Consensus summary statement of the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care: a statement for healthcare professionals from the Neurocritical Care Society and the European Society of Intensive Care Medicine

Neurocritical care depends, in part, on careful patient monitoring but as yet there are little data on what processes are the most important to monitor, how these should be monitored, and whether monitoring these processes is cost-effective and impacts outcome. At the same time, bioinformatics is a rapidly emerging field in critical care but as yet there is little agreement or standardization on what information is important and how it should be displayed and analyzed. The Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine, and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to begin to address these needs. International experts from neurosurgery, neurocritical care, neurology, critical care, neuroanesthesiology, nursing, pharmacy, and informatics were recruited on the basis of their research, publication record, and expertise. They undertook a systematic literature review to develop recommendations about specific topics on physiologic processes important to the care of patients with disorders that require neurocritical care. This review does not make recommendations about treatment, imaging, and intraoperative monitoring. A multidisciplinary jury, selected for their expertise in clinical investigation and development of practice guidelines, guided this process. The GRADE system was used to develop recommendations based on literature review, discussion, integrating the literature with the participants' collective experience, and critical review by an impartial jury. Emphasis was placed on the principle that recommendations should be based on both data quality and on trade-offs and translation into clinical practice. Strong consideration was given to providing pragmatic guidance and recommendations for bedside neuromonitoring, even in the absence of high quality data

Effect of 17beta-estradiol, o,p'-DDT, octylphenol and p,p'-DDE on gonadal development and liver and kidney pathology in juvenile male summer flounder (Paralichthys dentatus).

The intent of this study was to compare histopathologically the effect of 17beta-estradiol (E(2)), o,p'-DDT, octylphenol and p,p'-DDE on gonadal development and liver and kidney condition in sexually immature (juvenile) summer flounder (Paralichthys dentatus). The dorsal sinus of 2-year-old juvenile male summer flounder was injected with the appropriate amount of chemical incorporated in coconut oil. A second identical injection was administered 2 weeks later. Fish were sampled at 4, 6 and 8 weeks after the initial injection and observed histopathologically. In control fish, spermatogenesis was predominantly in mid to late maturation. In fish treated with 1.0 and 10.0 mg/kg E(2) spermatogenesis regressed to primary spermatogonia or an immature functional state. Testicular atrophy and spermatogonial proliferation was also observed. An eosin-positive, hyaline material was found in the gonad, liver and kidney. This eosinophilic material also stained positive with Periodic Acid Schiff (PAS) stain. Treatment of 30 or 60 mg/kg o,p'-DDT elicited altered gonadal development similar to that observed with E(2) treated fish. Octylphenol treatment of 100 mg/kg resulted in reduced testicular size, ducts full of sperm, numerous spermatogonia and PAS positive material in the testis with no developing sperm cysts. No effect on liver or gonad tissues was observed with p,p'-DDE at the concentrations tested. All chemicals tested, with exception of p,p'-DDE, altered gonadal development, whereas only E(2) caused histopathological changes in the liver and kidney. Estrogenic activity induced the liver to produce a vitellogenin (VtG)-like substance and inhibited testicular maturation. As a result, both the lack of target cells for VtG and a continuous supply of VtG from the liver allowed the hyaline material to accumulate in the liver, testis and kidney causing histopathological changes.

Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GRObeta.

SB-251353 is an N-terminal truncated form of the human CXC chemokine GRObeta. Recombinant SB-251353 was profiled in murine and rhesus monkey peripheral blood stem cell mobilization and transplantation models. SB-251353 rapidly and transiently mobilized hematopoietic stem cells and neutrophils into the peripheral blood after a single subcutaneous injection. Transplantation of equivalent numbers of hematopoietic stem cells mobilized by SB-251353 into lethally irradiated mice resulted in faster neutrophil and platelet recovery than stem cells mobilized by granulocyte colony-stimulating factor (G-CSF). A single injection of SB-251353 in combination with 4 days of G-CSF administration resulted in augmented stem and progenitor cell mobilization 5-fold greater than G-CSF alone. Augmented stem cell mobilization could also be demonstrated in mice when a single injection of SB-251353 was administered with only one-day treatment with G-CSF. In addition, SB-251353, when used as a single agent or in combination with G-CSF, mobilized long-term repopulating stem cells capable of hematopoietic reconstitution of lethally irradiated mice. In rhesus monkeys, a single injection of SB-251353 induced rapid increases in peripheral blood hematopoietic progenitor cells at a 50-fold lower dose than in mice, which indicates a shift in potency. These studies provide evidence that the use of SB-251353 alone or in combination with G-CSF mobilizes hematopoietic stem cells with long-term repopulating ability. In addition, this treatment may (1) reduce the number of apheresis sessions and/or amount of G-CSF required to collect adequate numbers of hematopoietic stem cells for successful peripheral blood cell transplantation and (2) improve hematopoietic recovery after transplantation.

Effects of estrogenic (o,p'-DDT; octylphenol) and anti-androgenic (p,p'-DDE) chemicals on indicators of endocrine status in juvenile male summer flounder (Paralichthys dentatus).

Laboratory experiments were conducted with male summer flounder to assess the value of selected measures of endocrine status in fish as indicators of exposure to endocrine-disrupting contaminants. Effects of 1,1,1-trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl) ethane (o,p'-DDT), octylphenol and 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (p,p'-DDE) on hepatosomatic and gonadosomatic indices, plasma steroid hormone levels, vitellogenin production, and gonadal development were evaluated in laboratory-raised, juvenile male summer flounder. Flounder were injected twice with test chemical in a coconut oil carrier. Each chemical was tested at three different concentrations. Estrogenic (o,p'-DDT; octylphenol) and anti-androgenic (p,p'-DDE) chemicals were evaluated alone and in combination (octylphenol plus o,p'-DDT or p,p'-DDE). Additionally, some fish were treated with the natural ligand for the estrogen receptor, 17beta-estradiol. Blood and tissues from different fish in each treatment were sampled 4, 6 and 8 weeks after the first injection. Fish exposed to a combination of o,p'-DDT plus octylphenol were also sampled after 15 weeks. In all cases, responses of fish exposed to a test chemical were compared to control fish sampled at the same time. The following significant differences, relative to controls, were observed in at least one sampling time or at least one concentration of chemical. 17beta-Estradiol-treated flounder exhibited decreased gonadosomatic index (GSI), altered hepatosomatic index (HSI), elevated plasma estradiol, reduced plasma testosterone, and high levels of plasma vitellogenin. Fish treated with o,p'-DDT showed lower GSI, no change in HSI or plasma estradiol, depression of plasma testosterone, and induction of vitellogenesis. Octylphenol treatment resulted in lower GSI, no change in HSI, initially increased plasma estradiol and decreased testosterone, and no vitellogenin production. p,p'-DDE treatment did not significantly alter any indicator relative to controls. In experiments using combinations of chemicals, flounder receiving o,p'-DDT plus octylphenol had lower GSI after 8 weeks and elevated plasma estradiol after 15 weeks exposure. Fish treated with p,p'-DDE plus octylphenol for 8 weeks exhibited a significantly lower GSI. Overall, lower GSI and plasma testosterone levels, relative to controls, were consistent indicators of exposure to estrogenic chemicals in juvenile male flounder. No indicators were found that would identify exposure to the mammalian anti-androgen p,p'-DDE.

Vitellogenin-induced pathology in male summer flounder (Paralichthys dentatus).

Male summer flounder (Paralichthys dentatus) were given two injections (initially and 2 weeks later) of 17beta-estradiol (E2) totaling 0.2 (2 x 0.1), 2.0 (2 x 1.0) or 20.0 (2 x 10.0) mg E2/kg body weight. Blood and tissue samples were collected 4, 6 and 8 weeks after the initial injection in the (2 x 0.1) mg/kg treatment, 4, 6, 8, and 15 weeks after the first injection in the (2 x 1.0) mg/kg treatment and at 4 weeks only in the (2 x 10.0) mg/kg treatment. Five of the 12 fish injected twice with 10.0 mg/kg were moribund before the first sampling period. Circulating levels of vitellogenin (VTG) in the blood of all E2-injected fish from all treatments were comparable with those concentrations found in the blood of wild male carp (Cyprinus carpio) and walleye (Stezostedion vitreum) previously collected near a sewage treatment plant (0.1-10.0 mg VTG/ml plasma). Excessive hyalin material accumulated in the livers, kidneys and testes of the treated fish. A portion of that material was identified as VTG by immunohistochemistry. The accumulation of VTG, and possibly other estrogen-inducible proteins, resulted in hepatocyte hypertrophy, disruption of spermatogenesis, and obstruction or rupture of renal glomeruli.

Clinical improvement related to thrombolysis of third ventricular blood clot in a patient with thalamic hemorrhage.

Intraventricular extension of hemorrhage after intraparenchymal hemorrhage is associated with significant morbidity and mortality. Clinical improvement is reported in a patient with thalamic hemorrhage with intraventricular extension after third and fourth ventricular blood clot resolution with instillation of urokinase intraventricularly. A 49-year-old man with hypertension collapsed while at work. A computed tomography (CT) scan of the head revealed a left thalamic hemorrhage with extension into the lateral, third, and fourth ventricles and associated hydrocephalus. A left frontal intraventricular catheter (IVC) was placed and intraventricular urokinase was administered at a dose of 25,000 U every 12 hours. The CT scan revealed resolution of the lateral ventricular dilatation and blood clot but no decrease in third or fourth ventricular hemorrhage. No clinical improvement was noted. The IVC was reinserted on the right side with the catheter tip placed through the foramen of Monroe into the third ventricle. Twelve hours after receiving the first dose of urokinase through the new catheter, the patient's condition improved. The CT scan showed a reduction in the volume of blood of the third and fourth ventricles. This case report shows that treatment of hydrocephalus with an IVC was not sufficient to provide a therapeutic effect. Substantial clinical improvement occurred only after the blood clot was cleared from the third and fourth ventricles.

Autoregulatory cerebral vasodilation occurs during orthostatic hypotension in patients with primary autonomic failure.

It is unclear whether patients with autonomic failure autoregulate cerebral blood flow during hypotension. The objective in this study was to examine cerebral autoregulatory capacity in patients with autonomic failure by studying changes in middle cerebral artery blood flow velocity using transcranial Doppler ultrasonography before, during, and after tilt-induced hypotension. Nine patients with primary autonomic failure were evaluated. Mean arterial pressure and middle cerebral artery blood flow velocity were simultaneously recorded while the patients were in the supine position, during 60 degrees head-up tilt, and after they were returned to the horizontal position. The results were as follows: during tilt-induced hypotension, mean arterial pressure decreased significantly more than middle cerebral artery mean blood flow velocity (58% versus 36%, p <0.0002). After return to the horizontal position, mean arterial pressure returned to baseline, and middle cerebral artery blood flow velocity transiently increased above pretilt value (p <0.02). It is concluded that cerebral autoregulatory vasodilation occurs in patients with autonomic failure. This was demonstrated by a more pronounced decline in mean arterial pressure than in middle cerebral artery blood flow velocity during hypotension and by a transient increase in middle cerebral artery blood flow velocity (ie, hyperemic response) after blood pressure was restored.

Accuracy of investigators' verbatim notes of their forensic interviews with alleged child abuse victims.

Verbatim contemporaneous accounts of 20 investigative interviews were compared with audiotaped recordings thereof. More than half (57%) of the interviewers' utterances along with 25% of the incident-relevant details provided by the children were not reported in the "verbatim" notes. The structure of the interviews was also represented inaccurately in these accounts. Fewer than half (44%) of the details provided by the children were attributed to the correct eliciting utterance type. Investigators systematically misattributed details to more open rather than more focused prompts. These results underscore the superiority of electronic recording when the content and structure of investigative interviews must be preserved.

Colorimetric determination of inhibition of hematopoietic progenitor cells in soft agar.

In vitro colony forming unit (CFU) assays have been used to measure the effects of compounds that regulate the growth of hematopoietic progenitor cells. These assays are time consuming and subjective and are therefore not amenable to high throughput of large numbers of compounds. Here we have shown that the traditional murine bone marrow CFU assay can be modified into a robust non-subjective colorimetric assay format. 3-[4,5-Dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) was added after colony formation in an agar based 96-well plate culture system. Optical density correlated with increasing cell input concentrations in the presence of growth factor. The linearity of this response was equivalent to the standard CFU assay. Several hematopoietic inhibitors were tested in both assays. Effects on colony number and size were compared to optical density. Compounds that reduced colony numbers with little effect on colony size had identical IC(50) values in both the colorimetric assay and CFU assay. The IC(50) values of compounds that also decreased colony size did not correlate in the two assays. These results demonstrate the utility of the colorimetric assay to rapidly screen for compounds that specifically inhibit hematopoietic progenitor cell colony formation in vitro.

Assessing the value of structured protocols for forensic interviews of alleged child abuse victims.

OBJECTIVE: To evaluate the effectiveness of a structured interview protocol (NICHD Investigative Interview Protocol) operationalizing universally recommended guidelines for forensic interviews. METHOD: The NICHD Investigative Protocol was designed to maximize the amount of information obtained using recall memory probes, which are likely to elicit more accurate information than recognition memory probes. Forensic investigators were trained to use the NICHD protocol while conducting feedback-monitored simulation interviews. The utility of the protocol was then evaluated by comparing 55 protocol interviews with 50 prior interviews by the same investigators, matched with respect to characteristics likely to affect the richness of the children's accounts. The comparison was based on an analysis of the investigators' utterance types, distribution, and timing, as well as quantitative and qualitative characteristics of the information produced. RESULTS: As predicted, protocol interviews contained more open-ended prompts overall as well as before the first option-posing utterance than non-protocol interviews did. More details were obtained using open-ended invitations and fewer were obtained using focused questions in protocol interviews than in non-protocol interviews, although the total number of details elicited did not differ significantly. In both conditions, older children provided more details than younger children did. CONCLUSION: The findings confirmed that implementation of professionally recommended practices affected the behavior of interviewers in both the pre-substantive and substantive phases of their interviews and enhanced the quality (i.e., likely accuracy) of information elicited from alleged victims.

Crystal structure of the functional domain of the splicing factor Prp18.

The splicing factor Prp18 is required for the second step of pre-mRNA splicing. We have isolated and determined the crystal structure of a large fragment of the Saccharomyces cerevisiae Prp18 that lacks the N-terminal 79 amino acids. This fragment, called Prp18Delta79, is fully active in yeast splicing in vitro and includes the sequences of Prp18 that have been evolutionarily conserved. The core structure of Prp18Delta79 is compact and globular, consisting of five alpha-helices that adopt a novel fold that we have designated the five-helix X-bundle. The structure suggests that one face of Prp18 interacts with the splicing factor Slu7, whereas the more evolutionarily conserved amino acids in Prp18 form the opposite face. The most highly conserved region of Prp18, a nearly invariant stretch of 19 aa, forms part of a loop between two alpha-helices and may interact with the U5 small nuclear ribonucleoprotein particles. The structure is consistent with a model in which Prp18 forms a bridge between Slu7 and the U5 small nuclear ribonucleoprotein particles.

Antiphosphatidyl serine antibodies are independently associated with ischemic stroke.

OBJECTIVE: To determine whether elevated titers of antiphosphatidyl serine antibodies (aPS) are associated with an increased risk of ischemic stroke in a general stroke population. BACKGROUND: aPS are members of the family of antiphospholipid antibodies that has been associated with increased stroke risk. Although aPS have been demonstrated to occur in 18% of a group of young patients with cerebrovascular symptoms, their prevalence in the general stroke population is unknown, and no controlled study to assess the strength of their association with ischemic stroke has been undertaken previously. METHODS: A case-control study comparing 267 acute ischemic stroke patients and 653 community controls. Sera were obtained immediately after acute stroke in patients. Titers of IgG aPS >16 IgG phospholipid units or IgM aPS >22 IgM phospholipid units were considered positive. Odds ratios (ORs) were obtained by logistic regression, adjusting for age, gender, race/ethnicity, history of hypertension, diabetes mellitus, cardiovascular disease, and cigarette smoking. RESULTS: The adjusted OR was 5.6 (95% confidence interval [CI] 1.8, 18.0) for IgG aPS and 2.9 (95% CI 1.6, 5.3) for IgM aPS. The adjusted OR for either an elevated IgG or IgM aPS was 3.2 (95% CI 1.8, 5.5). CONCLUSIONS: This study demonstrates that elevated IgG and IgM antiphosphatidyl serine antibodies titers are associated with increased risk of ischemic stroke. The prevalence of these antibodies is lower, but the associated stroke risk is comparable with that of anticardiolipin antibodies.

Elevated anticardiolipin antibody titer is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity.

BACKGROUND AND PURPOSE: Previous studies have produced conflicting results regarding the putative association between anticardiolipin antibodies (aCL) and infarction in the general stroke population. These inconsistencies may be a function of sample size and methodological differences among the studies. The purpose of the present study, the largest case-control study of this issue to date, was to assess aCL status as an independent risk factor for ischemic stroke in a multiethnic, urban population. METHODS: We obtained aCL titers in 524 hospitalized acute stroke patients and 1020 community controls enrolled in the Minorities Risk Factors and Stroke Study. The results were interpreted as negative (30.0 GPL or 15.0 MPL units). Odds ratios (ORs) were adjusted for age, sex, race/ethnicity, history of diabetes, hypertension, atrial fibrillation, coronary artery disease, and current cigarette smoking. RESULTS: A positive aCL titer was present in 11% (111/1020) of controls and 34% (180/524) of cases. The adjusted OR for any positive aCL titer was 4.0 (95% CI, 3.0 to 5.5). For any positive IgG aCL titer this value was 3.9 (95% CI, 2.8 to 5.5), and for any positive IgM aCL titer it was 3.4 (95% CI, 2.1 to 5.5). There were no significant differences in ORs associated with high- or low-positive IgG or IgM aCL titers. CONCLUSIONS: In the largest study of its kind to date, aCL antibodies were demonstrated to be independent stroke risk factors across the 3 ethnic groups studied, conferring a 4-fold increased risk of ischemic stroke. IgG and for the first time IgM aCL were each shown to be associated with increased stroke risk. The prevalence of these antibodies and the stroke risk associated appear greater than previously reported.

PHA applications: addressing the price performance issue: I. Tissue engineering.

This paper describes the development of medical applications for polyhydroxyalkanoates (PHAs), a class of natural polymers with a wide range of thermoplastic properties. Methods are described for preparing PHAs with high purity, modifying these materials to change their surface and degradation properties, and methods for fabricating them into different forms, including tissue engineering scaffolds. Preliminary reports characterizing their in vivo behavior are given, as well as methods for using the natural polymers in tissue engineering applications.

Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage.

OBJECTIVE: To determine the prognostic significance and pathophysiologic implication of intraventricular extension of supratentorial intracerebral hemorrhage. DESIGN: Prospective study. SETTING: Acute stroke and neurointensive care units of a tertiary care hospital. PATIENTS: One hundred twenty-nine patients with supratentorial intracerebral hemorrhage, managed medically. INTERVENTIONS: Two patients had intraventricular catheters placed for external drainage. No patient received thrombolytics or surgical evacuation of clot. MEASUREMENTS AND MAIN RESULTS: Of the 129 patients, 47 had intraventricular extension of their hemorrhages. These patients had larger intraparenchymal hemorrhages (36.6 cm3 vs. 15.0 cm3) and lower initial Glasgow Coma Scale scores (mean, 9.6 vs. 13.7). Their 30-day mortality rate was 43% compared with only 9% among those without ventricular extension. Univariate and multivariate logistic regression modeling was used to assess the prognostic significance of various measures of intraventricular hemorrhage. The presence of intraventricular hemorrhage, the number of ventricles containing blood, fourth ventricular blood, and intraventricular hemorrhage volume were each related to 30-day mortality in a univariate analysis, but only intraventricular hemorrhage volume contributed significantly to outcome prediction in the presence of Glasgow Coma Scale score. CONCLUSIONS: Volume of intraventricular hemorrhage is an important determinant of outcome in supratentorial intracerebral hemorrhage.

Reduction of cell lysate viscosity during processing of poly(3-hydroxyalkanoates) by chromosomal integration of the staphylococcal nuclease gene in Pseudomonas putida.

Poly(3-hydroxyalkanoates) (PHAs) are biodegradable thermoplastics which are accumulated by many bacterial species in the form of intracellular granules and which are thought to serve as reserves of carbon and energy. Pseudomonas putida accumulates a polyester, composed of medium-side-chain 3-hydroxyalkanoic acids, which has excellent film-forming properties. Industrial processing of PHA involves purification of the PHA granules from high-cell-density cultures. After the fermentation process, cells are lysed by homogenization and PHA granules are purified by chemical treatment and repeated washings to yield a PHA latex. Unfortunately, the liberation of chromosomal DNA during lysis causes a dramatic increase in viscosity, which is problematic in the subsequent purification steps. Reduction of the viscosity is generally achieved by the supplementation of commercially available nuclease preparations or by heat treatment; however, both procedures add substantial costs to the process. As a solution to this problem, a nuclease-encoding gene from Staphylococcus aureus was integrated into the genomes of several PHA producers. Staphylococcal nuclease is readily expressed in PHA-producing Pseudomonas strains and is directed to the periplasm, and occasionally to the culture medium, without affecting PHA production or strain stability. During downstream processing, the viscosity of the lysate from a nuclease-integrated Pseudomonas strain was reduced to a level similar to that observed for the wild-type strain after treatment with commercial nuclease. The nuclease gene was also functionally integrated into the chromosomes of other PHA producers, including Ralstonia eutropha.

Human ligands of the Notch receptor.

During development, the Notch signaling pathway is essential for the appropriate differentiation of many cell types in organisms across the phylogenetic scale, including humans. Notch signaling is also implicated in human diseases, including a leukemia and two hereditary syndromes known as Alagille and CADASIL. To generate tools for pursuing the role of the Notch pathway in human disease and development, we have cloned and analyzed the expression of three human homologues of the Notch ligands Delta and Serrate, human Jagged1 (HJ1), human Jagged2 (HJ2), and human Delta1 (H-Delta-1), and determined their chromosomal localizations. We have also raised antibodies to HJ1, and used these antibodies in conjunction with in situ hybridization to examine the expression of these ligands in normal and cancerous cervical tissue. We find that, as reported previously for Notch, the ligands are up-regulated in certain neoplastic tissues. This observation is consistent with the notion that Notch signaling is an important element in these pathogenic conditions, raising the possibility that modulation of Notch activity could be used to influence the fate of the cells and offering a conceivable therapeutic avenue.

Spontaneous caudate hemorrhage associated with ingestion of a decongestant containing phenylpropanolamine.

Intracerebral hemorrhage has been associated with phenylpropanolamine, a sympathomimetic agent contained in many over-the-counter medications. Caudate hemorrhage is infrequent, usually related to hypertension, and has not been reported following ingestion of medications containing phenylpropanolamine. We report an unusual case of caudate hemorrhage which developed in a patient taking an over-the-counter nasal decongestant containing phenylpropanolamine.

Stroke recurrence is more frequent in Blacks and Hispanics.

This study was designed to measure recurrent stroke rates and identify their determinants in a mixed ethnic population. A cohort of 299 patients (110 black, 57 Hispanic and 132 white) admitted to a large urban hospital with an acute stroke between November 1, 1991, and July 1, 1993, was followed for a mean of 17.8 months. Demographic and historical data and stroke subtype and severity were recorded at the time of the index stroke. The main outcome measure was stroke recurrence. The unadjusted relative risk of stroke recurrence for blacks, relative to white, was 2.0 (95% CI: 0.9-4.4) and for Hispanics, relative to whites, it was 2.6 (95% CI: 1.08-60). Ethnicity appeared to be associated with recurrence risk only among first-ever strokes: the risk for blacks, relative to whites, was 2.4 (95% CI: 1.02-5.5) and for Hispanics it was 2.9 (95% CI: 1.2-7.4). None of the other putative risk factors for stroke recurrence identified at the time of initial hospitalization were associated with risk of recurrence.