Pregnancy per artificial insemination during summer in lactating dairy cows after treatment with aspirin.

Embryonic loss in cattle may be related to a hormonal imbalance resulting in alterations in timing of prostaglandin F2α (PGF2α) secretion around the time of maternal recognition of pregnancy. The objective of this study was to examine effects of aspirin (a PGF2α inhibitor) on pregnancy per AI (P/AI), and progesterone (P4), and pregnancy specific protein B (PSPB) concentrations in lactating dairy cows inseminated more than once after parturition. Fourteen days after second or subsequent AI (Day 0 = Day of AI), 556 cows were assigned randomly to aspirin (187.2 g total; n = 277) or control (n = 279) groups. Aspirin was administered orally on Day 14 and 15, and control cows were subjected to sham bolus administration. On Day 25, blood samples were collected from a subset of cows (n = 194) to quantify P4 and PSPB, whereas pregnancy was determined in all cows at 35-42 days post-AI. Maximum daily ambient temperature ranged from 38-41 °C during the experiment. Mean parity, days in milk, and times bred before treatment (TBRD) did not differ between groups. There were no differences in P/AI between treatments (aspirin 21.6 % compared with control 27.5 %). Neither treatment, parity, TBRD, or any two-way interactions with treatment affected concentrations of P4. Moreover, there were no effects (P > 0.50) of treatment, or treatment by TBRD interaction on serum PSPB concentrations. A tendency (P = 0.07) occurred for multiparous cows to have greater serum PSPB concentrations compared with primiparous cows. Mean serum PSPB concentrations tended (P = 0.07) to be greater for second or third TBRD compared to fourth and greater TBRD. These results provide evidence that aspirin administered during periods of heat stress after the second and subsequent AI post-partum during the summer months does not improve P/AI or alter P4 and PSPB in lactating dairy cows.

Short communication: Reproduction outcomes in dairy heifers following a 14-d progesterone insert presynchronization protocol.

The objectives were to evaluate pregnancy per artificial insemination (AI), days to first AI, and proportion pregnant within 7 d of AI eligibility in dairy heifers subjected to presynchronization compared with dairy heifers not presynchronized. Thirty days before AI eligibility, Holstein heifers were assigned randomly to 1 of 3 groups: 14-d controlled internal drug release (CIDR; containing progesterone) presynchronization, PGF2α presynchronization, or control (no presynchronization). Heifers in the 14-d CIDR presynchronization treatment (n = 119) received a CIDR on d -30, which was removed on d -16, followed by an injection of PGF2α upon entry to the breeding program (d 0). Heifers in the PGF2α presynchronization treatment (n = 118) received an injection of PGF2α on d -11 and d 0. Control heifers (n = 121) were not presynchronized and received an injection of PGF2α on d 0. All heifers received tail paint on d 0 to facilitate once-daily detection of estrus (based on paint removal). Heifers detected in estrus received AI with conventional semen on the same morning as detected estrus. Generalized linear mixed models were used to assess mean treatment differences. Following PGF2α treatment on d 0, more heifers were detected in estrus in the first 7 d after eligibility in the 14-d CIDR group (95.8%) compared with the PGF2α (74.6%) and control (66.9%) groups. Days to first AI differed between treatments (14-d CIDR = 3.6 d vs. PGF2α = 5.0 d vs. control = 6.8 d). Pregnancy per AI for first AI within 7 d of eligibility was 71.9% (14-d CIDR), 58.0% (PGF2α), and 61.7% (control), and differed between 14-d CIDR and PGF2α heifers. Presynchronization with a 14-d CIDR increased the proportion of heifers pregnant in the first 7 d of eligibility (14-d CIDR = 68.9% vs. PGF2α = 43.2% vs. control = 41.3%). Projected days on feed (d 0 to projected calving date) were 295 (14-d CIDR), 302 (PGF2α), and 305 (control), and were different between the 14-d CIDR and control heifers. The potential economic benefit to the producer was $15.85 per heifer presynchronized with a 14-d CIDR protocol compared with the control group. Treatment of dairy heifers with a 14-d CIDR effectively presynchronized estrus, resulting in a greater proportion detected in estrus, reduced days to first AI, and an increased proportion of heifers pregnant within the first 7 d after breeding eligibility compared with heifers presynchronized with a single PGF2α injection and control heifers.

Cellular Uptake and Efflux of Palbociclib In Vitro in Single Cell and Spheroid Models.

Adequate drug distribution through tumors is essential for treatment to be effective. Palbociclib is a cyclin-dependent kinase 4/6 inhibitor approved for use in patients with hormone receptor positive, human epidermal growth factor receptor 2 negative metastatic breast cancer. It has unusual physicochemical properties, which may significantly influence its distribution in tumor tissue. We studied the penetration and distribution of palbociclib in vitro, including the use of multicellular three-dimensional models and mathematical modeling. MCF-7 and DLD-1 cell lines were grown as single cell suspensions (SCS) and spheroids; palbociclib uptake and efflux were studied using liquid chromatography-tandem mass spectrometry. Intracellular concentrations of palbociclib for MCF-7 SCS (C max 3.22 µM) and spheroids (C max 2.91 µM) were 32- and 29-fold higher and in DLD-1, 13- and 7-fold higher, respectively, than the media concentration (0.1 µM). Total palbociclib uptake was lower in DLD-1 cells than MCF-7 cells in both SCS and spheroids. Both uptake and efflux of palbociclib were slower in spheroids than SCS. These data were used to develop a mathematical model of palbociclib transport that quantifies key parameters determining drug penetration and distribution. The model reproduced qualitatively most features of the experimental data and distinguished between SCS and spheroids, providing additional support for hypotheses derived from the experimental data. Mathematical modeling has the potential for translating in vitro data into clinically relevant estimates of tumor drug concentrations. SIGNIFICANCE STATEMENT: This study explores palbociclib uptake and efflux in single cell suspension and spheroid models of cancer. Large intracellular concentrations of palbociclib are found after drug exposure. The data from this study may aid understanding of the intratumoural pharmacokinetics of palbociclib, which is useful in understanding how drug distributes within tumor tissue and optimizing drug efficacy. Biomathematical modelling has the potential to derive intratumoural drug concentrations from plasma pharmacokinetics in patients.

Pregnancy outcomes are not improved by administering gonadotropin-releasing hormone at initiation of a 5-day CIDR-Cosynch resynchronization protocol for lactating dairy cows.

Using a 5-d controlled internal drug-release (CIDR)-Cosynch resynchronization protocol, the objective of this study was to determine the effect of the initial GnRH injection on pregnancy per artificial insemination (P/AI) to the second artificial insemination in lactating Holstein dairy cows. On 37 ± 3 d (mean ± standard deviation) after the first artificial insemination, and upon nonpregnancy diagnosis (d 0 of the experiment), lactating cows eligible for a second artificial insemination (n = 429) were enrolled in a 5-d CIDR-Cosynch protocol. On d 0, all cows received a CIDR insert and were assigned randomly to receive the initial GnRH injection (GnRH; n = 226) of the protocol or no-GnRH (n = 203). Blood samples were collected from a sub-group of cows (n = 184) on d 0 and analyzed for progesterone (P4) concentration. On d 5, CIDR inserts were removed, and all cows received 1 injection of PGF2α. On d 6 and 7, cows were observed once daily by employees for tail-chalk removal, and cows detected in estrus on d 6 or 7 received artificial insemination that day (EDAI), and did not receive the final GnRH injection. The remaining cows not detected in estrus by d 8 received GnRH and timed artificial insemination (TAI). Pregnancy status was confirmed by transrectal palpation of uterine contents at 37 ± 3 d (mean ± standard deviation) after the second artificial insemination. Eliminating the initial GnRH injection had no effect on P/AI compared with cows receiving GnRH (27 vs. 21%), respectively. Similarly, method of insemination (EDAI vs. TAI) and its interaction with treatment had no effect on P/AI. Primiparous cows had greater P/AI than multiparous cows (31 vs. 21%). Mean P4 concentrations (n = 184) at the initiation of the protocol did not differ between treatments (4.51 ± 0.35 ng/mL no-GnRH vs. 3.96 ± 0.34 ng/mL of GnRH). When P4 concentrations were categorized as high (≥1 ng/mL) or low (<1 ng/mL), P/AI tended to be greater for high P4 concentrations (n = 136) compared with low (n = 48) P4 concentrations (26 vs. 16%, respectively). No differences were observed in the proportion of cows with high or low P4 between treatments. Collectively, these results provide evidence that eliminating the initial GnRH in a 5-d CIDR-Cosynch resynchronization protocol for lactating dairy cows did not reduce P/AI in this study.

Transvaginal ultrasound (TVUS)-guided biopsy is safe and effective in diagnosing peritoneal carcinomatosis and recurrent pelvic malignancy.

AIM: To assess safety and accuracy of transvaginal ultrasound (TVUS)-guided biopsy in achieving a diagnosis of peritoneal carcinomatosis (PC). MATERIALS AND METHODS: This was a retrospective study comprising a cohort of 54 consecutive women aged 18-85 years referred from the gynaecological oncology multidisciplinary team meeting (MDTM) who attended for TVUS-guided biopsy procedures in a tertiary oncology centre over a 4-year period (2010-2014). Clinicopathological validation was assessed using online patient records and radiological information systems. An independent oncologist assessed patient outcomes. RESULTS: The procedure was successful in all 19 patients with suspected recurrent malignancy with diagnosis validated against previous histology. Successful histological confirmation was achieved in 31 of 35 patients with suspected PC, which was thereafter validated by histology from subsequent surgery and favourable response to site-specific therapies (n=22). In three patients with suspected PC, the procedure did not result in biopsy as a suitable target could not be identified. Another woman had two false-negative biopsies. Thus overall a site-specific and subtype cancer diagnosis was obtained for 50 women giving an overall patient success rate of 93% (50/54). There were no procedure-related complications. CONCLUSION: TVUS core biopsy is a safe, effective, well-tolerated, and valuable technique in modern oncological management of PC when other diagnostic options are unavailable.

Analytical and numerical modeling of radio frequency electron cyclotron resonance power absorption within the cold plasma picture.

We present a one dimensional model of radio frequency (RF) power absorption in electron cyclotron resonance (ECR) ion sources based on a modified cold plasma dielectric description. The absorption is modeled by an imaginary collision frequency (damping coefficient) whose value is related to physical parameters such as magnetic field and its spatial derivative, electron temperature, and RF frequency and power. Properties and scaling laws of ECR power absorption are discussed within this model. Numerical benchmarking against a more accurate kinetic plasma code shows very good agreement.

Discriminative MRI features of fallopian tube masses.

Fallopian tube disease, both acute and chronic, is a common cause of a sonographically indeterminate adnexal mass and may mimic ovarian cancer. Magnetic resonance imaging (MRI) is now widely used as a problem-solving tool in these circumstances. The purpose of this review is to provide the discriminative MRI features of Fallopian tube masses and illustrate the key signs that establish their origin and nature. Familiarity with these characteristics enables distinction of tubal disease from malignant adnexal disease with major impact on management. On MRI, Fallopian tube disease exhibits features that parallel the classical sonographic findings, but which can be more reliably recognized due to improved contrast and spatial resolution, multiplanar capacity, effective field of view, and tissue characterization. Recognition of these characteristic morphological features and specific MRI signal patterns are key to a specific diagnosis. The anatomical and histopathological basis of these MRI signs is emphasized, covering also the differential diagnosis and pitfalls. Two new signs, "synechiae" and "amorphous shading", are also described that have not been well described previously in MRI of tubal disease.

Staging of endometrial cancer with MRI: guidelines of the European Society of Urogenital Imaging.

The purpose of this study was to define guidelines for endometrial cancer staging with MRI. The technique included critical review and expert consensus of MRI protocols by the female imaging subcommittee of the European Society of Urogenital Radiology, from ten European institutions, and published literature between 1999 and 2008. The results indicated that high field MRI should include at least two T2-weighted sequences in sagittal, axial oblique or coronal oblique orientation (short and long axis of the uterine body) of the pelvic content. High-resolution post-contrast images acquired at 2 min +/- 30 s after intravenous contrast injection are suggested to be optimal for the diagnosis of myometrial invasion. If cervical invasion is suspected, additional slice orientation perpendicular to the axis of the endocervical channel is recommended. Due to the limited sensitivity of MRI to detect lymph node metastasis without lymph node-specific contrast agents, retroperitoneal lymph node screening with pre-contrast sequences up to the level of the kidneys is optional. The likelihood of lymph node invasion and the need for staging lymphadenectomy are also indicated by high-grade histology at endometrial tissue sampling and by deep myometrial or cervical invasion detected by MRI. In conclusion, expert consensus and literature review lead to an optimized MRI protocol to stage endometrial cancer.

Indeterminate lesions in cancer imaging.

Indeterminate lesions are detected on cancer imaging examinations at all points along the patient pathway. Decisions made about indeterminate lesions may have profound impact on patient management, particularly when these may represent solitary sites of metastasis. In this process of decision making the radiologist, having detected a potential metastasis, must attempt to characterize the abnormality and then to make a judgement about its impact on management based on knowledge of the clinical context. Not every abnormality can be confidently characterized using the modality of detection and the indeterminate lesion may require further clarification through discussion in the format of a multidisciplinary meeting, planned further investigation, or intervention. In some circumstances the lesion remains indeterminate and a monitoring approach is appropriate. Uncertainty must not be regarded as a personal weakness of any individual, but may remain even after collective discussion in a multidisciplinary setting. The aim must be to develop a plan of action (or inaction) that is understandable, useful, and acceptable to the patient and clinician. In this review, the principles guiding these decisions are discussed in further detail and practical solutions to some commonly encountered indeterminate lesions are suggested, focusing on those that might represent solitary sites of disease and whose management impact may be profound.

Women with peritoneal carcinomatosis of unknown origin: Efficacy of image-guided biopsy to determine site-specific diagnosis.

OBJECTIVES: To evaluate the use of image-guided biopsy (IGB) in routine clinical practice to obtain site-specific diagnoses in women presenting with peritoneal carcinomatosis (PC). STUDY DESIGN: Retrospective case study. SETTING: Tertiary referral centre. POPULATION: A total of 149 consecutive women with PC who underwent IGB. METHODS: Biopsy was performed in women considered unsuitable for primary surgery because of poor performance status or disease unlikely to be optimally debulked, with a prior history of malignancy or where there was clinicoradiological uncertainty about primary tumour site. Standard haematoxylin-eosin histological analysis was supplemented with immunohistochemistry. MAIN OUTCOME MEASURES: The rate of site-specific diagnosis. RESULTS: A total of 149 women underwent IGB using computed tomography or ultrasound over a 6-year period. The only complication was one rectus sheath haematoma. In 138 (93%) women, a site-specific cancer diagnosis was made on the IGB (including 111 müllerian tract, 8 gastrointestinal tract, 4 breast and 3 lymphoma); in ten women, a repeat biopsy was necessary, giving an overall failure rate of 7%. In a further six women, malignancy was confirmed but a site-specific diagnosis could not be made, and in four women, biopsy showed benign tissue. A site-specific diagnosis was obtained in 29 of the 32 women (94%) with previous malignancy, of which 18/32 (56%) showed a new primary cancer. CONCLUSIONS: IGB is a safe and accurate technique for providing site-specific diagnoses in women with PC in routine clinical practice, including those with a previous relevant malignancy. IGB can replace laparoscopic or open biopsy in defining primary therapeutic options. The data would suggest that the biopsy should be performed with ultrasound where feasible.

MR staging of endometrial carcinoma.

Endometrial cancer is the second most common gynaecological malignancy. The usual presentation with post-menopausal bleeding results in an early diagnosis in most cases and thus there is opportunity for cure. Magnetic resonance (MR) imaging is pivotal in the decision-making process regarding treatment options. We present a review of the magnetic resonance (MR) findings to illustrate its role in the staging of endometrial cancer.

Image-guided biopsy in women with breast cancer presenting with peritoneal carcinomatosis.

When women with a history of breast cancer present with peritoneal carcinomatosis, the differential diagnosis lies between recurrent breast cancer or a new primary tumor. This scenario is of particular relevance to women with a BRCA gene mutation, who have a genetic predisposition to develop second primary tumors of the ovary, fallopian tube, and peritoneum. We describe the use of image-guided core biopsy as an alternative to laparoscopy or exploratory laparotomy in providing minimally invasive diagnosis in this increasingly common clinical dilemma.

Patients at high risk for upper tract urothelial cancer: evaluation of hydronephrosis using high resolution magnetic resonance urography.

PURPOSE: We assessed the potential of magnetic resonance urography (MRU) in the evaluation of hydronephrosis not explained by standard investigation in patients at high risk for upper tract urothelial cancer. MATERIALS AND METHODS: A total of 23 consecutive patients in a specialist urological unit with unexplained hydronephrosis prospectively underwent MRU which comprised overview heavily T2-weighted MR urographic images followed by focused high resolution turbo spin echo T2-weighted sequences obtained in an axial and coronal oblique plane through the level of urinary obstruction. All were at high risk for urothelial cancer and had either contraindications to or problems with standard investigations including poor contrast excretion due to obstruction or renal failure, failed ureteral cannulation or contrast allergy. Clinical events and imaging followup, subsequent endoscopic/surgical findings and histopathology validated MR findings. RESULTS: In 23 patients with a high clinical suspicion of upper tract transitional cell tumors (TCC), 8 ureteral and 5 renal pelvic TCCs (2 bilateral) were diagnosed by MR, and confirmed histologically. In a further 5 patients benign causes for the hydronephrosis were found. No intrinsic or extrinsic pathology was demonstrable in 5 patients whose imaging findings were stable during 1 year of followup. CONCLUSIONS: MRU is a valuable noninvasive investigation for evaluating hydronephrosis in this group of patients with suspected urothelial cancer in which routine investigation had failed to provide clinically important information. Focused high resolution T2-weighted images were reliable in the diagnosis of ureteral and renal pelvic TCCs, and were valuable in excluding these and other mass lesions as the cause of hydronephrosis.

Stable isotopic composition of the active pharmaceutical ingredient (API) naproxen.

A survey of the multi-stable isotopic composition of an active pharmaceutical ingredient (API), naproxen, was performed to assess the potential of Isotope Ratio Mass Spectrometry (IRMS) to distinguish the provenance of APIs. Twenty-six lots of naproxen from six manufacturers representing four countries (Italy, India, Ireland, and the USA) were analyzed for three isotope ratios (13C/12C, 18O/16O, and D/H). The samples were analyzed by either Elemental Analyzer/Isotope Ratio Mass Spectrometry (EA/IRMS: carbon (delta13C)) or by Thermal Conversion-EA/IRMS (TCEA/IRMS: hydrogen (deltaD) and oxygen (delta18O)). Bivariate and trivariate isotope ratio graphs for naproxen show marked clustering of the data for five out of the six naproxen manufacturers, suggesting that IRMS may be a plausible means to screen for manufacturer of given APIs.

Ponazuril inhibits the development of Eimeria vermiformis in experimentally infected outbred Swiss mice.

We evaluated a 15% paste formulation of ponazuril in outbred Swiss mice that were experimentally infected with Eimeria vermiformis. Thirty, 8-week-old female mice (approximately 20 g) were placed in one group of 10 mice and one group of 20 mice. Mice in both groups were gavaged with approximately 5,000 sporulated oocysts of E. vermiformis on day 0. Mice in group 2 (n=10) were treated orally on days 3 and 4 with ponazuril (suspended in 30% propylene glycol) at the rate of 20 mg/kg. Mice in group 1 (n=20) were gavaged with a similar volume of 30% propylene glycol. Rates of oocyst passage (oocysts/g feces) were determined on day 10 (peak patency) for treated and nontreated mice using a fecal aliquot oocyst counting technique. Oocysts were not observed in the feces of treated mice using the aliquot technique. Control mice passaged oocysts at a geometric mean rate of >104,000 oocysts/g feces. Control mice also produced significantly less feces on day 10. These results indicate that ponazuril is effective against E. vermiformis under the conditions utilized in this study, and that the E. vermiformis mouse model could be useful in predicting the efficacy of new anticoccidial drugs.

Disseminated toxoplasmosis in a captive ring-tailed lemur (Lemur catta).

A 3-yr-old secundiparous female ring-tailed lemur presented to the Auburn University Small Animal Clinic with signs of dyspnea, lethargy, and anorexia. The animal died before she could be examined, and a full necropsy was immediately performed. Provisional necropsy findings included moderate pneumonia and hepatopathy. Acute interstitial pneumonia and focal hepatocellular necrosis were confirmed histologically. Lung impression smears, histopathology, electron microscopy, immunohistochemistry, and tissue culture isolation resulted in a diagnosis of acute disseminated Toxoplasma gondii infection, which was confirmed by polymerase chain reaction. The isolate of T. gondii was avirulent for mice and was named AU Tgl and genetically is type II. The source of the infection remains unclear, but speculation suggests contaminated fruit or blackbirds (Passeriformes: Icteridae) acting as transport hosts for oocysts from nondomestic felids and feral cats on the property.