Neratinib and Ado-Trastuzumab-Emtansine for Pre-treated and Untreated HER2-positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium Trial 022.

PURPOSE: Treatment options for HER2-positive breast cancer brain metastases (BCBM) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab-emtansine (T-DM1) when given in combination. In TBCRC 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts (cohort 4A-previously untreated BCBM, cohorts 4B and 4C- BCBM progressing after local CNS-directed therapy without [4B] and with [4C] prior exposure to T-DM1). Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. Overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018-2021, 6, 17, and 21 patients enrolled to cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% (95% confidence interval [CI]: 4.3-77.7%), 35.3% (95% CI: 14.2-61.7%), and 28.6% (95% CI: 11.3-52.2%), respectively; 38.1-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). Median OS was 30.2 months (cohort 4A; 95% CI: 21.9, not reached [NR]), 23.3 months (cohort 4B; 95% CI: 17.6, NR), and 20.9 months (cohort 4C; 95% CI: 14.9, NR). CONCLUSION: We observed Intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pre-treated.

Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study.

PURPOSE: HER2-targeted therapies have substantially improved the outcome of patients with breast cancer, however, they can be associated with cardiac toxicity. Guidelines recommend holding HER2-targeted therapies until resolution of cardiac dysfunction. SAFE-HEaRt is the first trial that prospectively tests whether these therapies can be safely administered without interruptions in patients with cardiac dysfunction. METHODS: Patients with stage I-IV HER2-positive breast cancer candidates for trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with left ventricular ejection fraction (LVEF) 40-49% and no symptoms of heart failure (HF) were enrolled. All patients underwent cardiology visits, serial echocardiograms and received beta blockers and ACE inhibitors unless contraindicated. The primary endpoint was completion of the planned HER2-targeted therapies without developing either a cardiac event (CE) defined as HF, myocardial infarction, arrhythmia or cardiac death or significant asymptomatic worsening of LVEF. The study was considered successful if planned oncology therapy completion rate was at least 30%. RESULTS: Of 31 enrolled patients, 30 were evaluable. Fifteen patients were treated with trastuzumab, 14 with trastuzumab and pertuzumab, and 2 with TDM-1. Mean LVEF was 45% at baseline and 46% at the end of treatment. Twenty-seven patients (90%) completed the planned HER2-targeted therapies. Two patients experienced a CE and 1 had an asymptomatic worsening of LVEF to ≤ 35%. CONCLUSION: This study provides safety data of HER2-targeted therapies in patients with breast cancer and reduced LVEF while receiving cardioprotective medications and close cardiac monitoring. Our results demonstrate the importance of collaboration between cardiology and oncology providers to allow for delivery of optimal oncologic care to this unique population.

Decadal Change in Sediment Community Oxygen Consumption in the Abyssal Northeast Pacific.

Long time-series studies are critical to assessing impacts of climate change on the marine carbon cycle. A 27-year time-series study in the abyssal northeast Pacific (Sta. M, 4000 m depth) has provided the first concurrent measurements of sinking particulate organic carbon supply (POC flux) and remineralization by the benthic community. Sediment community oxygen consumption (SCOC), an estimate of organic carbon remineralization, was measured in situ over daily to interannual periods with four different instruments. Daily averages of SCOC ranged from a low of 5.0 mg C m-2 day-1 in February 1991 to a high of 31.0 mg C m-2 day-1 in June 2012. POC flux estimated from sediment trap collections at 600 and 50 m above bottom ranged from 0.3 mg C m-2 day-1 in October 2013 to 32.0 mg C m-2 day-1 in June 2011. Monthly averages of SCOC and POC flux correlated significantly with no time lag. Over the long time series, yearly average POC flux accounted for 63 % of the estimated carbon demand of the benthic community. Long time-series studies of sediment community processes, particularly SCOC, have shown similar fluctuations with the flux of POC reaching the abyssal seafloor. SCOC quickly responds to changes in food supply and tracks POC flux. Yet, SCOC consistently exceeds POC flux as measured by sediment traps alone. The shortfall of ~37 % could be explained by sediment trap sampling artifacts over decadal scales including undersampling of large sinking particles. High-resolution measurements of SCOC are critical to developing a realistic carbon cycle model for the open ocean. Such input is essential to evaluate the impact of climate change on the oceanic carbon cycle, and the long-term influences on the sedimentation record.

Overweight adolescents eat what? And when? Analysis of consumption patterns to guide dietary message development for intervention.

BACKGROUND: Little is known about overweight adolescent dietary consumption patterns, with challenges to collecting meaningful data making it difficult to develop targeted obesity interventions. The present study aimed to examine the timing and consumption of fruit, vegetables and junk food by time of the day and day of the week. METHODS: Overweight adolescents (n = 61), aged 12-16 years, completed 3-day food records. Negative binomial and binary logistic regression using generalised estimating equations were used to compare the amount and likelihood of the consumption of each food group between time periods. RESULTS: Overweight adolescent girls were more likely to eat fruit on weekdays than weekends [odds ratio (OR) = 5.0. P < 0.001], as were boys (OR = 2.5, P = 0.034). Adolescents consumed more fruit at school than other meals [girls: incident rate ratio (IRR) = 7.5, P < 0.001; boys: IRR = 4.0, P = 0.050]. Weekday dinner was the meal where girls were most likely to consume vegetables (OR = 3.0, P = 0.009) and when boys consumed the most vegetables (IRR = 30.9, P = 0.006). Fast food consumption was most likely for girls at dinner on the weekend (OR = 9.6, P = 0.042), whereas fast food intake for boys increased overall on the weekend (IRR = 3.6, P = 0.001). Intake of 'other junk' (e.g. crisps) peaked during school hours for girls (IRR = 7.2, P < 0.001) and sugar-sweetened beverage consumption increased for boys on the weekend (IRR = 3.3, P = 0.001). Overall, trends in fruit intake showed opposing times for high and low consumption compared to vegetable intake. CONCLUSIONS: These results represent the next step in using time of day and day of week consumption patterns to develop targeted, evidence-based dietary messages for interventions in overweight adolescents.

Phase I trial of dasatinib and ixabepilone in patients with solid tumors.

PURPOSE: Dasatinib is an oral tyrosine kinase inhibitor (TKI) of BCR-ABL and SRC family and ixabepilone is an epothilone B analog. Synergistic activity has been reported when combining dasatinib with chemotherapy. This study was conducted to determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) for this combination. PATIENTS AND METHODS: Patients with metastatic solid tumors who progressed on standard therapy received dasatinib orally daily and ixabepilone IV every 3 weeks at escalating doses using 3 + 3 design. An expansion cohort was studied after reaching the MTD. Pharmacokinetic studies were performed. RESULTS: Nineteen patients were enrolled. No DLTs were observed at dose level (DL) 1 (dasatinib 100 mg and ixabepilone 30 mg/m(2)). At DL 2 (dasatinib 100 mg and ixabepilone 40 mg/m(2)), one patient had multiple DLTs. At DL 3 (dasatinib 150 mg and ixabepilone 40 mg/m(2)), the first patient developed grade 3 AE during cycle 2, the second patient had a DLT and a grade 3 AE during cycle 2. The accrual to DL 3 was halted without reaching the maximally administered dose (MAD) and MTDs were determined to be dasatinib 100 mg and ixabepilone 40 mg/m(2) (DL 2). One patient had a partial response and 12 patients stable disease as their best response. Fourteen patients came off study due to toxicities. CONCLUSION: The combination of dasatinib and ixabepilone showed modest clinical activity with doses 100 mg orally daily and 40 mg/m(2) IV every 3 weeks, respectively. Treatment related toxicities were seen frequently.

Developmental activities of elite junior hockey players: an analysis of early sport specialization.

Early sport specialization is a popular and contentious topic in the scientific literature and popular media. The lure of extrinsic rewards has led to increasing rates of specialization among young athletes, while expert recommendations promote multisport participation. The purpose of this study was to describe and analyze developmental activities of a group of elite junior hockey players in Canada. Within this context, elements of specialization were investigated in accordance with existing theoretical frameworks and long-term athlete development models to enhance the literature. Fifteen participants from the Ontario Hockey League completed quantitative retrospective interviews, detailing past sport and recreational activities. Thirty-one developmental milestones were assessed. Accumulated hours of activity were categorized in accordance with Côté's (1999) Developmental Model of Sports Participation, along with the number and types of sports in which they participated during childhood. Jayanthi et al.'s (2015) continuum was utilized to determine the age at which the athletes became moderately and highly specialized. Accrued hours of deliberate practice reported by participants increased from ages 6 to 16 years, as did competition in organized hockey games. Reported hours of deliberate play peaked at 9 years of age and decreased thereafter. Participants played a combined 16 sports other than hockey, ranging from an average of 2.0 at age 6, to a maximum average of 5.6 at 12 years old, and decreasing each year to 2.3 by age 15. The greatest number of hours in other sports was accumulated at 12 years of age. Using a three-point scale, participants considered themselves "highly specialized" at 14 years old; however, other quantitative indicators suggested this may have occurred at 12 years of age. Relative to previous research on early sport specialization, participants in this study spent more time practicing hockey, while ceasing hockey-specific play and other sports at younger ages. Despite a diverse sport history, hockey competition was initiated earlier than recommended, showing high levels of sport commitment as young as 9 years old. The early specialization path remains a popular trajectory among coaches, parents, and athletes in Canadian ice hockey.

Climate, carbon cycling, and deep-ocean ecosystems.

Climate variation affects surface ocean processes and the production of organic carbon, which ultimately comprises the primary food supply to the deep-sea ecosystems that occupy approximately 60% of the Earth's surface. Warming trends in atmospheric and upper ocean temperatures, attributed to anthropogenic influence, have occurred over the past four decades. Changes in upper ocean temperature influence stratification and can affect the availability of nutrients for phytoplankton production. Global warming has been predicted to intensify stratification and reduce vertical mixing. Research also suggests that such reduced mixing will enhance variability in primary production and carbon export flux to the deep sea. The dependence of deep-sea communities on surface water production has raised important questions about how climate change will affect carbon cycling and deep-ocean ecosystem function. Recently, unprecedented time-series studies conducted over the past two decades in the North Pacific and the North Atlantic at >4,000-m depth have revealed unexpectedly large changes in deep-ocean ecosystems significantly correlated to climate-driven changes in the surface ocean that can impact the global carbon cycle. Climate-driven variation affects oceanic communities from surface waters to the much-overlooked deep sea and will have impacts on the global carbon cycle. Data from these two widely separated areas of the deep ocean provide compelling evidence that changes in climate can readily influence deep-sea processes. However, the limited geographic coverage of these existing time-series studies stresses the importance of developing a more global effort to monitor deep-sea ecosystems under modern conditions of rapidly changing climate.

Higher differentiation among subspecies of the house mouse (Mus musculus) in genomic regions with low recombination.

In the early stages of reproductive isolation, genomic regions of reduced recombination are expected to show greater levels of differentiation, either because gene flow between species is reduced in these regions or because the effects of selection at linked sites within species are enhanced in these regions. Here, we study the patterns of DNA sequence variation at 27 autosomal loci among populations of Mus musculus musculus, M. m. domesticus, and M. m. castaneus, three subspecies of house mice with collinear genomes. We found that some loci exhibit considerable shared variation among subspecies, while others exhibit fixed differences. We used an isolation-with-gene-flow model to estimate divergence times and effective population sizes (N(e) ) and to disentangle ancestral variation from gene flow. Estimates of divergence time indicate that all three subspecies diverged from one another within a very short period of time approximately 350,000 years ago. Overall, N(e) for each subspecies was associated with the degree of genetic differentiation: M. m. musculus had the smallest N(e) and the greatest proportion of monophyletic gene genealogies, while M. m. castaneus had the largest N(e) and the smallest proportion of monophyletic gene genealogies. M. m. domesticus and M. m. musculus were more differentiated from each other than either were from M. m. castaneus, consistent with greater reproductive isolation between M. m. domesticus and M. m. musculus. F(ST) was significantly greater at loci experiencing low recombination rates compared to loci experiencing high recombination rates in comparisons between M. m. castaneus and M. m. musculus or M. m. domesticus. These results provide evidence that genomic regions with less recombination show greater differentiation, even in the absence of chromosomal rearrangements.

Linkage scan of nicotine dependence in the University of California, San Francisco (UCSF) Family Alcoholism Study.

BACKGROUND: Nicotine dependence has been shown to represent a heritable condition, and several research groups have performed linkage analysis to identify genomic regions influencing this disorder though only a limited number of the findings have been replicated. METHOD: In the present study, a genome-wide linkage scan for nicotine dependence was conducted in a community sample of 950 probands and 1204 relatives recruited through the University of California, San Francisco (UCSF) Family Alcoholism Study. A modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) with additional questions that probe nicotine use was used to derive DSM-IV nicotine dependence diagnoses. RESULTS: A locus on chromosome 2q31.1 at 184 centiMorgans nearest to marker D2S2188 yielded a logarithm (base 10) of odds (LOD) score of 3.54 (point-wise empirical p=0.000012). Additional peaks of interest were identified on chromosomes 2q13, 4p15.33-31, 11q25 and 12p11.23-21. Follow-up analyses were conducted examining the contributions of individual nicotine dependence symptoms to the chromosome 2q31.1 linkage peak as well as examining the relationship of this chromosomal region to alcohol dependence. CONCLUSIONS: The present report suggests that chromosome 2q31.1 confers risk to the development of nicotine dependence and that this region influences a broad range of nicotine dependence symptoms rather than a specific facet of the disorder. Further, the results show that this region is not linked to alcohol dependence in this population, and thus may influence nicotine dependence specifically.

Abyssal Benthic Rover, an autonomous vehicle for long-term monitoring of deep-ocean processes.

The deep-ocean carbon cycle is poorly quantified. An abyssal benthic rover was developed to make long time-series measurements of seafloor processes related to organic carbon remineralization and sequestration. Benthic Rover II (BR-II) is an autonomous dual-tracked vehicle that measures bottom water temperature and oxygen concentration, current velocity, and sediment community oxygen consumption (SCOC; respiration). BR-II is programmed to transit with low surface-contact pressure across the seafloor, photograph bottom conditions, and stop regularly to occupy respirometer incubation sites, with deployment periods up to 1 year. Now, continuously operational at a 4000-m station in the northeast Pacific over 5 years, substantial weekly, seasonal, annual, and episodic events have been recorded, which are critical to assessing the deep-ocean carbon cycle. There was a significant increase in phytodetritus cover (P < 0.01) arriving on the seafloor from the overlying water column between 2015 and 2020 that was negatively correlated with bottom water dissolved oxygen concentration (P < 0.01). Over the continuous 5-year monitoring period from November 2015 to November 2020, SCOC was positively correlated with phytodetritus cover (P < 0.01) and increased significantly from 2015 to 2020 (P < 0.01). These results show important influences of biological processes on the carbon cycle. The demonstrated success of BR-II now creates opportunities to expand the long-term monitoring of the deep sea to resolve the coupling of water column and benthic processes key to understanding the oceanic carbon cycle on a planet engulfed in a changing climate.

Impacts on non-human biota from a generic geological disposal facility for radioactive waste: some key assessment issues.

This paper provides an overview of key issues associated with the application of currently available biota dose assessment methods to consideration of potential environmental impacts from geological disposal facilities. It explores philosophical, methodological and practical assessment issues and reviews the implications of test assessment results in the context of recent and on-going challenges and debates.

Coordinated changes in energy intake and expenditure following hypothalamic administration of neuropeptides involved in energy balance.

OBJECTIVE: The hypothalamic control of energy balance is regulated by a complex network of neuropeptide-releasing neurons. Although the effect of these neuropeptides on individual aspects of energy homoeostasis has been studied, the coordinated response of these effects has not been comprehensively investigated. We have simultaneously monitored a number of metabolic parameters following intracerebroventricular (ICV) administration of 1 and 3 nmol of neuropeptides with established roles in the regulation of feeding, activity and metabolism. Ad libitum- fed rats received the orexigenic neuropeptides neuropeptide Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin-A. Overnight-food-deprived rats received an ICV injection of the anorectic peptides alpha-melanocyte-stimulating hormone (MSH), corticotrophin-releasing factor (CRF) or neuromedin U (NMU). RESULTS: Our results reveal the temporal sequence of the effects of these neuropeptides on both energy intake and expenditure, highlighting key differences in their function as mediators of energy balance. NPY and AgRP increased feeding and decreased oxygen consumption, with the effects of AgRP being more prolonged. In contrast, orexin-A increased both feeding and oxygen consumption, consistent with an observed increase in activity. The potent anorexigenic effects of CRF were accompanied by a prolonged increase in activity, whereas NMU injection resulted in significant but short-lasting inhibition of food intake, ambulatory activity and oxygen consumption. alpha-MSH injection resulted in significant increases in both ambulatory activity and oxygen consumption, and reduced food intake following administration of 3 nmol of the peptide. CONCLUSION: We have for the first time, simultaneously measured several metabolic parameters following hypothalamic administration of a number of neuropeptides within the same experimental system. This work has shown the interrelated effects of these neuropeotides on activity, energy expenditure and food intake, thus facilitating comparison between the different hypothalamic systems.

Respiration of Benthopelagic Fishes: In situ Measurements at 1230 Meters.

The respiration rate in situ of two common benthopelagic fishes, Coryphaenoides acrolepis and Eptatretus deani, was monitored at 1230 meters in the San Diego Trough. The respiration rate of C. acrolepis was two orders of magnitude lower and that of E. deani was significantly lower (P < .05) than rates in comparable shallow-water species.

Plastics on the Sargasso sea surface.

Plastic particles, in concentrations averaging 3500 pieces and 290 grams per square kilometer, are widespread in the western Sargasso Sea. Pieces are brittle, apparently due to the weathering of the plasticizers, and many are in a pellet shape about 0.25 to 0.5 centimeters in diameter. The particles are surfaces for the attachment of diatoms and hydroids. Increasing production of plastics, combined with present waste-disposal practices, will undoubtedly lead to increases in the concentration of these particles. Plastics could be a source of some of the polychlorinated biphenyls recently observed in oceanic organisms.

Deep-Sea Benthic Community Respiration: An in situ Study at 1850 Meters.

The in situ oxygen uptake of sediments at 1850 meters on the continental slope south of New England is two orders of magnitude less than the uptake of sediments from shallow shelf depths. After treatment of the sediments with Formalin there was no measurable chemical oxygen uptake, which shows that the total uptake is biological (community respiration).

Effects of prepartum 2,4-thiazolidinedione on metabolism and performance in transition dairy cows.

Thiazolidinediones (TZD) are potent synthetic ligands for peroxisome proliferator-activated receptor-gamma that have been shown previously to reduce plasma nonesterified fatty acids and increase peripartal dry matter intake (DMI) in dairy cows. Data from Holstein cows (n = 36) entering their second or greater lactation were used to determine whether late prepartum administration of TZD would affect periparturient metabolism, milk production, and ovarian activity. Cows were administered 0, 2.0, or 4.0 mg of TZD/kg of BW by intrajugular infusion once daily from 21 d before expected parturition until parturition. Plasma samples were collected daily from 22 d before expected parturition through 21 d postpartum and twice weekly from wk 4 through 9 postpartum. In response to increasing TZD dosage, plasma nonesterified fatty acid concentrations decreased linearly during the postpartum period (d 0 to +21: 348, 331, 268 +/- 31 microEq/L, respectively). Plasma concentrations of glucose were highest in cows administered 4.0 mg of TZD/kg of BW during the peripartum and postpartum periods (d -7 to +7: 57.9, 57.8, 61.1 +/- 0.8 mg/dL and d 0 to +21: 51.6, 49.3, 54.7 +/- 1.1 mg/dL, respectively). Plasma concentrations of beta-hydroxybutyrate were increased during the peripartum period by TZD administration (9.6, 9.9, 10.2 +/- 0.3 mg/dL) but were not affected during the postpartum period. Plasma insulin was not affected by treatment during any time period. Postpartum liver triglyceride content was decreased linearly (11.0, 10.4, 4.2 +/- 1.6%) and glycogen content was increased linearly (2.16, 2.38, 2.79 +/- 0.19%) by prepartum TZD administration. Prepartum TZD administration linearly increased DMI during the peripartum period (d -7 to +7: 16.1, 17.2, 17.3 +/- 0.5 kg/d). Cows administered TZD prepartum maintained higher postpartum body condition scores than control cows (wk 1 through 9: 2.77, 2.89, 3.02 +/- 0.05). There was no effect of prepartum TZD on milk yield; however, yields of 3.5% fat-corrected milk (52.2, 54.6, 48.0 +/- 1.6 kg/d) and most other milk components were decreased in cows that received 4.0 mg of TZD/kg of BW prepartum. Prepartum TZD administration linearly decreased the number of days to first ovulation (29.3, 28.3, 19.0 +/- 3.6 d). These results suggest that prepartum administration of TZD improves metabolic health and DMI of periparturient dairy cows and may decrease reliance on body fat reserves during early lactation.

A Qualitative Investigation of the Impact of Home-Based Primary Care on Family Caregivers.

BACKGROUND: Home-based primary care (HBPC) provides team-based clinical care for homebound patients who have difficulty accessing typical outpatient care. Interdisciplinary team members also provide social and emotional support and serve as a resource for family caregivers, who often experience significant emotional stress. OBJECTIVES: This qualitative study explores the impact of HBPC on family caregivers to identify aspects of the program that caregivers find most helpful and meaningful as well as areas for improvement. DESIGN: Semi structured recorded interviews were conducted with family caregivers of frail, elderly homebound patients. Interviews included the following topics: overall program satisfaction and suggestions for improvement. SETTING: A HBPC program serving patients in Queens, Nassau and Suffolk counties in New York. PARTICIPANTS: Nineteen family caregivers: 13 women, 6 men; 10 were adult children; 6 were spouses, and 3 were other family members of patients in a HBPC program. MEASUREMENTS: Thematic coding of all recorded transcribed interviews was prepared by 3 qualitative coders. Interrater reliability was conducted to ensure reliability across coders before themes were disseminated and discussed until consensus was achieved with the larger group of investigators. RESULTS: Three main themes were identified: the importance of staff emotional support; the burden of caring for homebound patients; and the need for a broader range of home-based services. Multiple family members noted that the program not only had saved their loved one's life, but had also metaphorically saved their own. CONCLUSIONS: Family caregivers value the communication and accessibility of HBPC and report that the program has a positive impact on their stress and mental health. Results can inform key aspects that need to be retained or enhanced with the expansion in HBPC programs.

Constant pressure fluid infusion into rat neocortex from implantable microfluidic devices.

Implantable electrode arrays capable of recording and stimulating neural activity with high spatial and temporal resolution will provide a foundation for future brain computer interface technology. Currently, their clinical impact has been curtailed by a general lack of functional stability, which can be attributed to the acute and chronic reactive tissue responses to devices implanted in the brain. Control of the tissue environment surrounding implanted devices through local drug delivery could significantly alter both the acute and chronic reactive responses, and thus enhance device stability. Here, we characterize pressure-mediated release of test compounds into rat cortex using an implantable microfluidic platform. A fixed volume of fluorescent cell marker cocktail was delivered using constant pressure infusion at reservoir backpressures of 0, 5 and 10 psi. Affected tissue volumes were imaged and analyzed using epifluorescence and confocal microscropies and quantitative image analysis techniques. The addressable tissue volume for the 5 and 10 psi infusions, defined by fluorescent staining with Hoescht 33342 dye, was significantly larger than the tissue volume addressed by simple diffusion (0 psi) and the tissue volume exhibiting insertion-related cell damage (stained by propidium iodide). The results demonstrate the potential for using constant pressure infusion to address relevant tissue volumes with appropriate pharmacologies to alleviate reactive biological responses around inserted neuroprosthetic devices.

Metabolism of dairy cows as affected by prepartum dietary carbohydrate source and supplementation with chromium throughout the periparturient period.

Holstein cows (n = 72) entering second or later lactation were used to determine whether metabolic indices and hepatic capacities for oxidation and gluconeogenesis from propionate are affected by source of carbohydrate in the prepartum diet and chromium-l-methionine (Cr-Met) supplementation throughout the periparturient period. Cows were fed prepartum diets as total mixed rations with the concentrate portion based either on starch-based cereals [high nonfiber carbohydrate (NFC); 1.59 Mcal/kg of net energy for lactation (NE(L)), 14.4% crude protein (CP), 40.3% NFC] or nonforage fiber sources (low NFC; 1.54 Mcal/kg of NE(L), 14.5% CP, 33.6% NFC) from 21 d before expected parturition until parturition. After parturition all cows were fed a common lactation total mixed ration (1.74 Mcal/kg of NE(L), 16.5% CP, 40.0% NFC). The Cr-Met was supplemented once daily via gelatin capsule at dosages of 0, 0.03, or 0.06 mg of Cr/kg of BW(0.75). Thus, treatments were in a 2 (carbohydrate source) x 3 (Cr-Met) factorial arrangement. There was no effect of prepartum carbohydrate source on pre- and postpartum plasma concentrations of glucose, nonesterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), insulin, glucagon, or insulin to glucagon ratio. However, cows fed the low NFC diet during the prepartum period tended to have greater plasma NEFA and lower BHBA concentrations postpartum. Liver glycogen concentrations tended to be greater on d 1 postpartum for cows fed low NFC prepartum. Supplementing 0.03 mg/kg of BW(0.75) of Cr as Cr-Met increased prepartum plasma glucose and glucagon concentrations and tended to decrease prepartum plasma NEFA concentrations compared with either 0 or 0.06 mg of Cr/kg of BW(0.75). Postpartum plasma glucose concentrations decreased linearly and glucagon concentrations were increased quadratically by administering increasing amounts of Cr-Met. Supplementing Cr-Met did not affect prepartum plasma concentrations of insulin or BHBA, postpartum NEFA or BHBA, or liver composition. There was an interaction of prepartum carbohydrate source and Cr-Met supplementation such that in vitro hepatic conversion of [1-(14)C]propionate to both CO(2) and glucose was similar or increased when Cr-Met was supplemented to cows fed the low NFC diet but decreased when Cr-Met was supplemented to cows fed the high NFC diet. Insulin addition in vitro did not affect hepatic metabolism of propionate on d 1 postpartum. Overall, both the NFC content of the prepartum diet and Cr-Met had only modest effects on metabolic indices in this experiment.

Prepartum 2,4-thiazolidinedione alters metabolic dynamics and dry matter intake of dairy cows.

Thiazolidinediones (TZD) are potent, synthetic ligands for peroxisome proliferator activated receptor-gamma (PPAR-gamma) that reduce plasma nonesterified fatty acids (NEFA) and potentiate the action of insulin in peripheral tissues of several species. Holstein cows (n = 9) entering their second or greater lactation were used to determine whether late prepartum administration of TZD would affect periparturient metabolism and milk production. Cows were limit-fed a total mixed ration (TMR) during the prepartum period to provide no more than 130% of predicted energy requirements. During the postpartum period cows were fed a common TMR for ad libitum intake. Cows were administered either 2,4-TZD (4.0 mg/kg of body weight) or saline (control) by intrajugular infusion once daily from 25 d before expected parturition until parturition. Plasma samples were collected daily from 26 d before expected parturition through 7 d postpartum. Plasma NEFA concentrations decreased during the prepartum period (d -21 to -1; 70 vs. 83 +/- 4 microEq/L) and tended to be decreased during the peripartum period (d -7 to d +7; 113 vs. 205 +/- 32 microEq/L) due to prepartum TZD administration. Plasma concentrations of glucose were not affected by treatment; however, plasma beta-hydroxybutyrate concentrations decreased in TZD-treated cows (8.6 vs. 10.7 +/- 1.7 mg/dL) as parturition approached, and plasma insulin concentrations increased during the peripartum period (0.65 vs. 0.38 +/- 0.07 ng/mL). Postpartum liver triglyceride and glycogen content was not affected by treatment. Prepartum TZD administration tended to increase dry matter intake during the peripartum and postpartum periods (16.6 vs. 14.6 +/- 0.8 kg/d and 20.0 vs. 17.2 +/- 1.2 kg/d, respectively). Milk yield for the first 30 d postpartum and milk composition measured on d 8 postpartum were not affected by treatment. There was no effect of prepartum TZD administration on insulin-dependent glucose utilization assessed using insulin challenge during either the prepartum or postpartum periods. These results suggest that administration of TZD during the late prepartum period has the potential to improve metabolic health and DMI of periparturient dairy cows and warrants further investigation.