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The PtIV prodrug iproplatin has been actively loaded into liposomes using a calcium acetate gradient, achieving a 3‐fold enhancement in drug concentration compared to passive loading strategies. A strain‐promoted cycloaddition reaction (azide‐ dibenzocyclooctyne) was used to attach iproplatin‐loaded liposomes L(Pt) to gas‐filled microbubbles (M), forming an ultrasound‐responsive drug delivery vehicle [M−L(Pt)]. Ultrasound‐triggered release of iproplatin from the microbubble‐liposome construct was evaluated in cellulo. Breast cancer (MCF‐7) cells treated with both free iproplatin and iproplatin‐loaded liposome−microbubbles [M−L(Pt)] demonstrated an increase in platinum concentration when exposed to ultrasound. No appreciable platinum uptake was observed in MCF‐7 cells following treatment with L(Pt) only or L(Pt)+ultrasound, suggesting that microbubble‐mediated ultrasonic release of platinum‐based drugs from liposomal carriers enables greater control over drug delivery., Actively loading platinum(IV) prodrug iproplatin into liposomes has been achieved using a calcium acetate gradient. Microbubble‐mediated release and accumulation of the prodrug in MCF7 cancer cells following ultrasound treatment demonstrates that this strategy can enable greater control over drug delivery.

Surfactant-coated gas microbubbles are widely used as contrast agents in ultrasound imaging and increasingly in therapeutic applications. The response of microbubbles to ultrasound can be strongly influenced by their size and coating properties, and hence the production method. Ultrasonic emulsification (sonication) is the most commonly employed method and can generate high concentrations of microbubbles rapidly, but with a broad size distribution, and there is a risk of contamination and/or degradation of sensitive components. Microfluidic devices provide excellent control over microbubble size, but are often challenging or costly to manufacture, offer low production rates (6s−1), and are prone to clogging. In this study, a hybrid sonication-microfluidic or “sonofluidic” device was developed. Bubbles of ∼180 μm diameter were produced rapidly in a T-junction and subsequently exposed to ultrasound (71–73 kHz) within a microchannel, generating microbubbles (mean diameter: 1–2 μm) at a rate of >108s−1 using a single device. Microbubbles were prepared using either the sonofluidic device or conventional sonication, and their size, concentration, and stability were comparable. The mean diameter, concentration, and stability were found to be comparable between techniques, but the microbubbles produced by the sonofluidic device were all

Creep feeding is a management practice used to improve the weaning weights of livestock including meat goats. The effects of creep feeding on replacement doe performance have received little attention. This study examined creep feeding effects on fitness traits of replacement does over their first five years in the breeding herd. Doelings that were either creep-fed (CF; n = 79) from 30 days of age until weaning (90 days of age) or not creep-fed (NC; n = 71) entered the breeding herd at 18 months of age and remained until death or failure to wean offspring in a second year. Doe body weights, packed cell volume (PCV), and fecal egg counts (FEC) were recorded each year at breeding. Cumulative totals for survivability to 6 years of age (SURV), kids weaned (TKW), weight weaned (TWW), and weaning rate (TWR) were analyzed for each doe. Doe body weights, PCV, FEC, TKW, TWW and TWR were analyzed using SAS MIXED models. Treatment group along with the sire breed, litter type, and dam age as traits of the doe were used as model terms. SURV was tested using SAS GLIMMIX models. Treatment, sire breed, litter type, and dam age of the doe were used as main effects. For sire breed, does were either Kiko-, Spanish-, Myotonic-, or Savanna-sired. There was no weight advantage (P > 0.05) observed in CF does (CF = 34.8 ± 0.9 kg vs. NC = 34.1 ± 0.9 kg) at breeding. A previous study on the same group of did show a weight advantage for CF at weaning and at 1 year of age, but that significance was lost by entry into the breeding herd. However, sire breed (P < 0.05) did impact body weights. Kiko-sired does were the heaviest (P < 0.05) and Myotonic-sired does were the lightest (P < 0.05) at breeding. Creep feed did not (P > 0.05) impact TKW (CF = 2.8 ± 0.3 kids vs. NC = 2.4 ± 0.3 kids) or TWW (CF = 35.7 ± 3.8 kg vs. NC = 32.7 ± 4.0 kg). Sire breed impacted (P < 0.05) TWW. Kiko-sired does weaned more (P = 0.02) weight than Savanna-sired does (43.4 ± 4.7 kg vs. 21.8 ± 4.8 kg, respectively). TWR, SURV, FEC, and PCV were not affected (P > 0.05) by treatment group. Preliminary assessment suggested that creep feeding doelings did not affect their reproductive performance as adults under the conditions of this study.

In this study we compared three different microbubble-based approaches to the delivery of a widely used chemotherapy drug, gemcitabine: (i) co-administration of gemcitabine and microbubbles (Gem+MB); (ii) conjugates of microbubbles and gemcitabine-loaded liposomes (GemlipoMB); and (iii) microbubbles with gemcitabine directly bound to their surfaces (GembioMB). Both in vitro and in vivo investigations were carried out, respectively, in the RT112 bladder cancer cell line and in a murine orthotopic muscle-invasive bladder cancer model. The in vitro (in vivo) ultrasound exposure conditions were a 1 (1.1) MHz centre frequency, 0.07 (1.0) MPa peak negative pressure, 3000 (20,000) cycles and 100 (0.5) Hz pulse repetition frequency. Ultrasound exposure produced no significant increase in drug uptake either in vitro or in vivo compared with the drug-only control for co-administered gemcitabine and microbubbles. In vivo, GemlipoMB prolonged the plasma circulation time of gemcitabine, but only GembioMB produced a statistically significant increase in cleaved caspase 3 expression in the tumor, indicative of gemcitabine-induced apoptosis.

Purpose: Chemoradiation is the standard of care in muscle-invasive bladder. While agents such as gemcitabine can enhance tumour radiosensitisation, their side effects can limit patient eligibility and treatment efficacy. Here we investigate ultrasound and microbubbles for targeting gemcitabine delivery to reduce normal tissue toxicity in a murine orthotopic MIBC model. Materials and Methods: CD1-nude mice were injected orthotopically with RT112 bladder tumour cells. Conventional chemoradiation involved injecting gemcitabine (10 mg/kg) before 6 Gy targeted irradiation of the bladder area using a Small Animal Radiation Research Platform (SARRP). Ultrasound-mediated gemcitabine delivery (10 mg/kg gemcitabine) involved either co-administration of microbubbles with gemcitabine or conjugating gemcitabine onto microbubbles followed by exposure to ultrasound (1.1 MHz centre frequency, 1 MPa peak negative pressure, 1% duty cycle and 0.5 Hz pulse repetition frequency), prior to SARRP irradiation. The effect of ultrasound and microbubbles alone was also tested. Tumour volumes were measured by 3D ultrasound imaging. Acute normal tissue toxicity from 12 Gy to the lower bowel area was assessed using an intestinal crypt assay in mice culled. 3.75 days post-treatment. Results: Significant tumour growth delay was observed with conventional chemoradiation and both microbubble groups (p < 0.05 compared to radiation-only group). Transient weight loss was seen in the microbubble groups, which resolved within 10 days post-treatment. A positive correlation was found between weight loss Day 3 post-treatment and tumour growth delay (p < 0.05, R2 = 0.76). In contrast to conventional chemoradiation, ultrasound-mediated drug delivery methods did not exacerbate the acute intestinal toxicity using the crypt assay. Conclusions: Ultrasound and microbubbles offer a promising new approach for improving chemoradiation therapy in muscle-invasive bladder cancer, maintaining tumour growth delay but with reduced acute intestinal toxicity compared to conventional chemoradiation therapy.

Over four years, 564 performance records from 235 does were processed to determine if lameness during the breeding season affected reproductive outcomes in meat goats. Lameness cases were recorded during routine daily herd wellness checks and treated within a short time after diagnosis. Does were bred between September and January. Kids were weaned at 3 mo of age. Fall (September-November) and winter (December-February) records were used to classify does each year as having experienced lameness (LAME) or no recorded lameness case (NOLC) by season. In the fall (F) there were 396 NOLC does and 168 LAME does. Spring kidding rates were greater (P < 0.05) for NOLC-F than for LAME-F (77.1 ± 4.5% vs. 67.9 ± 6.1%). Whole-herd litter size at kidding was greater (P < 0.05) for NOLC-F than for LAME-F (1.18 vs. 1.02 ± 0.1 kids/doe). Summer weaning rates tended to differ (P = 0.08) between the fall lameness groups (NOLC = 68 ± 3.3%; LAME = 59.5 ± 4.6%). Whole-herd litter size at weaning was greater (P < 0.01) for NOLC-F than for LAME-F (0.97 ± 0.05 vs. 0.78 ± 0.06 kids). In the winter (W) there were 473 NOLC does and 87 LAME does. Spring kidding rates were greater (P < 0.01) for NOLC-W than for LAME-W (77.6 ± 4.1% vs. 58.6 ± 7.5%). Whole-herd litter size at kidding was greater (P < 0.01) for NOLC-W than for LAME-W (1.17 vs. 0.9 ± 0.09 kids). Summer weaning rates was higher (P < 0.01) for NOLC-W than for LAME-W (68.5 ± 3.2% vs. 53.0 ± 5.9%). Whole-herd litter size at weaning was higher (P = 0.01) for NOLC-W than for LAME-W (0.95 ± 0.05 vs. 0.73 ± 0.08 kids). Results suggest that lameness in does during the breeding season may negatively impact reproductive outcomes.

Over three years, the effects of winter hair shedding and service sire breed on cow-calf performance were assessed. Dexter cows were scored each spring for percentage of winter hair loss (0% = thick coat, 100% = smooth coat). Cows were exposed by natural service to Dexter (DEX) and Mashona (MAS) bulls in July. Calves were weighed at birth, 3.5 mo of age, and at weaning (7 mo). Based on hair scores in early June of each year, cows were classified as low shedders (LoS; 0 to 50%; n = 67) or high shedders (HiS; 51 to 100%; n = 130). Hair shed interacted (p < 0.05) with sire breed to affect pregnancy rates. HiS x MAS had a greater (p < 0.05) pregnancy rate than HiS x DEX (92.8 ± 3.8 vs. 60.9 ± 7.7%). Breeds did not differ (p > 0.05) within LoS. Pregnancy rate was greater (p < 0.05) for HiS than LoS (81.6 ± 4.8 vs. 63.1 ± 7.7%). Hair shed scores did not affect (p > 0.05) ADG. MAS calves had greater (p < 0.05) birth to 3.5 mo and birth to weaning ADG (0.77 ± 0.06 and 0.58 ± 0.05 kg/d, respectively) than DEX calves (0.64 ± 0.06 and 0.48 ± 0.05 kg/d, respectively). Across two complete production years, shedding group and service sire breed interacted (p < 0.05) for calf weight weaned per cow exposed. Within MAS, HiS weaned more weight (p < 0.05) than LoS (157.08 ± 24.27 vs. 48.47 ± 28.90 kg). Hair shedding was not important within DEX. Within HiS, MAS cows weaned more weight (p < 0.05) than DEX cows (157.08 ± 24.27 vs. 84.01 ± 24.01 kg). Service sire breed was not important within LoS. Hair shedding level and service sire breed influenced cow-calf performance.

A 3-yr-old Dexter cow and her yearling Dexter heifer calf exhibited polydactyly. Neither animal was linebred within 5 generations. This cow-calf pair represented the first reported occurrence of polydactyly in Dexter cattle in the US or abroad. Based upon external examination, the cow was classified as having a spontaneous unilateral case of polydactyly with an extra digit along the medial digit of the right front limb and the heifer was classified as having bilateral polydactyly because both front limbs exhibited an extra digit along the medial digit. Radiographic examination confirmed bilateral status of the heifer and revealed bilateral status of the cow. The front feet of the cow and heifer had extra bone formation consistent with an extra digit along the medial digit. Neither animal suffered from limited mobility to date or required hoof treatments. The cow produced a second calf from a different sire, a bull calf that did not appear polydactylous per external examination and was not examined radiographically. The two polydactylous animals will remain in the breeding herd to produce more study calves unless their fitness becomes compromised. Genetic aspects of the cases are discussed.

There are several limitations with monodrug cancer therapy, including poor bioavailability, rapid clearance and drug resistance. Combination therapy addresses these by exploiting synergism between different drugs against cancer cells. In particular, the combination of epigenetic therapies with conventional chemotherapeutic agents can improve the initial tumour response and overcome acquired drug resistance. Co-encapsulation of multiple therapeutic agents into a single polymeric nanoparticle is one of the many approaches taken to enhance therapeutic effect and improve the pharmacokinetic profile. In this study, different types of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), matrix and core–shell (CS), were investigated for simultaneous encapsulation of a demethylating drug, decitabine, and a potent anticancer agent, cisplatin. It was shown that by altering the configuration of the CS structure, the release profile could be tuned. In order to investigate whether this could enhance the anticancer effect compared to cisplatin, human ovarian carcinoma cell line (A2780) and its cisplatin resistant variant (A2780cis) were exposed to free cisplatin and the CS–NPs. A better response was obtained in both cell lines (11% and 51% viability of A2780 and A2780cis, respectively) using CS–NPs than cisplatin alone (27%, 82% viability of A2780 and A2780cis, respectively) or in combination with decitabine (22%, 96% viability of A2780 and A2780cis, respectively) at equivalent doses (10 μM).

Commercial mouse chow is designed to provide a complete, nutrient-rich diet, and it can contain upwards of 100 mg/kg manganese, an essential mineral. Manganese acts as a relaxation time-shortening contrast agent for both T1and T2, and where standard chow is hydrated in the gastrointestinal tract, bright signals are produced when using T1-weighted imaging (T1WI). As a result of peristalsis, gastrointestinal hyperintensities result in temporally unstable signals, leading to image ghosting and decreased resolution from that prescribed. To avoid the problem, various methods of gastrointestinal tract modulation, including the use of intestinal cleansing with laxatives and dietary modulation, have been reported. Here, dietary modulation has been extended to the use of a biologically innocuous, long-term change of diet. In this study, we report on the use of a commercially available manganese-free chow to improve the image quality of the gastrointestinal tract. This manganese-free chow, apart from the omitted manganese which is available in tap water, is a complete diet and readily available. We investigated the time-dependent, diet-related gastrointestinal intensities on short-TR T1WI magnetic resonance imaging; monitored body mass, food and water consumption and standard blood biochemistry analysis following diet change; and determined manganese concentration in blood plasma following a five-day change to manganese-free chow. We show that the manganese-free chow presents a refinement to other gastrointestinal tract modulation, as it avoids the need for invasive procedures for gut voiding and can be provided ad libitum so that animals can be maintained with no need for prescribed diet change before imaging.

Creep feeding and its possible interactions with other influential factors (genetics, litter type, and sex) for weaning traits were studied in meat goat kids and their dams. Kids across 3 yr were creep fed (254 kids; 5 pens) or not creep fed (255 kids; 5 pens) from 30 to 90 d of age. Creep-fed kids had higher (P ≤ 0.05) preweaning average daily weight gain and weaning weights (113.1 ± 13.0 g/d; 15.0 ± 0.8 kg) than kids not creep fed (99.8 ± 13.1 g/d; 14.0 ± 0.8 kg). However, financial returns were not higher (P > 0.05) for creep-fed kids compared with kids not creep fed. There was no difference (P > 0.05) in kid conformation score or survival rates between the treatment groups. The only important interaction among kid traits was treatment × litter type (P < 0.05) for FAMACHA scores. Within noncreep pens, single kids had lower (better; P < 0.05) FAMACHA scores (2.9 ± 0.3) than twin kids (3.9 ± 0.3). There was no litter-type effect on FAMACHA scores for kids within the creep feed pens. Dams of the creep-fed (n = 175) and noncreep (n = 178) kids were also evaluated. Treatment did not affect (P > 0.05) litter weights, dam weight change, gross revenue for weaned litters, or fecal egg counts. Treatment interacted with litter type (P < 0.05) to effect packed cell volume (PCV). In the noncreep group, dams raising singles had higher (better; P < 0.05) PCV (18.7 ± 1.3%) than dams rearing twin kids (15.7 ± 1.3%). The litter-type effect on dam PCV was not evident (P > 0.05) in the creep-fed group. Creep feeding improved some kid growth traits but did not improve dam traits or financial returns. Interactions of creep treatment with other factors were minimal for doe-kid traits.

This study evaluated how doeling traits at weaning influence their fitness as replacement does. Boer (n = 60), Kiko (n = 102), Spanish (n = 96), Boer-cross (n = 138) and Myotonic (n = 20) doelings were weaned at 3 months of age and classified by weaning litter type (single- or multiple-kid type), weaning weight ratio group (WWR; low, moderately low, moderately high, or high) and breed-type. Survival and reproductive output in the replacement does as 2-yr-olds were recorded. The herd was semi-intensively managed on humid subtropical pasture. Boer doelings had lower (P

Understanding fitness level among various breeds is essential for sustainable meat goat production. Research on the relative fitness of Boer F1 does and straightbred base breed has been limited. Meat goat does of various genotypes (Boer, Kiko, Spanish, Boer × Kiko reciprocal F1 crosses, and Boer × Spanish reciprocal F1 crosses) were studied to evaluate breed effects on doe fitness traits and the expression of heterosis over 7 production years. The herd was semi-intensively managed under humid subtropical pasture. Doe age affected (P 0.05) from Boer does for breeding weight. The body weights of Boer × Spanish and Boer × Kiko crosses did not differ (P > 0.05) from the weights of their respective Kiko and Spanish base cohorts at breeding, kidding, or weaning. Boer does had lower (P < 0.05) kidding rate (KR) and weaning rate (WR) than the other breeds and crosses. Boer × Kiko and Kiko were similar for KR and WR. Boer × Spanish and Spanish were also similar for KR and WR. However, the combined group of Boer F1 does had lower (P < 0.01) KR and WR than the combined purebred biotype group of Kiko and Spanish does. Boer does weaned smaller (P < 0.05) litter sizes per doe exposed compared with Kiko, Spanish, Boer × Kiko, and Boer × Spanish does with the latter four doe breedtypes not differing from each other. The combined Boer F1 doe group weaned smaller (P < 0.05) litter sizes per doe exposed than the combined purebred group of Kiko and Spanish does. Boer × Kiko dams had higher (P < 0.05) fecal egg counts at parturition than Kiko dams. Significant heterosis was observed for reproductive traits within each of the 2-breed diallels. Boer F1 does exhibited reproductive output similar to or lower than Kiko and Spanish straightbred does and higher than Boer straightbred does.

Treatment options for patients with pancreatic cancer are limited and survival prospects have barely changed over the past 4 decades. Chemoradiation treatment (CRT) has been used as neoadjuvant therapy in patients with borderline resectable disease to reduce tumour burden and increase the proportion of patients eligible for surgery. Antimetabolite drugs such as gemcitabine and 5-fluorouracil are known to sensitise pancreatic tumours to radiation treatment. Likewise, photodynamic therapy (PDT) has also been shown to enhance the effect of radiation therapy. However, PDT is limited to treating superficial lesions due to the attenuation of light by tissue. The ability of the related technique, sonodynamic therapy (SDT), to enhance CRT was investigated in two murine models of pancreatic cancer (PSN-1 and BxPC-3) in this study. SDT uses low intensity ultrasound to activate an otherwise non-toxic sensitiser, generating toxic levels of reactive oxygen species (ROS) locally. It is applicable to greater target depths than PDT due to the ability of ultrasound to propagate further than light in tissue. Both CRT and the combination of CRT plus SDT delayed tumour growth in the two tumour models. In the PSN-1 model, but not the BxPC-3 model, the combination treatment caused an increase in survival relative to CRT alone (p = 0.038). The improvement in survival conferred by the addition of SDT in this model may be related to differences in tumour architecture between the two models. MRI and US images showed that PSN-1 tumours were less well perfused and vascularised than BxPC-3 tumours. This poor vascularisation may explain why PSN-1 tumours were more susceptible to the effects of vascular damage exerted by SDT treatment.

Savanna sires were evaluated for kid preweaning and doe reproductive traits over six years. Savanna (n = 17) and Kiko (n = 13) sires were bred to Kiko-base does producing 600 kids. Savanna (n = 17) and Spanish (n = 11) sires were bred to Spanish-base does producing 456 kids. Doe traits were evaluated on 536 Kiko and 441 Spanish doe exposures. Kids were weighed at birth and when weaned at 3 mo of age. Non-genetic factors sex and litter size influenced (P < 0.05) kid performance traits as expected. Birth weights of kids from Kiko does were heavier (P < 0.01) for Savanna sires than Kiko sires (3.11 vs. 2.83 ± 0.08 kg). Birth weights of kids from Spanish does were heavier (P < 0.01) for Savanna sires than Spanish sires (3.05 vs. 2.76 ± 0.09 kg). Sire breed did not affect (P < 0.05) weaning weight from Kiko does (15.0 vs 14.8 ±0.6 kg). Savanna sires generated heavier (P < 0.05) weaning weights than Spanish sires (14.2 vs. 13.3 ± 0.6 kg) from Spanish does. Sire breed did not affect ADG or kid survival rates in either doe group. Non-genetic factors litter size and age of dam affected (P < 0.05) doe performance traits in both doe groups. Savanna sires produced heavier litters (P < 0.01) at birth compared to Kiko sires on Kiko does (10.7 vs. 9.7 ± 0.4 kg) and compared to Spanish sires on Spanish does (9.4 vs. 8.3 ± 0.5 kg). Service sire breed did not affect kidding or weaning rate, number of kids born or weaned, or litter weaning weight in either doe group. Savanna sires consistently increased birth weight values. Sire breed did not consistently affect weaning weight values and did not influence other preweaning kid traits or doe reproductive traits.

Microbubbles stabilized by an outer lipid shell have been studied extensively for both diagnostic and therapeutic applications. The shell composition can significantly influence microbubble behavior, but performing quantitative measurements of shell properties is challenging. The aim of this study is to investigate the use of spectral imaging to characterize the surface properties of a range of microbubble formulations representing both commercial and research agents. A lipophilic dye, C-laurdan, whose fluorescence emission varies according to the properties of the local environment, was used to compare the degree and uniformity of the lipid order in the microbubble shell, and these measurements were compared with the acoustic response and stability of the different formulations. Spectral imaging was found to be suitable for performing rapid and hence relatively high throughput measurements of microbubble surface properties. Interestingly, despite significant differences in lipid molecule size and charge, all of the different formulations exhibited highly ordered lipid shells. Measurements of liposomes with the same composition and the debris generated by destroying lipid microbubbles with ultrasound (US) showed that these exhibited a lower and more varied lipid order than intact microbubbles. This suggests that the high lipid order of microbubbles is due primarily to compression of the shell as a result of surface tension and is only minimally affected by composition. This also explains the similarity in acoustic response observed between the formulations, because microbubble dynamics are determined by the diameter and shell viscoelastic properties that are themselves a function of the lipid order. Within each population, there was considerable variability in the lipid order and response between individual microbubbles, suggesting the need for improved manufacturing techniques. In addition, the difference in the lipid order between the shell and lipid debris may be important for therapeutic applications in which shedding of the shell material is exploited, for example, drug delivery.

This study examined the influence of creep feeding and sire breed on post-weaning replacement doeling traits. Over 3 years, doelings by Kiko, Myotonic, Spanish and Savanna sires were creep-fed (CF; n = 116) for 60 d or not creep-fed (NC; n = 117). Sire breeds were balanced across creep treatments. Doelings were weighed at 3 mo old (weaning) and various postweaning ages. Doelings entered the breeding herd at 18 mo of age and fitness traits recorded. At 3-, 6-, and 12-mo of age CF (14.7 ± 0.6, 19.3 ± 1.2, and 24.6 ± 0.9 kg, respectively) were heavier (P < 0.05) than NC (13.8 ± 0.6, 17.9 ± 1.2, and 23.6 ± 0.9 kg, respectively). Treatment did not affect 18-mo weights. Sire breed did not affect 3-mo weight. Sire breed influenced (P < 0.05) 6-, 12-, and 18-mo weights. Myotonic-sired doelings were lightest (P < 0.05) and Kiko-sired doelings were heavier (P < 0.05) than Savanna-sired. Breed x treatment interacted (P < 0.05) for survival to 18 mo of age. Kiko-sired CF doelings had a higher (P < 0.05) survival rate than Savanna-sired CF (88.6 ± 6.0% vs. 44.6 ± 11.5%). Breed did not affect survival rate (P> 0.05) within the NC group. As a main effect, CF had a higher (P < 0.05) survival rate than NC (81.5 ± 6.3% vs. 65.6 ± 8.7%). Sire breed affected (P < 0.05) reproductive output. Cumulative kid crop weaned across the first 2 breeding years for the whole weaned doeling population was higher (P < 0.05) for Myotonic- and Kiko-sired (1.4 and 1.2 ± 0.2 kids) does than Savanna-sired (0.5 ± 0.1 kids). Creep feeding did not affect reproductive output. Creep feed supplementation and sire breed influenced post-weaning doeling weights. Only sire breed affected reproductive performance of the young does.

Few chemotherapeutics have had such an impact on cancer management as cis-diamminedichloridoplatinum(II) (CDDP), also known as cisplatin. The first member of the platinum based drug family, CDDP’s potent toxicity in disrupting DNA replication has led to its widespread use in multi-drug therapies, with particular benefit in patients with testicular cancers. However, CDDP also produces significant side effects that limit the maximum systemic dose. Various strategies have been developed to address this challenge including encapsulation within micro- or nanocarriers and the use of external stimuli such as ultrasound to promote uptake and release. The aim of this article is to look at these strategies and recent scientific and clinical developments.

Sustainable meat goat production begins with the identification and use of maternal breeds that demonstrate relatively enhanced levels of fitness under less-than-optimal conditions. The Myotonic goat is a heritage breed that is lacking in comparative assessment for female fitness. In this study, Boer ( = 73), Kiko ( = 115), Myotonic ( = 80), and Spanish ( = 114) meat goat does were compared for traits associated with health and reproduction. The herd was semi-intensively managed on humid subtropical pasture for 6 yr. The study included 838 doe-year matings and over 2,000 records for BW, fecal egg count (FEC), and packed cell volume (PCV). Body weights of Boer and Kiko does were heavier ( < 0.05) than for Spanish does, which, in turn, were heavier ( < 0.05) than for Myotonic does. In production does, FEC were lower ( < 0.05) for Myotonic does than for Boer does, whereas Kiko and Spanish does had intermediate FEC that differed ( < 0.05) from Myotonic and Boer does. Kiko, Myotonic, and Spanish does had greater ( < 0.05) PCV than Boer does. Doe age and physiological status also affected ( < 0.05) BW, FEC, and PCV. Annual kidding rates, weaning rates, doe retention rates, and kid crop weaned were greater ( < 0.05) for Kiko and Spanish does than for Boer does, whereas Myotonic does were intermediate and differed ( < 0.05) from the other 3 breeds. The results suggest that Kiko and Spanish does should be preferred over Boer and Myotonic does for sustainable meat goat doe performance under limited-input management conditions. Myotonic does maintained the lowest FEC among all doe breeds and warrant further evaluation as a genetic resource for controlling gastrointestinal parasitism.

Anthelmintic-resistant gastrointestinal nematode parasites are a threat to small ruminant industry sustainability. Meat goat does were administered one of four anthelmintics orally (ivermectin (n = 18), moxidectin (n = 18), levamisole hydrochloride (n = 17), or albendazole (n = 19)) or water (n = 18). Fecal samples were collected pretreatment and 12 days post-treatment. Fecal egg counts (FEC) were determined by the modified McMaster technique. The FEC reduction percentages (FECR%) were calculated using three equations. Log transformed FEC means were analyzed by treatment, sire breed of doe, and doe age. Sire breed affected (P

Commercial mouse chow is designed to provide a complete, nutrient-rich diet, and it can contain upwards of 100 mg/kg manganese, an essential mineral. Manganese acts as a relaxation time-shortening contrast agent for both T1 and T2, and where standard chow is hydrated in the gastrointestinal tract, bright signals are produced when using T1-weighted imaging (T1WI). As a result of peristalsis, gastrointestinal hyperintensities result in temporally unstable signals, leading to image ghosting and decreased resolution from that prescribed. To avoid the problem, various methods of gastrointestinal tract modulation, including the use of intestinal cleansing with laxatives and dietary modulation, have been reported. Here, dietary modulation has been extended to the use of a biologically innocuous, long-term change of diet. In this study, we report on the use of a commercially available manganese-free chow to improve the image quality of the gastrointestinal tract. This manganese-free chow, apart from the omitted manganese which is available in tap water, is a complete diet and readily available. We investigated the time-dependent, diet-related gastrointestinal intensities on short-TR T1WI magnetic resonance imaging; monitored body mass, food and water consumption and standard blood biochemistry analysis following diet change; and determined manganese concentration in blood plasma following a five-day change to manganese-free chow. We show that the manganese-free chow presents a refinement to other gastrointestinal tract modulation, as it avoids the need for invasive procedures for gut voiding and can be provided ad libitum so that animals can be maintained with no need for prescribed diet change before imaging.

The development of new modalities for high-efficiency intracellular drug delivery is a priority for a number of disease areas. One such area is urinary tract infection (UTI), which is one of the most common infectious diseases globally and which imposes an immense economic and healthcare burden. Common uropathogenic bacteria have been shown to invade the urothelial wall during acute UTI, forming latent intracellular reservoirs that can evade antimicrobials and the immune response. This behaviour likely facilitates the high recurrence rates after oral antibiotic treatments, which are not able to penetrate the bladder wall and accumulate to an effective concentration. Meanwhile, oral antibiotics may also exacerbate antimicrobial resistance and cause systemic side effects. Using a human urothelial organoid model, we tested the ability of novel ultrasound-activated lipid microbubbles to deliver drugs into the cytoplasm of apical cells. The gas-filled lipid microbubbles were decorated with liposomes containing the non-cell-permeant antibiotic gentamicin and a fluorescent marker. The microbubble suspension was added to buffer at the apical surface of the bladder model before being exposed to ultrasound (1.1 MHz, 2.5 Mpa, 5500 cycles at 20 ms pulse duration) for 20 s. Our results show that ultrasound-activated intracellular delivery using microbubbles was over 16 times greater than the control group and twice that achieved by liposomes that were not associated with microbubbles. Moreover, no cell damage was detected. Together, our data show that ultrasound-activated microbubbles can safely deliver high concentrations of drugs into urothelial cells, and have the potential to be a more efficacious alternative to traditional oral antibiotic regimes for UTI. This modality of intracellular drug delivery may prove useful in other clinical indications, such as cancer and gene therapy, where such penetration would aid in treatment.

Context In the past few years, research has suggested that molecular subtypes in muscle-invasive bladder cancer (MIBC) may be exploited to accelerate developments in clinical disease management and novel therapeutics. Objective To review MIBC mouse models from a molecular subtype perspective, their advantages and limitations, and their applications in translational medicine, based on a PubMed search for publications from January 2000 to February 2018. Evidence acquisition Publications relevant to MIBC mouse models and their molecular subtypes were identified in a literature review. Evidence synthesis We classified the models according to the technique used for their establishment. For xenotransplant and allograft models, the inoculated cells and inoculated locations are the major determinants of molecular subtypes. Although the cell lines used in xenotransplant models can cover most of the basal-squamous and luminal subtypes, allograft models offer a more realistic environment in which to reconstruct aspects of the associated stromal and immune features. Autochthonous models, using genetic and/or chemical stimuli to induce disease progression, can also generate models with basal-squamous and luminal subtypes, but further molecular characterisation is needed since other mutational variants may be introduced in these models. Conclusions We identified preclinical MIBC models with different subtype specifications and assessed their promise and current limitations. These models are versatile tools that can reproduce the molecular complexity of MIBC and support novel therapeutic development. Patient summary Understanding which models of muscle-invasive bladder cancer most accurately represent the clinical situation is important for the development of novel drugs and disease management strategies. We review the different models currently available and their relevance to different clinical subtypes.

Ultrasound-mediated drug delivery is a promising means of enhancing delivery, distribution and effectiveness of drugs within tumours. In this review, prospects for exploiting ultrasound to improve the tumour delivery and distribution of radiolabelled antibodies for radioimmunotherapy and to overcome barriers imposed by tumour microenvironment are discussed. Copyright © 2013 John Wiley & Sons, Ltd.

Three summer experiments compared responses to transportation-related events in 2- to 4-yr-old Brahman (Bos indicus) and Hereford (B. taurus) steers. In Exp. 1, steers were hauled round-trip (4 h) or fasted in holding pens. Transport transiently increased (P < 0.01) plasma cortisol and glucose concentrations, decreased (P < 0.05) plasma triglyceride concentrations, and increased total leukocyte counts. Blood constituents were not altered for steers fasting in holding pens. Treatment-day BW shrink was greater (P < 0.01) in transported steers than penned steers. Blood constituent responses were unaffected (P < 0.05) by subspecies. Hereford experienced greater (P < 0.05) transport-day BW shrink than Brahman across treatments. Steers in Exp. 2 were hauled to a new farm for a 1-wk relocation period or hauled round-trip an equal time (0.67 h) and returned to the home station. Both treatments similarly experienced transport-day BW shrink and increased (P < 0.01) plasma cortisol and glucose. Subspecies did not affect (P < 0.05) blood constituent responses to transport. Hereford experienced greater (P < 0.05) transport-day shrink than Brahman. Relocation did not elicit (P < 0.05) changes in blood profiles beyond the day of transport. In Exp. 3, steers were loaded and unloaded without transport, transported round-trip (1 h), or fasted in a holding pen for 3 h. Cortisol increased (P < 0.01) after transport and after loading/unloading. Leukocytes and glucose increased (P < 0.01) after the 1 h transport. Steers transported experienced greater treatment-day BW shrink than those fasted or loaded and unloaded (P < 0.01; -3.13 vs. -1.36 and -0.35 ± 0.76%, respectively). The subspecies did not vary (P < 0.05) for blood constituent responses or shrink in Exp. 3. Animal responses were not evident 24 h after treatments in each experiment. In summary, transport caused stress, but Brahman steers were not more sensitive than Herefords. Hereford steers were susceptible to greater transport BW shrink than Brahman under the summer conditions.

In previous work we demonstrated that microbubble mediated gene delivery can be enhanced in vitro through simultaneous exposure of cells to ultrasound and magnetic fields in the presence of magnetically loaded microbubble ultrasound contrast agents. The aim of this preliminary study was to investigate the feasibility of the technique for in vivo applications. Phospholipid coated microbubbles loaded with a hydrocarbon suspension of magnetic nanoparticles were prepared through sonication and sized using optical microscopy (concentration 1.4 × 108 bubbles/ml). Plasmid pGL4.13, which encodes for firefly luciferase, was prepared at a concentration of 4 μg/μl in endotoxin-free water. A Siemens Acuson Sequioa clinical imaging system with a 26 mm linear array transducer (15L8) was used throughout the investigation. 20, 6–8 week old CD1 female mice were injected with of 150 μl of microbubble suspension and 50 μl plasmid intra-venously through the tail vein. Mice were anaesthetized using isoflurance and imaged with the transducer above the left lung (14 MHz, 0.06 MI) to locate the thoracic region. Immediately following injection, a NdFeB permanent magnet was positioned over the right lung and the acoustic output was increased (H7MHz, 1.7 MI, focal depth 7.5 mm). Exposure to ultrasound and/or magnetic field was maintained for two minutes. 20 mice were exposed to ultrasound and magnetic field, two to ultrasound only and two to magnetic field only. On the third day post treatment, luciferase substrate (D-luciferin) was administered through intra-peritoneal injection and allowed to catalyse the transfected substrate for 10 minutes before animals were sacrificed and their organs recovered for individual bioluminescence imaging (IVIS 100, Xenogen) and quantification (Living Image Software, Xenogen). Animals treated with both ultrasound and the magnetic field showed transfection in the right lung, while no animals showed transfection in the contralateral organs. Of the 20 mice treated, 17 showed transfection at a level greater than for ultrasound alone and 12 greater than that of magnetic field alone. The results of this preliminary study indicate that microbubbles which include magnetic nanoparticles within their shells may be used to control the location of transfection in vivo. Further work is required to improve microbubble formulations and magnetic array design to allow more accurate targeting of transfection.

We describe a cost-effective and simple method to fabricate PDMS-based microfluidic devices by combining micromilling with replica moulding technology. It relies on the following steps: (i) microchannels are milled in a block of acrylic; (ii) low-cost epoxy adhesive resin is poured over the milled acrylic block and allowed to cure; (iii) the solidified resin layer is peeled off the acrylic block and used as a mould for transferring the microchannel architecture onto a PDMS layer; finally (iv) the PDMS layer is plasma bonded to a glass surface. With this method, microscale architectures can be fabricated without the need for advanced technological equipment or laborious and time-consuming intermediate procedures. In this manuscript, we describe and validate the microfabrication procedure, and we illustrate its applicability to emulsion and microbubble production. Electronic supplementary material The online version of this article (doi:10.1007/s10544-015-0027-x) contains supplementary material, which is available to authorized users.

Gas microbubbles are used routinely to improve contrast in medical diagnostic imaging. The emerging fields of microbubble-enhanced quantitative imaging and microbubble-enhanced drug delivery have further enhanced the drive toward microbubble characterization and design techniques. The quest to improve efficiency, particularly in the field of drug delivery, presents a requirement to develop methods to manipulate microbubble properties to improve utility. This article presents an investigation in to the feasibility of influencing albumin shelled microbubble properties through the variation of albumin availability during fabrication. Microbubbles were fabricated from albumin suspensions of varying concentration before thorough physical and acoustic characterization. Microbubbles with shells fabricated from a 2% albumin suspension had a greater scattering to attenuation ratio (STAR) than 10% albumin preparations (4.4% and 2.2%, respectively) and approximately double the nonlinear STAR (from 0.7% to 1.5%). The 2% microbubbles also exhibited greater (up to 40%), more violent radial oscillations during high speed imaging than 5% and 10% preparations. The results show that microbubble characteristics can be simply manipulated in the lab and indicate that for a given application this may provide the opportunity to further enhance favorable characteristics.

Ultrasound and microbubble mediated gene transfection has great potential for site-selective, safe gene delivery. Albumin-based microbubbles have shown the greatest transfection efficiency but have not been optimised specifically for this purpose. Additionally, few studies have highlighted desirable properties for transfection specific microbubbles. In this article, microbubbles were made with 2% or 5% (w/v) albumin and 20% or 40% (w/v) dextrose solutions, yielding four distinct bubble types. These were acoustically characterised and their efficiency in transfecting a luciferase plasmid (pGL4.13) into female, CD1 mice myocardia was measured. For either albumin concentration, increasing the dextrose concentration increased scattering, attenuation and resistance to ultrasound, resulting in significantly increased transfection. A significant interaction was noted between albumin and dextrose; 2% albumin bubbles made with 20% dextrose showed the least transfection but the most transfection with 40% dextrose. This trend was seen for both nonlinear scattering and attenuation behaviour but not for resistance to ultrasound or total scatter. We have determined that the attenuation behaviour is an important microbubble characteristic for effective gene transfection using ultrasound. Microbubble behaviour can also be simply controlled by altering the initial ingredients used during manufacture.

Tall fescue is one of the primary pasture forages used to manage goats in the United States. Data are limited on how the wild-type endophyte (Neotyphodium coenophialum) found in most tall fescue stands affects meat goat performance. In two experiments across four summers, nulliparous yearling does were fed diets containing tall fescue seed to assess the effect of endophyte infection on goat growth and feed intake. In Experiment 1, does were fed endophyte-infected or endophyte-free tall fescue seeds added to the diets for 10 weeks. Feed refusals were weighed daily. The endophyte-infected diet reduced (P

Bucklings (n = 275) from a complete diallel of Boer, Kiko, and Spanish meat goats were slaughtered at 7 mo of age (4 mo postweaning) to evaluate genetic effects on carcass yield. Breed of sire did not affect (P > 0.05) live, carcass, and primal weights. Conversely, breed of dam was a consistently significant source of variation for carcass weight traits. Kiko dams produced kids with heavier (P 0.05) from Boer or Kiko. Subjective conformation scores for muscularity were affected (P 0.05) by breeds of sire or dam. Direct effects of Boer were negative for carcass weight, dressing percent, and shoulder weight and positive for proportional leg weight. Direct effects of Kiko were positive for carcass weight and shoulder weight and negative for proportional leg weight. Direct effects of Spanish did not differ (P > 0.10) from 0 for any trait tested. Heterosis levels were similar among breed pairings. Heterosis was substantial (P ≤ 0.05) for live, carcass, and primal weights (5 to 9%) but not for dressing percent, proportional boneless meat yield, or primal weight proportions (

Ultrasound and microbubble-mediated gene transfection are potential tools for safe, site-selective gene therapy. However, preclinical trials have demonstrated a low transfection efficiency that has hindered the progression of the technique to clinical application. In this paper it is shown that simple changes to the method of intravenous injection can lead to an increase in transfection efficiency when using 6-MHz diagnostic ultrasound and the ultrasound contrast agent, SonoVue. By using needles of progressively smaller gauge, i.e., larger internal diameter (ID), from 29 G (ID 0.184 mm) to 25 G (ID 0.31 mm), the transfection of a luciferase plasmid (pGL4.13) was significantly increased threefold in heart-targeted female CD1 mice. In vitro work indicated that the concentration and size distribution of SonoVue were affected by increasing needle gauge. These results suggest that the process of systemic delivery alters the bubble population and adversely affects transfection. This is exacerbated by using high-gauge needles. These findings demonstrate that the needle with the largest possible ID should be used for systemic delivery of microbubbles and genetic material.

Boer, Kiko, and Spanish meat goats were semi-intensively managed in a complete 3-breed diallel mating scheme to evaluate genetic effects on preweaning kid performance. Over a 6-yr period, 1,547 kids were born in March and May with 1,173 kids raised by their dams to weaning at 3 mo of age. March-born kids were lighter (P 0.10). Maternal Boer effects were negative (P 0.5) for preweaning ADG or weaning weight. Heterosis for birth weight was exhibited (P < 0.01) for each pair of breed crosses, but only between Boer and Kiko for ADG and weaning weight. Kiko and Spanish dams had greater (P < 0.01) preweaning kid survival rates than Boer dams, but the former 2 did not differ (P = 0.72). Significant genetic variation was observed between meat goat breeds for kid performance to weaning. Maternal breed effects were more influential than direct breed effects. Boer goats were not superior to Kiko or Spanish for preweaning kid performance when semi-intensively managed on humid, subtropical pasture. Kiko should be a preferred breed and to a lesser extent Spanish for enhancing birth to weaning kid performance. Findings of this study emphasize the importance of proper doe breed selection in achieving desired kid performance to weaning in meat goats.

Boer (n = 132), Kiko (n = 92), and Spanish (n = 79) straightbred does were studied across 6 yr to assess doe fitness on southeastern US pastures. Does were exposed to Boer, Kiko, and Spanish bucks in a complete 3-breed diallel mating scheme each fall for spring kidding in March or May. A total of 1,041 doe-yr units were observed with does (ranging from 2 to 8 yr of age) managed together in a semi-intensive manner. The proportion of buck-exposed does delivering at least 1 live kid was less (P 0.15) by breed of dam. By weaning at 3 mo, the proportion of available does weaning at least 1 kid was less (P < 0.01) for Boer does (53%) than for Kiko (84%) and Spanish does (82%). For does weaning kids, litter size at weaning was greater (P = 0.01) for Spanish does (1.74 kids) than for Kiko (1.59 kids) and Boer does (1.47 kids). Litter weaning weight was lighter (P < 0.01) for Boer dams (23.0 kg) than for Kiko (27.2 kg) and Spanish dams (26.5 kg). The efficiency ratio of litter weight to dam weight at weaning differed (P < 0.05) among all 3 dam breeds: Boer = 51%; Kiko = 62%; Spanish = 68%. Annual rates of lameness, endoparasitism, and attrition, respectively, were greater (P < 0.01) for Boer does (69, 53, and 28%) than for Kiko (32, 24, and 10%) and Spanish does (42, 22, and 11%). Postpartum fecal egg counts for endoparasite loads were less (P < 0.05) for Spanish dams (346 eggs/g) than for Kiko (524 eggs/g) and Boer does (675 eggs/g). Whole-herd annual doe productivity based on all available does was less (P < 0.01) for Boer does (11.7 kg weaned/doe) compared with Kiko (22.0 kg weaned/doe) and Spanish does (21.1 kg weaned/doe). Boer does expressed substantially decreased levels of fitness compared with Kiko and Spanish does when semi-intensively managed on humid, subtropical pasture. Kiko and Spanish should be preferred as maternal breeds in meat goat production systems under conditions reflective of this study.

Data policy is an important element of the initiative on Global Monitoring for Environment and Security (GMES), which aims to establish a European capacity for the provision and use of operational information for monitoring and management of the environment and civil security by 2008. This paper documents the data policies of the variety of information providers likely to be involved in GMES, identifies the obstacles and draws conclusions on ways to improve data policy coherence. It addresses the main policy issues associated with Earth observation data, as well as with other types of environmental data.

著者人数：48名, Accepted: 2002-12-31, 資料番号: SA1002070000

The X-ray solar monitor (XSM) is a calibration instrument of the demonstration of compact imaging X-ray spectrometer (D-CIXS) experiment, with a separate Silicon detector unit on the SMART-1 spacecraft. The non-imaging HPSi PIN sensor has a wide field-of-view (FOV) to enable Sun visibility during a significant fraction of the mission lifetime, which is essential for obtaining calibration spectra for the X-ray fluorescence measurements by the imaging D-CIXS spectrometer. The energy range (1– 20 keV ), spectral resolution (about 250 eV at 6 keV ), and sensitivity (about 7000 cps at flux level of 10 −4 W m −2 in the range 1– 8 A ) are tuned to provide optimal knowledge about the Solar X-ray flux on the Lunar surface, matching well with the activating energy range for the fluorescence measured by D-CIXS. The independent science of the XSM will also be valuable, since the XSM energy range is very sensitive to solar flares. The countrate during the top of an X1 flare will be about 35 times higher than the average quiescent countrate at solar maximum. The relative increase will be the same for an M1 flare during the SMART-1 mission, which will be closer to the next solar minimum. Since the XSM will observe the Sun as a star, and the energy range and spectral resolution are close to those of present astronomical X-ray satellites (e.g., XMM-Newton, ASCA, Chandra), we will obtain an X-ray database of the Sun which can be related with the stellar X-ray observations more easily than the data from present solar X-ray instruments. In this publication we give a detailed description of the design, performance, and tasks of the XSM instrument, and view the science perspectives.