The impact of fertility preservation on the timing of breast cancer treatment, recurrence, and survival.

BACKGROUND: Many young women with breast cancer undergo fertility preservation (FP) before cancer treatment. This study examined the impact of FP on breast cancer outcomes. METHODS: The authors performed a retrospective cohort study of 272 women aged 20 to 45 years with newly diagnosed stage 0 to III breast cancer who underwent an FP consultation between 2005 and 2017. Among these women, 123 (45.2%) underwent FP (fertility preservation-positive [FP+]). The remaining 149 women did not undergo FP (fertility preservation-negative [FP-]). RESULTS: The characteristics at enrollment were similar with the exception of ethnicity (FP+, 87.8% White; FP-, 67.8% White; P = .002) and BRCA status (FP+, 27.7% BRCA+; FP-, 15.5% BRCA+; P = .021). The median follow-up was approximately 4 years. Women who underwent FP had longer times to first treatment (FP+, 37 days; FP-, 31 days; adjusted hazard ratio [aHR], 0.74; confidence interval [CI], 0.56-0.99) and neoadjuvant chemotherapy (FP+, 36 days; FP-, 26 days; aHR, 0.41; CI, 0.24-0.68) and from surgery to adjuvant chemotherapy (FP+, 41 days; FP-, 33 days; aHR, 0.58; CI, 0.38-0.90). Adjusted 3- and 5-year invasive disease-free survival (IDFS) rates were comparable between the 2 groups (3-year IDFS: FP+, 85.4%; FP-, 79.4%; P = .411; 5-year IDFS: FP+, 73.7%; FP-, 67.1%; P = .288). Similarly, no difference in overall survival (OS) was observed between the 2 groups (3-year OS: FP+, 95.5%; FP-, 93.5%; P = .854; 5-year OS: FP+, 84.2%; FP-, 81.4%; P = .700). CONCLUSIONS: FP after a breast cancer diagnosis delays the time to treatment by a small amount, but this delay does not lead to inferior IDFS or OS.

Electronic whiteboard implementation as a quality management tool optimizes IVF laboratory standardization and improves clinical outcomes.

PURPOSE: To test whether an electronic whiteboard in the IVF laboratory increases the likelihood that critical evaluation procedures are performed within optimum pre-set time ranges. METHODS: A retrospective cohort study of oocyte retrievals in our IVF clinic between 06/01/2012 and 05/31/2018 was included. The electronic whiteboard was introduced on 04/06/2014. Prior to implementation, embryologists strived to adhere to the set evaluation times without a formal guide. The primary outcomes were the proportion of embryologist evaluations performed in optimum time ranges and the proportion of usable embryos per patient. RESULTS: A total of 4645 retrievals met inclusion criteria. Implementation of the whiteboard was associated with (1) an increase in the proportion of fertilization checks performed within the optimum time range for ICSI cycles (+ 5.1%, RR = 1.06, CI = 1.02-1.10); (2) an increase in the proportion of day 3 evaluations performed within the optimum time range, whether assisted hatching was performed (+ 23.6%, RR = 1.48, CI = 1.36-1.60) or not (+ 13.8%, RR = 1.23, CI = 1.12-1.35); and (3) an increase in the proportion of day 5 evaluations within the optimum time range (+ 15.5%, RR = 1.23, CI = 1.12-1.35). Additionally, the mean number of usable embryos per patient increased from 2.8 to 4.5 after the whiteboard was implemented (RR = 1.25, CI = 1.19-1.31). CONCLUSION: The use of an electronic whiteboard that posts optimum times for performing critical procedures significantly increases the proportion of evaluations that occur within these ranges. Such improved standardization led to positive downstream effects on the number of usable embryos per patient. We suggest that electronic whiteboard implementation driven by real-time data collection should be considered in all IVF laboratories.

Fertility preservation outcomes in women with gliomas: a retrospective case-control study.

PURPOSE: With advances in cancer therapy, reproductive-aged women can look forward to a life post-malignancy. Fortunately, fertility preservation (FP) may provide relief from potential infertility caused by cancer or associated caustic treatments. Outcomes of FP in pre-treatment reproductive-aged women with gliomas have not been previously characterized. METHODS: Between 2007 and 2018, 10 patients undergoing FP prior to chemotherapy and/or radiation treatment for gliomas were identified at Brigham and Women's Hospital. They were matched 3:1 to male-factor infertility patients by age ± 1 year. RESULTS: Patients with gliomas had significantly lower baseline anti-Müllerian hormone levels than male-factor infertility controls (2.37 vs 5.16 ng/mL, p = 0.002, log transformed). Despite higher starting (350 vs. 240 IU, p = 0.004) and total gonadotropin doses (4270 vs. 2270 IU, p < 0.001) over a similar stimulation duration (12.1 vs. 11.1 days, p = 0.219), cancer patients had lower peak estradiol levels (1420 vs. 2245 pg/mL, p = 0.003). The total number of follicles on the day of trigger (14.1 vs. 15.6, p = 0.284), the number of oocytes retrieved (18.4 vs. 20.5, p = 0.618), and the percentage of mature oocytes (69.9 vs. 73.8%, p = 0.076) were similar between cases and controls. One patient returned for a cryopreserved embryo transfer and delivered a healthy child. CONCLUSIONS: Patients undergoing FP prior to chemotherapy and/or radiation for a glioma achieve satisfactory FP outcomes and should be appropriately counseled regarding the opportunity to family-build after treatment.

Caring for Women After Hypertensive Pregnancies and Beyond: Implementation and Integration of a Postpartum Transition Clinic.

Purpose We developed a postpartum transition clinic to better support women after hypertensive pregnancy. Description Our program goals were (1) early postpartum hypertension medical management, (2) patient and provider education around CVD risk, (3) transition to primary care provider (PCP) and (4) a sustainable clinical model reimbursed by private and public insurances. We focused on women immediately postpartum in this analysis. Assessment Over the course of 5 years, a racially and socioeconomically diverse population of 412 immediately postpartum women received care for one, two or more appointments. Referral diagnoses included antepartum preeclampsia (PET) 51% (210/412), postpartum preeclampsia/hypertension (PP-PET) 22.3% (92/412), preeclampsia superimposed on chronic hypertension (siPET) 10.2% (42/412), chronic hypertension (cHTN) 8.8% (37/412), and gestational hypertension (gHTN) 7.8% (31/412). Almost half of women had 2-3 visits 47.3% (195/412) with no difference by diagnosis (p = 0.18). No show rates were consistently around 25%. Acquisition of home blood pressure monitors increased from 56.8% (44/94) to 93.8% (61/65) over the 5 years (p < 0.0001). Nearly half of patients seen had antihypertensive medication adjustments 48.3% (199/412). Of those patients scheduled, 86.8% (79/91) attended a nutrition consultation. For patients with PCPs within our system, 79.5% (105/132) kept their scheduled follow up PCP appointments. Conclusion We report a postpartum transition clinic after hypertensive pregnancy. In this diverse population, patients attended 2-3 visits, incorporated home blood pressure monitoring, adjusted antihypertensive medications and initiated prevention measures such as nutrition referrals and PCP follow-up. An internist salary was sustained through billings and collections from private and public insurance.

Association between blastocyst morphology and pregnancy and perinatal outcomes following fresh and cryopreserved embryo transfer.

PURPOSE: To assess the importance of each blastocyst morphological criteria with pregnancy and perinatal outcomes. METHODS: This single-center retrospective cohort study included blastocyst single embryo transfers (SET) performed between 1/2012-2/2018. Poisson regression was used to evaluate pregnancy outcomes following fresh and cryopreserved embryo transfer (CET) for association with blastocyst expansion, inner cell mass (ICM) quality, and trophectoderm (TE) quality. Among cycles resulting in live birth, associations with preterm birth, small for gestational age (SGA) and large for gestational age (LGA), were evaluated using logistic regression. RESULTS: A total of 1023 fresh and 1222 CET cycles were included, of which 465 (45.1%) fresh and 600 (48.5%) CET cycles resulted in singleton live birth. Clinical pregnancy rates increased with increasing expansion among fresh transfers (p for trend = 0.001) but not CET (p = 0.221), and with TE quality for both fresh and CET cycles (p = 0.005 and < 0.0001, respectively). Live birth rates increased with increasing expansion (fresh p = 0.005, CET p = 0.018) and TE quality (fresh p = 0.028, CET p = 0.023). ICM grade was not associated with pregnancy outcomes; however, higher ICM quality among CET cycles was associated with increased chance of preterm birth (p = 0.005). CONCLUSIONS: In blastocyst SET, blastocyst expansion and TE quality were each associated with clinical pregnancy and live birth. While higher ICM quality was associated with increased chance of preterm birth among CET, no other associations with perinatal outcomes were identified. Clinicians can be reassured that pregnancies from blastocysts with lower expansion, ICM, or TE qualities are not more likely to result in adverse perinatal outcomes.

The effect of endometriosis on the antimüllerian hormone level in the infertile population.

PURPOSE: To determine whether the presence of endometriosis in infertile women without prior ovarian surgery influences markers of ovarian reserve, AMH and FSH. METHODS: A retrospective cohort study included three groups of women who presented for IVF treatment at our tertiary care center from 04/27/2015 to 05/31/2017: women with endometriosis and prior ovarian surgery (EnSx), women with endometriosis without prior ovarian surgery (En), and women with a primary diagnosis of male factor infertility (MF; reference group). RESULTS: There were 671 patients that met inclusion criteria (78 EnSx, 60 En, and 533 MF). Compared to the MF group (3.6 ± 3.0), a lower mean AMH level (ng/mL) was observed in the EnSx group (2.5 ± 2.5; aß - 1.21; 95% CI [- 1.79, -0.62]) and in the En group (2.5 ± 2.2; aß - 1.11; 95% CI [- 1.68, - 0.54]). Both endometriosis groups had a statistically significantly higher proportion of patients with an AMH < 1 (EnSx, 24.4%; OR, 2.39 [95% CI, 1.31, 4.36]; En, 28.3%; OR, 2.67 [95% CI, 1.41, 5.08]) compared to the MF group (13.9%). The mean baseline FSH level (lU/L) was statistically significantly higher in both endometriosis groups (EnSx, 8.6 ± 4.3; ß, 1.37 [95% CI, 0.39, 2.34]; En, 8.4 ± 3.7; ß, 0.96 [95% CI, 0.04, 1.87]) compared to the MF group (7.3 ± 2.2). CONCLUSIONS: Among infertility patients with endometriosis, with and without a history of ovarian surgery, ovarian reserve markers were worse (lower AMH and higher FSH) and a higher proportion had decreased ovarian reserve as measured by AMH compared to women with MF.

Role of nuclear receptors in lipid dysfunction and obesity-related diseases.

This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 12 meeting in San Diego, CA. The presentations discussed the roles of a number of nuclear receptors in regulating glucose and lipid homeostasis, the pathophysiology of obesity-related disease states, and the promise associated with targeting their activities to treat these diseases. While many of these receptors (in particular, constitutive androstane receptor and pregnane X receptor) and their target enzymes have been thought of as regulators of drug and xenobiotic metabolism, this symposium highlighted the advances made in our understanding of the endogenous functions of these receptors. Similarly, as we gain a better understanding of the mechanisms underlying bile acid signaling pathways in the regulation of body weight and glucose homeostasis, we see the importance of using complementary approaches to elucidate this fascinating network of pathways. The observation that some receptors, like the farnesoid X receptor, can function in a tissue-specific manner via well defined mechanisms has important clinical implications, particularly in the treatment of liver diseases. Finally, the novel findings that agents that selectively activate estrogen receptor ß can effectively inhibit weight gain in a high-fat diet model of obesity identifies a new role for this member of the steroid superfamily. Taken together, the significant findings reported during this symposium illustrate the promise associated with targeting a number of nuclear receptors for the development of new therapies to treat obesity and other metabolic disorders.

Hepatocyte nuclear factor 4 alpha and farnesoid X receptor co-regulates gene transcription in mouse livers on a genome-wide scale.

PURPOSE: Farnesoid X receptor (Fxr) is a ligand-activated nuclear receptor critical for liver function. Reports indicate that the functions of Fxr in the liver may overlap with those of hepatocyte nuclear factor 4α (Hnf4α), but studies of their precise genome-wide interaction to regulate gene transcription in the liver are lacking. Thus, we compared the genome-wide binding of Fxr and Hnf4α in the liver of mice and characterized their cooperative activity on binding to and activating target gene transcription. METHODS: Genome-wide ChIP-Seq data of Fxr and Hnf4α in mouse liver were analyzed by MACS, BEDTools, and DAVID. Co-immunoprecipitation, ChIP-qPCR, and luciferase assays were done to test for protein-protein interaction and cooperative binding. RESULTS: ChIP-seq analysis showed nearly 50% binding sites of Fxr and Hnf4α in mouse liver overlap and Hnf4α bound to shared target sites upstream and in close proximity to Fxr. Moreover, genes co-bound by Fxr and Hnf4α are enriched in complement and coagulation cascades and drug metabolism. A direct Fxr-Hnf4α protein interaction dependent on Fxr activity was detected and transcriptional assays suggest that Hnf4α can increase Fxr transcriptional activity. Conversely, binding assays showed Hnf4α can be either Fxr-dependent or -independent at different shared binding sites. CONCLUSION: Our results showed that Fxr cooperates with Hnf4α in the liver to modulate gene transcription. This study provides the first evidence on a genome-wide scale of both cooperative and independent interactions between Fxr and Hnf4α in regulating gene transcription in the liver.

Estimated fetal weight by ultrasound: a modifiable risk factor for cesarean delivery?

OBJECTIVE: The purpose of this study was to investigate whether knowledge of ultrasound-obtained estimated fetal weight (US-EFW) is a risk factor for cesarean delivery (CD). STUDY DESIGN: Retrospective cohort from a single center in 2009-2010 of singleton, term live births. CD rates were compared for women with and without US-EFW within 1 month of delivery and adjusted for potential confounders. RESULTS: Of the 2329 women in our cohort, 50.2% had US-EFW within 1 month of delivery. CD was significantly more common for women with US-EFW (15.7% vs 10.2%; P < .001); after we controlled for confounders, US-EFW remained an independent risk factor for CD (odds ratio, 1.44; 95% confidence interval, 1.1-1.9). The risk increased when US-EFW was >3500 g (odds ratio, 1.8; 95% confidence interval, 1.3-2.7). CONCLUSION: Knowledge of US-EFW, above and beyond the impact of fetal size itself, increases the risk of CD. Acquisition of US-EFW near term appears to be an independent and potentially modifiable risk factor for CD.

Cryptococcus neoformans: the model organism for yeast antifungal drug susceptibility testing.

We describe an approach to antifungal susceptibility testing of the yeast Cryptococcus neoformans that shows promise for predicting the mycological response in patients to treatment. Quantitative cultures of the cerebrospinal fluid provide a direct measure of the patient's mycological response to treatment and have been used in multiple studies to identify the most promising antifungal drugs for subsequent testing in larger clinical studies. Using these quantitative measures of response, a modified macrobroth dilution assay system shows the potential for predicting the response of an individual patient to treatment with amphotericin B, fluconazole, or the combination of amphotericin B plus flucytosine. We describe this modified macrobroth dilution assay method, the statistical approach for assessing susceptibility, and the clinical decisions that can be guided by this in vitro antifungal drug susceptibility testing.

Genome-wide tissue-specific farnesoid X receptor binding in mouse liver and intestine.

UNLABELLED: Farnesoid X receptor (FXR) is a bile acid-activated transcription factor belonging to the nuclear receptor superfamily. FXR is highly expressed in liver and intestine and crosstalk mediated by FXR in these two organs is critical in maintaining bile acid homeostasis. FXR deficiency has been implicated in many liver and intestine diseases. However, regulation of transcription by FXR at the genomic level is not known. This study analyzed genome-wide FXR binding in liver and intestine of mice treated with a synthetic FXR ligand (GW4064) by chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq). The results showed a large degree of tissue-specific FXR binding, with only 11% of total sites shared between liver and intestine. The sites were widely distributed between intergenic, upstream, intragenic, and downstream of genes, with novel sites identified within even known FXR target genes. Motif analysis revealed a half nuclear receptor binding site, normally bound by a few orphan nuclear receptors, adjacent to the FXR response elements, indicating possible involvement of some orphan nuclear receptors in modulating FXR function. Furthermore, pathway analysis indicated that FXR may be extensively involved in multiple cellular metabolic pathways. CONCLUSION: This study reports genome-wide FXR binding in vivo and the results clearly demonstrate tissue-specific FXR/gene interaction. In addition, FXR may be involved in regulating broader biological pathways in maintaining hepatic and intestinal homeostasis.

Intramuscular progesterone versus 8% Crinone vaginal gel for luteal phase support following blastocyst cryopreserved single embryo transfer: a retrospective cohort study.

BACKGROUND: The optimal route of progesterone administration for luteal support in cryopreserved embryo transfer (CET) has been the subject of much debate. While most published research has pertained to day 3 transfers, recent data on blastocyst CET has suggested that intramuscular progesterone (IMP) is superior to twice daily vaginal Endometrin suppositories for luteal phase support, resulting in significantly higher ongoing pregnancy rates. This study aimed to determine whether IMP is similarly superior to 8% Crinone vaginal gel for luteal phase support following blastocyst CET. METHODS: Autologous and donor oocyte blastocyst cryopreserved single embryo transfer (SET) cycles from January 2014-January 2019 utilizing either 50 mg IMP daily or 90 mg 8% Crinone gel twice daily for luteal support were included. The primary outcome was live birth. Secondary outcomes included biochemical pregnancy, spontaneous abortion, and clinical pregnancy. All analyses were adjusted a priori for oocyte age. Log-binomial regression analysis was performed with differences in outcomes reported as relative risk (RR) with 95% confidence intervals (CI). RESULTS: A total of 1710 cycles were included, of which 1594 utilized IMP and 116 utilized 8% Crinone gel. Demographic and cycles characteristics were similar between the two groups. Compared to cycles utilizing IMP, cycles utilizing Crinone gel resulted in similar rates of live birth (RR 0.91; 95% CI 0.73-1.13), biochemical pregnancy (RR 1.12, 95% CI 0.65-1.92), spontaneous abortion (RR 1.41, 95% CI 0.90-2.20), and clinical pregnancy (RR 1.00, 95% CI 0.86-1.17). CONCLUSIONS: Compared to cryopreserved blastocyst SET cycles utilizing IMP for luteal support, cycles utilizing 8% Crinone gel resulted in similar likelihood of live birth.

Public perspectives on placing age limits on men and women seeking fertility treatment.

OBJECTIVE: To assess public attitudes toward placing age limits on men and women seeking fertility treatment. DESIGN: Cross-sectional web-based survey. SETTING: Not applicable. PATIENT(S): A nationally representative sample of 1,427 adults in the United States. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Support for placing age limits on people seeking fertility treatment. RESULT(S): Sixty-seven percent of respondents supported placing age limits on women, whereas 57% supported placing age limits on men seeking fertility treatments. Sixty-four percent agreed with current American Society for Reproductive Medicine guidelines that ET should not be undertaken beyond age 55 years. Whereas 55% of respondents supported placing age limits on both men and women, 12% supported age limits on women but not men, and 3% supported age limits on men but not women. Men were more likely to answer discordantly when compared with female respondents. Individuals older than 50 years, who lived in the western United States, or with a personal knowledge of someone who used assisted reproductive technology were more likely to support age limits on both women and men seeking fertility treatments. Sexual minorities, people without biological children, and single, long-term partnered or divorced/widowed respondents were less likely to support age limits on men or women seeking fertility treatments. CONCLUSION(S): Fifty-five percent of respondents in a nationally representative sample support upper age limits on both men and women seeking fertility treatments. Support was associated with various demographic characteristics. Men were more likely than women to support age limits only on women.

Infant size and the association between maternal circulating angiogenic factors and preeclampsia.

OBJECTIVE: To assess the effect of infant size as a marker of placental function on the association between preeclampsia and the ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF). STUDY DESIGN: The angiogenic factors sFlt-1 and PlGF were measured prospectively at 26 weeks gestation in 2322 women. Pregnancies were stratified by whether or not they were complicated by preeclampsia, the timing of delivery, and birthweight Z-score. RESULT: Independent of preeclampsia status, women with small infants (Z < -1.0) have an increased sFlt-1/PlGF ratio, and women with large infants (Z > 1.0) have a decreased ratio. Among pregnancies yielding small infants, the sFlt-1/PlGF ratio is markedly elevated in preeclamptic pregnancies requiring delivery before 37 weeks (110.0 vs. 17.9, p < 0.0001) but not in preeclamptic pregnancies delivered at term. The strength of the association between preeclampsia and the sFlt-1/PlGF ratio is increased for small infants compared to normal-sized or large infants. CONCLUSION: The sFlt-1/PlGF ratio in the late second trimester is similarly elevated in women with preeclampsia and in women with small infant size and more markedly elevated in a syndrome of placental dysfunction characterized by preeclampsia, preterm delivery, and growth restriction.

Alanine-glutamine dipeptide (AGD) inhibits expression of inflammation-related genes in hemorrhagic shock.

BACKGROUND: Inflammatory factors play an important role in the production of cellular damage after shock and reperfusion. Glutamine has been used to modulate the inflammatory response. Alanine-glutamine dipeptide (AGD) is a glutamine source. The hypothesis of the present study is that AGD given during resuscitation will suppress postshock expression of messenger ribonucleic acid (mRNA) for tumor necrosis factor (TNF-alpha), interleukin-1 (IL-1beta) and inducible nitric oxide synthase (iNOS). METHODS: Male Sprague-Dawley rats (n = 74, 350 g +/- 30 g) were randomly assigned to 5 groups. Under isoflurane anesthesia, the femoral artery and vein were cannulated. Hemorrhagic shock was induced by withdrawing blood through the arterial cannula until the mean arterial pressure (MAP) was 25-30 mm Hg and maintained at the level for 30 minutes with further withdrawals. Resuscitation was carried out by giving 21 mL/kg Ringer's lactate (LR) with or without the administration of AGD (936 mg/kg) and returning the shed blood. Controls were normal (anesthesia only), sham (surgical preparation), and shock (preparation and shock). Rats (n = 45, 9 per group) were killed 30 minutes after completion of resuscitation. Liver samples were collected, and total RNA was isolated for reverse transcription-polymerase chain reaction analysis of mRNA (TNF-alpha, IL-1beta, iNOS, and beta-actin). RESULTS: MAP recovered more quickly in the AGD group than in the LR group. Increased expression of liver mRNA for TNF-alpha, IL-1beta, and iNOS was seen after hemorrhagic shock and resuscitation. AGD treatment significantly reduced mRNA expression for all 3. CONCLUSIONS: AGD modified the expression of genes controlling cytokines and iNOS in the liver. This agent is a potential treatment for hemorrhagic shock.

Crocetin inhibits mRNA expression for tumor necrosis factor-alpha, interleukin-1beta, and inducible nitric oxide synthase in hemorrhagic shock.

BACKGROUND: Inflammatory factors play an important role in cellular damage after shock and resuscitation. Crocetin, a saffron-derived carotenoid, has been shown to improve postshock recovery of cellular adenosine triphosphate (ATP) and to increase overall survival in an experimental model of hemorrhagic shock. The hypothesis of the present study is that treatment with crocetin at the beginning of resuscitation suppresses subsequent expression of messenger ribonucleic acid (mRNA) for tumor necrosis factor (TNF-alpha), interleukin-1 (IL-1beta) and inducible nitric oxide synthase (iNOS). METHODS: Male Sprague-Dawley rats (n = 45, 350 +/- 30 g) were randomly assigned to 5 groups of 9 animals each. After anesthesia with isoflurane, the femoral artery and vein were surgically cannulated. Hemorrhagic shock was induced by withdrawing blood through the arterial cannula until the mean arterial pressure (MAP) was 25-30 mm Hg and maintained at the level for 30 minutes with further withdrawals. Resuscitation was carried out by giving 21 mL/kg Ringer's lactate (LR) and returning the shed blood, with or without the initial administration of crocetin (2 mg/kg). Controls were normal (anesthesia only), sham (surgical preparation), and shock (preparation and shock). Rats were killed 30 minutes after completion of resuscitation. Liver samples were collected for reverse transcription-polymerase chain reaction (RT-PCR) analysis of mRNA (TNF-alpha, IL-1beta, iNOS, and beta-actin). RESULTS: Liver mRNA expression for TNF-alpha, IL-1beta, and iNOS was found in more animals in the shock and shock-plus-resuscitation groups than in the sham control group. The group resuscitated from shock with crocetin had mRNA expression for TNF-alpha, IL-1beta, and iNOS in fewer animals than either of the other shock groups and was no different from the sham control group. CONCLUSIONS: Crocetin modified the hepatic mRNA expression of cytokines and iNOS in a shock model. This agent continues to show promise as a potential treatment for hemorrhagic shock.

Dose-response impact of various tocotrienols on serum lipid parameters in 5-week-old female chickens.

The cholesterol-suppressive action of the tocotrienol-rich-fraction (TRF) of palm oil may be due to the effect of its constituent tocotrienols on beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase activity. The tocotrienols, modulate HMG-CoA reductase activity via a post-transcriptional mechanism. As a consequence small doses (5-200 ppm) of TRF-supplemented diets fed to experimental animals lower serum cholesterol levels. These findings led us to evaluate the safety and efficacy of large supplements of TRF and its constituents. Diets supplemented with 50, 100, 250, 500, 1000, or 2000 ppm of TRF, alpha-tocopherol, alpha-tocotrienol, gamma-tocotrienol, or 6-tocotrienol were fed to chickens for 4 wk. There were no differences between groups or within groups in weight gain, or in feed consumption at the termination of the feeding period. Supplemental TRF produced a dose-response (50-2000 ppm) lowering of serum total and LDL cholesterol levels of 22% and 52% (P < 0.05), respectively, compared with the control group. alpha-Tocopherol did not affect total or LDL-cholesterol levels. Supplemental alpha-tocotrienol within the 50-500 ppm range produced a dose-response lowering of total (17%) and LDL (33%) cholesterol levels. The more potent gamma and delta isomers yielded dose-response (50-2,000 ppm) reductions of serum total (32%) and LDL (66%) cholesterol levels. HDL cholesterol levels were minimally impacted by the tocotrienols; as a result, the HDL/LDL cholesterol ratios were markedly improved (123-150%) by the supplements. Serum triglyceride levels were significantly lower in sera of pullets receiving the higher supplements. The safe dose of various tocotrienols for human consumption might be 200-1000 mg/d based on this study.

Fetal adrenal gland volume and preterm birth: a prospective third-trimester screening evaluation.

OBJECTIVE: Given the importance of the fetal adrenal gland in producing hormones critical to labor, we sought to evaluate whether sonographic three-dimensional measurements of the adrenal gland are a useful screening tool for spontaneous preterm birth (SPTB). METHOD: We prospectively screened 128 non-anomalous singletons from 24 to 36 weeks' gestation with volumetric measurements of the fetal adrenal gland at their indicated antenatal sonogram. Labor and delivery outcomes were assessed and compared with respect to adrenal volume. RESULTS: When corrected for estimated fetal weight, the 11 women (9%) who delivered following SPTB had smaller adrenals than those who did not, 0.33 cm(3)/kg compared with 0.57 cm(3)/kg, respectively (p = 0.006). There was no difference in volumes between those who delivered by SPTB within 7 days or greater than 14 days from measurement (0.34 cm(3)/kg versus 0.33 cm(3)/kg, p = 0.79). Among women at increased risk of SPTB, those with SPTB had smaller adrenals than those who did not: 0.32 cm(3)/kg versus 0.53 cm(3)/kg, p = 0.06. CONCLUSION: We found fetal adrenal glands significantly smaller for those delivering preterm. Given the prior literature and our asymptomatic population, our data support multiple pathways leading to SPTB.

Leaf development in Lolium temulentum L.: characterization of a slow-to-green mutant.

A nuclear-gene mutation of the C3 grass Lolium temulentum L., which arose following cell suspension culture and plant regeneration, is manifested as delayed and incomplete greening, which occurs from the leaf tip downwards. Many plastids in the mutant exhibit abnormal morphology when examined by transmission electron microscopy; the plastid outer envelope lacks integrity and thylakoids, while still stacked, are spread over a wide area surrounded by diffuse stromal contents. These aberrant plastids can coexist with apparently normal chloroplasts in the same cell of mutant plants. Levels of chlorophyll a and b, and carotenoids, are all lower in the mutants than in normal Lolium temulentum. Leaf length, absolute growth rate, and number of cells per unit length at the leaf base, are greatly reduced (20-30% the normal values) in slow-to-green plants, but relative growth rate, duration of leaf growth, length of cell division zone and proportion of cells dividing are little affected. This novel mutant is a potentially valuable resource for studying interrelationships between photosynthetic function and leaf extension growth in grasses.