Recombinant tissue plasminogen activator to restore catheter patency: efficacy and safety analysis from a multihospital NICU system.

OBJECTIVE: In 2001, the US Food and Drug Administration approved recombinant tissue plasminogen activator (alteplase, Cathflo Activase) to reestablish patency of central catheters occluded, presumably, by a fibrin clot. We conducted a multicenter quality improvement study to determine the value of this procedure in our Neonatal Intensive Care Unit (NICUs), including analyses of efficacy, safety and costs. STUDY DESIGN: We conducted a retrospective quality analysis of neonates in level III NICUs, who received alteplase for the purpose of reestablishing patency of occluded central catheters. RESULTS: Alteplase was administered to 169 neonates, each given one to four doses, totaling 205 episodes of administration. The most common type of catheter where alteplase was used was percutaneously inserted central catheter (PICC) lines (78% of uses), 8% were umbilical venous catheters (UVCs), 6% arterial lines, 5% chest tubes and 3% other catheters. Postnatal age at first dose ranged from 0 to 132 days (median, 12); dosed patients were 22 to 41 weeks gestation at birth (median, 31). Fifty-eight percentage of administrations restored catheter function. Success was more likely at younger postnatal age (10±2 days old in successful vs 14±1 days in unsuccessful treatments; P=0.023). Seventy-two percentage of the re-canalized catheters remained functional until they were no longer needed (2 to 30 days later). Nine percentage of episodes were treated with a second dose 1 to 17 days later for re-occlusion and 50% of those were successful. Bleeding consequences were identified in only one case, where three separate lines were treated (chest tube, PICC and UVC) within a 6-h period. Costs to the health system of doses, minus savings to the system by not needing to replace lines, averaged a net of $34 per dose. CONCLUSIONS: The apparent safety and favorable value analysis prompted us to develop a consistent approach to alteplase usage in the Intermountain Healthcare NICUs, using the data in this report to standardize the guidelines across our health system.

The menstrual bleeding questionnaire: development and validation of a comprehensive patient-reported outcome instrument for heavy menstrual bleeding.

OBJECTIVE: To develop and validate a patient-reported outcome measure for women with heavy menstrual bleeding (HMB). STUDY DESIGN: Prospective cohort and cross-sectional studies. SETTING: Outpatient women's health facility. POPULATION: Women aged between 18 and 55 years with and without self-reported HMB. METHODS: Using data from patients and clinicians, we developed a patient-reported outcome measure for HMB; the Menstrual Bleeding Questionnaire (MBQ). Participants in the validation studies completed demographic and general health questionnaires and either (1) bleeding and quality of life data collected daily on handheld computers and the MBQ after 1 month or (2) the MBQ at enrolment only. A subset of women also completed the Short-form-36 (SF-36) generic quality of life questionnaire. We performed psychometric analyses of the MBQ to assess its internal consistency as well as its content and concurrent validity and ability to discriminate between women with and without HMB. MAIN OUTCOME MEASURES: Psychometric properties of the questionnaire. RESULTS: Overall, 182 women participated in the MBQ validation studies. We found that the MBQ domains were internally consistent (Cronbach's α = 0.87-0.94). There was excellent correlation between daily bleeding-related symptom data and the MBQ completed at 1 month (ρ > 0.7 for all domains). We found low to moderate correlation between the MBQ scores and SF-36 scores (ρ = -0.15 to -0.45). The MBQ clearly discriminated between women with and without HMB (mean MBQ score = 10.6 versus 30.8, P < 0.0001). CONCLUSIONS: The MBQ is a valid patient-reported outcome measure for HMB that has the potential to improve the evaluation of women with self-reported HMB in research and clinical practice.

Cardiopulmonary Bypass in a Patient with Factor XII Deficiency.

The performance of cardiopulmonary bypass (CPB) in the factor XII-deficient patient is challenging in that the normal method for monitoring anticoagulation is ineffective as a result of an impaired contact activation system. We report the case of a factor XII-deficient patient who underwent surgical revascularization on CPB. His factor XII level was replenished with fresh-frozen plasma immediately before surgery. This management strategy lowered the baseline activated clotting time (ACT) to near normal, providing a meaningful ACT value for CPB. Factor XII is also a key component in the fibrinolytic system and its deficiency is associated with increased thrombosis. Because the factor XII level quickly returns to baseline postoperatively, perioperative care must include strategies to avoid postoperative thromboembolic events.

Axial transport within bidisperse granular media in horizontal rotating cylinders.

The discrete element method has been used to examine axial dispersion within rotating cylinders containing two sizes of particle. Two bed configurations are considered: initially segregated, which consists of a pulse (narrow axial band) of small particles within a bed of large particles, and initially mixed, in which the cylinder is loaded with a homogeneous mixture of the two particle sizes. The dispersion of the small particles within initially segregated beds is found to depend strongly on the initial length of the pulse of small particles. Initially mixed beds are found to undergo a transient period in which the small particles disperse rapidly. Following this transient, axial dispersion of both particles sizes is found to follow Fick's second law, in that the mean squared deviation of the axial position of the particles is proportional to time. Axial dispersion coefficients have been calculated for initially mixed beds that have reached steady state; the axial dispersion coefficients of both particle sizes decrease as the volume fraction of small particles is increased.

Regional anaesthesia and analgesia on the front line.

Deployment to a combat zone with the military poses many challenges to the anaesthetist. One of these challenges is the safe, rapid and comfortable initial wound management and repatriation of wounded combat soldiers to their home country or tertiary treatment facility for definitive care and rehabilitation. The current conflict in Afghanistan is associated with injury patterns that differ from wars such as Vietnam or Korea. This report describes the experience of an Australian military anaesthetist and the value of regional anaesthesia and analgesia for the care of the wounded combat soldier

Untangling the roles of fire, grazing and rainfall on small mammal communities in grassland ecosystems.

In grassland systems across the globe, ecologists have been attempting to understand the complex role of fire, grazing and rainfall in creating habitat heterogeneity and the consequences of anthropogenic control of these factors on ecosystem integrity and functioning. Using a South African grassland ecosystem as a model, we investigated the impact of fire and grazing pressure on small mammal communities during three differing periods of a rainfall cycle. Over 2 years, 15,203 trap nights revealed 1598 captures of 11 species (nine rodents, one macroscelid and one insectivore). Results highlighted the importance of the interplay between factors and showed that the role of fire, grazing and rainfall in determining small mammal abundance was species-dependant. While no two species were affected by the same environmental variables, grass cover or height was important to 56% of species. Considered independently, high rainfall had a positive influence on small mammal abundance and diversity, although the lag period in population response was species-specific. High grazing negatively affected overall abundance, but specifically in Mastomys coucha; fire alone had little immediate impact on small mammal diversity. Six months after the fire, vegetation cover had recovered to similar levels as unburned areas, although small mammal diversity and richness were higher in burned areas than unburned areas. Grazing levels influenced the rate of vegetation recovery. In conclusion, low-level grazing and burning can help to maintain small mammal biodiversity, if conducted under appropriate rainfall levels. A too high grazing pressure, combined with fire, and/or fire conducted under drought conditions can have a negative impact on small mammal biodiversity. To maintain small mammal diversity in grassland ecosystems, the combined effects of the previous year's rainfall and existing population level as well as the inhibition of vegetation recovery via grazing pressure need to be taken into consideration before fire management is applied.

Design, synthesis, and analysis of a polyethelene glycol-modified (PEGylated) small molecule inhibitor of integrin {alpha}4{beta}1 with improved pharmaceutical properties.

Integrin alpha4beta1 plays an important role in inflammatory processes by regulating the migration of leukocytes into inflamed tissues. Previously, we identified BIO5192 [2(S)-{[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino}-4-[4-methyl-2(S)-(methyl-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-pentanoylamino]-butyric acid], a highly selective and potent (K(D) of 9 pM) small molecule inhibitor of alpha4beta1. Although BIO5192 is efficacious in various animal models of inflammatory disease, high doses and daily treatment of the compound are needed to achieve a therapeutic effect because of its relatively short serum half-life. To address this issue, polyethylene glycol modification (PEGylation) was used as an approach to improve systemic exposure. BIO5192 was PEGylated by a targeted approach in which derivatizable amino groups were incorporated into the molecule. Two sites were identified that could be modified, and from these, five PEGylated compounds were synthesized and characterized. One compound, 2a-PEG (K(D) of 19 pM), was selected for in vivo studies. The pharmacokinetic and pharmacodynamic properties of 2a-PEG were dramatically improved relative to the unmodified compound. The PEGylated compound was efficacious in a rat model of experimental autoimmune encephalomyelitis at a 30-fold lower molar dose than the parent compound and required only a once-a-week dosing regimen compared with a daily treatment for BIO5192. Compound 2a-PEG was highly selective for alpha4beta1. These studies demonstrate the feasibility of PEGylation of alpha4beta1-targeted small molecules with retention of activity in vitro and in vivo. 2a-PEG, and related compounds, will be valuable reagents for assessing alpha4beta1 biology and may provide a new therapeutic approach to treatment of human inflammatory diseases.

An assessment of the mechanistic differences between two integrin alpha 4 beta 1 inhibitors, the monoclonal antibody TA-2 and the small molecule BIO5192, in rat experimental autoimmune encephalomyelitis.

Integrin alpha 4 beta 1 plays an important role in inflammatory processes by regulating the migration of lymphocytes into inflamed tissues. Here we evaluated the biochemical, pharmacological, and pharmacodynamic properties and efficacy in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, of two types of alpha 4 beta 1 inhibitors, the anti-rat alpha 4 monoclonal antibody TA-2 and the small molecule inhibitor BIO5192 [2(S)-[[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino]-4-[4-methyl-2(S)-(methyl-[2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl]-amino)-pentanoylamino]-butyric acid]. TA-2 has been extensively studied in rats and provides a benchmark for assessing function. BIO5192 is a highly selective and potent (KD of <10 pM) inhibitor of alpha 4 beta 1. Dosing regimens were identified for both inhibitors, which provided full receptor occupancy during the duration of the study. Both inhibitors induced leukocytosis, an effect that was used as a pharmacodynamic marker of activity, and both were efficacious in the EAE model. Treatment with TA-2 caused a decrease in alpha 4 integrin expression on the cell surface, which resulted from internalization of alpha 4 integrin/TA-2 complexes. In contrast, BIO5192 did not modulate cell surface alpha 4 beta 1. Our results with BIO5192 indicate that alpha 4 beta 7 does not play a role in this model and that blockade of alpha 4 beta 1/ligand interactions without down-modulation is sufficient for efficacy in rat EAE. BIO5192 is highly selective and binds with high affinity to alpha 4 beta 1 from four of four species tested. These studies demonstrate that BIO5192, a novel, potent, and selective inhibitor of alpha 4 beta 1 integrin, will be a valuable reagent for assessing alpha 4 beta 1 biology and may provide a new therapeutic for treatment of human inflammatory diseases.

Lymphangioma-like Kaposi's sarcoma: etiology and literature review.

Much confusion surrounds a rare and occasionally described variant of Kaposi's sarcoma (KS) known as lymphangioma-like or bullous KS. We describe the typical clinical and histologic features and elucidate the etiologic cell in lymphangioma-like KS. A computer-based review of the English-language literature was performed. Routine histologic and immunoperoxidase techniques were performed on formalin-fixed tissue. Immunoperoxidase staining for anti-CD31, anti-CD34, and anti-factor VIII-related antigen suggests that the etiologic cell of origin is the vascular endothelial cell. Lymphangioma-like KS has been described for more than a century and given various names. Dilated vascular spaces correlate with the clinically bullous lesions, which are veritable KS and not a secondary reaction to it.

Anaesthetic management of a parturient with a colloid cyst of the third ventricle.

A colloid cyst in the third ventricle near the foramen of Monroe can obstruct cerebrospinal fluid (CSF) flow from the lateral ventricles. Any change in the CSF pressure on either side of the cyst can lead to displacement and thus precipitate acute hydrocephalus. Management of the confinement of a patient with a colloid cyst must therefore aim to minimize changes in CSF pressure. We describe our management of a patient with a small colloid cyst who was permitted to labour with the assistance of patient-controlled epidural analgesia. The available alternatives are discussed.

Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding.

Adenosine kinase (AK) is a key purine metabolic enzyme from the opportunistic parasitic protozoan Toxoplasma gondii and belongs to the family of carbohydrate kinases that includes ribokinase. To understand the catalytic mechanism of AK, we determined the structures of the T. gondii apo AK, AK:adenosine complex and the AK:adenosine:AMP-PCP complex to 2.55 A, 2.50 A and 1.71 A resolution, respectively. These structures reveal a novel catalytic mechanism that involves an adenosine-induced domain rotation of 30 degrees and a newly described anion hole (DTXGAGD), requiring a helix-to-coil conformational change that is induced by ATP binding. Nucleotide binding also evokes a coil-to-helix transition that completes the formation of the ATP binding pocket. A conserved dipeptide, Gly68-Gly69, which is located at the bottom of the adenosine-binding site, functions as the switch for domain rotation. The synergistic structural changes that occur upon substrate binding sequester the adenosine and the ATP gamma phosphate from solvent and optimally position the substrates for catalysis. Finally, the 1.84 A resolution structure of an AK:7-iodotubercidin:AMP-PCP complex reveals the basis for the higher affinity binding of this prodrug over adenosine and thus provides a scaffold for the design of new inhibitors and subversive substrates that target the T. gondii AK.

Peer-Led Alcohol Education program: a pharmacy student-led program for seventh-graders.

OBJECTIVE: To delay or discourage the use of alcohol by seventh-grade students through peer-led education. Peer-Led Alcohol Education (PLAE) program objectives were to: (1) educate students about alcohol use and (2) assess the differences between pharmacy student presenters and high school student (peer) presenters. SETTING: Middle schools in rural Nebraska. DESIGN: PLAE focuses on normative beliefs, personal values, and pledging. Pharmacy students and high school students were trained to deliver alcohol education presentations to seventh-grade students. Evaluation results were compared among groups of seventh-grade students who received PLAE presentations from peer presenters and from pharmacy student presenters. RESULTS: PLAE presentations were made to 342 seventh-grade students at 11 schools. Evaluation results suggest that pharmacy students projected more confidence in their presentations, used more creative prop selections, and were more effective communicators. High-school presenters had a greater ability to "relate" to the seventh-graders and thus were deemed more on-target with the information. CONCLUSION: Evaluation findings suggest that rural seventh-grade students in Nebraska perceived that the PLAE program provides useful information to aid them in their decisions regarding alcohol use.

Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding.

Adenosine kinase (AK) is a key purine metabolic enzyme from the opportunistic parasitic protozoan Toxoplasma gondii and belongs to the family of carbohydrate kinases that includes ribokinase. To understand the catalytic mechanism of AK, we determined the structures of the T. gondii apo AK, AK:adenosine complex and the AK:adenosine:AMP-PCP complex to 2.55 A, 2.50 A and 1.71 A resolution, respectively. These structures reveal a novel catalytic mechanism that involves an adenosine-induced domain rotation of 30 degrees and a newly described anion hole (DTXGAGD), requiring a helix-to-coil conformational change that is induced by ATP binding. Nucleotide binding also evokes a coil-to-helix transition that completes the formation of the ATP binding pocket. A conserved dipeptide, Gly68-Gly69, which is located at the bottom of the adenosine-binding site, functions as the switch for domain rotation. The synergistic structural changes that occur upon substrate binding sequester the adenosine and the ATP gi phosphate from solvent and optimally position the substrates for catalysis. Finally, the 1.84 A resolution structure of an AK:7-iodotubercidin:AMP-PCP complex reveals the basis for the higher affinity binding of this prodrug over adenosine and thus provides a scaffold for the design of new inhibitors and subversive substrates that target the T. gondii AK.

Fibrous hamartoma of infancy.

Fibrous harmartoma of infancy is a benign soft tissue tumor that occurs in the first few years of life. Although the lesion is not distinctive clinically, it has a characteristic microscopic appearance. Only 12 cases of fibrous hamartoma of infancy have been reported in the dermatology literature.

Effectiveness of student assistance programs in Nebraska schools.

BACKGROUND: This study investigated whether Nebraska schools with Student Assistance Programs (SAP) are associated with reduced adolescent alcohol use and a higher level of academic achievement than students from schools without a SAP. METHODS: In 1992, the Toward a Drug Free Nebraska (TDFN) survey was administered to 3,454 students in grades seven to twelve at eighty-three Nebraska schools. A second survey, the TDFN "team activity report" collected from each school's team, the presence of a SAP (n = 34 schools) or absence of a SAP (n = 49 schools). Student responses for alcohol use and academic achievements were linked with the presence of a SAP through use of a school identification number on both surveys. RESULTS: Students from schools with a SAP reported a lower use of alcohol in the last thirty days, compared with students from schools without a SAP program (p < 0.05), and they also reported a significant difference in academic achievement (p < 0.05). CONCLUSIONS: While this study used post hoc analysis of data, the results suggest lower alcohol use and higher academic achievement among students from SAP schools. Given SAPs' popularity, these trends suggest that further research should be conducted to demonstrate the effectiveness of student assistance programs.

Cytologic-pathologic correlations: fine needle aspiration of three cases of steatocystoma multiplex.

Steatocystoma multiplex is a rare condition characterized by multiple subcutaneous nodules classically located on the anterior chest. Diagnosis usually is made clinically or by biopsy. The lesions may be numerous, and surgical treatment may not be practical or the results may be unsatisfactory. Three patients with multiple subcutaneous nodules underwent fine needle aspiration, which produced smears with acellular debris. A diagnosis was possible in the first patient because of close collaboration with a dermatologist. The lesions in the other patients were recognized clinically and were confirmed cytologically by fine needle aspiration. A syringe holder allows the use of thin needles (22-gauge) to aspirate very small lesions (4 to 5 mm). Fine needle aspiration may provide a useful alternative to surgical methods in the treatment of these lesions because it is inexpensive, well-tolerated by the patients, and has no associated morbidity.

Characterization of genes encoding translation initiation factor eIF-2gamma in mouse and human: sex chromosome localization, escape from X-inactivation and evolution.

The Delta Sxrb interval of the mouse Y chromosome is critical for spermatogenesis and expression of the male-specific minor transplantation antigen H-Y. Several genes have been mapped to this interval and each has a homologue on the X chromosome. Four, Zfy1 , Zfy2 , Ube1y and Dffry , are expressed specifically in the testis and their X homologues are not transcribed from the inactive X chromosome. A further two, Smcy and Uty , are ubiquitously expressed and their X homologues escape X-inactivation. Here we report the identification of another gene from this region of the mouse Y chromosome. It encodes the highly conserved eukaryotic translation initiation factor eIF-2gamma. In the mouse this gene is ubiquitously expressed, has an X chromosome homologue which maps close to Dmd and escapes X-inactivation. The coding regions of the X and Y genes show 86% nucleotide identity and encode putative products with 98% amino acid identity. In humans, the eIF-2gamma structural gene is located on the X chromosome at Xp21 and this also escapes X-inactivation. However, there is no evidence of a Y copy of this gene in humans. We have identified autosomal retroposons of eIF-2gamma in both humans and mice and an additional retroposon on the X chromosome in some mouse strains. Ark blot analysis of eutherian and metatherian genomic DNA indicates that X-Y homologues are present in all species tested except simian primates and kangaroo and that retroposons are common to a wide range of mammals. These results shed light on the evolution of X-Y homologous genes.

A preliminary study of immunologic and hematologic profiles of peripheral blood from Nebraska farmers who apply pesticides to their fields.

OBJECTIVE: Laboratory studies have documented a wide range of pesticide-induced changes in the hematopoietic and lymphoreticular systems. Some of these are expressed as altered serum values, blood cell counts, and leucocyte functions. The goal of the present study was to determine whether these alterations were evident in peripheral blood of Nebraska farmers who applied pesticides to their fields. METHODS: An invitation to participate was mailed to 100 residents (70 farmers; 30 controls) of Butler County, Nebraska. All respondents (51 farmers and 21 controls) were enrolled and surveyed by written questionnaire for health status and pesticide use. Our analysis included 45 farmers and 18 controls. The farmers were divided into a high (n = 23) and a low (n = 22) pesticide use group. Statistical correlations of ten blood values with both pesticide use and age were evaluated, since pesticide use correlated with age. RESULTS: Four of the ten blood values correlated with pesticide use and age (Spearman Rho). In a multiple regression model, pesticide use (not age) proved to be a predictor of red blood cell count and hematocrit. In the same model, pesticide use was not a predictor of mean red cell volume or candida antigen-induced T-lymphocyte proliferation. Serum complement activity did not correlate with pesticide use among the farmers (n = 45) but was significantly reduced (ANOVA) in the high pesticide use group, compared to controls. CONCLUSIONS: A preliminary study of blood values in a small cohort of Nebraska farmers found no pesticide-associated effects on 1) leucocyte count, 2) antigen- and mitogen-stimulated T-cell proliferation, 3) mitogen-stimulated B-cell proliferation, and 4) concentrations of serum IgG and IgM. The study found small but statistically significant pesticide-associated effects on red blood cells and serum complement.