Two Consecutive Invasive Surgeries Utilizing Zymogen Protein C (ZPC) That Enhanced Patient Safety and Reduced Costs.

This case report describes a major surgical procedure for a protein C-deficient, hypercoagulable patient who underwent two back-to-back invasive surgeries, hip replacement, and spinal stenosis correction. The patient, an 84-year-old male with a history of deep vein thromboses (DVT) and pulmonary emboli (PE), was treated pre-, peri-, and postoperatively with zymogen protein C (ZPC-Baxter, International) and recovered without clotting or increased bleeding. During the procedure, the patient was not administered any other anticoagulants. There have now been several case reports on different patients with unrelated teams in various locations worldwide using zymogen protein C during surgical procedures. Thus, this procedure is becoming a viable choice for patients with a high probability of clotting during and after invasive surgery. This case focuses on accomplishing safer surgery and reducing costs, by using less ZPC while accomplishing two surgeries in one procedure. As a result, this procedure might be useful for many medical situations where acquired protein C deficiency could be a problem (e.g., sepsis, pregnancy, etc.). This approach may have greater application to medical conditions other than protein C deficiency, where clotting and inflammation can become issues.

A Compelling Case for the Use of Perioperative Zymogen Protein C for Increased Patient Safety.

It is imperative to maintain normal blood flow to provide adequate oxygen supply to specific organs and cells, as well as for the removal of metabolic byproducts. Therefore, any situation that results in blood clotting can injure or kill living tissues. In this paper, we describe a case where a protein C deficient subject who would, by all medical indicators, be at 100 % risk of experiencing thrombophlebitis, deep vein thrombosis, and or lung emboli, is able to escape all pathologies by using perioperative zymogen protein C (ZPC). This protein C deficient patient has a long history of blood clotting, particularly from surgical procedures. The patient is 81 years old and first experienced clotting due to hernia surgery in 1964, when he was hospitalized for 16 days post-surgery with life threatening complications. It was later determined in 1980, after many episodes, that the patient had hereditary protein C deficiency at the 38 % level. In his hernia surgery, perioperative ZPC was used along with accepted anticoagulation procedures with no blood clots or other related side effects occurring. This procedure can greatly benefit protein C deficient patients, and could potentially find use for non-PC deficient patients in surgeries and a variety of other medical treatments. This particular case helps to validate the importance of ZPC in effecting safer surgery in high-risk patients. It also supports the mechanism of ZPC acting as an anticoagulant without causing bleeding. Most importantly, each clinical case study represents a unique combination of surgeon, hematologist, medical staff, and patient functioning as a coordinated team. In this case, smaller amounts of very expensive ZPC achieved safe and efficacious results, which is hugely important for future clinical applications when considering the production cost of ZPC. More studies must be done to establish minimum dosing while achieving safe and efficacious outcomes.

Heritability of changes in genetic evaluations of dairy bulls from first to later records of daughters.

Objectives of this study were to investigate changes in predicted transmitting abilities (PTA) of yields from evaluations based on first records to evaluations based on first and later records of daughters and determine whether these changes are heritable. Data were USDA sire evaluations of July 1989 through May 2000 on Holstein bulls in standard progeny testing programs. Changes in PTA for milk, fat, and protein from evaluations based on first records of daughters to evaluations on first and second were obtained on 2001 bulls. These were divided into two sets: subset 1 (n = 889) included bulls first evaluated before 1995 and subset 2 (n = 1112) included bulls first evaluated in 1995 and later. Changes in PTA from first-record evaluation to most recent evaluation (May 2000) were obtained on 2524 bulls first evaluated in 1995 or later. Mean changes in PTA for bulls first evaluated in 1995 and later were smaller than mean changes for bulls evaluated earlier but standard deviations were similar. Regressions of changes in PTA on changes in parent average showed that a change of 1.0 kg in parent average resulted in 1.1 to 1.2 kg change in PTA. Heritabilities estimated with animal model ranged from 0.14 to 0.23 for changes from first-record evaluation to evaluation on first and second, and 0.27 to 0.35 for changes from first-record evaluation to most recent evaluation. Heritabilities of this magnitude allow for identifying bulls that decrease in PTA.

Proven and young Holstein bulls compared for daughter yields, productive life, somatic cell score, and inbreeding.

The objective of this study was to compare daughters of proven (progeny-tested) and young sampling bulls available for use at the same time for yield traits, productive life, somatic cell score, and inbreeding. Data were from USDA sire evaluations of July 1989 through July 1994. Proven bulls used between 1989 and 1994 were identified based on the change in number of daughters. Young bulls were identified based on age and date a bull first entered artificial insemination. Young bulls were classified into two categories: one included all young bulls available in one year and the other included the top 50% on parent average for milk. Daughter deviations for yields, productive life and somatic cell scores, and average inbreeding were obtained from May 2000 evaluation. Daughter deviation milk was not different between proven and top 50% young bulls but was lower for all young bulls. Young bulls (all and top 50%) exceeded proven bulls in daughter deviation fat and protein. Progeny of proven bulls had favorably higher productive life in most years but unfavorably higher somatic cell score than progeny of young bulls. Inbreeding was consistently higher for daughters of young bulls than for those of proven bulls. Results indicate that young bulls were competitive with proven bulls. Use of young bulls from among the top 50% should result in equal or higher genetic progress in yields compared to contemporaries by proven bulls.

Prediction of most recent evaluations of Holstein bulls from first available pedigree information.

The objectives of this study were to predict most recent evaluations of young bulls entering artificial insemination (AI) sampling programs from pedigree information available at time of sampling and investigate whether prediction equations differ among AI organizations. Data were pedigree information and most recent USDA evaluations on bulls entering AI sampling programs from 1989 through 1994. Pedigree information included earliest available parent average, predicted transmitting abilities (PTA) of sire, dam, and maternal grand sire. Most recent evaluations were from May 2000 evaluations and included PTA and daughter yield deviations for milk, fat, and protein. Regression coefficients on PTA of sire and PTA of dam were less than the expected coefficient of 0.50. Accuracy of prediction as determined by R-square values was less than 12%. Inclusion of PTA of maternal grand sire after PTA of sire and dam increased the accuracy of prediction by less than 1%, but regression coefficients on PTA of maternal grand sire differed from 0. Regressions on parent average were not different among AI organizations for prediction of PTA and daughter yield deviations. Partial regression coefficients on PTA of sire differed among AI organizations for prediction of fat and protein but did not differ for milk. Coefficients on PTA of dam did not differ among organizations. These results indicate that AI organizations put different emphasis on PTA of sire in selection of sons for fat and protein.

Relationships of productive life evaluations with changes in evaluations for yields.

The objective of this work was to investigate the relationships of productive life with changes in bull evaluations for yield traits. Two datasets were analyzed. In the first, predicted differences for change in milk yield from first to second lactation of daughters of artificial insemination (AI) Holstein bulls used widely in the southeastern United States were available from a previous study. These were correlated with predicted transmitting abilities (PTA) of productive life from May 2000 USDA sire evaluations. Based on bulls with at least 10 daughters (n = 560) the correlation of PTA productive life with predicted differences for the change in milk yield was 0.30. The correlation increased to 0.36 for bulls with at least 50 daughters (n = 319) and to 0.40 for bulls with at least 75 daughters (n = 284). The second analysis included data on 1831 AI sampled Holstein bulls evaluated by USDA between July 1989 and May 2000. Changes in PTA yields were calculated as PTA from evaluations based on first and second records of daughters minus those from first-record evaluations. Correlation analyses showed that PTA yields from first-record evaluation and changes in PTA yields were positively associated with productive life. Regression coefficients on changes in PTA yields were all positive indicating that increases in PTA for yield traits as daughters aged corresponded with longer productive life. Using changes in AI bull evaluations for yields could improve prediction of productive life for little cost.

Biomarker correlations of urinary 2,4-D levels in foresters: genomic instability and endocrine disruption.

Forest pesticide applicators constitute a unique pesticide use group. Aerial, mechanical-ground, and focal weed control by application of herbicides, in particular chlorophenoxy herbicides, yield diverse exposure scenarios. In the present work, we analyzed aberrations in G-banded chromosomes, reproductive hormone levels, and polymerase chain reaction-based V(D)J rearrangement frequencies in applicators whose exposures were mostly limited to chlorophenoxy herbicides. Data from appliers where chlorophenoxy use was less frequent were also examined. The biomarker outcome data were compared to urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D) obtained at the time of maximum 2,4-D use. Further comparisons of outcome data were made to the total volume of herbicides applied during the entire pesticide-use season.Twenty-four applicators and 15 minimally exposed foresters (control) subjects were studied. Categorized by applicator method, men who used a hand-held, backpack sprayer in their applications showed the highest average level (453.6 ppb) of 2,4-D in urine. Serum luteinizing hormone (LH) values were correlated with urinary 2,4-D levels, but follicle-stimulating hormone and free and total testosterone were not. At the height of the application season; 6/7 backpack sprayers, 3/4 applicators who used multinozzle mechanical (boom) sprayers, 4/8 aerial applicators, and 2/5 skidder-radiarc (closed cab) appliers had two or more V(D)J region rearrangements per microgram of DNA. Only 5 of 15 minimally exposed (control) foresters had two or more rearrangements, and 3 of these 5 subjects demonstrated detectable levels of 2,4-D in the urine. Only 8/24 DNA samples obtained from the exposed group 10 months or more after their last chlorophenoxy use had two rearrangements per microgram of DNA, suggesting that the exposure-related effects observed were reversible and temporary. Although urinary 2,4-D levels were not correlated with chromosome aberration frequency, chromosome aberration frequencies were correlated with the total volume of herbicides applied, including products other than 2,4-D. In summary, herbicide applicators with high urinary levels of 2,4-D (backpack and boom spray applications) exhibited elevated LH levels. They also exhibited altered genomic stability as measured by V(D)J rearrangement frequency, which appears reversible months after peak exposure. Though highly detailed, the limited sample size warrants cautious interpretation of the data.

Genetic change in milk, fat, days open, and body weight after calving based on three methods of sire selection.

Three Holstein lines, were compared, based on different methods of sire selection, for genetic change in 3.7% FCM, fat yield, days open, and predicted body weight after calving. The three lines were 1) evaluated sires selected only for 3.7% FCM (milk line), 2) evaluated sires selected on an index that included 3.7% FCM and type traits (index line), and 3) young bulls selected on pedigree for 3.7% FCM (young line). Cows from these lines were born in 1971 through 1993 in five experimental herds owned by the State Farm Division of North Carolina Department of Agriculture. Breeding values of cows in each line computed with a repeatability model were averaged by and regressed on birth year to estimate genetic change. Genetic gains in 3.7% FCM were 81 kg/yr for the milk line, 61 kg/yr for the line selected on index, and 68 kg/yr for the young sire line. Estimates of genetic gain in fat yield were 2.99, 2.16, and 2.54 kg/ yr in the three lines, respectively. Genetic gains in 3.7% FCM and fat yield in the milk line were significantly different from the index and young sire lines, but the index and young sire lines were not significantly different. Estimates of genetic change in days open were 0.71, 0.57, and 0.63 d/yr in the milk, index, and young sire lines, respectively. These estimates were not significantly different. Average breeding values for body weight decreased for births from 1971 to 1981 then rapidly increased for later births in all lines.

Genetic parameters and trends of milk, fat, days open, and body weight after calving in North Carolina experimental herds.

The main objective of this study was to estimate genetic trends for 3.7% FCM, fat yield, days open, and predicted body weight after calving in six experimental dairy herds owned by the State Farm Division of the North Carolina Department of Agriculture. Body weights were predicted from heart girths measured at or before the first test day after calving. Data analyzed were 23,052 records from 8575 cows, daughters of 681 bulls. Heritabilities and breeding values were estimated using the multiple-trait, derivative-free REML programs and a single-trait repeatability model. Breeding values of cows were averaged by and regressed on birth year to estimate genetic trends. Genetic correlations between traits were estimated by correlating breeding values. Estimates of heritability were 0.25 for 3.7% FCM, 0.28 for fat yield, 0.03 for days open, and 0.17 for predicted body weight. Unfavorable genetic relationships were found between yields and days open and between yields and body weight. Genetically, cows that were heavier after calving produced less milk and fat but conceived earlier than smaller cows. Genetic changes in yields and days open were greater for cows born after 1970, but the greatest genetic changes were after 1980 (FCM, 94.7 kg/yr; fat yield, 3.46 kg/yr; days open, 1.1 d/yr). Breeding values for body weight increased for cows born from 1950 to 1970, decreased until 1980, and increased for later parities. The results of our study suggest that AI organizations may need to include fertility traits in progeny testing and relax the emphasis on increased body weight.

Acquired hemophilia in patients with hematologic malignancies.

OBJECTIVES: To evaluate the occurrence of acquired hemophilia in patients with hematologic malignancies and to assess their response to treatment. DESIGN: Data on 8 patients with hematologic neoplastic disorders and inhibitor against factor VIII were analyzed retrospectively. SETTING: Three large tertiary-care centers. RESULTS: All 8 patients presented with spontaneous or posttraumatic hemorrhages. The mean inhibitor titer at the time of diagnosis was 79 Bethesda units (BU), and residual factor VIII activity was detectable in 3 patients. The inhibitor disappeared in 5 patients after a mean of 92 days, but persisted in the 3 other patients. The patients who achieved complete resolution of their circulating anticoagulant had lower mean inhibitor titers at the time of diagnosis than those who had persistent inhibitor (27 BU vs. 167 BU, respectively). Two patients died as a result of major hemorrhages that did not respond to treatment. CONCLUSIONS: Antibodies against factor VIII may be responsible for some bleeding episodes in patients with lymphoid or myeloid malignancies. Acquired hemophilia in this setting should be differentiated from other causes of bleeding because the approach to treatment is different. No conclusion can be drawn regarding the association between the activity of the underlying illness and the inhibitor titer, although it appears that at least in some patients such a relationship may exist. The underlying pathogenetic mechanisms responsible for the production of autoantibodies against factor VIII remain unclear, but we provide a few explanations in this article.

Recurrent warfarin-induced skin necrosis in kindreds with protein S deficiency.

Warfarin-induced skin necrosis is a rare complication of anticoagulant treatment. The incidence of this complication is undetermined, but it has been estimated to occur between 1:100 and 1:10,000 of patients treated with anticoagulants. Coumarin skin necrosis occurs almost exclusively in patients with venous thrombosis between the 3rd and 10th day after beginning anticoagulation. Although protein C deficiency is the most common underlying hypercoagulable state reportedly associated with warfarin skin necrosis, very few cases have been linked to congenital protein S deficiency. This article addresses the association of hereditary protein S deficiency and warfarin skin necrosis, and provides suggestions for management.

Genetic instability in patients with Hodgkin's disease undergoing chemotherapy.

We have studied the effect of chemotherapy on the level of a particular kind of genetic instability in patients with Hodgkin's disease. The particular type of genetic instability assayed is exemplified by trans-rearrangements between two (rather than within one) T cell antigen receptor. 16 patients were studied during their course of treatment. Presentation samples were available for 13 of these patients; 9 of them showed an increase in the level of trans-rearrangements during their exposure to chemotherapeutic agents (P < 0.043). All patients for whom posttherapy samples were available (10 out of 16) showed a return to baseline levels of trans-rearrangements 1-5 mo after completion of therapy (P < 0.03). Thus, this assay appears to be a marker for the "destabilizing" effects of certain chemotherapeutic agents.

Cell cycle distribution defect in PHA-stimulated T lymphocytes of sickle cell disease patients.

T lymphocytes from normal human controls and sickle cell disease (SCD) patients were isolated from peripheral blood and cultured for 72 hours following addition of phytohemagglutinin. The ratio for the fraction of cells in DNA synthesis (S phase) over the fraction in G2 phase (S/G2) was significantly higher in SCD patients in comparison to the controls (mean +/- SD) (4.01 +/- 0.78 vs. 2.78 +/- 0.76, P less than 0.02). Following in vivo zinc supplementation to two subjects, the S/G2 ratio was normalized. We conclude that the distribution of T lymphocytes in cell cycle is altered in SCD patients and that this effect may be zinc-dependent.

Lymphocyte subpopulation abnormalities in sickle cell anemia: a distinctive pattern from that of AIDS.

In this study, we evaluated lymphocyte subpopulations in 23 adults with SCA. When compared to controls, SCA patients had higher lymphocyte counts with normal numbers of T101+ cells (T-lymphocytes) and T4+ cells. T8+ cells were significantly increased in SCA patients in comparison to controls (1684 +/- 243 vs 980 +/- 367, p less than .001). This increment was largely dependent on a T101-, T8+ cell population. The SCA patients as a group had significantly decreased T4/T8 ratio (p less than .0001). The SCA patients with history of blood transfusions had higher T4+ cells numbers and higher T4/T8 ratio, but no other significant differences from nontransfused patients were noted. Our results are different from those reported for nontransfused children with SCA who showed normal T4/T8 ratio. Thus, a distinct pattern of abnormalities is seen in the lymphocyte subpopulations of adult SCA patients, unrelated to their exposure to blood transfusions.

Impaired IgM antibody responses to an influenza virus vaccine in adults with sickle cell anemia.

Type-specific IgM and IgG antibody responses to a polyvalent influenza vaccine were evaluated in 16 adults with sickle cell anemia, with the use of an enzyme-linked immunosorbent assay. When compared to healthy controls, 8 out of the 16 patients had decreased or undetectable postvaccination anti-influenza IgM antibody levels. These patients were found to have significantly lower serum IgM levels and nondetectable splenic tissue (by 99Tc scans), as compared to those with normal IgM responses. Impaired IgM antibody primary immune responses may play a role in the pathogenesis of infectious complications seen in adult patients with sickle cell anemia.