ABSTRACT
We have evaluated the use of genomic coancestry coefficients based on shared segments for the maintenance of genetic diversity through optimal contributions methodology for populations of three different Austrian cattle breeds. This coancestry measure has been compared with the genomic coancestry coefficient calculated on a SNP-by-SNP basis and with pedigree-based coancestry. The regressions of the shared segments coancestry on the other two coefficients suggest that the former mainly reflect Identity By Descent but with the advantage over pedigree-based coancestry of providing the realized Identity By Descent rather than an expectation. The effective population size estimated from the rate of coancestry based on shared segments was very similar to those obtained with the other coefficients and of small magnitude (from 26.24 to 111.90). This result highlights the importance of implementing active management strategies to control the increase of inbreeding and the loss of genetic diversity in livestock breeds, even when the population size is reasonably large. One problem for the implementation of coancestry based on shared segments is the need of estimating the gametic phases of the SNPs which, given the techniques used to obtain the genotypes, are a priori unknown. This study shows, through computer simulations, that using estimates of gametic phases for computing coancestry based on shared segments does not lead to a significant loss in the diversity maintained. This has been shown to be true even when the size of the population is very small as it is usually the case in populations subjected to conservation programmes.
Subject(s)
Cattle/genetics , Genetic Variation , Animals , Computer Simulation , Female , Genetics, Population , Male , Polymorphism, Single NucleotideABSTRACT
Genotype imputation is widely used as a cost-effective strategy in genomic evaluation of cattle. Key determinants of imputation accuracies, such as linkage disequilibrium patterns, marker densities, and ascertainment bias, differ between Bos indicus and Bos taurus breeds. Consequently, there is a need to investigate effectiveness of genotype imputation in indicine breeds. Thus, the objective of the study was to investigate strategies and factors affecting the accuracy of genotype imputation in Gyr (Bos indicus) dairy cattle. Four imputation scenarios were studied using 471 sires and 1,644 dams genotyped on Illumina BovineHD (HD-777K; San Diego, CA) and BovineSNP50 (50K) chips, respectively. Scenarios were based on which reference high-density single nucleotide polymorphism (SNP) panel (HDP) should be adopted [HD-777K, 50K, and GeneSeek GGP-75Ki (Lincoln, NE)]. Depending on the scenario, validation animals had their genotypes masked for one of the lower-density panels: Illumina (3K, 7K, and 50K) and GeneSeek (SGGP-20Ki and GGP-75Ki). We randomly selected 171 sires as reference and 300 as validation for all the scenarios. Additionally, all sires were used as reference and the 1,644 dams were imputed for validation. Genotypes of 98 individuals with 4 and more offspring were completely masked and imputed. Imputation algorithms FImpute and Beagle v3.3 and v4 were used. Imputation accuracies were measured using the correlation and allelic correct rate. FImpute resulted in highest accuracies, whereas Beagle 3.3 gave the least-accurate imputations. Accuracies evaluated as correlation (allelic correct rate) ranged from 0.910 (0.942) to 0.961 (0.974) using 50K as HDP and with 3K (7K) as low-density panels. With GGP-75Ki as HDP, accuracies were moderate for 3K, 7K, and 50K, but high for SGGP-20Ki. The use of HD-777K as HDP resulted in accuracies of 0.888 (3K), 0.941 (7K), 0.980 (SGGP-20Ki), 0.982 (50K), and 0.993 (GGP-75Ki). Ungenotyped individuals were imputed with an average accuracy of 0.970. The average top 5 kinship coefficients between reference and imputed individuals was a strong predictor of imputation accuracy. FImpute was faster and used less memory than Beagle v4. Beagle v4 outperformed Beagle v3.3 in accuracy and speed of computation. A genotyping strategy that uses the HD-777K SNP chip as a reference panel and SGGP-20Ki as the lower-density SNP panel should be adopted as accuracy was high and similar to that of the 50K. However, the effect of using imputed HD-777K genotypes from the SGGP-20Ki on genomic evaluation is yet to be studied.
Subject(s)
Cattle/genetics , Genotype , Oligonucleotide Array Sequence Analysis/veterinary , Polymorphism, Single Nucleotide , Animals , Female , Male , Oligonucleotide Array Sequence Analysis/methodsABSTRACT
BACKGROUND: Breast cancer 1 (BRCA1) protein inactivation in sporadic ovarian carcinoma (OC) is common and low BRCA1 expression is linked with platinum sensitivity. The clinical validation of BRCA1 as a prognostic marker in OC remains unresolved. PATIENTS AND METHODS: In 251 patient samples from the NCIC CTG clinical trial, OV.16, BRCA1 protein expression was determined by immunohistochemistry. RESULTS: For all patients, when BRCA1 score was analyzed as a continuous variable, there was no significant correlation between BRCA1 protein expression and progression-free survival (PFS) [adjusted hazard ratio (HR) = 1.15 (0.96-1.37), P = 0.12] or response rate [HR = 0.89 (0.70-1.12), P = 0.32]. In the 116 patients with minimal residual disease (RD), higher BRCA1 expression correlated significantly with worse PFS [HR = 1.40 (1.04-1.89), P = 0.03]. Subgroup analysis divided patients with minimal RD into low (BRCA1 ≤2.5) and high (BRCA1 >2.5) expression groups. Patients with low BRCA1 expression had a more favorable outcome [median PFS was 24.7 and 16.6 months in patients with low and high BRCA1, respectively; HR = 0.56 (0.35-0.89), P = 0.01]. CONCLUSIONS: This study suggests that BRCA1 protein is a prognostic marker in sporadic OC patients with minimal RD. Further research is needed to evaluate BRCA1 as a predictive biomarker and to target BRCA1 expression to enhance chemotherapeutic sensitivity.
Subject(s)
BRCA1 Protein/biosynthesis , Biomarkers, Tumor/biosynthesis , Neoplasms, Glandular and Epithelial/drug therapy , Neoplasms, Glandular and Epithelial/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , BRCA1 Protein/genetics , Biomarkers, Tumor/genetics , Carboplatin/administration & dosage , Carcinoma, Ovarian Epithelial , Cisplatin/administration & dosage , Disease-Free Survival , Female , Humans , Immunohistochemistry , Middle Aged , Neoplasm Staging , Neoplasms, Glandular and Epithelial/genetics , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Paclitaxel/administration & dosage , Prognosis , Topotecan/administration & dosageABSTRACT
The bifunctional compound, ethylene-glycol bis(N-hydroxysuccinimidylsuccinate) (EGNHS), stabilizes horseradish peroxidase C (HRP) by reaction with the enzyme's lysine residues. In this study we compare native and modified HRP by proteolytic fragmentation, peptide sequencing, and mass spectroscopy, and identify the sites of modification. Most significantly, EGNHS is shown to form a crosslink between Lys232 and Lys241 of HRP and modifies Lys174 without formation of a crosslink. These findings are in agreement with the lysine side-chain reactivities predicted from the surface accessibility of the amino groups, and the maximal span of 16 A of the EGNHS crosslinker.
Subject(s)
Cross-Linking Reagents/chemistry , Ethylene Glycols/chemistry , Horseradish Peroxidase/chemistry , Succinates/chemistry , Chromatography, High Pressure Liquid , Electrophoresis, Polyacrylamide Gel , Lysine/chemistry , Mass Spectrometry , Models, Chemical , Peptide Mapping , Peptides/chemistry , Protein Binding , Protein Structure, Tertiary , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Temperature , Time FactorsABSTRACT
Clinical and epidemiological studies have supported the belief that human beings exposed to stressful life events are vulnerable to the symptomatology consistent with posttraumatic stress disorder (PTSD). However, early detection of symptoms consistent with PTSD oftentimes does not occur within the medicolegal arena. The importance of an early and accurate diagnosis is emphasized. Fortunately, the diagnosis of PTSD has become more clearly conceptualized in the DSM-IV criteria. Many of the characteristics consistent with this diagnosis are measured through the use of relatively recently developed and refined psychometric measures including the Posttraumatic Stress Diagnostic Scale, the Trauma Symptom Inventory, and the Personality Assessment Inventory-2. Additional measures including the Computerized Response Bias Test, the Word Memory Test, and the Validity Indicator Profile can detect exaggeration of symptoms without using specific tests for symptom validity. These measures, as well as biochemical determinations, are reviewed and presented along with the over-all structured clinical interviews and mental status examinations of two patients for a better understanding of the multimethod approach which establishes the reliability of the PTSD diagnosis.
Subject(s)
Stress Disorders, Post-Traumatic/diagnosis , Adult , Clinical Protocols , Cognitive Behavioral Therapy , Diagnosis, Differential , Female , Humans , Life Change Events , MMPI/statistics & numerical data , Male , Malingering/diagnosis , Malingering/psychology , Middle Aged , Personality Assessment/statistics & numerical data , Personality Inventory/statistics & numerical data , Psychiatric Status Rating Scales/statistics & numerical data , Psychometrics , Psychotropic Drugs/therapeutic use , Rehabilitation, Vocational , Reproducibility of Results , Severity of Illness Index , Stress Disorders, Post-Traumatic/psychology , Stress Disorders, Post-Traumatic/therapyABSTRACT
OBJECTIVE: Hyperandrogenic anovulation is the principal risk factor for non-insulin-dependent diabetes mellitus (NIDDM) in young women. Since many of these women undergo depilatory therapy, the purpose of this study was to estimate the probability of undiagnosed glucose intolerance associated with hyperandrogenic anovulation among premenopausal women requesting electrolysis. DESIGN: Case-series study. INTERVENTIONS: Women (N = 791) attending one of 27 electrology clinics in the United States, Canada and Germany received questionnaires requesting anthropometric data; personal information regarding age, surgery and medication use, and family histories of excess hair growth in female relatives and diabetes in parents or siblings. RESULTS: Of 652 respondents less than age 50 years, 643 (98.6%) women had hirsutism, of whom 465 had regular menstrual cycles. One hundred seventy-eight (27.3%) women less than 50 years of age had hirsutism with irregular menses, and one-half of these women also were obese. Regardless of adiposity, one-third of hirsute women with menstrual irregularity knew the cause of their androgen excess, while the remaining two-thirds were unaware of the reason for their excess hair growth. CONCLUSIONS: Assuming a 20% risk of glucose intolerance in obese hyperandrogenic anovulatory women by the fourth decade of life, the estimated prevalence of undiagnosed glucose intolerance from hyperandrogenic anovulation is 1.7% among women requesting electrolysis before age 50 years.
Subject(s)
Anovulation/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Electrolysis/statistics & numerical data , Hirsutism/epidemiology , Adolescent , Adult , Androgens/blood , Anovulation/complications , Canada/epidemiology , Child , Cohort Studies , Contraceptives, Oral/administration & dosage , Data Collection , Diabetes Mellitus, Type 2/etiology , Female , Germany/epidemiology , Hirsutism/blood , Hirsutism/complications , Hirsutism/therapy , Humans , Menstruation Disturbances/complications , Middle Aged , Obesity/complications , Polycystic Ovary Syndrome/complications , Predictive Value of Tests , Prevalence , Risk Factors , Surveys and Questionnaires , United States/epidemiologyABSTRACT
OBJECTIVES: To determine the exposure to, and evaluate the potential toxicity from, the plasticizer, di(2-ethylhexyl)phthalate (DEHP) during extracorporeal membrane oxygenation (ECMO) therapy. DESIGN: Protocol 1 consisted of a prospective comparison of three ECMO circuit designs in vitro. Protocol 2 consisted of a prospective, comparative clinical study evaluating DEHP plasma concentrations in ECMO vs. non-ECMO patients with respiratory failure. SETTING: Neonatal intensive care unit at The Children's National Medical Center, Washington, DC. PATIENTS: In protocol 2, 28 consecutive term infants were referred for ECMO therapy. Eighteen infants required ECMO; ten control patients received conventional ventilation and improved without ECMO. INTERVENTIONS: In protocol 1, three ECMO circuit designs were primed in vitro with normal saline, albumin, and human blood, which was maintained at 37 degrees C and recirculated at 400 mL/min for 48 hrs. Plasma samples were obtained at time 0, 1 hr, and every 6 hrs. In protocol 2, ventilatory and cardiovascular management of the patients in the study was conducted by the attending physician. Patients were placed on ECMO when they met the institutional criteria for ECMO therapy. Daily plasma concentrations for DEHP were collected until 3 days after decannulation from bypass in the ECMO group. Control patients were sampled daily until extubation. Evidence of cardiac, liver, or lung toxicity was evaluated by Chest Radiographic Scores, liver function studies, and echocardiograms obtained on day 1, day 3, and the day of decannulation in the ECMO group, or at the time of extubation in the control group. Sedation, blood product transfusions as indicated, antibiotics, and hyperalimentation were administered to all patients. MEASUREMENTS AND MAIN RESULTS: All DEHP plasma concentrations were measured by gas chromatography. In protocol 1, three circuits were studied: circuit A (small surface area); circuit B (larger surface area); and circuit C (surface area of A but with heparin-bonded tubing in the circuit). DEHP leached from circuit A at 0.32 +/- 0.12 microgram/ mL/hr, compared with 0.57 +/- 0.14 microgram/mL/hr from circuit B (p < .05). This amount of DEHP extrapolates in the ECMO patient to a potential exposure of 20 to 70 times that exposure from other medical devices or procedures, such as transfusions, dialysis, or short-term cardiopulmonary bypass. Circuit C showed almost no leaching from the circuit; DEHP concentrations decreased at a rate of 0.2 +/- 0.04 microgram/mL/ hr. In protocol 2, DEHP was undetected in the control patients. DEHP concentrations in ECMO patients were greater in the early course of ECMO. However, most patients cleared this compound from the plasma before decannulation. In contrast to the in vitro results in protocol 1, the average highest concentration at any time on bypass was 8.3 +/- 5.7 micrograms/mL or 2 mg/kg. CONCLUSIONS: DEHP leaches from ECMO circuits, with potential exposure concentrations related to the surface area of the tubing in the ECMO circuit. Heparin bonding of the tubing eliminates this risk. Although significant concentrations of DEHP leach from the nonheparin-bonded circuits over time, our in vivo studies showed that the DEHP plasma concentrations were less than the previously reported values and do not correlate with any observable short-term toxicity. This compound may be either efficiently metabolized by the newborn, or redistributed into various tissues. Although signs of toxicity were not found in this study, long-term complications from chronic exposure to DEHP have not been determined.
Subject(s)
Diethylhexyl Phthalate/metabolism , Extracorporeal Membrane Oxygenation/adverse effects , Extracorporeal Membrane Oxygenation/instrumentation , Diethylhexyl Phthalate/analysis , Equipment Safety , Female , Heart Diseases/chemically induced , Humans , Infant, Newborn , Liver Function Tests , Lung Diseases/chemically induced , Male , Prospective Studies , Respiratory Insufficiency/blood , Respiratory Insufficiency/therapyABSTRACT
Spinal cord injury affects about 200,000 people in the United States. This article discusses the disease process after acute hospitalization and the role of the nurse in the care and empowerment of the spinal cord injured patient during the rehabilitation phase. In addition to a review of didactic information concerning spinal cord injuries, this article will focus on the role of the nurse as "teacher." The manuscript stresses the importance of patient involvement and that the ultimate goal of successful rehabilitation (a lifelong process) is for the patient to direct and plan his or her own care.
Subject(s)
Spinal Cord Injuries/rehabilitation , Humans , Nursing Assessment , Patient Education as Topic , Self Care , Spinal Cord Injuries/complications , Spinal Cord Injuries/nursingABSTRACT
Extracorporeal membrane oxygenation (ECMO), designed to support the lungs in respiratory failure, is less familiar to the nurse who cares for ECMO patients when it is used to support the smaller child or neonate after cardiac surgery. An overview of ECMO, a description of the physiologic response to the ECMO circuit, and a discussion of myocardial function of the patient receiving ECMO are presented. The article focuses on the challenges posed by cardiac ECMO and the nursing care required to meet them. The unique problems addressed include variations in patient cannulation, left ventricular venting, hemostasis issues, the need for hemofiltration, and problems associated with evaluating cardiac function of the patient receiving ECMO.
Subject(s)
Cardiac Surgical Procedures/nursing , Extracorporeal Membrane Oxygenation/nursing , Intensive Care, Neonatal , Child , Critical Care , Humans , Infant , Infant, Newborn , Myocardial Contraction/physiology , Postoperative CareABSTRACT
Previous studies have shown that cardiac performance decreases in infants undergoing extracorporeal membrane oxygenation (ECMO). Some infants have an exaggerated decrease in cardiac performance during ECMO. This syndrome has been called cardiac stun. To better understand this phenomenon, we reviewed the records of infants with cardiac stun and compared them with infants who did not have the syndrome. Cardiac stun was detected in 12 of 240 infants (5.0%) undergoing ECMO. The diagnoses were congenital diaphragmatic hernia (7/12), meconium aspiration syndrome (3/12), respiratory distress syndrome (1/12), and persistent pulmonary hypertension of the newborn (1/12). The weight, gestational age, inotropic support, and time to start of ECMO were similar to infants without cardiac stun. Arterial oxygen tension was lower, carbon dioxide tension was higher, and pH was lower before ECMO in infants in whom cardiac stun developed (p less than or equal to 0.03). Cardiac arrests were more common, before ECMO, in infants in whom cardiac stun developed (6/12; p less than or equal to 0.01). Cardiac stun began at an average 2 1/2 hours after beginning ECMO (range 0.1 to 7 hours). Pulse pressure decreased from 20 mm Hg (range 10 to 45 mm Hg) before stun to 8 mm Hg (range 4 to 12 mm Hg) after stun. Heart rate did not change. Cardiac stun lasted for 33 hours (range 1 to 64 hours) on ECMO and recurred in three infants. Decreases in pump flow and increases in preload, afterload reduction, and inotropic agents did not improve cardiac performance. Survival was lower in the infants in whom cardiac stun developed (p less than or equal to 0.001). Only 5 of 12 infants (42%) survived ECMO when cardiac stun occurred. Our findings show that cardiac stun occurs infrequently during ECMO and is transient in most infants. Infants in whom cardiac stun develops appear to be more ill before ECMO and have a higher mortality after ECMO.
Subject(s)
Extracorporeal Membrane Oxygenation/adverse effects , Heart/physiopathology , Aorta/physiopathology , Blood Flow Velocity , Blood Pressure , Carbon Dioxide/blood , Echocardiography , Electrocardiography , Heart Rate , Humans , Infant , Infant, Newborn , Oxygen/bloodABSTRACT
A phase I trial and pharmacokinetic study of 5-aza-2'-deoxycytidine (5-aza-dCyd) were conducted in 21 patients with advanced solid tumors. The drug was given as three 1-h infusions, separated by intervals of 7 h. Treatment was repeated every 3-6 weeks. Forty-six cycles of 5-aza-dCyd were administered at 7 dose levels ranging from 25 to 100 mg/m2 in three infusions. The dose-limiting toxicity was myelosuppression, with a delayed white blood cell nadir, occurring at Day 22. Other toxicities included a mild, reversible elevation of serum creatinine in three patients, minimal nausea and vomiting in six patients, and transient fatigue in three patients. In this study one partial response in a patient with an undifferentiated carcinoma of the ethmoid sinus was observed. Plasma and urinary concentrations of 5-aza-dCyd were measured using a bioassay based on growth inhibition of L1210 leukemia cells in vitro. For 75 and 100 mg/m2 given as 1-h infusions, mean peak plasma concentrations of 0.93 and 2.01 microM, respectively, were attained. In seven of nine courses at doses of 25-60 mg/m2, plasma 5-aza-dCyd concentration was less than 0.01 microM. In one case at 30 mg/m2 and another at 60 mg/m2, peak plasma drug concentrations were determined to be 0.244 and 0.409 microM, respectively. Following cessation of the infusion rapid disappearance of drug from plasma was observed with a t1/2 alpha and t1/2 beta of 7 and 35 min, respectively. High clearance values and a total urinary excretion of less than 1% of the administered dose suggest that 5-aza-dCyd is eliminated rapidly and largely by metabolic processes. For the present schedule studied, a dose of 75 mg/m2 in three infusions, every 5 weeks, is recommended for phase II trials in solid tumors.
Subject(s)
Azacitidine/analogs & derivatives , Neoplasms/drug therapy , Adult , Aged , Azacitidine/adverse effects , Azacitidine/metabolism , Azacitidine/therapeutic use , Creatine/blood , Decitabine , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Evaluation , Female , Humans , Kinetics , Leukocyte Count , Male , Metabolic Clearance Rate , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Platelet Count , Temperature , Time FactorsABSTRACT
To the best of our knowledge papillary adenocarcinoma in situ of the bladder has not been reported previously. We describe a case of transitional cell carcinoma in situ of the bladder associated with papillary adenocarcinoma in situ. While it is believed that most nonurachal adenocarcinomas of the bladder originate within cystitis glandularis, such transition is difficult to document. We assume that severe dysplasia of a papillary adenomatous component adjacent to papillary adenocarcinoma in situ represents an intermediate morphological change between cystitis glandularis and adenocarcinoma. Electron microscopic evaluation of glandular epithelium indicates that it represents the process of aberrant differentiation rather than a metaplastic phenomenon.
Subject(s)
Adenocarcinoma, Papillary/pathology , Carcinoma in Situ/pathology , Carcinoma, Transitional Cell/pathology , Neoplasms, Multiple Primary/pathology , Urinary Bladder Neoplasms/pathology , Urinary Bladder/pathology , Aged , Humans , Male , Microscopy, ElectronABSTRACT
Isolated renal mucormycosis is very rare and we describe such a case masquerading as a hypernephroma in a poorly-controlled diabetic.