Use of renin angiotensin system inhibitors in patients with chronic kidney disease.

Current guidelines recommend renin angiotensin system inhibitors (RASI) as key components of treatment of hypertension in patients with chronic kidney disease (CKD), because of their effect on reducing the future rate of loss of glomerular filtration rate (GFR). A common risk of RASI in CKD is a haemodynamically mediated, and reversible, fall in GFR of varying severity and duration, any time after commencement of the Inhibitors. A benefit of the acute reduction in filtration rate with RASI may be a reduction in the future rate of loss in GFR: the greatest benefit likely to be in those patients with a greater rate of loss of GFR prior to, and a lesser acute loss of GFR after, introduction of RASI; and in those patients with significant proteinuria. An acute loss of GFR of >25% following the introduction of RASI is an indication to cease the RASI. An acute loss of GFR < 25% requires consideration of the likely risks of the lower GFR and benefits of any future reduced rate of loss of GFR. A fall in GFR in patients while on RASI is usually associated with a remediable cause. When the cause for the fall in GFR is not revealed, and the fall is less than 25%, hopeful expectancy is recommended. Hyperkalaemia in patients with CKD on RASI is more common with more severe disease, potassium retaining diuretics and hypoaldosteronism. Treatment should be modified to maintain a plasma potassium <6 mmol/L.

Management of small-cell lung cancer with radiotherapy-a pan-Canadian survey of radiation oncologists.

BACKGROUND: The management of small-cell lung cancer (sclc) with radiotherapy (rt) varies, with many treatment regimens having been described in the literature. We created a survey to assess patterns of practice and clinical decision-making in the management of sclc by Canadian radiation oncologists (ros). METHODS: A 35-item survey was sent by e-mail to Canadian ros. The questions investigated the role of rt, the dose and timing of rt, target delineation, and use of prophylactic cranial irradiation (pci) in limited-stage (ls) and extensive-stage (es) sclc. RESULTS: Responses were received from 52 eligible ros. For ls-sclc, staging (98%) and simulation or dosimetric (96%) computed tomography imaging were key determinants of rt suitability. The most common dose and fractionation schedule was 40-45 Gy in 15 once-daily fractions (40%), with elective nodal irradiation performed by 31% of ros. Preferred management of clinical T1/2aN0 sclc favoured primary chemoradiotherapy (64%). For es-sclc, consolidative thoracic rt was frequently offered (88%), with a preferred dose and fractionation schedule of 30 Gy in 10 once-daily fractions (70%). Extrathoracic consolidative rt would not be offered by 23 ros (44%). Prophylactic cranial irradiation was generally offered in ls-sclc (100%) and es-sclc (98%) after response to initial treatment. Performance status, baseline cognition, and pre-pci brain imaging were important patient factors assessed before an offer of pci. CONCLUSIONS: Canadian ros show practice variation in sclc management. Future clinical trials and national treatment guidelines might reduce variability in the treatment of early-stage disease, optimization of dose and targeting in ls-sclc, and definition of suitability for pci or consolidative rt.

Comparison of single-trait to multi-trait national evaluations for yield, health, and fertility.

Flexible software was designed to replace the current animal model programs used for national genetic evaluations. Model improvements included (1) multi-trait processing, (2) multiple fixed class and regression variables, (3) differing models for different traits, (4) random regressions, and (5) foreign data included using pseudo-records. Computational improvements included (6) parallel processing, (7) renumbering class variables to equation numbers within the program so that estimated effects are output with original identification numbers, and (8) reliability computed within the same program. When applied to 3 fertility traits of 27,971,895 cows and heifers, the new model used daughter pregnancy rate as a correlated trait to improve heifer and cow conception rate evaluations for older animals and in herd-years where records are missing, and also added information from crossbreds. When applied to 7 traits and 76,846,327 lactation records of 30,064,300 cows, gains in accuracy were small for yield and somatic cell score, moderate for daughter pregnancy rate, and larger for productive life for recent bulls compared with single-trait evaluations. For very old bulls, multi-trait gains were also large for protein because lactation records were available only for milk and fat. Multi-trait productive life was computed with exact rather than approximate methods; however, correlated information from conformation was excluded, reducing advantages of the new model over the previous software. Estimates of breed differences, inbreeding depression, and heterosis were similar to previous estimates; new estimates were obtained for conception rates. Predictions were compared by truncating 4 yr of data, and genetic trend validation was applied to all breed-trait combinations. The estimates of trend account for increases in inbreeding across time. Incorporation of foreign data gave correlations above 0.98 for new with previous evaluations of foreign Holstein bulls, but lower for other breeds. The 7-trait model required 35 GB of memory and 3 d to converge using 7 processors. The new software was implemented for fertility traits in 2013 and is scheduled for implementation with yield, somatic cell score, and productive life in 2014. Further revision of the models and software may be needed in the near future to account for genomic preselection.

Short communication: genetic evaluation of mobility for Brown Swiss dairy cattle.

Genetic parameters were estimated for mobility score and 16 linear type traits of Brown Swiss dairy cattle. Mobility is an overall assessment trait that measures a cow's ability to move, as well as the structure of her feet, pasterns, and legs. Scores from 50 to 99 were assigned by appraisers for the Brown Swiss Cattle Breeders' Association of the USA beginning in June 2007. Only scores made before 69 mo of age were used. After edits, 32,710 records were available for 19,472 cows in 819 herds. The model included fixed effects for the interaction of herd and appraisal date (2,109 groups), appraisal age within parity (46 groups), and lactation stage within parity (21 groups), as well as random effects for animal, permanent environment, and residual error. A multi-trait analysis was conducted using canonical transformation, multiple diagonalization, and a decelerated expectation-maximization REML algorithm. Heritability was estimated to be 0.21 for mobility and ranged from 0.06 to 0.37 for the other 16 type traits. The traits with the highest genetic correlation with mobility were final score (0.78), rear legs (rear view; 0.74), rear udder width (0.52), and foot angle (0.51). Predicted transmitting ability (PTA) for mobility was calculated using the Brown Swiss multi-trait type evaluation system but included only appraisals for which all traits had been scored. For the 1,868 bulls evaluated, PTA for mobility ranged from 1.6 to -1.8 with a standard deviation of 0.5 and was most highly correlated with PTA for final score (0.88), rear legs (rear view; 0.77), rear udder height (0.70), and rear udder width (0.69), as expected from the trait correlations. When matched with official US national evaluations from August 2011, PTA mobility had moderately high correlations with PTA for milk, fat, and protein yields, as well as productive life (0.31-0.41). The mobility trait may provide a more accurate assessment of the structural soundness required for longevity than does the feet-legs composite.

Factors associated with frequency of abortions recorded through Dairy Herd Improvement test plans.

Frequency of abortions recorded through Dairy Herd Improvement (DHI) testing was summarized for cows with lactations completed from 2001 through 2009. For 8.5 million DHI lactations of cows that had recorded breeding dates and were >151 d pregnant at lactation termination, the frequency of recorded abortions was 1.31%. Effects of year, herd-year, month, and pregnancy stage at lactation termination; parity; breed; milk yield; herd size; geographic region; and state within region associated with DHI-recorded abortion were examined. Abortions recorded through DHI (minimum gestation of 152 d required) were more frequent during early gestation; least squares means (LSM) were 4.38, 3.27, 1.19, and 0.59% for 152 to 175, 176 to 200, 201 to 225, and 226 to 250 d pregnant, respectively. Frequency of DHI-recorded abortions was 1.40% for parity 1 and 1.01% for parity ≥ 8. Abortion frequency was highest from May through August (1.42 to 1.53%) and lowest from October through February (1.09 to 1.21%). Frequency of DHI-recorded abortions was higher for Holsteins (1.32%) than for Jerseys (1.10%) and other breeds (1.27%). Little relationship was found between DHI-recorded abortions and herd size. Abortion frequencies for effects should be considered to be underestimated because many abortions, especially those caused by genetic recessives, go undetected. Therefore, various nonreturn rates (NRR; 60, 80, …, 200 d) were calculated to document pregnancy loss confirmed by the absence of homozygotes in the population. Breeding records for April 2011 US Department of Agriculture sire conception rate evaluations were analyzed with the model used for official evaluations with the addition of an interaction between carrier status of the service sire (embryo's sire) and cow sire (embryo's maternal grandsire). Over 13 million matings were examined using various NRR for Holstein lethal recessive traits (brachyspina and complex vertebral malformation) and undesirable recessive haplotypes (HH1, HH2, and HH3) as well as >61,000 matings for a Brown Swiss haplotype (BH1), and 670,000 matings for a Jersey haplotype (JH1). Over 80% of fertility loss occurred by 60 d after breeding for BH1, HH3, and JH1, by 80 d for HH2, by 100 d for BY, and by 180 d for HH1. For complex vertebral malformation, fertility loss increased from 40 to 74% across gestation. Association of undesirable recessives with DHI-recorded abortions ranged from 0.0% for Jerseys to 2.4% for Holsteins.

Potential consequences of selection to change gestation length on performance of Holstein cows.

Genetic evaluations for gestation length (GL) for Holstein service sires were studied to determine their effectiveness in predicting GL in an independent data set. Consequences of selection on GL were also assessed by examining correlated changes in milk and fitness traits. Holstein bulls with ≥ 300 calvings between 1998 and 2005 were stratified into the following 7 groups using predicted transmitting ability (PTA) for service sire GL: <-3.00, -3.00 to -2.01, …, 1.00 to 1.99, and ≥ 2.00 d. An independent set of 261,598 first-parity cows mated later to the same bulls and calving between 2006 and 2009 were segregated by the service sire PTA GL groups (group had 8,317 to 73,324 gestations), and these mates' GL were examined to determine effectiveness of service sire PTA GL. The model included fixed effects for herd-year and service sire group, plus covariates for conception dates to account for time opportunity among mates. Mean GL for mates by service sire group (from lowest to highest PTA GL) were 275.3, 276.5, 277.8, 278.6, 279.5, 280.6, and 281.7 d. Thus, service sire PTA GL was effective in identifying bulls that modified GL. Subsequent yield and fitness traits were also examined for the (independent) mates with the same service sire groups. Intermediate service sire PTA GL was optimal for yield traits and days open; performance for productive life and culling generally became less favorable as service sire PTA GL increased. A second examination was made by replacing service sire PTA GL groups in the model with phenotypic cow GL groups. Relationships between GL and subsequent performance for milk yield and fitness traits were examined using 9 phenotypic cow GL groups: ≤ 271, 272-273, …, 284-285, and ≥ 286 d. Performance generally improved for subsequent lactation yield as cow GL increased; however, intermediate GL was optimal for productive life, calving ease, stillbirth, culling, and days open. Results indicated that neither shortening nor increasing the mean for GL in the Holstein breed provided much overall benefit when all traits were considered. The same traits examined in the cows for the correlated effect from various GL were also examined in their offspring to determine whether the GL producing the calf had any influence on these same traits when the offspring reached their own productive period. Little carryover occurred from GL on the dam to the other traits observed on the offspring when examined a generation later.

Consequence of alternative standards for bulk tank somatic cell count of dairy herds in the United States.

Noncompliance with current US and European Union (EU) standards for bulk-tank somatic cell count (BTSCC) as well as BTSCC standards recently proposed by 3 US organizations was evaluated using US Dairy Herd Improvement Association (DHI) herds and herds supplying milk to 4 Federal Milk Marketing Orders (FMO). Herds with 15 to 26 tests (frequently monthly) from January 2009 through October 2010 were included. Somatic cell scores (SCS) from 14,854 herds and 164,794 herd-tests were analyzed for DHI herds with ≥10 cows for all tests. Herd test-day SCC was derived as a proxy for BTSCC and was the basis for determining noncompliance and percentage of the milk it represented. For FMO herds, actual milk marketed and BTSCC were available from 27,759 herds and 325,690 herd-tests. A herd was noncompliant for the current EU BTSCC standard after 4 consecutive rolling 3-test geometric means (geometric method) were >400,000 cells/mL. A herd was noncompliant for the current US BTSCC standard after 3 of 5 consecutive monthly BTSCC shipments (frequency method) were >750,000 cells/mL. Alternative proposed standards (600,000, 500,000, or 400,000 cells/mL) also were examined. A third method designated noncompliance when a single 3-mo geometric mean of >550,000 or >400,000 cells/mL and a subsequent test exceeded the same level. Results were examined based on herd size or milk shipped by month. Noncompliance for the current US standard for the 12 mo ending October 2010 in DHI and FMO herds was 0.9 and 1.0%, respectively, compared with 7.8 and 16.1% for the current EU standard. Noncompliance was always greater for the frequency method than for the geometric method and was inversely related to herd size or milk shipped. Using the frequency method at 400,000 cells/mL, noncompliance was 19.1% for DHI herd-tests in herds with <50 cows compared with 1.1% for herds with ≥ 1,000 cows. For FMO herds shipping <900 t, noncompliance was 44.5% using the frequency method at 400,000 cells/mL compared with 8.0% for herds marketing >9,000 t. All methods proposed increased the percentages of herds and shipped milk that exceeded the regulatory limit. Producers will need to place more emphasis on reducing the incidence and prevalence of subclinical mastitis through known management practices such as proper milking techniques, well-functioning milking machines, postmilking teat disinfectant, dry cow treatment, and culling of problem cows to meet any of the proposed new standards.

Response to alternative genetic-economic indices for Holsteins across 2 generations.

Four US genetic-economic indices for dairy cattle were retrofitted to illustrate differences in phenotypic response observed for retrospective selection over 2 generations for currently evaluated traits, even though producers did not have evaluations available at the time for direct selection for those traits. Differences among cows were compared based on ranking of their sires and maternal grandsires (MGS) for the 4 retrofitted indices. Holstein artificial insemination bulls (106,471) were categorized by quintile for each index, and 25 cow groups were formed based on quintiles for sire and MGS (2 generations). Data included records from 1,756,805 cows in 26,106 herds for yield traits, productive life, pregnancy rate, and somatic cell score; 692,656 cows in 9,967 herds for calving difficulty; and 270,564 cows in 4,534 herds for stillbirths. For each index, least squares differences between the 25 cow groups were examined for 8 first-parity traits (milk, fat, and protein yields; productive life; somatic cell score; pregnancy rate; calving difficulty; and stillbirth) that had been standardized for age. Analysis removed effects of herd and cow birth year. Seven of 25 cow groups were consolidated into 3 groups based on index ranking for their male ancestors (low, medium, and high). The cow group with high sire and MGS rankings for the 2006 net merit index produced more milk (219 kg), fat (21 kg), and protein (11 kg) and had longer productive life (6.3 mo), lower somatic cell score (0.21), higher pregnancy rate (1.2 percentage units), fewer difficult births in heifers (3.8 percentage units), and lower stillbirth rate (4.6 percentage units) than did the group with low sire and MGS rankings. For cow groups based on sire and MGS rankings for 1971 (milk and fat) and 1977 (milk, fat, and protein) indices, advantages for the group with high sire and MGS rankings were much larger for yield traits but smaller (and sometimes even unfavorable) for other traits. Cow groups based on sire and MGS rankings for the 1994 net merit index generally had differences that were intermediate to groups based on sire and MGS rankings for the 1977 and 2006 indices. Phenotypic differences revealed retrospectively between genetic-economic indices indicate that genetic improvement should be made for all traits included in recent net merit indices.

Sec6/8 complexes on trans-Golgi network and plasma membrane regulate late stages of exocytosis in mammalian cells.

Sec6/8 complex regulates delivery of exocytic vesicles to plasma membrane docking sites, but how it is recruited to specific sites in the exocytic pathway is poorly understood. We identified an Sec6/8 complex on trans-Golgi network (TGN) and plasma membrane in normal rat kidney (NRK) cells that formed either fibroblast- (NRK-49F) or epithelial-like (NRK-52E) intercellular junctions. At both TGN and plasma membrane, Sec6/8 complex colocalizes with exocytic cargo protein, vesicular stomatitis virus G protein (VSVG)-tsO45. Newly synthesized Sec6/8 complex is simultaneously recruited from the cytosol to both sites. However, brefeldin A treatment inhibits recruitment to the plasma membrane and other treatments that block exocytosis (e.g., expression of kinase-inactive protein kinase D and low temperature incubation) cause accumulation of Sec6/8 on the TGN, indicating that steady-state distribution of Sec6/8 complex depends on continuous exocytic vesicle trafficking. Addition of antibodies specific for TGN- or plasma membrane-bound Sec6/8 complexes to semiintact NRK cells results in cargo accumulation in a perinuclear region or near the plasma membrane, respectively. These results indicate that Sec6/8 complex is required for several steps in exocytic transport of vesicles between TGN and plasma membrane.

Alternatives for examining daughter performance of progeny-test bulls between official evaluations.

In August 2007, the USDA changed from calculating official genetic evaluations quarterly to triannually in conjunction with the schedule change for international evaluations. To offset part of the delay in providing genetic information because of the reduced frequency of official evaluations, industry cooperators requested that interim evaluations be initiated for progeny-test (PT) bulls based on first-lactation records from PT daughters and their contemporaries that calved recently in cooperator herds. Alternatives for interim evaluations were studied to determine which would characterize genetic merit of PT bulls most accurately. Four alternative Holstein data sources were examined based on maximum data interval (most recent 12 or 18 mo of first calvings) and minimum number of PT daughters in herd (> or =1 or > or = 5). The highest correlation between August 2006 interim and official evaluations for milk yield was 0.980 for interim evaluations based on the most recent 18 mo of first calvings from cooperator herds with > or =1 PT daughter. That high correlation confirmed that interim evaluations based on limited data could provide genetic estimates of value between official evaluations. With the support of the Council on Dairy Cattle Breeding, the USDA initiated 3 interim evaluations each year with release limited to PT bulls with > or =10 daughters and an increase in reliability since the most recent official evaluation.

Impact of genetic merit for milk somatic cell score of sires and maternal grandsires on herd life of their daughters.

A retrospective study of the impact of the estimated breeding values of sires and maternal grandsires for somatic cell score (SCS) on productive life (PL) of Holsteins and Jerseys was conducted. Data included records from 2,626,425 Holstein and 142,725 Jersey cows. The sires and maternal grandsires of cows were required to have been available through artificial insemination and to have predicted transmitting ability (PTA) SCS evaluations based on 35 or more daughters. A weighted function (WPTA) of sire and maternal grandsire PTA for SCS was used: (sire PTA + 0.5 maternal grandsire PTA)/1.5. The 3 dependent variables were PL, frequency of cows culled for mastitis, and first-lactation SCS. The model included effects of herd, birth year, and WPTA (WPTA was categorized into groups: <2.70, 2.70 to 2.79, ..., 3.20 to 3.29, > or =3.30). For analysis of first-lactation SCS, calving year and calving month were substituted for birth year. Differences among WPTA groups were highly significant: as WPTA increased, PL decreased, whereas percentage culled for mastitis and first-lactation SCS increased. The range in PL from lowest to highest WPTA was 5.07 mo for Holsteins and 4.73 mo for Jerseys. Corresponding differences for percentage culled for mastitis were 7.0 and 5.6% and for SCS were 0.95 and 1.04 (for Holsteins and Jerseys, respectively). Although phenotypic studies suggest that cows with extremely low SCS were less resistant to mastitis, our results showed consistent improvements in PL, percentage culled for mastitis, and SCS of daughters when bulls were chosen for low PTA SCS.

Genetic and environmental factors that affect gestation length in dairy cattle.

Genetic and environmental factors that might affect gestation length (GL) were investigated. Data included information from >11 million parturitions from 1999 through 2006 for 7 US dairy breeds. Effects examined were year, herd-year, month, and age within parity of conception; parturition code (sex and multiple-birth status); lactation length and standardized milk yield of cow; service sire; cow sire; and cow. All effects were fixed except for service sire, cow sire, and cow. Mean GL for heifers and cows, respectively, were 277.8 and 279.4 d for Holsteins, 278.4 and 280.0 d for Jerseys, 279.3 and 281.1 d for Milking Shorthorns, 281.6 and 281.7 d for Ayrshires, 284.8 and 285.7 d for Guernseys, and 287.2 and 287.5 d for Brown Swiss. Estimated standard deviations of GL were greatly affected by data restrictions but generally were approximately 5 to 6 d. Year effects on GL were extremely small, but month effects were moderate. For Holstein cows, GL was 2.0 d shorter for October conceptions than for January and February conceptions; 4.7 and 5.6 d shorter for multiple births of the same sex than for single-birth females and males, respectively; 0.8 d longer for lactations of < or =250 d than for lactations of > or =501 d; and 0.6 d shorter for standardized yield of < or =8,000 kg than for yield of > or =14,001 kg. Estimates for GL heritability from parities 2 to 5 were 33 to 36% for service sire and 7 to 12% for cow sire; corresponding estimates from parity 1 were 46 to 47% and 10 to 12%. Estimates of genetic correlations between effects of service sire and cow sire on GL were 0.70 to 0.85 for Brown Swiss, Holsteins, and Jerseys, which indicates that those traits likely are controlled by many of the same genes and can be used to evaluate each other. More accurate prediction of calving dates can help dairy producers to meet management requirements of pregnant animals and to administer better health care during high-risk phases of animals' lives. However, intentional selection for either shorter or longer GL is not recommended without consideration of its possible effect on other dependent traits (e.g., calving ease and stillbirth).

Reproductive status of Holstein and Jersey cows in the United States.

Reproductive information since 1995 from the USDA national dairy database was used to calculate yearly Holstein and Jersey means for days to first breeding after calving (DFB), 70-d nonreturn rate, conception rate (CR), number of breedings per lactation (NB), interval between first and last breedings during the lactation, days to last breeding after calving (DLB), pregnancy rate (PR), calving interval (CI), and interval between consecutive breedings. Data were from nearly 20 million breedings during >8 million lactations of >5 million cows in >23,000 herds. Means were also calculated for some traits by parity and breeding number for both breeds and by geographical region and synchronization status for Holsteins. The DFB declined for Holsteins from 92 d in 1996 to 85 d in 2007; the trend in yearly differences was not as consistent for Jerseys. First- and all-breeding 70-d nonreturn rate declined 5 to 9 percentage units over time. First- and all-breeding CR declined 2 to 4 percentage units. The DFB were longer for later parities of Holsteins than for early parities. Second- and third-breeding CR were sometimes 1 to 2 percentage units above first-breeding CR for Holsteins but lower (1 to 7 percentage units) for Jerseys. The CR within breeding number declined across parities for both breeds. The NB increased by 0.3 to 0.4 breedings over time but remained constant (2.5 or 2.6 breedings) across parities for Holsteins and increased (from 2.2 to 2.4 breedings) for Jerseys. Holstein DFB were fewest in the Northwest (78 d) and greatest in the Mountain region (92 d). Regional CR was highest for the Northeast and Southwest (33%) and lowest for the Southeast (26%); NB was fewest for the Northeast (2.3) and greatest for the Southeast (2.7). Mean DLB was fewest for the Southwest (127 d) and greatest for the Mountain region (157 d); CI was shortest for the Southwest (406 d) and longest for the Mideast (434 d). Mean PR was highest for the Southwest (28.3%) and lowest for the Mideast and Southeast (22.2%). Use of timed artificial insemination following synchronized estrus appears to have reduced DFB, lowered CR, and increased NB while reducing DLB and CI. However, synchronized breeding was not a primary cause of Holstein regional differences for reproductive traits. Since 2002, phenotypic performance for CR, DLB, and CI as well as genetic merit for daughter PR have stopped their historical declines and started to improve.

MEDiastinal Irradiation and CArdio-Toxic Effects (MEDICATE): Exploring the Relationship between Cardiac Irradiation and High Sensitivity Troponins.

AIMS: Radiation-induced heart disease is a late effect of cardiac irradiation and has been shown in patients with lymphoma and thoracic cancers. There is no established measurement tool to detect acute cardiac damage. However, high sensitivity troponin I and T (HsTnI and HsTnT) and echocardiograms have shown promise in some studies. A pilot trial was conducted to characterise whether these instruments may detect subclinical radiotherapy-induced cardiac damage. MATERIALS AND METHODS: Eligible patients received high cardiac doses defined by either at least 30 Gy to 5% of cardiac volume or a mean dose of 4 Gy. HsTnI and HsTnT were measured before radiotherapy and after 2 and 4 weeks of radiotherapy; three-dimensional echocardiograms were completed before and 1 year after radiotherapy. RESULTS: Of 19 patients, the median 'mean left ventricular dose' was 3.1 Gy and the 'mean cardiac dose' was 8.6 Gy. Significant positive associations between HsTnI and HsTnT were observed at all time points, but there was no significant association with cardiac dose. The mean left ventricular dose and the maximum left ventricular dose were, however, associated with a decrease in ejection fraction (P = 0.054, 0.043) as well as an increase in left ventricular strain (P = 0.058). CONCLUSION: This study suggests that HsTnI and HsTnT are intimately related, but detection of acute cardiac damage was not shown, potentially due to limitations of these markers or low radiotherapy doses using conformal techniques. Our results also suggest subacute damage at 1 year may depend on the dose to the left ventricle. Further studies are needed, as identification of early damage could facilitate the ability to closely monitor and intervene in patients at risk for radiation-induced heart disease.

Long-term survival and function of intraportal porcine and human islet xenografts in nondiabetic nude mice.

Instant blood-mediated inflammatory reaction (IBMIR) is a serious obstacle to both clinical islet allotransplantation and future islet xenotransplantation via the portal vein. We have previously observed uniform long-term tilapia (fish) islet xenograft survival when islets were transplanted intraportally into nondiabetic nude mice (nDNM), but not in diabetic nude mice (DNM). In this study, we examined whether human islets (HI) and adult porcine islets (API) can tolerate intraportal transplantation into nDNM like tilapia islets. HI and API were transplanted intraportally into nDNM. Recipients were humanely killed either 14 or 28 days after transplantation and livers were processed for histology. Human insulin and human C-peptide were measured in the terminal serum samples of HI recipients. In six of seven HI and seven of seven API recipients, liver histology showed insulin-positive islet xenografts. In recipients with HI, the numbers of islets/ductal structures seen histologically correlated well with serum sample results. These results show that HI and API can survive and function long term after intraportal transplantation into nDNM recipients. Our previous and present data indicated that DNM and nDNM could be useful models to study "glucose toxicity" and the role of IBMIR in the fate of intraportal islet grafts.

Death losses for lactating cows in herds enrolled in dairy herd improvement test plans.

Factors that affect frequency of death of lactating cows were studied for cows with records that terminated from 1995 through 2005. Analyses included effects of herd, year, month, parity, and lactation stage at lactation termination as well as cow breed and milk yield. A national data set (15,025,035 lactations in 45,032 herds) was analyzed with PROC GLM. Overall death frequency was 3.1% per lactation (5.7% per cow). Death frequency increased by 1.6% from 1995 to 2005, with a sudden increase of 0.9% from 2003 to 2004, probably because of a USDA requirement in late 2003 for euthanizing downer cows. Death frequency was 16.5% greater for lactations that terminated at or=251 d. Death frequency increased with parity (2% greater for eighth parity and later than for first parity) and with lactation milk yield (0.4%/1,000 kg for Holsteins and Jerseys and 0.5%/1,000 kg for other breeds). Deaths were most frequent in July and least frequent in November. Within-herd breed differences (Holstein, Jersey, and other breeds) were small. The heritability of likelihood of death estimated from a sample of 79,162 Holstein cows was 1.3%. Death losses are increasing, perhaps partly because of increased milk yield and more intensive management regimens.

Surfactant protein A suppresses reactive nitrogen intermediates by alveolar macrophages in response to Mycobacterium tuberculosis.

Mycobacterium tuberculosis attaches to, enters, and replicates within alveolar macrophages (AMs). Our previous studies suggest that surfactant protein A (SP-A) can act as a ligand in the attachment of M. tuberculosis to AMs. Reactive nitrogen intermediates (RNIs) play a significant role in the killing of mycobacteria. We have demonstrated that RNI levels generated by AMs were significantly increased when interferon-gamma-primed AMs were incubated with M. tuberculosis. However, the RNI levels were significantly suppressed in the presence of SP-A (10 microg/ml). The specificity of SP-A's effect was demonstrated by the use of F(ab')2 fragments of anti-SP-A monoclonal antibodies and by the use of mannosyl-BSA, which blocked the suppression of RNI levels by SP-A. Furthermore, incubation of deglycosylated SP-A with M. tuberculosis failed to suppress RNI by AMs, suggesting that the oligosaccharide component of SP-A, which binds to M. tuberculosis, is necessary for this effect. These results show that SP-A-mediated binding of M. tuberculosis to AMs significantly decreased RNI levels, suggesting that this may be one mechanism by which M. tuberculosis diminishes the cytotoxic response of activated AMs.

Consistency of maturity rate for milk yield across countries and generations.

Differences among bulls in maturity rate of their daughters for milk yield were investigated. Milk records for US Holsteins with first-parity calving dates between 1960 and 1998 were used to calculate 3 evaluations for bulls based on daughter records from parity 1, parities 1 and 2, and parities 1, 2, and 3. The 3 evaluations were used to estimate parity-specific evaluations for parities 2 and 3. Maturity rate of Holstein bull daughters in Canada and The Netherlands was compared with that for daughters of the same bulls in the United States by using official November 2004 Canadian and August 2005 Dutch parity-specific evaluations. For bulls with > or = 500 first-parity daughters, correlations among parity-specific evaluations within country and birth year of bull were 0.88 between parities 1 and 2, 0.84 between parities 1 and 3, and 0.96 between parities 2 and 3 for the United States; 0.90, 0.86, and 0.97, respectively, for Canada; and 0.92, 0.89, and 0.98, respectively, for The Netherlands. Correlations between Canada and the United States for within-country differences between evaluations for parities 1 and 2 were 0.72 for bulls with > or = 50 first-parity daughters and 0.89 for bulls with > or = 500 first-parity daughters; corresponding correlations between The Netherlands and the United States were 0.66 and 0.82. Correlations between countries for differences between evaluations for parities 1 and 3 were slightly less, and corresponding correlations between evaluations for parities 2 and 3 were still lower. To establish whether differences between parity-specific evaluations were genetic, comparisons were made across a generation. Coefficients for regression of son on sire within country and birth years of sire and son for parity-specific evaluations and differences between parity-specific evaluations ranged from 0.35 to 0.53, with standard errors of < or = 0.04. Differences in maturity rate of bull daughters were quite consistent across country, and those differences were transmitted to the sons' daughters. Modeling to account for maturity differences should increase the accuracy of US evaluations and reduce fluctuation between evaluations, especially for bulls with daughters that deviate substantially from the population mean for maturity rate for milk yield.

Selection on yield and fitness traits when culling holsteins during the first three lactations.

Emphasis by dairy producers on various yield and fitness traits when culling cows was documented for US Holstein calvings since 1982. Least squares differences between cows retained for additional parities and those culled were estimated for milk, fat, and protein yields; somatic cell score (SCS); days open (DO); dystocia score (DS), final score (FS), and 14 type traits. Compared with cows culled during first lactation, superiority for first-parity milk yield was 569 to 1,175 kg for cows with 2 lactations, 642 to 1,283 kg for cows with > or =2 lactations, 710 to 1,350 kg for cows with 3 lactations, and 663 to 1,331 kg for cows with > or =4 lactations. Cows retained for > or =2 lactations had first-parity SCS that were 0.34 to 0.62 lower (more favorable) than those of cows culled during first lactation; first-parity SCS for cows retained for 3 or > or =4 lactations were even more favorable than those of cows with 1 or 2 lactations. The negative genetic relationship between yield and fertility contributed to increased DO as selection for higher milk yield persisted across time despite considerable preference for early conception when culling cows. In 1982, cows retained in the herd for 2, 3, and > or =4 lactations conceived earlier during first lactation (19, 17, and 23 fewer DO, respectively) than those culled during first lactation; those differences had increased to 34, 41, and 52 fewer DO by 2000. Although DS has a negative relationship with survival, first-parity DS were only slightly lower (by 0.10 to 0.14) for survivors than for cows culled during first lactation. Cows retained for > or =2 lactations had greater first-parity FS by 1.4 to 1.9 points than those culled during first lactation. On a standardized basis, the most intense selection during first lactation was for milk and protein yields with less for fat (74 to 86% of that for milk), DO (18 to 74%), FS (22 to 38%), SCS (19 to 37%), and DS (7 to 15%). Producers continued to emphasize the same traits when culling during second and third lactations. Trait priority by producers during culling could aid in setting trait emphasis when selecting bulls for progeny test and could also be useful in developing software for index-based culling guides.

Survival rates and productive herd life of dairy cattle in the United States.

Survival rates and productive herd life were examined for 13.8 million US dairy cows that calved from January 1, 1980, through March 2, 2005. Cows that left the herd for dairy purposes or were from herds that discontinued Dairy Herd Improvement testing were excluded from any calculations to prevent underestimation of population longevity. Mean lactation length for cows without subsequently recorded lactations ranged from 205 to 235 d across breed-parity subsets and were 4 to 29 d longer for parities 2 through 7 than for parity 1. Mean survival rates were 73% to parity 2; 50% to parity 3; 32% to parity 4; and 19, 10, 5, and 2% to parities 5 through 8, respectively. The mean number of parities for Holsteins declined from 3.2 for those first calving in 1980 to 2.8 for those first calving in 1994. Mean numbers of parities for other breeds first calving in 1994 were 2.9 for Ayrshires and Brown Swiss, 2.4 for Guernseys, and 3.2 for Jerseys. Breed means for productive herd life (through parity 8) ranged from 28 to 36 mo. All regressions of mean number of parities or mean productive herd life on year were negative. The trend for decline of many of those indicators of longevity slowed or ended after the early 1990s. Between 31 (Jersey) and 39% (Guernsey) of herds were made up of first-calf heifers.