parvalbumin (PV) inhibitory interneurons is reported to serve as a critical endogenous negative-feedback mechanism to repress brain epileptogenesis. Here, we investigated the seizure susceptibility and the role of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures for rats subject to early life hypoxia. Neonatal postnatal day 5 (P5) rats were exposed to intermittent hypoxia (IH) or control (CON) room air for 10 days. In the prefrontal cortex (PFC) of P54 rats, we determined the impact of neonatal IH exposures on the expression of PV, NRG1, ErbB4, and phosphorylated ErbB4 (p-ErbB4) during the seizure induction. Seizure susceptibility tests with the common convulsant agent pentylenetetrazole (PEN) at P54 revealed that rats subject to neonatal hypoxia exposure developed faster and more serious epileptic seizures. Neonatal IH exposures (1) decreased the number of PV cells in the PFC of P54 rats; (2) interrupted the expression of NRG1 gene; and (3) altered the activity of NRG1 on PV interneurons in the PFC after the seizure induction. Intracerebroventricular delivery of exogenous NRG1 before seizure induction by PEN significantly reduced the seizure susceptibility for neonatal IH-exposed rats. The ErbB4 inhibitor AG1478 inhibited the exogenous NRG1's effects on seizure susceptibility. Environmental enrichment (EE) rescued the abovementioned pathophysiological alterations and significantly attenuated the epileptic seizures after the seizure induction for neonatal IH-exposed rats. Our study indicated early life hypoxia exposure might increase the seizure susceptibility for rats and contribute to pathophysiological dysfunction of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures. EE might attenuate the increased seizure susceptibility for neonatal IH-exposed rats through rescuing pathophysiological alterations of NRG1-ErbB4 signaling in PV interneurons.

Chronic intermittent hypoxia transiently increases hippocampal network activity in the gamma frequency band and 4-Aminopyridine-induced hyperexcitability in vitro.

Chronic intermittent hypoxia (CIH) is the most distinct feature of obstructive sleep apnea (OSA), a common breathing and sleep disorder that leads to several neuropathological consequences, including alterations in the hippocampal network and in seizure susceptibility. However, it is currently unknown whether these alterations are permanent or remit upon normal oxygenation. Here, we investigated the effects of CIH on hippocampal spontaneous network activity and hyperexcitability in vitro and explored whether these alterations endure or fade after normal oxygenation. Results showed that applying CIH for 21 days to adult rats increases gamma-band hippocampal network activity and aggravates 4-Aminopyridine-induced epileptiform activity in vitro. Interestingly, these CIH-induced alterations remit after 30 days of normal oxygenation. Our findings indicate that hippocampal network alterations and increased seizure susceptibility induced by CIH are not permanent and can be spontaneously reverted, suggesting that therapeutic interventions against OSA in patients with epilepsy, such as surgery or continuous positive airway pressure (CPAP), could be favorable for seizure control.

The Phenomenon of Trombley-Brennan Terminal Tissue Injury in a Neonate: A Case Study.

BACKGROUND: Trombley-Brennan terminal tissue injury (TB-TTI), also known as skin failure, was first identified in 2009 among critically ill adults receiving palliative care. Identification of this skin injury can be misinterpreted as a pressure ulcer. However, this phenomenon is now accepted as an early sign of impending death among critically ill adults. CLINICAL FINDINGS: This case study describes TB-TTI in a terminally ill infant in a neonatal intensive care unit evidenced by intact, 2-cm oval skin discoloration on the lateral side of both knees with rapid progression in size. PRIMARY DIAGNOSIS: TB-TTI was identified on the day of death in an infant with a primary diagnosis of hypoxic-ischemic encephalopathy born at 32 weeks' gestation. INTERVENTIONS: The neonatal intensive care unit (NICU) team mobilized the NICU advanced care team, institution's ethical council, and "Team Lavender" to provide infant comfort measures and emotional support to the family and care givers. OUTCOMES: Infant death occurred 8 hours after TB-TTI was identified. PRACTICE RECOMMENDATIONS: To our knowledge, this case study of TB-TTI in a terminally ill neonate in the NICU has not been previously described in the neonatal or pediatric population. Early recognition of the phenomenon can enable the healthcare team to provide timely emotional, spiritual, and psychosocial support to the family and allow time to "be present" with the infant at "end of life." Future work should explore additional signs of TB-TTI and the occurrence rate.

Proposed safe apnea test using positive end-expiratory pressure valve and short-term blood gas analysis: Observational study.

The apnea test is an essential examination for the determination of brain death; however, hypotension, hypoxemia, and other complications during the apnea test can affect the stability of brain-dead patients, as well as organ function for recipients. Therefore, it is necessary to establish standard guidelines for apnea testing.The modified apnea test (MAT) comprises delivery of 100% oxygen through the endotracheal tube connected to manual resuscitator (Ambu bag) with the positive end-expiratory pressure (PEEP) valve after disconnection of the mechanical ventilator for maintenance of PEEP. Forty-nine instances of the conventional apnea test (CAT) were performed in 25 brain-dead patients; 77 instances of the MAT were performed in 39 brain-dead patients.The mean duration of the apnea test was 3.5 ±â€Š1.4 minutes in the CAT group and 3.0 ±â€Š1.2 minutes in the MAT group. There were no significant changes in PaCO2, PaO2, or pH between the CAT and MAT groups (P = .341, .593, and .503, respectively). In overweight patients (body mass index ≥ 23 kg/m), MAT prevented dramatic reductions in PaO2 and SaO2 (P < .05 for both). In the patients who had hypoxic brain injury due to hanging, differences in PaO2 and SaO2 in the MAT group were significantly smaller than in the CAT group (P < .05).Although MAT, which was invented to maintain PEEP, was not efficient for all brain-dead patients, it could be helpful in selected patient groups, such as overweight patients or those who had hypoxic injury due to hanging. And clinicians should consider short-term apnea test to avoid unnecessarily prolonged hypoxemia.

Feasibility and Safety of Transnasal High Flow Air to Reduce Core Body Temperature in Febrile Neurocritical Care Patients: A Pilot Study.

BACKGROUND: Fever is an important determinant of prognosis following acute brain injury. Current non-pharmacologic techniques to reduce fever are limited and induce a shivering response. We investigated the safety and efficacy of a novel transnasal unidirectional high flow air device in reducing core body temperature in the neurocritical care unit (NCCU) setting. METHODS: This pilot study included seven consecutive patients in the NCCU who were febrile (> 37.5 °C) for > 24 h despite standard non-pharmacologic and first-line antipyretic agents. Medical grade high flow air was delivered transnasally using a standard continuous positive airway pressure machine with a positive pressure of 20 cmH2O for 2 h. Core esophageal and tympanic temperature were continuously monitored. RESULTS: Mean age was 40 ± 14 yo, and 72% (5/7 patients) were men. Five patients had intracerebral or intraventricular hemorrhage, one subject had transverse myelitis, and the remaining patient had anoxic brain injury due to a cardiac arrest. After 2 h of cooling, core temperature was significantly lower than the baseline pre-cooling temperature (37.3 ± 0.5 °C vs. 38.4 ± 0.6 °C; p < 0.002). Mean transnasal airflow rate was 57.5 ± 6.5 liters per minute. Five of the seven subjects were normothermic at the end of the 2-h period. One subject with severe hyperthermia (39.7 °C) and the other with multiple interruptions to therapy due to technical reasons did not cool. The core temperature within 30 min of cessation of airflow increased and was similar to the pre-cooling baseline temperature (38.3 ± 0.4 °C vs. 38.4 ± 0.6 °C, p = NS). Rate of core cooling was 0.6 ± 0.15 °C per hour at this flow rate. No shivering response was observed. No protocol-related adverse events occurred. CONCLUSIONS: High flow transnasal air in a unidirectional fashion lowers core body temperature in febrile patients in the NCCU setting. No adverse events were seen, and the process showed no signs of shivering or any other serious side effects during short-term exposure. This pilot study should inform further investigation.

[Case of pneumonia associated sepsis accompaning pulmonary myiasis]. / Pulmoner miyazisin eslik ettigi pnömoniye bagli sepsis olgusu.

Myiasis; is defined as the infestation of dead or living tissues of humans and animals by the diptera larvae. It is prevalent all over the world, especially in tropical and subtropical countries with low socioeconomic status. Myiasis of humans has been associated with low socioeconomic status, alcoholism, mental or neurological diseases, poor personal hygiene, patients with varicose veins, diabetes, malnutrition, advanced stage cancer, pediculosis, immunosuppression, sexually transmitted disease, gingivitis and other oral cavity lesions. Myiasis is most commonly seen as skin invasion in the human body, but can be observed in many areas such as eye, ear, nose, throat, urogenital, intestinal, cerebral and tracheopulmonary. Tracheo pulmonary myiasis is a very rare condition. This report presents a case of pneumonia-associated sepsis in a patient with a tracheostomy accompanied by third-stage larval Sarcophagidae. A 51-year-old male patient developed hypoxic brain injury after myocardial infarction 10 months ago before his admission to the hospital. Tracheostomy and percutaneous endoscopic gastrostomy were performed. Shortness of breath and fever were present for five days. The patient has been admitted to the emergency service with the reason for the deterioration of the general situation. The patient was unconscious. Purulent secretion in the tracheostomy area and bilateral crepitation rales in the lung bases were detected. Leukocyte level was normal with C reactive protein (CRP) 14 mg/dl. Nodular infiltration was detected bilaterally in the middle and lower zones, more prominently in the right thoracic computerized tomography. Seftriaxon, moxifloxacin and fluid therapy were initiated in the patient who was admitted with pneumonia-related sepsis diagnosis. The tracheostomy cannula has changed. On the fourth day of admission, Sarcophagidae third stage larvae were detected in deep tracheal aspiration. Treatment of piperacillin/tazobactam and teicoplanin was started by discontinuing the current antibiotherapy of the patient who had no clinical response and elevated CRP level, 18 mg/dl. The patient was discharged on the 25th day of hospitalization with improved clinical and laboratory responses. Complete healing was observed in the control performed by the home care unit. Bed-dependent, lack of self-care, and poor tracheostomy hygiene were risk factors for this patient. In this case, fluid therapy and antibiotic treatment for sepsis was given but no treatment for myiasis. Larva has been considered to have prepared a base for pneumonia due to the foreign body effect and secretion accumulation. Untreated injuries, especially those with impaired oxygenation, leave the eggs of adult flies and provide a suitable environment for larval development. Therefore, should be given importance to combat with flies and regular tracheostomy care in bedside and tracheostomized patients.

Ameliorative Effect of Trans-Sinapic Acid and its Protective Role in Cerebral Hypoxia in Aluminium Chloride Induced Dementia of Alzheimer's Type.

BACKGROUND: Trans-Sinapic Acid is a bioactive compound. Recent studies showed that it has a significant potential to attenuate various chemically induced Neurodegenerative toxicities. AIM: The present study investigates the potential of trans-Sinapic Acid as neuromodulator and its effect on release of Monoamine Oxidase (MAO-A, MAO-B), TNF-α, Acetylcholine esterase Enzyme, in cognitive dysfunctions associated with experimental dementia. Experiment: Aluminium chloride was administered at a dose of 175mg/kg, p.o. for a period of 25 days in rats and then divided into different groups, i.e. Treatment group, negative control and two groups of trans- Sinapic Acid, (at a dose of 30 and 60mg/kg, p.o.), where these groups treated and observed until the 35th day of experimental trial. Morris water Maze (MWM) and Photoactometer was used to access learning, memory and ambulatory movements on 5th, 16th, 26th and 36th day of experiment. Later, the animals were sacrificed for biochemical and histopahological studies. The oxidative stress was measured by estimating the levels of Glutathion (GSH), Superoxide dismutase (SOD), Nitrite, Catalase. Brain acetylcholine esterase (Ache) activity and Monoamine oxidase (MAO-A, MAO-B) were also estimated. The Brain level of TNF-α was measured as a marker of inflammation. RESULTS: Aluminium chloride (AlCl3) produced a marked decline in MWM performance and ambulatory movements' of animals, reflecting impairment of memory and learning. Trans-Sinapic Acid treatment significantly modulates AlCl3 induced memory deficits, biochemical and pathological alterations. The findings demonstrate that the memory restorative ability of trans-Sinapic Acid may be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory potential.

Resection of neurogenic heterotopic ossification (NHO) of the hip.

Neurogenic heterotopic ossification of the hip is secondary to neurologic lesions such as cranial trauma, stroke, medullary injury or cerebral anoxia. We shall not deal here with the other etiologies of heterotopic ossification. There are numerous locations within the hip, depending on etiology and relations with adjacent neurovascular structures are sometimes close. Preoperative work-up should include contrast-enhanced CT; scintigraphy is non-contributive. Indications for surgery are decided in a multidisciplinary team meeting, with a contract laying out expected functional gain. It is this contract that determines the extent of resection, without seeking complete resection, which would incur an increased risk of complications. The surgical approach and resection strategy depend on lesion location and any resulting neurovascular compression. The most common complications are infection and postoperative hematoma. No adjuvant treatments have demonstrated efficacy against recurrence.

Sonic Hedgehog Agonist Protects Against Complex Neonatal Cerebellar Injury.

The cerebellum undergoes rapid growth during the third trimester and is vulnerable to injury and deficient growth in infants born prematurely. Factors associated with preterm cerebellar hypoplasia include chronic lung disease and postnatal glucocorticoid administration. We modeled chronic hypoxemia and glucocorticoid administration in neonatal mice to study whole cerebellar and cell type-specific effects of dual exposure. Chronic neonatal hypoxia resulted in permanent cerebellar hypoplasia. This was compounded by administration of prednisolone as shown by greater volume loss and Purkinje cell death. In the setting of hypoxia and prednisolone, administration of a small molecule Smoothened-Hedgehog agonist (SAG) preserved cerebellar volume and protected against Purkinje cell death. Such protective effects were observed even when SAG was given as a one-time dose after dual insult. To model complex injury and determine cell type-specific roles for the hypoxia inducible factor (HIF) pathway, we performed conditional knockout of von Hippel Lindau (VHL) to hyperactivate HIF1α in cerebellar granule neuron precursors (CGNP) or Purkinje cells. Surprisingly, HIF activation in either cell type resulted in no cerebellar deficit. However, in mice administered prednisolone, HIF overactivation in CGNPs resulted in significant cerebellar hypoplasia, whereas HIF overactivation in Purkinje cells caused cell death. Together, these findings indicate that HIF primes both cell types for injury via glucocorticoids, and that hypoxia/HIF + postnatal glucocorticoid administration act on distinct cellular pathways to cause cerebellar injury. They further suggest that SAG is neuroprotective in the setting of complex neonatal cerebellar injury.

Vertical Head Thrusting in Acquired Supranuclear Vertical Ophthalmoplegia.

Patients with congenital ocular motor apraxia (OMA) typically show head thrusts while attempting to shift gaze. In congenital OMA, this compensatory head motion mostly occurs in the horizontal plane. Two patients with acquired palsy of voluntary vertical gaze and continuous upward gaze deviation, one from aortic surgery and the other from multiple infarctions involving the mesodiencephalic junction, showed intermittent downward head thrusting to redirect the eyes straight ahead or downward. The head thrusting behavior improved markedly after surgical correction of the upward gaze deviation in one patient. Vertical head thrusting may be a characteristic sign of acquired vertical gaze palsy when combined with vertical gaze deviation.

Internal carotid artery blood flow in healthy awake subjects is reduced by simulated hypovolemia and noninvasive mechanical ventilation.

Intact cerebral blood flow (CBF) is essential for cerebral metabolism and function, whereas hypoperfusion in relation to hypovolemia and hypocapnia can lead to severe cerebral damage. This study was designed to assess internal carotid artery blood flow (ICA-BF) during simulated hypovolemia and noninvasive positive pressure ventilation (PPV) in young healthy humans. Beat-by-beat blood velocity (ICA and aorta) were measured by Doppler ultrasound during normovolemia and simulated hypovolemia (lower body negative pressure), with or without PPV in 15 awake subjects. Heart rate, plethysmographic finger arterial pressure, respiratory frequency, and end-tidal CO2 (ETCO2) were also recorded. Cardiac index (CI) and ICA-BF were calculated beat-by-beat. Medians and 95% confidence intervals and Wilcoxon signed rank test for paired samples were used to test the difference between conditions. Effects on ICA-BF were modeled by linear mixed-effects regression analysis. During spontaneous breathing, ICA-BF was reduced from normovolemia (247, 202-284 mL/min) to hypovolemia (218, 194-271 mL/min). During combined PPV and hypovolemia, ICA-BF decreased by 15% (200, 152-231 mL/min, P = 0.001). Regression analysis attributed this fall to concurrent reductions in CI (ß: 43.2, SE: 17.1, P = 0.013) and ETCO2 (ß: 32.8, SE: 9.3, P = 0.001). Mean arterial pressure was maintained and did not contribute to ICA-BF variance. In healthy awake subjects, ICA-BF was significantly reduced during simulated hypovolemia combined with noninvasive PPV Reductions in CI and ETCO2 had additive effects on ICA-BF reduction. In hypovolemic patients, even low-pressure noninvasive ventilation may cause clinically relevant reductions in CBF, despite maintained arterial blood pressure.

Visuo-spatial memory deficits following medial temporal lobe damage: A comparison of three patient groups.

The contributions of the hippocampal formation and adjacent regions of the medial temporal lobe (MTL) to memory are still a matter of debate. It is currently unclear, to what extent discrepancies between previous human lesion studies may have been caused by the choice of distinct patient models of MTL dysfunction, as disorders affecting this region differ in selectivity, laterality and mechanisms of post-lesional compensation. Here, we investigated the performance of three distinct patient groups with lesions to the MTL with a battery of visuo-spatial short-term memory tasks. Thirty-one subjects with either unilateral damage to the MTL (postsurgical lesions following resection of a benign brain tumor, 6 right-sided lesions, 5 left) or bilateral damage (10 post-encephalitic lesions, 10 post-anoxic lesions) performed a series of tasks requiring short-term memory of colors, locations or color-location associations. We have shown previously that performance in the association task critically depends on hippocampal integrity. Patients with postsurgical damage of the MTL showed deficient performance in the association task, but performed normally in color and location tasks. Patients with left-sided lesions were almost as impaired as patients with right-sided lesions. Patients with bilateral post-encephalitic lesions showed comparable damage to MTL sub-regions and performed similarly to patients with postsurgical lesions in the association task. However, post-encephalitic patients showed additional impairments in the non-associative color and location tasks. A strikingly similar pattern of deficits was observed in post-anoxic patients. These results suggest a distinct cerebral organization of associative and non-associative short-term memory that was differentially affected in the three patient groups. Thus, while all patient groups may provide appropriate models of medial temporal lobe dysfunction in associative visuo-spatial short-term memory, additional deficits in non-associative memory tasks likely reflect damage of regions outside the MTL. Importantly, the choice of a patient model in human lesion studies of the MTL significantly influences overall performance patterns in visuo-spatial memory tasks.

Dopamine treatment during acute hypoxia is neuroprotective in the developing sheep brain.

Dopamine is often used to treat hypotension in preterm infants; these infants are at risk of developing brain injury due to impaired autoregulation and cerebral hypoperfusion. However the effects of dopamine on the immature brain under conditions of cerebral hypoxia are not known. We hypothesized that pretreatment with dopamine would protect the immature brain from injury caused by cerebral hypoxia. Preterm fetal sheep were used to determine the effects of intravenous dopamine on hypoxia-induced brain injury. In 16 pregnant sheep at 90days of gestation (0.6 of term, term=147days) catheters were implanted aseptically into the fetal carotid artery and jugular vein; an inflatable occluder was placed loosely around the umbilical cord for later induction of fetal hypoxemia. At 5days after surgery, dopamine (10µg/kg/min, n=7 fetuses) or saline (n=9 fetuses) was infused for 74h. Two hours after commencing the dopamine/saline infusion, we induced umbilical cord occlusion (UCO) for up to 25min to produce fetal asphyxia. Fetuses were allowed to recover, and brains were collected 72h later for assessment of neuropathology. Un-operated twin fetuses were used as age-matched non-UCO controls (n=8). In UCO+saline fetuses, microglial and apoptotic cell density in the subcortical and periventricular white matter, caudate nucleus and hippocampus was greater than that in age-matched controls; oxidative stress was elevated in the subcortical and periventricular white matter and caudate nucleus compared to that in age-matched controls. In UCO+dopamine fetuses microglial density and oxidative stress in the cerebral white matter and caudate nucleus were not different to that of age-matched controls. Apoptotic cell death was decreased in the cerebral white matter of UCO+dopamine brains, relative to UCO+saline brains. We conclude that pretreatment with dopamine does not exacerbate hypoxia-induced injury in the immature brain and may be neuroprotective because it led to decreased apoptosis, oxidative stress and neuroinflammation in the cerebral white matter and decreased neuroinflammation in the caudate nucleus.

Thymosin ß4 inhibits microglia activation through microRNA 146a in neonatal rats following hypoxia injury.

Neuroinflammation mediated by activated microglia plays a pivotal role in the pathogenesis of neurological disorders, including hypoxic injury of the developing brain. Thymosin ß4 (Tß4), the major G-actin-sequestering molecule, has an anti-inflammatory effect and has been used to treat various neurological diseases. However, the effect of Tß4 on hypoxia-induced microglia activation in the developing brain remains unclear. We investigate here the effect of Tß4 on microglia activation of neonatal rats after hypoxia exposure. Tß4 treatment was carried out on 1-day-old rats and BV-2 cells. Tß4 expression in microglia was determined by quantitative real time-PCR, western blotting, and immunofluorescence staining. Secretion of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and nitric oxide (NO) was assessed by enzyme-linked immunosorbent assay and colorimetric assay. mRNA expression of TNF-α and IL-1ß, and microRNA 146a expression was determined by quantitative real time-PCR. We showed that Tß4 treatment significantly inhibited secretion of inflammatory mediators in the cerebellum of neonatal rats following hypoxia injury. Increased expression of endogenous Tß4 in microglia was observed both in hypoxic rats and in BV-2 cells. Tß4 treatment significantly inhibited the expression and secretion of hypoxia-induced TNF-α, IL-1ß, and NO. Remarkably, microRNA 146a expression was found to have increased in Tß4-treated BV-2 cells. We demonstrated the anti-inflammatory effect of Tß4 in neonatal rats following hypoxic brain injury. More importantly, our data reveal, for the first time, that Tß4 inhibits microglia activation in vitro. Therefore, this study contributes to understanding the role and mechanism of Tß4 function in central nervous system diseases.