Pharmacologic Management of Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) remains a condition with suboptimal functional outcomes, especially in the young population. Pharmacotherapy has an accepted role in several aspects of the disease and an emerging role in several others. No preventive pharmacologic interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events after endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence-based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as statins have demonstrated early potential; however, they failed to provide significant evidence for the use in preventing DCI. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase 2 trial. Clazosentane, a potent endothelin receptor antagonist, did not translate to improve functional outcomes. Various other neuroprotective agents have been used to prevent DCI; however, the results have been, at best inconclusive. The prevention of DCI and improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by which DCI is propagated is clearly needed. In this article, we review the current pharmacologic approaches that have been evaluated in SAH and highlight the areas in which further research is needed.

Predictive markers in traumatic brain injury: opportunities for a serum biosignature.

The current diagnostic criteria for traumatic brain injury (TBI) are heavily reliant on an accurate clinical history of events. Diagnosis of mild injury relies on one or more of the following: confusion or disorientation, loss of consciousness (LOC) for 30 min or less, post-ictus amnesia for less than 24 h and/or other transient neurological abnormalities and a Glasgow Coma Score (GCS). Given the nature of the condition it is obvious that significant clinical challenges remain to identify in the cases of mild TBI, and additionally to grade more severe forms so that appropriate treatment is received. The lack of clinically useful biomarkers in the serum of TBI patients is a significant barrier to improving their outlook. Discovery of such markers would aid the timely diagnosis of novel and recurrent disease in a minimally invasive manner. A PubMed search was performed to identify studies reporting serum biomarkers in traumatic brain injury. Details regarding the biomarkers analysed, specificity, indications for outcome and statistical significance were recorded. A total of 40 manuscripts reporting 11 biomarkers were identified in the literature. All but a few studies reported statistically significant differences in biomarker expression between groups. We conclude that serum biomarkers of TBI are an effective means for investigating the condition. However, the lack of novel markers identified in this mass of studies highlights the need to adopt new measure of biomarker identification.

Is there a role for treating inflammation in moyamoya disease?: a review of histopathology, genetics, and signaling cascades.

Moyamoya disease is a slowly progressing steno-occlusive condition affecting the cerebrovasculature. Affecting the terminal internal carotid arteries (ICA) and there branches, bilaterally, a resulting in a fine vascular network in the base of the brain to allow for compensation of the stenosed vessels. While there is obvious evidence of the involvement of inflammatory proteins in the condition, this has historically not been acknowledged as a causal factor. Here we describe the fundamental histopathology, genetics, and signaling cascades involved in moyamoya and debate whether these factors can be linked as causal factor for the condition or whether they are simply a secondary result of the ischemia described in the condition. A particular focus has been placed on the multitude of signaling cascades linked to the condition as these are viewed as having the greatest therapeutic potential. As such we hope to draw some novel insight into potential diagnostic and therapeutic inflammatory targets in the condition.

In vitro and in vivo radiosensitization induced by hydroxyapatite nanoparticles.

BACKGROUND: Previous study showed that hydroxyapatite nanoparticles (nano-HAPs) inhibited glioma growth in vitro and in vivo; and in a drug combination, they could reduce adverse reactions. We investigated the possible enhancement of radiosensitivity induced by nano-HAPs. METHODS: In vitro radiosensitization of nano-HAPs was measured using a clonogenic survival assay in human glioblastoma U251 and breast tumor brain metastatic tumor MDA-MB-231BR cells. DNA damage and repair were measured using γH2AX foci, and mitotic catastrophe was determined by immunostaining. The effect of nano-HAPs on in vivo tumor radiosensitivity was investigated in a subcutaneous and an orthotopic model. RESULTS: Nano-HAPs enhanced each cell line's radiosensitivity when the exposure was 1 h before irradiation, and they had no significant effect on irradiation-induced apoptosis or on the activation of the G2 cell cycle checkpoint. The number of γH2AX foci per cell was significantly large at 24 h after the combination modality of nano-HAPs + irradiation compared with single treatments. Mitotic catastrophe was also significantly increased at an interval of 72 h in tumor cells receiving the combined modality compared with the individual treatments. In a subcutaneous model, nano-HAPs caused a larger than additive increase in tumor growth delay. In an orthotopic model, nano-HAPs significantly reduced tumor growth and extended the prolongation of survival induced by irradiation. CONCLUSIONS: These results show that nano-HAPs can enhance the radiosensitivity of tumor cells in vitro and in vivo through the inhibition of DNA repair, resulting in an increase in mitotic catastrophe.

Biomarkers of pediatric brain tumors.

UNLABELLED: Background and Need for Novel Biomarkers: Brain tumors are the leading cause of death by solid tumors in children. Although improvements have been made in their radiological detection and treatment, our capacity to promptly diagnose pediatric brain tumors in their early stages remains limited. This contrasts several other cancers where serum biomarkers such as cancer antigen (CA) 19-9 and CA 125 facilitate early diagnosis and treatment. AIM: The aim of this article is to review the latest literature and highlight biomarkers which may be of clinical use in the common types of primary pediatric brain tumor. METHODS: A PubMed search was performed to identify studies reporting biomarkers in the bodily fluids of pediatric patients with brain tumors. Details regarding the sample type [serum, cerebrospinal fluid (CSF), or urine], biomarkers analyzed, methodology, tumor type, and statistical significance were recorded. RESULTS: A total of 12 manuscripts reporting 19 biomarkers in 367 patients vs. 397 controls were identified in the literature. Of the 19 biomarkers identified, 12 were isolated from CSF, 2 from serum, 3 from urine, and 2 from multiple bodily fluids. All but one study reported statistically significant differences in biomarker expression between patient and control groups. CONCLUSION: This review identifies a panel of novel biomarkers for pediatric brain tumors. It provides a platform for the further studies necessary to validate these biomarkers and, in addition, highlights several techniques through which new biomarkers can be discovered.

Specific TNF-alpha inhibition in cerebral aneurysm formation and subarachnoid hemorrhage.

The signal transduction of tumor necrosis factor-alpha (TNF-alpha) is complex and regulated via a vast number of interconnecting pathways. The TNF-alpha signaling pathway plays a major role in the pathogenesis of subarachnoid hemorrhage (SAH). The advent of molecular mimicry has provided a number of opportunities to tackle disease with improved specificity. Here we review the mechanisms of their action and the potential for TNF-alpha inhibitors as a treatment for subarachnoid hemorrhage. Searches were performed using PubMed with the search terms "subarachnoid haemorrhage", "TNF alpha", "novel drugs" TNF alpha inhibition", "management", "cerebral aneurysm", and "vasospasm" from 1970 to February, 2012. Articles were also identified through searches of the Cochrane library and searches of the authors' own files. Only papers published in English were reviewed. In conclusion, there is considerable theoretical evidence for the potential of TNF-alpha inhibitors to impact on the pathogenesis of aneurismal SAH. Such indications demonstrate the potential for specific targeting of molecular signaling pathways to prevent the growth and rupture of cerebral aneurysm.

Non-steroidal anti-inflammatory drugs used as a treatment modality in subarachnoid hemorrhage.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed therapies worldwide. Meta-analysis data indicate the potential for myocardial infarction, cerebrovascular incident, heart failure, renal failure and arterial hypertension. Here we review the mechanisms of their actions and the potential for therapeutic use in subarachnoid hemorrhage. Searches were performed using PubMed with the search terms "subarachnoid hemorrhage", "NSAID", "treatment", "management", "cerebral aneurysm", and "vasospasm" from 1970 to February, 2012. Articles were also identified through searches of the Cochrane library and searches of the authors' own files. Only papers published in English were reviewed.There are considerably mixed views on the potential impact of NSAIDs on the treatment and prevention of SAH. Whilst theoretically, the potential for positive intervention in the condition is huge, little effect appears to be measurable in clinical practice.

Exploring the use of estrogen & progesterone replacement therapy in subarachnoid hemorrhage.

The hypothesis that alterations in hormone levels can impact on subarachnoid hemorrhage (SAH) is rapidly gaining momentum. Specifically, the concept that post-menopausal women are more susceptible to the condition has convinced many of the protective roles of estrogen and progesterone. Here we review the mechanisms of their actions and the potential for estrogen and progesterone replacement therapy in subarachnoid hemorrhage. Searches were performed using PubMed with the search terms "subarachnoid hemorrhage", "estrogen", "progesterone "treatment", "management", "cerebral aneurysm", and "vasospasm" from 1970 to February, 2012. Articles were also identified through searches of the Cochrane library and searches of the authors' own files. Only papers published in English were reviewed. In conclusion, there is significant theoretical evidence for the potential role of estrogen and progesterone use in altering the pathogenesis of SAH. Nevertheless, this has received mixed reviews in both case controlled studies and cohort analysis within the literature.

Spontaneous otogenic pneumocephalus presenting with occipital subcutaneous emphysema as primary symptom: could tension gas cause the destruction of cranial bones?

The authors report, to the best of their knowledge, the first case of a spontaneous tension pneumocephalus with subcutaneous emphysema. Hyperpneumatization of the cranium and mechanical compression contributed jointly to the formation of a fistula, and air pressure caused a subsequent disruption of the suture and air leakage into the subcutaneous space. A minimally invasive otological procedure proved efficacious for resolution.

Effects of yoga versus walking on mood, anxiety, and brain GABA levels: a randomized controlled MRS study.

OBJECTIVES: Yoga and exercise have beneficial effects on mood and anxiety. γ-Aminobutyric acid (GABA)-ergic activity is reduced in mood and anxiety disorders. The practice of yoga postures is associated with increased brain GABA levels. This study addresses the question of whether changes in mood, anxiety, and GABA levels are specific to yoga or related to physical activity. METHODS: Healthy subjects with no significant medical/psychiatric disorders were randomized to yoga or a metabolically matched walking intervention for 60 minutes 3 times a week for 12 weeks. Mood and anxiety scales were taken at weeks 0, 4, 8, 12, and before each magnetic resonance spectroscopy scan. Scan 1 was at baseline. Scan 2, obtained after the 12-week intervention, was followed by a 60-minute yoga or walking intervention, which was immediately followed by Scan 3. RESULTS: The yoga subjects (n = 19) reported greater improvement in mood and greater decreases in anxiety than the walking group (n = 15). There were positive correlations between improved mood and decreased anxiety and thalamic GABA levels. The yoga group had positive correlations between changes in mood scales and changes in GABA levels. CONCLUSIONS: The 12-week yoga intervention was associated with greater improvements in mood and anxiety than a metabolically matched walking exercise. This is the first study to demonstrate that increased thalamic GABA levels are associated with improved mood and decreased anxiety. It is also the first time that a behavioral intervention (i.e., yoga postures) has been associated with a positive correlation between acute increases in thalamic GABA levels and improvements in mood and anxiety scales. Given that pharmacologic agents that increase the activity of the GABA system are prescribed to improve mood and decrease anxiety, the reported correlations are in the expected direction. The possible role of GABA in mediating the beneficial effects of yoga on mood and anxiety warrants further study.

Lead encephalopathy due to traditional medicines.

Traditional medicine use is common in developing countries and increasingly popular in the western world. Despite the popularity of traditional medicines, scientific research on safety and efficacy is limited. However documented fatalities and severe illness due to lead poisoning are increasingly recognized to be associated with traditional medicine use. As society becomes more globalized, it is imperative for pharmacists and health care providers to learn about the safety of traditional medical practices. The information presented educates and alerts pharmacists and health care providers about the potential of traditional medicines to cause lead encephalopathy. Case reports were located through systematic literature searches using MEDLINE, CINAHL, AMED, CISCOM, EMBASE and The Cochrane library from 1966 to the February 2007. Reference lists of identified articles and the authors' own files were also searched. Inclusion criteria were cases of human lead encephalopathy associated with traditional medical practices. There were no restrictions regarding the language of publication. Data were subsequently extracted and summarized in narrative and tabular form. We found 76 cases of lead encephalopathy potentially associated with traditional medicine. Ayurvedic medicines were associated with 5 cases (7%), Middle eastern traditional medicines with 66 cases (87%) and 5 cases (7%) with other traditional medicines. Of the 76 cases, 5% were in adults and 95% were in infants and young children. Of the 4 adult cases, at least one was left with residual neurological impairment. In infants and young children, among 72 cases 8 (11%) were fatal, and at least 15 (21%) had residual neurological deficits. Traditional medicine users should be screened for lead exposure and strongly encouraged to discontinue metal-containing remedies. Therefore, the United States Food and Drug Administration and corresponding agencies in other countries should require and enforce heavy metal testing for all imported traditional medicines and "dietary supplements".