Hyperosmolar therapy in the treatment of severe head injury in children: mannitol and hypertonic saline

Traumatic brain injury is the result of a primary, acute injury and is complicated by the development of secondary injury due to hypotension and hypoxia. Cerebral edema due to brain injury compromises the delivery of essential nutrients and alters normal intracranial pressure. The Monroe-Kellie Doctrine defines the principles of intracranial pressure homeostasis. Treatment for intracranial hypertension is aimed at reducing the volume of 1 of the 3 intracranial compartments, brain tissue, blood, and cerebrospinal fluid. Hyperosmolar therapy is one treatment intervention in the care of patients with severe head injury resulting in cerebral edema and intracranial hypertension. The effect of hyperosmolar solutions on brain tissue was first studied nearly 90 years ago. Since that time, mannitol has become the most widely used hyperosmolar solution to treat elevated intracranial pressure. Increasingly, hypertonic saline solutions are being used as an adjunct to mannitol in basic science research and clinical studies. Hyperosmolar solutions are effective in reducing elevated intracranial pressure through 2 distinct mechanisms: plasma expansion with a resultant decrease in blood hematocrit, reduced blood viscosity, and decreased cerebral blood volume; and the creation of an osmotic gradient that draws cerebral edema fluid from brain tissue into the circulation. The pediatric section of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies adapted previously published guidelines for the treatment of adult brain injury into guidelines for the treatment of children with traumatic brain injury. These guidelines offer recommendations for the management of children with severe head injury, including the use of mannitol and hypertonic saline to treat intracranial hypertension. Acute and critical care pediatric advanced practice nurses caring for children with severe head injury should be familiar with management guidelines and the use of hyperosmolar solutions. The purpose of this article is to assist the advanced practice nurse in understanding the role of hyperosmolar therapy in the treatment of pediatric traumatic brain injury and review current guidelines for the use of mannitol and hypertonic saline.     

Antigenic analysis of human haemopoietic progenitor cells expressing the growth factor receptor c-kit

The cell surface molecule encoded by the protooncogene c-kit has recently been identified as the receptor for a growth factor variously termed stem cell factor (SCF), mast cell growth factor or steel factor. Using the c-kit antibody 17F11 we analysed, in triple staining experiments, the surface molecule profile and scatter characteristics of c-kit+CD34+ human haemopoietic progenitor cells. In 10 normal bone marrow samples we found 19-51% of CD34+ bone marrow progenitor cells to coexpress c-kit. These c-kit+CD34+ bone marrow cells turned out to represent a phenotypically heterogeneous population. A considerable proportion coexpressed CD33 (52 +/- 23%), and/or CD71 (62 +/- 26) antigens, marker molecules previously shown to be expressed by committed in vitro colony forming cells but not by their precursors. In line with a relatively differentiated phenotype c-kit+CD34+ cells also gave rise to on average higher forward and right-angle light scattering signals. The proportions of CD38 and/or HLA-D expressing cells were similar in the c-kit+ and in the c-kit- subsets of CD34+ progenitor cells. Coexpression of CD19 was found to be less frequent in the c-kit+ (4 +/- 5%) as compared to the c-kit- (17 +/- 14%) fraction of CD34+ cells. CD7+ CD34+ bone marrow cells were hardly detectable and their numbers too low to allow further subdivision in c-kit+ and c-kit- subsets.     

Polymorphisms in the P450 c17 (17-hydroxylase/17,20-Lyase) and P450 c19 (aromatase) genes: association with serum sex steroid concentrations and bone mineral density in postmenopausal women

The CYP 17 and CYP 19 genes encode 17alpha-hydroxylase/17,20-lyase and aromatase, respectively, both involved in sex hormone synthesis. We investigated the association between 2 common polymorphisms in 1) the promoter region (T-->C substitution) of CYP 17, and 2) exon 3 (G-->A) of CYP 19, bone mineral density (BMD) and serum androgen/estradiol, in a case-control study of 252 postmenopausal women aged 64.5 +/- 9.2 yr (mean +/- SD). There was no significant difference in serum estradiol concentrations between cases (n = 136) and controls (n = 116). The CYP 19 genotype was significantly associated with serum estradiol (P = 0.002). Women with the AA genotype had higher serum estradiol concentrations compared with those with the GG genotype (P = 0.03). In older women, those with the CYP 19 GA and GG genotypes had an increased prevalence of osteoporosis (P = 0.04) and fractures (P = 0.003). We found no significant association between CYP 17 genotype and serum androgens and estradiol concentrations. However, a significant association was seen between BMD values at the femoral neck with CYP 17 genotype in cases (P = 0.04) and in the whole study population (P = 0.012). Subjects with the CC genotype had significantly lower BMD (mean +/- SD: TT, 0.7 +/- 0.16; CC, 0.6 +/- 0.08 g/cm(2); P = 0.006). In conclusion, both CYP 17 and CYP 19 are candidate genes for osteoporosis in postmenopausal women.     

The Kv7 potassium channel activator retigabine decreases alcohol consumption in rats

Background: Activation of Kv7 potassium channels may decrease the reactivity of mesolimbic dopaminergic neurons that are implicated in mediating the reinforcing effects of ethanol. Objectives: The objective of this study was to determine whether the administration of the Kv7 potassium channel opener retigabine would decrease ethanol intake in Long Evans rats. Methods: A limited access two-bottle choice model of alcohol (10% solution) consumption was used in this study. A separate group of animals was tested to evaluate the actions of retigabine on sucrose (5% solution) consumption to determine whether this drug might produce non-selective impairment of the ability of rats to drink liquids. Animals were treated with either vehicle or increasing doses (2.5–7.5?mg/kg SC) of retigabine administered over a 3-day period. Results: Compared to vehicle, retigabine at a dose of 7.5?mg/kg produced a reduction in the amount of ethanol consumed. These effects did not occur in association with significant changes in water consumption. A significant time effect was found for the actions of retigabine in sucrose-drinking rats with a trend for an increase in sucrose intake with the highest dose of retigabine administered. Conclusions: These results indicate that the administration of retigabine may produce a decrease in ethanol consumption by rats at doses that do not significantly reduce the drinking of either water or a sucrose solution. These findings are consistent with the hypothesis that activation of Kv7 channels facilitates the reduction of alcohol consumption in the rat.     

Integrative neurobiology of the alcohol withdrawal syndrome--from anxiety to seizures

This article represents the proceedings of a symposium presented at the 2003 Research Society on Alcoholism meeting in Ft. Lauderdale, Florida, organized and chaired by Carl L. Faingold. The presentations were (1) Overview, by Carl L. Faingold; (2) Stress, Multiple Alcohol Withdrawals, and Anxiety, by Darin Knapp; (3) Relationship Between Genetic Differences in Alcohol Drinking and Alcohol Withdrawal, by Julia Chester; (4) Neuronal Mechanisms in the Network for Alcohol Withdrawal Seizures: Modulation by Excitatory Amino Acid Receptors, by Carl L. Faingold; and (5) Treatment of Acute Alcohol Withdrawal and Long-Lasting Alterations in Hippocampal Neuronal Networks, by Larry P. Gonzalez. The presentations emphasized the importance of using intact behaving animals to advance the understanding of the human alcohol withdrawal syndrome. This involves applying and amplifying the neurophysiological and neurotransmitter findings observed in vitro to the network-based neurobiological mechanisms that are involved in several important aspects of the specific behaviors observed clinically. The symposium provided evidence that the organizational aspects of neuronal networks in the intact nervous system add another nexus for the action of alcohol and drugs to treat alcohol withdrawal that may not be readily studied in isolated neural elements used in in vitro approaches.     

Neisseria gonorrhoeae strains inhibited by vancomycin in selective media and correlation with auxotype

Strains of Neisseria gonorrhoeae that failed to grow on Thayer-Martin (T-M) and Martin-Lewis (M-L) media accounted for 2.0% of isolates at the University of Colorado Hospital and its Venereal Disease Clinic. A total of 31 inhibited and 31 control strains were compared by agar dilution testing for their susceptibilities to 13 antimicrobial agents used for treatment or in selective media. All 62 isolates were resistant to lincomycin, colistin, nystatin, amphotericin B, trimethoprim lactate, polymyxin B, and anisomycin. Vancomycin was the inhibitory antibiotic for N. gonorrhoeae in both T-M and M-L media. The vancomycin-inhibited strains were also significantly more sensitive to penicillin and ampicillin than were the control strains (P less than 0.001). The presence of the other antibiotics in selective media did not affect the minimum inhibitory concentrations of vancomycin for gonococci. All 31 inhibited strains were sensitive to 8.0 micrograms of vancomycin per ml, and 26 of these were sensitive to 2.0 microgram/ml. Decreasing the size of inoculum of gonococci results in greater inhibition by any given concentration of vancomycin. The vancomycin-sensitive strains contained significantly more arginine- hypoxanthine-, and uracil-requiring auxotypes (28 out of 31) than did the control strains (9 out of 31). As with T-M medium, some strains of gonococci will be missed when M-L medium with 4.0 micrograms of vancomycin per ml is the only medium used for the diagnosis of gonorrhea. This may be of particular importance in the confirmation of disseminated infection with Arg- Hyx- Ura- auxotypes of N. gonorrhoeae when cultures of blood, joint fluid, or skin lesions are negative.     

Suppression of eicosanoid biosynthesis during coronary angioplasty by fish oil and aspirin

BACKGROUND. Percutaneous transluminal coronary angioplasty (PTCA) is an acute, localized stimulus to platelet and vascular function. Periprocedural cardiovascular complications are reduced by moderate-dose aspirin (ASA), presumably due to inhibition of thromboxane (TX) A2. METHODS AND RESULTS. Excretion of TXA2 and prostacyclin (PGI2) metabolites in urine increased during PTCA. Pretreatment for 3 days with either moderate- (325 mg/day) or low-dose (80 mg/day) ASA inhibited the increase in both eicosanoids. Pretreatment for 3 weeks with fish oil (10 g/day) only partially suppressed TXA2. Formation of trienoic eicosanoids and accumulation of omega-3 fatty acids in platelet membranes confirmed fish oil ingestion. Although basal PGI2 was not inhibited, the PTCA-related increment was suppressed. CONCLUSIONS. PTCA results in an acute, transient alteration of eicosanoid biosynthesis consistent with accelerated platelet-vascular interactions. Pretreatment for 3 days with moderate or low doses of ASA suppresses TXA to a similar extent during PTCA, and their effects on acute cardiovascular complications of this procedure are likely to be comparable. It is unlikely that even prolonged pretreatment with fish oil can substitute for the platelet inhibitory action of ASA during PTCA. Suppression of PGI2 may contribute to the residual acute periprocedural complication rate in patients taking ASA.     

Effect of platelet-activating factor (PAF) on human platelets

The effect of pure synthetic PAF (1-0-alkyl-2-acetyl-sn-glycero-3- phosphorylcholine) was studied in human platelets. PAF (0.2--2.0 micrograms/ml) produced a dose-dependent aggregation in human platelet- rich plasma (PRP) or platelet suspension obtained by gel-filtration (GFP). In addition, PAF (0.8 microgram/ml) induced secretion of 14C- serotonin (45% +/- 10%; mean +/- SD, n = 9) and platelet factor 4 (PF4) (12.89 +/- 3.81 micrograms/10(9) platelets; n = 9) in PRP. Similar results were obtained in GFP. Aggregation and release of 14C-serotonin and PF4 were inhibited by the metabolic inhibitors 2-deoxyglucose (16.7 mM) and antimycin-A (8.3 micrograms/ml), by the membrane-active drugs mepacrine (10 microM) and chlorpromazine (0.025 mM), by PGI2 (5.34 nM), which elevates intracellular c-AMP, by indomethacin (10 microM) or aspirin (100 microM). The ADP scavengers, creatine phosphate and creatine phosphokinase (CP/CPK), inhibited the second wave of aggregation but not secretion. These data suggest that the major effect of PAF on human platelets is mediated through the cyclo-oxygenase pathway and not through a third pathway.     

Follicular Lymphoma Evaluation Index (FLEX): A new clinical prognostic model that is superior to existing risk scores for predicting progression-free survival and early treatment failure after frontline immunochemotherapy

Patients with advanced-stage follicular lymphoma (FL) who progress early after receiving first-line therapy have poor overall survival (OS). Currently applied clinical prognostic models such as FL International Prognostic Index [FLIPI], FLIPI-2 and PRIMA-Prognostic Index [PRIMA-PI] have suboptimal sensitivity and specificity to predict this poor prognosis subgroup. The primary objective was to develop a novel prognostic model, the FL Evaluation Index (FLEX) score, to identify high-risk patients and compare its performance with FLIPI, FLIPI-2 and PRIMA-PI. Progression-free survival (PFS) after first-line immunochemotherapy was the key endpoint, while OS and progression of disease within 24 months (POD24) were also assessed. The model, which includes nine clinical variables, was developed using a cohort of patients with previously untreated advanced-stage FL from the phase 3 GALLIUM trial (NCT01332968). The performance of the model was validated using data from the SABRINA trial (NCT01200758). In GALLIUM (n = 1004; 127 with and 877 without POD24), FLEX increased the intergroup (low-risk/high-risk) difference in 2-year and 3-year PFS rates and demonstrated superior intergroup differences in 2-year and 3-year OS rates compared with FLIPI, FLIPI-2 and PRIMA-PI. Sensitivity for a high-risk score to predict POD24 was 60% using FLEX compared with 53% for FLIPI and FLIPI-2, and 69% for PRIMA-PI, while specificity was 68% for FLEX compared with 58% for FLIPI, 59% for FLIPI-2 and 48% for PRIMA-PI. The prognostic value of FLEX in SABRINA was similar to FLIPI. Therefore, FLEX appears to perform better than existing prognostic models in previously untreated FL, in particular for the newer treatment regimens.