Xiao-Xu-Ming decoction prevented hemorrhagic transformation induced by acute hyperglycemia through inhibiting AGE-RAGE-mediated neuroinflammation.

Stroke is one of the leading causes of death worldwide. Hemorrhagic transformation (HT) is a common serious complication of ischemic stroke (IS) and is related to poor prognosis. Hyperglycemia after stroke is associated with the occurrence of HT and seriously affects the clinical treatment of stroke. Our previous experiments demonstrated that the Xiao-Xu-Ming decoction effective components group (XXMD), which is a Chinese medicine formula reconstituted by active ingredients, has multiple pharmacological effects in the treatment of IS. However, the effects of XXMD on HT after IS remain unclear. Thus, we investigated the preventive effects of XXMD on hyperglycemia-induced HT and further explored the underlying mechanism. Acute hyperglycemia combined with the electrocoagulation cerebral ischemia model was used to establish the HT model. XXMD (37.5, 75, 150 mg/kg/d) was given by gavage for 5 days. Network pharmacology was used to predict potential targets and pathways of XXMD in HT occurrence, and further studies confirmed the related targets. The results showed that hyperglycemia aggravated neurological deficits and blood-brain barrier (BBB) disruption, leading to intracerebral hemorrhage. Pretreatment with XXMD improved neurological function and BBB integrity and inhibited HT occurrence. Network pharmacology revealed that AGE-RAGE-mediated neuroinflammation may be associated with hyperglycemia-induced HT. Further studies confirmed that hyperglycemia activated the AGE-RAGE signaling pathway, increased the expression of HMGB1, TLR4 and p-p65, and induced the release of inflammatory factors and neutrophil infiltration, leading to HT. XXMD could inhibit AGE-RAGE-mediated neuroinflammation. These findings indicated that pretreatment with XXMD alleviated hyperglycemia-induced HT, which may be associated with the inhibition of AGE-RAGE-mediated neuroinflammation. Therefore, XXMD may be a potential therapeutic drug for HT.

Salvianolic acid A prevented cerebrovascular endothelial injury caused by acute ischemic stroke through inhibiting the Src signaling pathway.

Stroke is an acute cerebrovascular disease caused by ruptured or blocked blood vessels. For the prevention of ischemic stroke, the coagulation state of blood and cerebrovascular protection should be considered. Our previous study has shown that salvianolic acid A (SAA), which is a water-soluble component from the root of Salvia Miltiorrhiza Bge, prevents thrombosis with a mild inhibitory effect on platelet aggregation. In this study we investigated the preventive effects of SAA on cerebrovascular endothelial injury caused by ischemia in vivo and oxygen-glucose deprivation (OGD) in vitro, and explored the underlying mechanisms. An autologous thrombus stroke model was established in SD rats by electrocoagulation. SAA (10 mg/kg) was orally administered twice a day for 5 days before the operation. The rats were sacrificed at 24 h after the operation. We showed that pretreatment with SAA significantly improved the neurological deficits, intracerebral hemorrhage, BBB disruption, and vascular endothelial dysfunction as compared with model group. In human brain microvascular endothelial cells (HBMECs), pretreatment with SAA (10 µM) significantly inhibited OGD-induced cell viability reduction and degradation of tight junction proteins (ZO-1, occludin, claudin-5). Furthermore, we found that SAA inhibited the upregulation of Src signaling pathway in vivo and vitro and reversed the increased expression of matrix metalloproteinases (MMPs) after ischemic stroke. In conclusion, our results suggest that SAA protects cerebrovascular endothelial cells against ischemia and OGD injury via suppressing Src signaling pathway. These findings show that pretreatment with SAA is a potential therapeutic strategy for the prevention of ischemic stroke.

Protective effects of medicinal plant breviscapine on postcerebral hemorrhage in rats.

Medicinal plant breviscapine is shown to exhibit a protective role in tissue damage after cerebral hemorrhage. The effects of breviscapine on neurological deficit score, brain tissue water content, brain pathological tissue changes, blood-brain barrier bidirectional regulation, and inflammatory factors after cerebral hemorrhage in rats were observed. Western blot and real-time quantitative polymerase chain reaction were performed to explore how Periostin and nuclear factor kappa-B pathway-related factors protein expression contribute to the protective effects of breviscapine on brain injury. Breviscapine inhalation could reduce neurological deficit scores and brain tissue water content. Hematoxylin-eosin staining showed that breviscapine could improve the pathological changes of brain tissue and alleviate brain damage. Breviscapine reduced the abnormal increase of Evans blue content caused by a cerebral hemorrhage, and could significantly inhibit the levels of inflammatory factors interleukin-6 and tumor necrosis factor-α. Also, breviscapine significantly inhibited the expressions of Periostin and nuclear factor kappa-B pathway-related factors after cerebral hemorrhage, and alleviate brain damage by down-regulating Periostin expression and inhibiting nuclear factor kappa-ß signaling pathway.

Implementing Delayed Umbilical Cord Clamping in Cesarean Birth Using a Novel Method: A Pilot Study of Feasibility and Safety.

INTRODUCTION: Although delayed cord clamping (DCC) is regarded as the standard of care for all vigorous newborns, those born via cesarean birth are less likely to be afforded this option, especially for longer than 30 to 60 seconds. This pilot study was undertaken to determine whether removal of the placenta before cord clamping to allow for DCC of at least 3 minutes during term, uncomplicated cesarean birth is feasible and without apparent safety issues in order to support a large prospective study on the benefits of this method. METHODS: Women having a term, uncomplicated cesarean birth who consented to the study were enrolled. Safety was assessed by comparing estimated maternal blood loss, newborn Apgar scores, temperatures, transcutaneous bilirubin levels, need for phototherapy, and neonatal intensive care unit admissions with a matched historical control group of women whose newborns had immediate cord clamping. Feasibility was measured by evaluating staff and maternal comfort with the intervention and by the ability to complete the protocol steps. RESULTS: Seventeen women consented to participate. The protocol was successfully completed in 94% of births. There were no differences in maternal and neonatal safety outcome measures between groups. There was high comfort level with the protocol among staff, and there was universal maternal satisfaction. DISCUSSION: This method of DCC in cesarean birth appears feasible and safe in this small pilot study and was associated with high maternal satisfaction and clinician comfort. Major organizations such as the American College of Nurse-Midwives and the World Health Organization have called for DCC of up to 3 to 5 minutes in all births, and this simple method has the potential to reach that goal in cesarean birth with minimal apparent risk. A large randomized controlled trial is warranted to determine the neonatal and maternal benefits and safety of this technique compared with a 30-to-60-second delay.

Verbascoside attenuates acute inflammatory injury in experimental cerebral hemorrhage by suppressing TLR4.

Cerebral hemorrhage (ICH) is a common cerebrovascular condition with high mortality, disability and recurrence rates. TLR4-mediated acute inflammatory injury plays a pivotal role in ICH. Verbascoside (VB) is an active component of multiple medicinal plants, and exerts neuroprotective effects in ischemic stroke by targeting the inflammatory response. However, the effects of VB on ICH and the underlying mechanisms remain unclear. In this study, we analyzed the therapeutic effects of VB on acute ICH, and the possible involvement of TLR4-mediated inflammation. VB improved the behavioral score and reduced the hematoma volume, brain edema and neuronal apoptosis in a murine model of acute ICH. Mechanistically, VB attenuated macroglia activation and decreased inflammatory factor levels, which in turn protected the neurons. Furthermore, TLR4 knockout abolished the effects of VB both in vivo and in vitro. Taken together, VB attenuates the symptoms of ICH by targeting the TLR4-mediated acute inflammatory response.

Disrupting interaction of PSD-95 with nNOS attenuates hemorrhage-induced thalamic pain.

Hemorrhages occurring within the thalamus lead to a pain syndrome. Clinical treatment of thalamic pain is ineffective, at least in part, due to the elusive mechanisms that underlie the induction and maintenance of thalamic pain. The present study investigated the possible contribution of a protein-protein interaction between postsynaptic density protein 95 (PSD-95) and neuronal nitric oxide synthase (nNOS) to thalamic pain in mice. Thalamic hemorrhage was induced by microinjection of type IV collagenase into unilateral ventral posterior medial/lateral nuclei of the thalamus. Pain hypersensitivities, including mechanical allodynia, heat hyperalgesia, and cold allodynia, appeared at day 1 post-microinjection, reached a peak 5-7 days post-microinjection, and persisted for at least 28 days post-microinjection on the contralateral side. Systemic pre-treatment (but not post-treatment) of ZL006, a small molecule that disrupts PSD-95-nNOS interaction, alleviated these pain hypersensitivities. This effect is dose-dependent. Mechanistically, ZL006 blocked the hemorrhage-induced increase of binding of PSD-95 with nNOS and membrane translocation of nNOS in thalamic neurons. Our findings suggest that the protein-protein interaction between PSD-95 and nNOS in the thalamus plays a significant role in the induction of thalamic pain. This interaction may be a promising therapeutic target in the clinical management of hemorrhage-induced thalamic pain.

Sodium tanshinone IIA sulfonate promotes endothelial integrity via regulating VE-cadherin dynamics and RhoA/ROCK-mediated cellular contractility and prevents atorvastatin-induced intracerebral hemorrhage in zebrafish.

Impaired vascular integrity leads to serious cerebral vascular diseases such as intracerebral hemorrhage (ICH). In addition, high-dose statin therapy is suggested to cause increased ICH risk due to unclear effects of general inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) on the vascular system. Here we evaluated the protective effects of sodium tanshinone IIA sulfonate (STS), which has high efficacy and safety in clinical studies of ischemic stroke, by using atorvastatin (Ator) induced ICH zebrafish embryos and human umbilical vein endothelial cells (HUVECs). By using double transgenic Tg(fli1a:EGFP)y1 & Tg(gata1a:dsRed)sd2 zebrafish, we demonstrated that STS effectively reduced the occurrence and area of hemorrhage induced by Ator in zebrafish and restored impairment in motor function. We further demonstrated that Ator-induced disruption in VE-cadherin (VEC)-containing cell-cell adherens junctions (AJs) in HUVECs by enhancing Src-induced VEC internalization and RhoA/ROCK-mediated cellular contraction. STS inhibited Ator-induced Src activation and subsequent VEC internalization and actin depolymerization near cell borders, reducing lesions between neighboring cells and increasing barrier functions. STS also inhibited the Ator-induced RhoA/ROCK-mediated cellular contraction by regulating downstream LIMK/cofilin and MYPT1/MLC phosphatase signaling. These results showed that STS significantly promoted the stability of cell junctions and vascular integrity. Moreover, we observed that regulations of both Src and RhoA/ROCK are required for the maintenance of vascular integrity, and Src inhibitor (PP2) or ROCK inhibitors (fasudil and H1152) alone could not reduce the occurrence Ator-induced ICH. Taken together, we investigated the underlying mechanisms of Ator-induced endothelial instability, and provided scientific evidences of STS as potential ICH therapeutics by promoting vascular integrity.

Miconazole protects blood vessels from MMP9-dependent rupture and hemorrhage.

Hemorrhagic stroke accounts for 10-15% of all strokes and is strongly associated with mortality and morbidity worldwide, but its prevention and therapeutic interventions remain a major challenge. Here, we report the identification of miconazole as a hemorrhagic suppressor by a small-molecule screen in zebrafish. We found that a hypomorphic mutant fn40a, one of several known ß-pix mutant alleles in zebrafish, had the major symptoms of brain hemorrhage, vessel rupture and inflammation as those in hemorrhagic stroke patients. A small-molecule screen with mutant embryos identified the anti-fungal drug miconazole as a potent hemorrhagic suppressor. Miconazole inhibited both brain hemorrhages in zebrafish and mesenteric hemorrhages in rats by decreasing matrix metalloproteinase 9 (MMP9)-dependent vessel rupture. Mechanistically, miconazole downregulated the levels of pErk and Mmp9 to protect vascular integrity in fn40a mutants. Therefore, our findings demonstrate that miconazole protects blood vessels from hemorrhages by downregulating the pERK-MMP9 axis from zebrafish to mammals and shed light on the potential of phenotype-based screens in zebrafish for the discovery of new drug candidates and chemical probes for hemorrhagic stroke.

Electroacupuncture Exerts Neuroprotection through Caveolin-1 Mediated Molecular Pathway in Intracerebral Hemorrhage of Rats.

Spontaneous intracerebral hemorrhage (ICH) is one of the most devastating types of stroke. Here, we aim to demonstrate that electroacupuncture on Baihui (GV20) exerts neuroprotection for acute ICH possibly via the caveolin-1/matrix metalloproteinase/blood-brain barrier permeability pathway. The model of ICH was established by using collagenase VII. Rats were randomly divided into three groups: Sham-operation group, Sham electroacupuncture group, and electroacupuncture group. Each group was further divided into 4 subgroups according to the time points of 6 h, 1 d, 3 d, and 7 d after ICH. The methods were used including examination of neurological deficit scores according to Longa's scale, measurement of blood-brain barrier permeability through Evans Blue content, in situ immunofluorescent detection of caveolin-1 in brains, western blot analysis of caveolin-1 in brains, and in situ zymography for measuring matrix metalloproteinase-2/9 activity in brains. Compared with Sham electroacupuncture group, electroacupuncture group has resulted in a significant improvement in neurological deficit scores and in a reduction in Evans Blue content, expression of caveolin-1, and activity of matrix metalloproteinase-2/9 at 6 h, 1 d, 3 d, and 7 d after ICH (P < 0.05). In conclusion, the present results suggested that electroacupuncture on GV20 can improve neurological deficit scores and reduce blood-brain barrier permeability after ICH, and the mechanism possibly targets caveolin-1/matrix metalloproteinase/blood-brain barrier permeability pathway.

Comparative effects of plant oils on the cerebral hemorrhage in stroke-prone spontaneously hypertensive rats.

OBJECTIVES: Since oils and fats can induce metabolic syndrome, leading to cardiovascular and cerebrovascular diseases, the present study was performed to find out whether the plant oils affect the cerebral hemorrhage in stroke-prone spontaneously hypertensive (SHR-SP) rats. METHODS: From 47 days of age, male SHR-SP rats were given drinking water containing 1% NaCl to induce hypertension, and simultaneously fed semi-purified diets containing 10% perilla oil, canola oil, or shortening. The onset time of convulsion following cerebral hemorrhage was recorded, and the areas of hemorrhage and infarction were analyzed in the stroke brains. RESULTS: In comparison with 58-day survival of SHR-SP rats during feeding NaCl alone, perilla oil extended the survival time to 68.5 days, whereas canola oil shortened it to 45.7 days. Feeding perilla oil greatly reduced the total volume of cerebral hemorrhage from 17.27% in the control group to 4.53%, while shortening increased the lesions to 21.23%. In a microscopic analysis, perilla oil also markedly decreased the hemorrhagic and infarction lesions to 1/10 of those in control rats, in contrast to an exacerbating effect of shortening. In blood analyses, perilla oil reduced blood total cholesterol and low-density lipoproteins which were increased in SHR-SP, but canola oil further increased them and markedly lowered platelet counts. DISCUSSION: Perilla oil delayed and attenuated cerebral hemorrhage by improving hyperlipidemia in hypertensive stroke animals, in contrast to the aggravating potential of canola oil and shortening. It is suggested that perilla oil should be the first choice oil for improving metabolic syndrome in hypertensive persons at risk of hemorrhagic stroke.

Hyperbaric Oxygen Preconditioning Attenuates Hemorrhagic Transformation Through Reactive Oxygen Species/Thioredoxin-Interacting Protein/Nod-Like Receptor Protein 3 Pathway in Hyperglycemic Middle Cerebral Artery Occlusion Rats.

OBJECTIVES: To clarify whether hyperbaric oxygen preconditioning can attenuate hyperglycemia-enhanced hemorrhagic transformation and to establish a role for Nod-like receptor protein 3 inflammasome in the pathophysiology of hemorrhagic transformation. DESIGN: Controlled prospective animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 260-280 g. INTERVENTIONS: Rats received 1-hour-long hyperbaric oxygen preconditioning for five consecutive days. Hyperglycemic middle cerebral artery occlusion model was induced at 24 hours after the last hyperbaric oxygen exposure. Reactive oxygen species scavenger (N-acetyl-L-cysteine), thioredoxin-interacting protein small interfering RNA, and Nod-like receptor protein 3 small interfering RNA were given in different groups separately to verify the possible pathway. MEASUREMENTS AND MAIN RESULTS: Rats were randomly divided into sham, middle cerebral artery occlusion, middle cerebral artery occlusion + dextrose, middle cerebral artery occlusion + dextrose + normobaric oxygen preconditioning, middle cerebral artery occlusion + dextrose + hyperbaric oxygen, middle cerebral artery occlusion + dextrose + hyperbaric oxygen + N-acetyl-L-cysteine, middle cerebral artery occlusion + dextrose + hyperbaric oxygen + control small interfering RNA, middle cerebral artery occlusion + dextrose + hyperbaric oxygen + thioredoxin-interacting protein small interfering RNA, and middle cerebral artery occlusion + dextrose + hyperbaric oxygen + Nod-like receptor protein 3 small interfering RNA groups. Hyperglycemia was induced by administration of 50% dextrose (6 mL/kg) intraperitoneally 30 minutes before middle cerebral artery occlusion. Control small interfering RNA/thioredoxin-interacting protein small interfering RNA or Nod-like receptor protein 3 small interfering RNA (500 pmol/5 µL) were injected intracerebroventricularly 72 hours before middle cerebral artery occlusion for intervention. The neurologic scores, infarction and hemorrhage volumes, the expression of Nod-like receptor protein 3, and its downstream targets were analyzed. Hyperbaric oxygen preconditioning decreased both infarction and hemorrhage volumes and improved neurobehavioral function. In addition, hyperbaric oxygen preconditioning provided additional protective effects in hemorrhagic transformation, which was independent of infarction volume. The benefits of hyperbaric oxygen preconditioning on hyperglycemic middle cerebral artery occlusion rats were reversed after blocking the reactive oxygen species/thioredoxin-interacting protein/Nod-like receptor protein 3 pathway. CONCLUSIONS: Nod-like receptor protein 3 inflammasome played an important role in hyperglycemia-enhanced hemorrhagic transformation. Hyperbaric oxygen preconditioning attenuated hemorrhagic transformation through reactive oxygen species/thioredoxin-interacting protein/Nod-like receptor protein 3 pathway.

Oily fish consumption is inversely correlated with cerebral microbleeds in community-dwelling older adults: results from the Atahualpa Project.

BACKGROUND: Oily fish is a major dietary source of omega-3 polyunsaturated fatty acids (ω-3 PUFAs). These nutrients improve endothelial dysfunction, reduce ß-amyloid induced damage of neurovascular units, and might prevent the occurrence of cerebral microbleeds. However, this relationship has not been investigated so far. AIM: To evaluate the association between oily fish intake and cerebral microbleeds in a population of frequent fish consumers living in coastal Ecuador. METHODS: Cerebral microbleeds were identified by gradient-echo MRI and oily fish consumption was calculated in community-dwellers aged ≥60 years enrolled in the Atahualpa Project. The association between cerebral microbleeds and fish servings was examined in regression models adjusted for relevant confounders. A predictive model was constructed using quintiles of fish servings to take into account the non-linearity in the relationship. RESULTS: Out of 311 eligible individuals, 293 (94 %) were enrolled. Cerebral microbleeds were recognized in 37 (13 %) individuals. Mean fish consumption was 8.8 ± 5.4 servings per week (ω-3 PUFAs estimates: 10.2 ± 7.1 g). Multivariate analysis showed an inverse relationship between cerebral microbleeds and fish consumption (p < 0.001). Predictive margins of CMB were higher for individuals in the lowest (≤4.3) than for those in the highest (≥13.1) quintile of fish servings (17.4 vs 2.3 %, p < 0.001). CONCLUSIONS: This study shows a lower cerebral microbleed presence among older adults eating large amounts of oily fish (13 servings per week, equivalent to about 15 g of ω-3 PUFAs). These high requirements can be more readily accomplished in other populations by taking fish oil preparations. Longitudinal studies are warranted to assess whether these interventions reduce incident cerebral microbleeds in high-risk individuals.

Minocycline reduces spontaneous hemorrhage in mouse models of cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine whether spontaneous intracerebral hemorrhage could be reduced. METHODS: Tg2576 (n=16) and 5xFAD/ApoE4 knockin mice (n=16), aged 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, IP) or saline every other day for 2 months. Brains were extracted and stained with X-34 (to quantify amyloid), Perls' blue (to quantify hemorrhage), and immunostained to examined ß-amyloid peptide load, gliosis (glial fibrillary acidic protein [GFAP], Iba-1), and vascular markers of blood-brain barrier integrity (zonula occludins-1 [ZO-1] and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes. RESULTS: Minocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5xFAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (matrix metalloproteinase-9, NOX4, CD45, S-100b, and Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls. CONCLUSIONS: Minocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in 2 different mouse models of CAA, supporting the importance of matrix metalloproteinase-related and inflammatory pathways in intracerebral hemorrhage pathogenesis. As a Food and Drug Administration-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related intracerebral hemorrhage.

Hyperbaric oxygen preconditioning attenuates hemorrhagic transformation through increasing PPARγ in hyperglycemic MCAO rats.

Hyperbaric oxygen preconditioning (HBO-PC) has been demonstrated to attenuate hemorrhagic transformation (HT) after middle cerebral artery occlusion (MCAO) in hyperglycemic rats. However, the mechanisms remain to be illustrated. Recently, HBO-PC has been shown to activate peroxisome proliferator-activated receptor-gamma (PPARγ) by increasing 15d-PGJ2 in primary cultured neurons. We hypothesize that HBO-PC reduces HT by suppressing inflammation through increasing 15d-PGJ2 and activating PPARγ in hyperglycemic MCAO rats. HBO (2.5ATA) was administered for 1h daily for 5 consecutive days. The PPARγ inhibitor GW9662 was administered intraperitoneally to designated animals. Infarction volume, hemorrhage volume, neurological scores and mortality were analyzed. The levels of 15d-PGJ2, PPARγ, TNF-α and IL-1ß, tight junction proteins as well as the activity of MMP-2 and MMP-9 were evaluated 24h after MCAO. HBO-PC reduced HT, improved neurological function, down-regulated inflammatory molecules and inhibited the activation of MMP-9 by increasing 15d-PGJ2 and PPARγ at 24h after MCAO. The results suggested that HBO-PC might be an alternative measure to decrease HT in ischemic stroke.

Effectiveness of vitamin A in the prevention of complications of prematurity.

BACKGROUND: To assess the effectiveness of vitamin A supplementation in very low birth weight (VLBW) infants to prevent complications of prematurity. METHODS: This was a retrospective cohort study to determine the effectiveness of vitamin A in preventing complications of prematurity in VLBW infants. Vitamin A was delivered intramuscularly at a dose of 5000 IU, three times weekly during the first 28 days of life. RESULTS: Of the 187 eligible VLBW infants, we excluded from the analysis (due to death or transfer to another hospital), 16 infants weighing <1000 g and 17 weighing 1000-1500 g. Sixty VLBW infants received the vitamin supplement. We observed no differences between the groups in the duration of oxygen therapy or in the risk of bronchopulmonary dysplasia. The risk of sepsis was up to three times higher among the infants who were given the vitamin A supplement. CONCLUSION: Given the increased risk of sepsis in patients weighing >1000 g, the risk associated with repeated intramuscular injections of vitamin A and the modest clinical results described, we do not believe the universal administration of vitamin A to VLBW infants to be justified as prophylaxis for bronchopulmonary dysplasia.

Obstetricians' attitudes and beliefs regarding umbilical cord clamping.

OBJECTIVE: Although delayed umbilical cord clamping has been demonstrated to reduce the incidence of intraventricular hemorrhage and neonatal sepsis, and decrease the need for neonatal transfusions (without affecting cord pH, Apgar scores or the need for phototherapy), the extent to which this practice is being employed is unknown. We conducted a survey of US obstetricians to assess their attitudes and beliefs about cord clamping. STUDY DESIGN: Questionnaires were randomly mailed to members of the American College of Obstetricians and Gynecologists (ACOG), and the Collaborative Ambulatory Research Network (CARN). The data were analyzed using Chi-square and Student t tests. RESULTS: The response rates for the CARN and other ACOG members were 47% and 21%, respectively. Most (88%) responders reported their hospital had no umbilical cord clamping policy. The most frequent response for optimal timing of umbilical cord clamping, regardless of gestational age, was "don't know". Potential for neonatal red blood cell transfusion was the only concern cited as a reason for being somewhat or very inclined to delay umbilical cord clamping (51%). Delayed neonatal resuscitation (76%) was listed as a reason to clamp the cord immediately, despite the paucity of literature to support immediate cord clamping in this cohort. CONCLUSION: Despite substantial evidence supporting the practice of delayed cord clamping, few institutions have policies regarding this practice. Moreover, obstetricians' beliefs about the appropriate timing for umbilical cord clamping are not consistent with the evidence that demonstrates its beneficial impact on neonatal outcomes.

Estudio prospectivo y randomizado de suplementación de hierro temprana versus tardía en niños con peso al nacer menor de 1.301 g / Prospective randomized study of early versus late enteral iron supplementation in children who weighed < 1, 301 grams at birth

Objetivo: Determinar si la suplementación temprana de hierro disminuye la necesidad, el número y volúmen de glóbulos rojos transfundidos, en relación a la suplementación tardía de hierro en niños con peso de nacimiento menor a 1.301 g. Pacientes y Método: Recién nacidos de muy bajo peso (RNMPN) fueron randomi-zados a recibir suplementación temprana de hierro de 3 mg/kg/día, tan pronto estaban tolerando alimentación enteral de 100 ml/kg/día, o a los 61 días de vida como suplementación tardía. Se midió niveles de hemoglobina al inicio de la suplementación temprana de hierro y a los 2 meses de vida. La transfusión de glóbulos rojos fue restringida de acuerdo a las guías de transfusión y no se administró eritropoyetina. Resultados: No hay diferencias en el número de transfusiones de glóbulos rojos entre los grupos y en relación a las morbilidades asociadas con la prematuridad no habría diferencias significativas. Conclusiones: La suplementación temprana de hierro cuando el niño este tolerando 100 ml/kg/día de leche, no disminuiría la incidencia de las transfusiones de glóbulos rojos en relación al inicio tardío de hierro a los 61 días de vida y probablemente sea segura en los niños menores de 1.301 g.

Objective: Determine whether early iron supplementation would decrease the need, the number and volume of transfused red blood cells in relation to late iron supplementation in children with birth weight less than 1,301 g. Patients and Methods: Very low birth weight (VLBW) infants were randomly assigned to receive early iron supplementation of 3 mg/kg/day as soon as they could tolerate enteral feeding of 100 ml/kg/day, or at 61 days of life as late supplementation. Hemoglobin levels were measured at the beginning of early iron supplementation and at 2 months of age. The red blood cell transfusion was performed according to transfusion guidelines and erythropoietin was not administered. Results: No differences were observed regarding the number of red cell transfusions between the groups. Morbidities associated with prematurity presented no significant differences. Conclusions: Early iron supplementation to a child that is tolerating 100 mL/kg/day of milk, does not decrease the incidence of red blood cell transfusions compared to late start iron at 61 days of life, and it is probably safe in infants with birth weight < 1,301 g.

Hyperbaric oxygen preconditioning attenuates hyperglycemia-enhanced hemorrhagic transformation by inhibiting matrix metalloproteinases in focal cerebral ischemia in rats.

Hyperglycemia dramatically aggravates brain infarct and hemorrhagic transformation (HT) after ischemic stroke. Oxidative stress and matrix metalloproteinases (MMPs) play an important role in the pathophysiology of HT. Hyperbaric oxygen preconditioning (HBO-PC) has been proved to decrease oxidative stress and has been demonstrated to be neuroprotective in experimental stroke models. The present study determined whether HBO-PC would ameliorate HT by a pre-ischemic increase of reactive oxygen species (ROS) generation, and a suppression of MMP-2 and MMP-9 in hyperglycemic middle cerebral artery occlusion (MCAO) rats. Rats were pretreated with HBO (100% O2, 2.5 atmosphere absolutes) 1 h daily for 5 days before MCAO. Acute hyperglycemia was induced by an injection of 50% dextrose. Neurological deficits, infarction volume and hemorrhagic volume were assessed 24 h and 7 days after ischemia. ROS scavenger n-acetyl cysteine (NAC), hypoxia-inducible factor-1α (HIF-1α), inhibitor 2-methoxyestradiol (2ME2) and activator cobalt chloride (CoCl2), and MMP inhibitor SB-3CT were administrated for mechanism study. The activity of MMP-2 and MMP-9, and the expression HIF-1α were measured. HBO-PC improved neurological deficits, and reduced hemorrhagic volume; the expression of HIF-1α was significantly decreased, and the activity of MMP-2 and MMP-9 was reduced by HBO-PC compared with vehicle group. Our results suggested that HBO-PC attenuated HT via decreasing HIF-1α and its downstream MMP-2 and MMP-9 in hyperglycemic MCAO rats.

[Novel oral anticoagulants and atrial fibrillation in the elderly]. / Les nouveaux anticoagulants oraux et la fibrillation atriale du sujet âgé

Atrial fibrillation treatment relies on anticoagulation therapy that reduces the risk of stroke. Vitamin K antagonists (VKA) were the only oral anticoagulant drugs for more than 50 years, but they are difficult to manage especially in the elderly. In France, VKA are the main cause of iatrogenic hospitalizations with about 17,000 hospitalizations per year and around 4,000 to 5,000 deaths per year. Pharmacologic properties of VKA, especially the narrow therapeutic margin explain the complexity of their management. Several studies have shown that patients treated with VKA were on average only 50% of the time with an INR in the therapeutic range. In other words, patients are, half of the time, either-under treated or over-treated. Within this framework, development of new oral anticoagulant drugs appeared necessary, in order to obtain drugs with larger therapeutic margin and a better risk/benefit profile than VKA. Three large randomized clinical trials including almost 50,000 patients with 20,000 subjects over 75 years old and 8,000 over 80 years old, show a better risk/benefit profile of the new oral anticoagulants (NOAC) than VKA, characterized by a 50% reduction of cerebral hemorrhages, 22% reduction of stroke and 12% reduction of total mortality. Meanwhile, their renal elimination and the lack of control of the biological efficacy need to be taken into account for their prescription. Renal failure (estimated glomerular filtration rate according to Cockcroft formula < 30 mL/min) contraindicates their use. Their half-life is shorter than that of VKA and the biological monitoring is not available, thus a good adherence to the treatment is important. Studies specifically conducted among geriatric older population with poly-pathologies and frail are therefore needed to evaluate tolerance of NOAC in real life conditions.