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The potential of IR absorption and Raman spectroscopy for rapid identification of novel psychoactive substances (NPS) has been tested using a set of 221 unsorted seized samples suspected of containing NPS. Both IR and Raman spectra showed large variation between the different sub-classifications of NPS and smaller, but still distinguishable, differences between closely related compounds within the same class. In initial tests, screening the samples using spectral searching against a limited reference library allowed only 41% of the samples to be fully identified. The limiting factor in the identification was the large number of active compounds in the seized samples for which no reference vibrational data were available in the libraries rather than poor spectral quality. Therefore, when 33 of these compounds were independently identified by NMR and mass spectrometry and their spectra used to extend the libraries, the percentage of samples identified by IR and Raman screening alone increased to 76%, with only 7% of samples having no identifiable constituents. This study, which is the largest of its type ever carried out, therefore demonstrates that this approach of detecting non-matching samples and then identifying them using standard analytical methods has considerable potential in NPS screening since it allows rapid identification of the constituents of the majority of street quality samples. Only one complete feedback cycle was carried out in this study but there is clearly the potential to carry out continuous identification/updating when this system is used in operational settings.

A set of seized "legal high" samples and pure novel psychoactive substances have been examined by surface-enhanced Raman spectroscopy using polymer-stabilized Ag nanoparticle (Poly-SERS) films. The films both quenched fluorescence in bulk samples and allowed identification of μg quantities of drugs collected with wet swabs from contaminated surfaces.

Enumeration of circulating tumor cells (CTCs) by the CellSearch system provides prognostic information in metastatic colorectal cancer, regardless of metastatic site. We found that CTCs generally represent <1% of observed events with CellSearch analysis and adapted scoring criteria to classify other peripheral blood events. Examination of twenty two metastatic colorectal cancer patients' blood revealed that patients with high CEA or liver metastases, but not lung or distant lymph node metastases, possessed significant numbers of apoptotic CTCs prior to treatment initiation by Fischer's exact test. Six out of eleven patients with liver metastasis possessed apoptotic CTCs whereas one of nine patients with other metastases had measurable apoptotic CTCs. An elevated CTC number was not necessarily associated with apoptotic CTCs or CTC debris by Spearman's correlation, suggesting the metastatic site rather than CTCs per se as contributing to the origin of these events.

Mephedrone (4-methylmethcathinone) is the beta-keto analogue of 4-methylmethylamphetamine. Before its control in April 2010, it became popular as a legal high in the United Kingdom, displacing methylenedioxymethylamphetamine as the stimulant drug of choice. The drug has stimulant and psychoactive properties, and therefore has forensic significance in criminal and morbid toxicology. The purpose of this study was to survey casework involving the drug (impaired driving and sudden death). The cases were received in the laboratory for analysis between late 2009 and the end of 2010. Analysis of blood samples for mephedrone was conducted by liquid chromatography-mass spectrometry (LC-MS). Routine screening for alcohol and a range of other pharmaceuticals and drugs of abuse was conducted using a combination of enzyme-linked immunoassay, gas chromatography (GC) headspace, GC-MS and high-performance liquid chromatography with diode array detection. Mephedrone was detected in a total of 12 fatal cases. Most of these cases involved death by mechanical means; in two cases, death was attributed directly to mephedrone intoxication (blood concentrations of 2.1 and 1.94 mg/L). Mephedrone was detected in a total of 32 impaired driving cases. Blood concentrations ranged up to 0.74 mg/L (mean 0.21, median 0.10). The casework evidence in this study indicated that recreational use of the drug can produce to blood levels as high as 0.74 mg/L, although the most common value encountered is likely to lie between 0.2 and 0.3 mg/L.

Raman spectra of a representative range of β-ketophenethylamine (β-KP), the rapidly growing family of cathinone-related "legal high" recreational drugs, have been recorded. These spectra showed characteristic changes that were associated with the pattern of substitution on the aromatic rings, for example, the compounds carrying substituents at the 4- position could be distinguished from 3,4-methylenedioxy "ecstasy" derivatives. They also showed small but detectable changes with differences in substitution on the ethylamine substituent. These features allowed the β-KPs present in seized casework samples to be identified. The seized samples typically contained only small amounts of bulking agents, which meant that the band intensities of these components within averaged data were very small. In contrast, grid sampling normally gave at least some spectra which had a higher than average proportion of the bulking agent(s), which allowed them to also be identified. This study therefore demonstrates that Raman spectroscopy can be used both to provide a rapid, non-destructive technique for identification of this class of drugs in seized samples and to detect minor constituents, giving a composition profile which can be used for drugs intelligence work., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

The number of circulating tumor cells (CTCs) in the peripheral blood of metastatic breast cancer patients is now an established prognostic marker. While the central nervous system is a common site of metastasis in breast cancer, the standard marker for disease progression in this setting is cerebrospinal fluid (CSF) cytology. However, the significance of CSF cytology is unclear, requires large sample size, is insensitive and subjective, and sometimes yields equivocal results. Here, we report the detection of breast cancer cells in CSF using molecular markers by adapting the CellSearch system (Veridex). We used this platform to isolate and enumerate breast cancer cells in CSF of breast cancer patients with central nervous system (CNS) metastases. The number of CSF tumor cells correlated with tumor response to chemotherapy and were dynamically associated with disease burden. This CSF tumor cell detection method provides a semi-automated molecular analysis that vastly improves the sensitivity, reliability, objectivity, and accuracy of detecting CSF tumor cells compared to CSF cytology. CSF tumor cells may serve as a marker of disease progression and early-stage brain metastasis in breast cancer and potentiate further molecular analysis to elucidate the biology and significance of tumor cells in the CSF.

Upon infection with many RNA viruses, the cytoplasmic retinoic acid inducible gene-I (RIG-I) pathway activates the latent transcription factor IRF-3, causing its nuclear translocation and the induction of many antiviral genes, including those encoding interferons. Here, we report a novel and distinct activity of IRF-3, in virus-infected cells, that induces apoptosis. Using genetically defective mouse and human cell lines, we demonstrated that, although both pathways required the presence of RIG-I, IPS1, TRAF3 and TBK1, only the apoptotic pathway required the presence of TRAF2 and TRAF6 in addition. More importantly, transcriptionally inactive IRF-3 mutants, such as the one missing its DNA-binding domain, could efficiently mediate apoptosis. Apoptosis was triggered by the direct interaction of IRF-3, through a newly identified BH3 domain, with the pro-apoptotic protein Bax, their co-translocation to the mitochondria and the resulting activation of the mitochondrial apoptotic pathway. Thus, IRF-3 is a dual-action cytoplasmic protein that, upon activation, translocates to the nucleus or to the mitochondrion and triggers two complementary antiviral responses of the infected cell.

Objective: Our objective was to determine the impact of Newborn Individualized Developmental Care and Assessment Program (NIDCAP)-based care on length of stay of very low birth weight (VLBW) infants. Secondary outcome measures were days of ventilation, incidence of chronic lung disease, and 18-month neurodevelopmental outcomes., Methods: This cluster-randomized, controlled trial took place in a large NICU in Canada, with follow-up evaluation at 18 months of age, from September 1999 to September 2004. One hundred VLBW singleton infants and 10 VLBW twin sets were assigned randomly to NIDCAP-based or control care, and 90% participated in follow-up assessments. The intervention was NIDCAP-based care (N = 56), that is, care by NIDCAP-educated staff members and behavioral observations. The control group (N = 55) received standard NICU care. Statistical analyses were adjusted for cluster randomization. Although the intervention was not blinded, the pediatricians making the decisions to discharge the infants were not involved in the study, and the follow-up staff members were blinded with respect to group., Results: NIDCAP group infants had reduced length of stay (median: NIDCAP: 74 days; control: 84 days; P = .003) and incidence of chronic lung disease (NIDCAP: 29%; control: 49%; odds ratio: 0.42 [95% confidence interval: 0.18-0.95]; P = .035). At 18 months of adjusted age, NIDCAP group infants had less disability, specifically mental delay (NIDCAP: 10%; control: 30%; odds ratio: 0.25 [95% confidence interval: 0.08-0.82]; P = .017)., Conclusion: NIDCAP-based care for VLBW infants improved short- and long-term outcomes significantly.

The optimal wound therapy for healing infected wounds post surgery or surgical debridement has not been established. Negative pressure wound therapy and acoustic pressure wound therapy are advanced wound-healing modalities that apply forms of mechanical pressure to wound tissue in an effort to promote healing by stimulating cellular proliferation. Using a combination of negative pressure wound therapy and acoustic pressure wound therapy was evaluated in a series of six patients with large, infected surgical wounds presenting with moderate to large amounts of serosanguineous drainage. After concurrent treatment with both modalities (range: 4 to 12 weeks), wound volume was reduced by 99% to 100% in all wounds except one wound for which depth at end of treatment was not measurable due to hypergranulation. Similarly, wound surface area was reduced by 82% to 100%, with the exception of the hypergranular wound, which decreased in size by 60%. Serosanguineous wound drainage was reduced in four wounds and remained unchanged in two wounds.

2,5,-Dimethoxy-4-bromoamphetamine (DOB) is of particular interest among the various "ecstasy" variants because there is an unusually long delay between consumption and effect, which dramatically increases the danger of accidental overdose in users. Screening for DOB in tablets is problematic because it is pharmacologically active at 0.2-3 mg, which is c. 50 times less than 3,4-methylenedioxy-N-methylamphetamine (MDMA) and makes it more difficult to detect in seized tablets using conventional spot tests. The normal Raman spectra of seized DOB tablets are dominated by the bands of the excipient with no evidence of the drug component. Here we report the first use of on-tablet surface-enhanced Raman spectroscopy (SERS) to enhance the signal from a low concentration drug. Raman studies (785-nm excitation) were carried on series of model DOB/lactose tablets (total mass c. 400 mg) containing between 1 mg and 15 microg of DOB and on seized DOB tablets. To generate surface-enhanced spectra, 5 microL of centrifuged silver colloid was dispensed onto the upper surface of the tablets, followed by 5 microL of 1.0 mol/dm(3) NaCl. The probe laser was directed onto the treated area and spectra accumulated for c. 20 sec (10 sec x 2). It was found that the enhancement of the DOB component in the model tablets containing 1 mg DOB/tablet and in the seized tablets tested was so large that their spectra were completely dominated by the vibrational bands of DOB with little or no contribution from the unenhanced lactose excipient. Indeed, the most intense DOB band was visible even in tablets containing just 15 microg of the drug. On-tablet surface-enhanced Raman spectroscopy is a simple method to distinguish between low dose DOB tablets and those with no active constituent. The fact that unique spectra are obtained allows identification of the drug while the lack of sample preparation and short signal accumulation times mean that the entire test can be carried out in <1 min.

Innate immune response to viral infection is often triggered by Toll-like receptor 3 (TLR3)-mediated signaling by double-stranded (ds) RNA, which culminates in the activation of the transcription factor NF-kappaB and induction of NF-kappaB-driven genes. We demonstrated that dsRNA-induced phosphorylation of two specific tyrosine residues, 759 and 858, of TLR3 was necessary and sufficient for complete activation of the NF-kappaB pathway. When Tyr-759 of TLR3 was mutated, gene induction was inhibited, although NF-kappaB was partially activated. It was released from IkappaB and translocated to the nucleus but failed to bind to the kappaB site of the target A20 gene promoter. This defect could be attributed to incomplete phosphorylation of the RelA (p65) subunit of NF-kappaB, as revealed by two-dimensional gel analyses of p65, isolated from dsRNA-treated cells expressing either wild type TLR3 or the Tyr-759 --> Phe mutant TLR3. Thus, two phosphotyrosine residues of TLR3 activate two distinct pathways, one leading to NF-kappaB release and the other leading to its phosphorylation.

Double-stranded RNA (dsRNA), a frequent byproduct of virus infection, is recognized by Toll-like receptor 3 (TLR3) to mediate innate immune response to virus infection. TLR3 signaling activates the transcription factor IRF-3 by its Ser/Thr phosphorylation, accompanied by its dimerization and nuclear translocation. It has been reported that the Ser/Thr kinase TBK-1 is essential for TLR3-mediated activation and phosphorylation of IRF-3. Here we report that dsRNA-activated phosphorylation of two specific tyrosine residues of TLR3 is essential for initiating two distinct signaling pathways. One involves activation of TBK-1 and the other recruits and activates PI3 kinase and the downstream kinase, Akt, leading to full phosphorylation and activation of IRF-3. When PI3 kinase is not recruited to TLR3 or its activity is blocked, IRF-3 is only partially phosphorylated and fails to bind the promoter of the target gene in dsRNA-treated cells. Thus, the PI3K-Akt pathway plays an essential role in TLR3-mediated gene induction.

Double-stranded (ds) RNA induces transcription of the 561 gene by activating IFN regulatory factor (IRF) transcription factors, whereas similar induction of the IFN-beta gene is thought to require additional activation of NFkappaB and AP-1. In mutant P2.1 cells, dsRNA failed to activate NFkappaB, IRF-3, p38, or c-Jun N-terminal kinase, and transcription of neither 561 mRNA nor IFN-beta mRNA was induced. The defect in the IRF-3 pathway was traced to a low cellular level of this protein because of its higher rate of degradation in P2.1 cells. As anticipated, in several clonal derivatives of P2.1 cells expressing different levels of transfected IRF-3, activation of IRF-3 and induction of 561 mRNA by dsRNA was restored fully, although the defects in other responses to dsRNA persisted. Surprisingly, IFN-beta mRNA also was induced strongly in these cells in response to dsRNA, demonstrating that the activation of NFkappaB and AP-1 is not required. This conclusion was confirmed in wild-type cells overexpressing IRF-3 by blocking NFkappaB activation with the IkappaB superrepressor and AP-1 activation with a p38 inhibitor. Therefore, IRF-3 activation by dsRNA is sufficient to induce the transcription of genes with simple promoters such as 561 as well as complex promoters such as IFN-beta.

Objective: BRCA-1 and BRCA-2 germline mutations increase the risk of ovarian and breast cancer. Primary cancer of the fallopian tube is rare; however, recent evidence suggests that patients harboring a germline mutation conferring an increased risk of ovarian cancer may be at risk for fallopian tube cancer as well. We discuss the finding of occult fallopian tube cancer diagnosed at surgical prophylaxis in women harboring BRCA-1 mutations., Methods/results: Two patients undergoing surgical prophylaxis to address an increase in ovarian cancer risk were discovered to harbor occult primary fallopian tube carcinoma on final pathology review. Mutational analysis confirmed the presence of a deleterious mutation in BRCA-1 in both patients., Conclusion: Currently, consensus opinions regarding ovarian cancer surgical prophylaxis in gene mutation carriers do not include hysterectomy as part of the preventative procedure. This report as well as a growing number of cases of fallopian tube cancer reported in known BRCA-1 and BRCA-2 mutation carriers has important implications for recommendations regarding surgical prophylaxis in these women.

In the clinical setting, fetal and infant movement is used as an indicator of central nervous system and neurobehavioral developmental status. Current models of neurobehavioral development include the synactive theory of neonatal behavioral organization, which defines and describes the interaction between five subsystems. Results of testing synchronous interaction between two of those systems--the autonomic and motoric subsystems in preterm infants--are reported here.

P56 is the most abundant protein induced by interferon (IFN) treatment of human cells. To facilitate studies on its induction pattern and cellular functions, we expressed recombinant P56 as a hexahistidine-tagged protein in Escherichia coli and purified it to apparent homogeneity using affinity chromatography. A polyclonal antibody raised against this recombinant protein was used to show that P56 is primarily a cytoplasmic protein. Cellular expression of P56 by transfection did not inhibit the replication of vesicular stomatitis virus and encephalomyocarditis virus. P56 synthesis was rapidly induced by IFN-beta, and the protein had a half-life of 6 h. IFN-gamma or poly(A)(+) could not induce the protein, but poly(I)-poly(C) or an 85-bp synthetic double-stranded RNA efficiently induced it. Similarly, infection of GRE cells, which are devoid of type I IFN genes, by vesicular stomatitis virus, encephalomyocarditis virus, or Sendai virus caused P56 induction. Surprisingly, Sendai virus could also induce P56 in the mutant cell line P2.1, which cannot respond to either IFN-alpha/beta or double-stranded RNA. Induction of P56 in the P2.1 cells and the parental U4C cells by virus infection was preceded by activation of IRF-3 as judged by its translocation to the nucleus from the cytoplasm., (Copyright 2000 Academic Press.)

Infant handling and disruptions in the neonatal intensive care unit are environmental stressors over which nurses have the most control. Two of the major goals of developmental care are individualizing care by decreasing infant disruptions and handling by caregivers, and modulating or attenuating infant responses to the care they receive. However, it has yet to be established to what extent these goals have been achieved. This article will provide a comparative review of selected literature to ascertain what effect, if any, the introduction of developmental care has had on infant handling or disruption in the neonatal intensive care unit.

The cellular Bcr protein consists of an N-terminal serine/threonine kinase domain, a central guanine nucleotide exchange factor homology region and a C-terminal GTPase-activating protein domain. Previous work in our laboratory established that Bcr is a major transformation-related substrate for the v-Fps tyrosine kinase, and tyrosine phosphorylation of Bcr induces Bcr-Grb-2/SOS association in vivo through the Src homology 2 (SH2) domain of Grb-2. In the present study, we mapped the region of Bcr tyrosine phosphorylation by c-Fes, the human homologue of v-Fps, to Bcr N-terminal amino acids 162-413 by using a baculovirus/Sf-9 cell co-expression system. Tyrosine phosphorylation of Bcr by Fes greatly enhanced the binding of Bcr to the SH2 domains of multiple signalling molecules in vitro, including Grb-2, Ras GTPase activating protein, phospholipase C-gamma, the 85,000 M(r) subunit of phosphatidylinositol 3'-kinase, and the Abl tyrosine kinase. In contrast with SH2 binding, tyrosine phosphorylation of Bcr reduced its ability to associate with the 14-3-3 protein Bap-1 (Bcr-associated protein-1), a Bcr substrate and member of a family of phosphoserine-binding adaptor proteins. These experiments provide in vitro evidence that tyrosine phosphorylation may modulate the interaction of Bcr with multiple growth-regulatory signalling pathways.

The human c-fes protooncogene encodes a protein-tyrosine kinase (c-Fes) distinct from c-Src, c-Abl and other nonreceptor tyrosine kinases. Although originally identified as the cellular homolog of several transforming retroviral oncoproteins, Fes was later found to exhibit strong expression in myeloid hematopoietic cells and to play a direct role in their differentiation. Recent work has shown that Fes exhibits a more widespread expression pattern in both developing and adult tissues, suggesting a general physiological function for this kinase and its closely related homolog, Fer. This review highlights the unique aspects of Fes structure, regulation, and function that set it apart from other tyrosine kinase families.

Background: Axillary dissection remains a standard component of the treatment of invasive carcinoma of the breast. The presence of metastases to the regional lymph nodes guides adjuvant therapy and aids in determining prognosis. Mammography results in the discovery of small and often node-negative carcinomas of the breast., Study Design: This 15-year, retrospective analysis investigated whether certain patients with small tumors could be spared the morbidity of axillary dissection., Results: Medical records showed that from January 1980 to May 1995, 4,543 needle localization biopsies were done at York Hospital because of abnormalities detected on mammograms. Of these, 703 (15.5 percent) proved to be carcinoma. Of the carcinomas, 68 percent were infiltrating ductal carcinoma, 26 percent were ductal carcinoma in situ, and 5.4 percent were infiltrating lobular carcinoma. Axillary dissection was done on 588 patients, and 88.1 percent of the patients had no metastases to axillary lymph nodes. No axillary metastases were present in 109 patients with ductal carcinoma in situ who underwent axillary lymph node dissection or in 21 patients with microscopic invasive tumors. Only two of 54 patients with a T1a tumor (tumor [T], < or = 0.5 cm) had positive axillary nodes. Only one of 29 patients with a well-differentiated T1b tumor (T, > 0.5 to < or = 1 cm) had metastatic axillary nodes. In the presence of negative axillary lymph nodes, 19.2 percent of patients with a T1a tumor, 33.7 percent of patients with a T1b tumor, 60 percent of patients with a T1c tumor (T, > 1 to < or = 2 cm), and 78.9 percent of patients with a T2 tumor (T, > 2 cm) were given adjuvant chemotherapy or hormonal therapy., Conclusions: Patients with ductal carcinoma in situ and microscopic invasive tumors do not require node dissections. Possibly patients with T1a tumors and patients with well-differentiated, estrogen-receptor positive, progesterone-receptor positive, T1b tumors can also be spared axillary node dissection. By following this approach on occasion, patients with positive nodes might not undergo axillary lymph node dissection, but they may still be offered adjuvant therapy.

The human c-fes proto-oncogene encodes a cytoplasmic tyrosine kinase (Fes) that is associated with multiple hematopoietic cytokine receptors. Fes tyrosine autophosphorylation sites may regulate kinase activity and recruit downstream signaling proteins with SH2 domains. To localize the Fes autophosphorylation sites, full-length Fes and deletion mutants lacking either the unique N-terminal or SH2 domain were autophosphorylated in vitro and analyzed by CNBr cleavage. Identical phosphopeptides of 10 and 4 kDa were produced with all three proteins, localizing the tyrosine autophosphorylation sites to the C-terminal kinase domain. Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kDa phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. CNBr cleavage analysis of Fes isolated from 32PO4-labeled 293T cells showed that Tyr-713 and Tyr-811 are also autophosphorylated in vivo. Mutagenesis of Tyr-713 reduced both autophosphorylation of Tyr-811 and transphosphorylation of Bcr, a recently identified Fes substrate, supporting a major regulatory role for Tyr-713. Wild-type Fes transphosphorylated a kinase-inactive Fes mutant on Tyr-713 and Tyr-811, suggesting that Fes autophosphorylation occurs via an intermolecular mechanism analogous to receptor tyrosine kinases.

The human bcr gene encodes a protein with serine/threonine kinase activity, CDC24/dbl homology, a GAP domain, and an SH2-binding region. However, the precise physiological functions of BCR are unknown. Coexpression of BCR with the cytoplasmic protein-tyrosine kinase encoded by the c-fes proto-oncogene in Sf-9 cells resulted in stable BCR-FES protein complex formation and tyrosine phosphorylation of BCR. Association involves the SH2 domain of FES and a novel binding domain localized to the first 347 amino acids of the FES N-terminal region. Deletion of the homologous N-terminal BCR-binding domain from v-fps, a fes-related transforming oncogene, abolished transforming activity and tyrosine phosphorylation of BCR in vivo. Tyrosine phosphorylation of BCR in v-fps-transformed cells induced its association with GRB-2/SOS, the RAS guanine nucleotide exchange factor complex. These data provide evidence that BCR couples the cytoplasmic protein-tyrosine kinase and RAS signaling pathways.

Age-specific reference ranges for serum prostate-specific antigen (PSA) may improve this test for detecting prostate cancer. We have analyzed PSA levels from 10,024 men to determine the potential effects of these reference ranges. PSA levels (ng/ml) were grouped by patient age for comparison between standard (all ages: PSA < or = 4.0) and age-specific (< or = 49 years: PSA < or = 2.5; 50-59 years: PSA < or = 3.5; 60-69 years: PSA < or = 4.5; > or = 70 years: PSA < or = 6.5) reference ranges. Serum PSA correlated significantly with age (r = 0.33; p < 0.001). Fewer men > or = 60 years had elevated levels when age-specific reference ranges were applied (1,373 vs. 1,967; p < 0.001). Prostate biopsies and prebiopsy PSA levels from 865 men were reviewed. Sensitivities and specificities were calculated using both reference ranges. A significant increase in specificity with the age-specific reference ranges was seen for men > or = 70 years (58.6 vs. 34.2%; p < 0.001). There was, however, a concomitant decrease in sensitivity (77.6 vs. 91.7%; p < 0.001). We conclude serum PSA increases with age and we support the concept of age-specific reference ranges. However, the specificity of this test remains low, illustrating its limitations for prostate cancer detection.

To evaluate the recently published Utstein algorithm (Ann Emerg Med 1991;20:861), the authors conducted a retrospective review of all advanced life support (ALS) trip sheets and hospital records of patients with prehospital cardiac arrests between January 1988 and December 1989. Telephone follow-up was used to determine 1-year survival rates. Of 713 arrests in the 24-month study period, 601 were of presumed cardiac etiology. Approximately 599 of these charts were available for analysis. One hundred ninety-three (32.2%) of these had return of spontaneous circulation (ROSC), 36 (6.0%) survived to hospital discharge, and 24 were alive at 1-year follow-up (4.0% of total or 67% of survivors to discharge). The Utstein style was found to be a useful algorithmic format for reporting prehospital cardiac arrest data in a manner that should allow direct comparison between emergency medical service (EMS) systems. Existing prehospital record-keeping practices (trip sheets) are easily adapted to this style of data collection, although certain data for the template (eg, resuscitations not attempted and alive at 1-year) are more difficult to ascertain. Additionally, the authors report their own experience during a 2-year period, including data that suggest that the majority of patients with cardiac arrest who survive to hospital discharge are still alive at 1 year.

The c-fes proto-oncogene product is expressed predominantly in hematopoietic cells of the myeloid lineage and has been implicated in the regulation of myeloid differentiation. The c-fes locus encodes a 93-kDa protein tyrosine kinase (p93c-fes) that possesses several structural features characteristic of the cytoplasmic class of protein tyrosine kinases, including a consensus sequence for autophosphorylation surrounding Tyr-713 and a src homology 2 (SH2) domain. To assess the effect of each of these potential regulatory sites on p93c-fes protein tyrosine kinase activity, we specifically deleted the c-fes SH2 domain using the polymerase chain reaction and replaced Tyr-713 with phenylalanine by oligonucleotide-directed mutagenesis (Y713F mutant). The resulting mutants were expressed in Escherichia coli and assayed for changes in protein tyrosine kinase activity using an immune complex kinase assay. Both mutations produced a marked decrease in the rate and extent of autophosphorylation and phosphorylation of the model substrate, enolase. To test whether the c-fes SH2 domain could interact with the autophosphorylated kinase domain, the SH2 domain was expressed as a fusion protein with glutathione S-transferase and immobilized on glutathione-agarose. The recombinant c-fes SH2 domain precipitated p93c-fes as readily as a monoclonal antibody. Binding of the SH2 domain to p93c-fes was completely dependent upon autophosphorylation, as a kinase-defective mutant of p93c-fes was not precipitated by the SH2 domain. High-affinity binding was also observed with recombinant SH2 domains from v-src and v-fps, raising the possibility of protein-protein interactions between various members of the cytoplasmic PTK family. These results indicate that the c-fes SH2 domain and consensus autophosphorylation site (Tyr-713) play major roles in the positive regulation of p93c-fes tyrosine kinase activity, possibly through intramolecular interaction.

Ninety-five infants of 37 weeks' gestation or greater with evidence of hypoxic-ischemic encephalopathy following perinatal asphyxia were prospectively identified in the neonatal period. The degree of encephalopathy was graded the staging system of Sarnat and Sarnat. Six infants died, 78 infants were sequentially followed in the Neonatal Follow-up Clinic, and in five additional infants, follow-up information was available. The mean duration of follow-up was 19.3 months. Fifty-eight (65%) of the 89 infants followed were normal or mildly handicapped, six (7%) died, and the remainder had significant handicap. There was no significant relationship between any of over 100 obstetrical antepartum or intrapartum variables and outcome. Infants with five-minute Apgar scores of 0 to 3, seizures within the first day of life, Stage II or III encephalopathy, or a suppressed electroencephalogram had a significantly greater incidence of severe handicap or death. In addition, although there were fewer females, they had a significantly greater incidence of handicap. There appeared to be an improved outcome in the last two years (1977-1978) compared to the first two years (1975-1976), suggesting that improved recognition and neonatal management may lead to a decrease in significant sequelae.

Twenty neonates requiring mechanical ventilation for respiratory failure, including 13 with hyaline membrane disease, were studied to assess the effects of alterations in ventilator settings on mean airway pressure (MAP), blood gases, and intracranial pressure (ICP). The study involved random alterations in peak inspiratory pressure (PIP), positive end-expiratory pressure (PEEP), and inspiratory/expiratory ratio while MAP, PaO2, ICP, and end-tibal PCO2 were continuously monitored. The results showed a significant relationship between MAP and PaO2 that was expressed as the change in PaO2 per millimeter of mercury change in MAP (delta PaO2/delta MAP) with a mean delta PaO2/delta MAP of 4.92. The delta PaO2/delta MAP was highest for changes in PEEP (6.08), followed by PIP (5.07), and inspiratory/expiratory ratio (1.9). There was a significant relationship between alterations in PEEP and PIP vs PaCO2 and pH. Increases in PEEP and decreases in PIP resulted in an elevated PaCO2 and a lowered pH, and decreases in PEEP and increases in PIP resulted in a decreased PaCO2 and an elevated pH. There was no significant relationship between MAP and ICP, but there was a significant association between delta ICP and delta PaCO2 during alterations in PIP (r = .64, P less than .001). Increases in PEEP will lead to the greatest increase in PaO2 per change in MAP, followed by increase in PIP and inspiratory/expiratory ratio using a pressure-limited ventilator.

Forty-nine term infants were prospectively shown to have hypoxic-ischemic encephalopathy (HIE). All infants survived the neonatal period, and all but two infants (seen at 12 months) were followed up to at least 27 months of age. Factors that significantly correlated with outcome included the Sarnat encephalopathy stage and the occurrence of intractable seizures not controlled by phenobarbital sodium alone. There was no association between the one- or five-minute Apgar score, the need for early ventilation, the EEG, the occurrence of seizures, and the subsequent outcome. There was no significant difference in outcome for those infants who received dexamethasone sodium phosphate (n = 29) v those who did not receive the drug (n = 20). A review of 97 term infants with HIE from a regional perinatal program during a one-year period (1979), including 35 of the 49 infants in the present study, did show a significant increase in morbidity and mortality for transported infants.

Patient histories of 29 infants were reviewed whose birth weights were less than 2,000 gm and who had received ventricular shunts in the neonatal period for posthemorrhagic hydrocephalus. This procedure was performed at a time when routine screening of low birth weight infants for intracranial hemorrhage was not undertaken and serial lumbar puncture usually was not employed. The overall outcome was poor, with 62% of shunted infants either dying or surviving with moderate or severe handicap. Neurodevelopmental outcome was associated with the interval between the diagnosis of hydrocephalus and shunting; an adverse outcome was associated with an increased interval. Current practices for treating posthemorrhagic hydrocephalus are discussed.

In an effort to characterize the performance of self-inflating resuscitators, three examples of three models were subjected to laboratory testing: the Ohio Hope II resuscitator (Ohio Medical Products, Madison, WI), the PMR-2 resuscitator (Puritan Medical Products, Lenexa, KS), and the Laerdal resuscitator (AS Laerdal, Stavanger, Norway). The devices were connected to a test lung and compressed at frequencies of from 10 to 60 and at greater than 60 breaths per minute at 5, 10, and 15 L/min of flow. These devices were used with and without a reservoir and were compressed at less than and more than the pop-off valve pressures. The results revealed that all devices equipped with reservoirs delivered a significantly higher oxygen concentration than those without (P less than .001), and that activation of the pop-off valve significantly reduced Fio2 under all conditions (P less than .005). The pop-off valves for each device were activated throughout a wide range of pressures, the Laerdal 41 to 72 cm H2O, PMR-2 51 to 97 cm H2O, and the Ohio Hope II 38 to 106 cm H2O, well in excess of the manufacturer's specifications. Only the Laerdal with reservoir was able to deliver an Fio2 of greater than 0.9 when compressed at more than the pop-off valve pressure at rates of up to 30 breaths per minute using flows of 10 L/min, and it was the only device to produce Fio2 values of greater than 0.9 at all rates to 60 breaths per minute when compressed at less than the pop-off valve pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

In an attempt to determine the role of vitamin E in retrolental fibroplasia (RLF) we report our experience with 191 infants of less than 1500 g birth weight. Of these infants, 16.75% had evidence of acute RLF in hospital, 8.4% had cicatricial RLF at follow-up, and four infants (2.1%) were blind, none of whom had received supplementary vitamin E. The incidence of cicatricial RLF at follow-up was significantly lower in infants who received vitamin E early after birth (12 h) than in those who did not (3 of 105 versus 13 of 86, X2 = 9.26, P = 0.002), as was the incidence of Grade III or greater cicatrix (0 of 105 versus 7 of 86, X2 with Yates = 6.72, P = 0.01). Stepwise multiple linear regression analysis revealed three factors distinguishing infants who developed cicatricial RLF from those who did not: the lack of early vitamin E supplements (P = 0.0023), the significantly larger number of arterial PO2 values over 100 mmHg (P = 0.0056), and the presence of an intraventricular haemorrhage (P = 0.0032). The incidence and severity of necrotizing enterocolitis was similar in infants who received vitamin E and in those who did not. It is recommended that vitamin E be given within the first 12 hours of birth to all infants of less than 1500 g who require supplementary oxygen.

Twelve premature infants with significant apnea of prematurity while receiving therapeutic doses of aminophylline were given an intravenous infusion of doxapram, 2 or 2.5 mg/kg/hr. The ventilatory effects of the medication were monitored by means of face mask spirometry and airway occlusion studies. Doxapram therapy was associated with significant increases in minute ventilation, tidal volume, mean inspiratory flow, and airway pressure 100 msec after occlusion. Respiratory frequency and the relative duration of inspiration and expiration were unchanged. Paco2 decreased significantly during the infusion. The apnea attack rate, monitored by continuous recording, was significantly reduced after the first 6 hours of therapy. Six hours after starting doxapram, mean arterial blood pressure was significantly elevated, and continued to increase during the 24 hours of therapy. Doxapram is effective in treatment of apnea of prematurity refractory to aminophylline, and appears to act by increasing respiratory center output.

19 infants admitted with a diagnosis of infantile apnea who were found to have periodic breathing were given oral theophylline to determine its effect. They were studied at a mean age of 7.1 weeks (1-16.4 week). Each infant was studied during two naps, immediately before and 7 days following the institution of theophylline therapy, which averaged 2.8 h in duration during which electro-oculograms, end-tidal CO2, heart rate, impedance respirations, and transcutaneous pO2 (tcpO2) were continuously monitored. Theophylline therapy (mean dose 2.3 mg/kg q. 6 h) was associated with a significant reduction of apnea attack rates in both REM and non-REM sleep. Periodic breathing and the number of minutes per hour of sleep during which the TC pO2 was between 40-50 mm Hg in non-REM sleep also decreased. There was no significant reduction in the number of obstructive apneas, the number of bradycardias with apnea, nor the largest single fall in tcpO2. Theophylline can significantly reduce central apnea and periodicity in the age group studied, but the long-term effects of such therapy require further assessment.

Although vitamin E has been shown to reduce the incidence of severe sequelae from retrolental fibroplasia, there have been recent suggestions that its use may be associated with an increased incidence of necrotizing enterocolitis (NEC). A review was made of experience with vitamin E, both intramuscular and oral, and NEC over a 4 1/2-year period. Of 418 infants of birth weight less than 1,500 g admitted during this period, 28/209 infants who had received vitamin E had definite NEC (13.4%) compared with 12/209 who had not received vitamin E (5.74%, chi 2 = 7.07, P = .008). For infants of birth weight less than 1,250 g, 16/103 infants who received vitamin E developed NEC v 1/159 who had not (chi 2 = 21.1, P less than .001); the incidence of NEC was not significantly different between the two groups for infants with birth weight between 1,250 to 1,500 g. The early mortality (less than seven days) for infants with birth weight of 1,500 g or less was significantly greater for those who had not received vitamin E (43.5% v 13.8%, chi 2 = 44.9, P less than .001), most probably a reflection of the omission of this drug for the most critically ill infants in this retrospective review. The incidence of NEC was not different for infants with birth weight of 1,500 g or less who received intramuscular vitamin E compared with control infants from the same period. For those infants for whom serum tocopherol levels were available, no infant who developed NEC and who had received only oral vitamin E had a serum tocopherol levels of greater than 3.5 mg/100 mL.(ABSTRACT TRUNCATED AT 250 WORDS)