Management of bone metastasis and cancer treatment-induced bone loss during the COVID-19 pandemic: An international perspective and recommendations.

Optimum management of patients with cancer during the COVID-19 pandemic has proved extremely challenging. Patients, clinicians and hospital authorities have had to balance the risks to patients of attending hospital, many of whom are especially vulnerable, with the risks of delaying or modifying cancer treatment. Those whose care has been significantly impacted include patients suffering from the effects of cancer on bone, where delivering the usual standard of care for bone support has often not been possible and clinicians have been forced to seek alternative options for adequate management. At a virtual meeting of the Cancer and Bone Society in July 2020, an expert group shared experiences and solutions to this challenge, following which a questionnaire was sent internationally to the symposium's participants, to explore the issues faced and solutions offered. 70 respondents, from 9 countries (majority USA, 39%, followed by UK, 19%) included 50 clinicians, spread across a diverse range of specialties (but with a high proportion, 64%, of medical oncologists) and 20 who classified themselves as non-clinical (solely lab-based). Spread of clinician specialty across tumour types was breast (65%), prostate (27%), followed by renal, myeloma and melanoma. Analysis showed that management of metastatic bone disease in all solid tumour types and myeloma, adjuvant bisphosphonate breast cancer therapy and cancer treatment induced bone loss, was substantially impacted. Respondents reported delays to routine CT scans (58%), standard bone scans (48%) and MRI scans (46%), though emergency scans were less affected. Delays in palliative radiotherapy for bone pain were reported by 31% of respondents with treatments often involving only a single dose without fractionation. Delays to, or cancellation of, prophylactic surgery for bone pain were reported by 35% of respondents. Access to treatments with intravenous bisphosphonates and subcutaneous denosumab was a major problem, mitigated by provision of drug administration at home or in a local clinic, reduced frequency of administration or switching to oral bisphosphonates taken at home. The questionnaire also revealed damaging delays or complete stopping of both clinical and laboratory research. In addition to an analysis of the questionnaire, this paper presents a rationale and recommendations for adaptation of the normal guidelines for protection of bone health during the pandemic.

Risk of recurrent stillbirth: a cohort study.

OBJECTIVES: To evaluate the recurrence risk of stillbirth. DESIGN: Retrospective cohort study. SETTING AND POPULATION: All births 1992-2017, Alberta, Canada. METHODS: Retrospective cohort study. MAIN OUTCOME MEASURES: Stillbirth was defined as the death in utero of a fetus with gestational age ≥20 weeks or weighing ≥500 g. Stillbirths were further subdivided into those occurring before labour and those in labour. RESULTS: We identified 744 897 births from 308 478 women. Of these, 3698 women experienced a stillbirth and, of these, 97.7%, experienced only one. For women with a small-for-gestational- age stillbirth in the first birth, their risk of a subsequent antepartum stillbirth was increased substantially: 4.09%, relative risk (RR) 10.39, 95% CI 5.81-18.59. For women with a first birth appropriate-for-gestational-age stillbirth with no risk factors such as pregnancy induced hypertension, the risk with pre-existing diabetes mellitus or hypertension was also increased but to a much lesser degree (RR 2.46, 95% CI 1.23-4.91). For women who had experienced a first birth intrapartum stillbirth, the risk of another intrapartum stillbirth was very high (3.59%, RR 36.50, 95% CI 20.17-66.05). Most of these births also occurred prior to 24 weeks' gestation: 83% (10/12). CONCLUSIONS: The risk of recurrent antepartum stillbirth is low. The increase in risk in instances where the antepartum stillbirth was not growth-restricted is not clinically meaningful. Given the very low risk in any given gestational week, fetal surveillance is unlikely to be effective and may lead to unnecessary interventions. Intrapartum stillbirth has a very high recurrence risk but may not be preventable. TWEETABLE ABSTRACT: Stillbirth recurrence is rare.

Severe neonatal hypoglycaemia and intrapartum glycaemic control in pregnancies complicated by type 1, type 2 and gestational diabetes.

AIMS: To determine if in-target intrapartum glucose control is associated with neonatal hypoglycaemia in women with type 1, type 2 or gestational diabetes. METHODS: This was a retrospective cohort study of pregnant women with diabetes and their neonates. The primary exposure was in-target glucose control, defined as all capillary glucose values within the range 3.5-6.5 mmol/l during the intrapartum period. The primary outcome, neonatal hypoglycaemia, was defined as treatment with intravenous dextrose therapy. Multiple logistic regression was used to examine the association between maternal intrapartum glycaemic control and neonatal hypoglycaemia, adjusting for covariates. RESULTS: Intrapartum glucose testing was available for 157 (86.3%), 267 (76.3%) and 3256 (52.4%) women with type 1, type 2 and gestational diabetes, respectively. In the univariate analysis, in-target glycaemic control was significantly associated with neonatal hypoglycaemia in women with gestational diabetes, but not in women with type 1 or 2 diabetes. However, after adjustment for important neonatal factors (large for gestational age, preterm delivery and infant sex), intrapartum in-target glycaemic control was not significantly associated with neonatal hypoglycaemia in women regardless of diabetes type [adjusted odds ratios 0.4 (95% CI 0.1, 1.4), 0.7 (95% CI 0.3, 1.3) and 0.7 (95% CI 0.5, 1.0) for women with type 1, type 2 and gestational diabetes, respectively]. CONCLUSIONS: There was no significant association between in-target glycaemic control and neonatal hypoglycaemia after adjustment for neonatal factors. Given the high risk of maternal hypoglycaemia and the resources required, future trials should consider whether more relaxed intrapartum glycaemic targets may be safer and yield similar neonatal outcomes.

Association of serum amyloid A protein and peptide fragments with prognosis in renal cancer.

BACKGROUND: In renal cell carcinoma (RCC), the discovery of biomarkers for clinical use is a priority. This study aimed to identify and validate diagnostic and prognostic serum markers using proteomic profiling. METHODS: Pre-operative sera from 119 patients with clear cell RCC and 69 healthy controls was analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry with stringent in-house quality control and analysis routines. Following identification of one prognostic peak as a fragment of serum amyloid A (SAA), total serum SAA and CRP were also determined by immunoassay for further validation. RESULTS: Several peptides were identified as having independent prognostic but not diagnostic significance on multivariable analysis. One was subsequently identified as a 1525 Da fragment of SAA (hazard ratio (HR)=0.26, 95% CI 0.08-0.85, P=0.026). This was weakly negatively correlated with total SAA, which was also of independent prognostic significance (HR=2.46, 95% CI 1.17-5.15, P=0.017). Both potentially strengthened prognostic models based solely on pre-operative variables. CONCLUSIONS: This is the first description of the prognostic value of this peptide in RCC and demonstrates proof of principle of the approach. The subsequent examination of SAA protein considerably extends previous studies, being the first study to focus solely on pre-operative samples and describing potential clinical utility in pre-operative prognostic models.

Adaptive upregulation of gastric and hypothalamic ghrelin receptors and increased plasma ghrelin in a model of cancer chemotherapy-induced dyspepsia.

Chemotherapy treatment can lead to delayed gastric emptying, early satiety, anorexia, nausea and vomiting, described collectively as the cancer-associated dyspepsia syndrome (CADS). Administration of ghrelin (GHRL), an endogenous orexigenic peptide known to stimulate gastric motility, has been shown to reduce the symptoms of CADS induced in relevant animal models with the potent chemotherapeutic agent, cisplatin. We examined the effects in the rat of cisplatin (6 mg/kg i.p.) treatment on the expression of GHRL and ghrelin receptor (GHSR) mRNAs in the hypothalamus and the stomach at a time-point (2 days) when the effects of cisplatin are pronounced. In addition, plasma levels of GHRL (acylated and total including des-acyl GHRL) were measured and the effect on these levels of treatment with the synthetic glucocorticoid dexamethasone (2 mg/kg s.c. bd.) was investigated. Cisplatin increased GHSR mRNA expression in the stomach (67%) and hypothalamus (52%) but not GHRL mRNA expression and increased the percentage of acylated GHRL (7.03+/-1.35% vs. 11.38+/-2.40%) in the plasma. Dexamethasone reduced the plasma level of acylated GHRL and the percentage of acylated GHRL to values below those in animals treated with saline alone (7.03+/-1.35% vs. 2.60+/-0.49%). Our findings support the hypothesis that an adaptive upregulation of the ghrelin receptor may occur during cancer chemotherapy-associated dyspepsia. This may have a role in defensive responses to toxic challenges to the gut. In addition, our results provide preliminary evidence for glucocorticoid modulation of plasma ghrelin levels.

The risk of unexplained antepartum stillbirth in second pregnancies following caesarean section in the first pregnancy.

OBJECTIVE: To determine if a previous caesarean section increases the risk of unexplained antepartum stillbirth in second pregnancies. STUDY DESIGN: Retrospective cohort study. SETTING: Large Canadian perinatal database. POPULATION: 158 502 second births. METHODS: Data were obtained from a large perinatal database, which supplied data on demographics, pregnancy complications, maternal medical conditions, previous caesarean section and pregnancy outcomes. MAIN OUTCOME MEASURES: Total and unexplained stillbirth. RESULTS: The antepartum stillbirth rate was 3.0/1000 in the previous caesarean section group compared with 2.7/1000 in the previous vaginal delivery group (P= 0.46). Multivariate logistic regression modelling, including terms for maternal age (polynomial), weight >91 kg, smoking during pregnancy, pre-pregnancy hypertension and diabetes, did not document an association between previous caesarean section and unexplained antepartum stillbirth (OR 1.27, 95% CI 0.92-1.77). CONCLUSION: Caesarean section in the first birth does not increase the risk of unexplained antepartum stillbirth in second pregnancies.

Response to intensity of reproduction in mouse lines resistant or susceptible to fescue toxicosis.

Our objective was to examine whether mouse lines divergently selected for response to fescue toxicosis differed in the impact of increasing reproductive intensity on growth, final weight or first and second parity reproduction. Resistant (R) and susceptible (S) females were never mated (NR), mated only once (low reproduction, LR), mated after their first litter was weaned (moderate reproduction, MR) or paired continuously with a male (high reproduction, HR), allowing concurrent pregnancy and lactation. Final weight was significantly higher in mated than in not mated females (31.6 +/- 0.6, 35.9 +/- 0.6, 36.8 +/- 0.6 and 37.2 +/- 0.5 g for NR, LR, MR and HR females respectively), but the effect of increasing reproductive intensity was similar in both lines. Neither genetic line, reproductive treatment (LR and MR versus HR) nor their interaction affected first parity traits of dams or pups. In second parity, S dams produced larger litters at birth and weaning and heavier litters at birth than R dams, and MR dams produced more pups and heavier litters than HR dams. As with first litters, however, line by reproductive treatment interactions were not significant or important. Concurrent pregnancy and lactation (the HR treatment) had a similar dampening impact on the expected increase in litter size between first and second parity of both lines. Thus, lines divergently selected for toxicosis response did not differ significantly in the impact of increasing reproductive intensity on dam or pup growth, reproductive output through two parities or mature size. This conclusion should not be generalized. Selection responses in livestock should be monitored to ensure that improvement in one trait does not lead to deterioration in others.

Efficacy of intramammary infusion of ceftiofur hydrochloride at drying off for treatment and prevention of bovine mastitis during the nonlactating period.

This study evaluated the efficacy of intramammary infusion of ceftiofur hydrochloride for the treatment of intramammary infections present at the last milking of lactation and for prevention of new intramammary infections during the nonlactating period. Cows were randomly assigned to five treatments (untreated negative control, 125, 250, and 500 mg of ceftiofur, and a positive control group receiving 300 mg cephapirin benzathine). A dose of 125 mg of ceftiofur per mammary quarter was effective for treatment of existing infections present at the time of milk cessation, but only the 500-mg dose of ceftiofur per mammary quarter was effective for both treatment of existing intramammary infections at the time of milk cessation and for prevention of new intramammary infections during the nonlactating period.

The risk of stillbirth in pregnancies before and after the onset of diabetes.

AIMS: There is significant controversy as to whether or not stillbirth is increased in pregnancies prior to the onset of diabetes. An observed increase may be indicative of risks associated with untreated gestational diabetes. It is generally accepted that the risk of stillbirth in pregnancies that occur after the onset of diabetes has been diminished by modern obstetric care. However, the degree of residual risk is not well quantified. This study sought to examine the rates of stillbirth before and after the onset of diabetes compared with the general population. METHODS: Retrospective cohort and nested case-control study. The study population was drawn from the UK-based General Practice Research Database, comprising some 300 practices, with data collection from the late 1980s until September 1999. From the base population, 913 diabetic women who had had a pregnancy were identified and 10,000 subjects without diabetes were randomly chosen as controls. Stillbirth was defined as death in utero after 20 weeks or with birth weight >500 g. RESULTS: The stillbirth rates were higher in prediabetic pregnancies (19.7/1000), and in those occurring after the diagnosis of diabetes (33.7/1000), compared with the non-diabetic population (5.5/1000). Stillbirths were matched to four live births by maternal age and year of birth. Prediabetic pregnancy and pregnancy after the onset of diabetes were strongly associated with stillbirth: odds ratio (OR)=4.68 (1.67, 13.08) and OR=4.39 (2.22, 8.64), respectively. CONCLUSIONS: The risk of stillbirth was increased in both prediabetic and post-diabetic pregnancy.

Impaired spatial and sequential learning in rats treated neonatally with D-fenfluramine.

D-Fenfluramine, a serotonin releaser, was administered to neonatal rats on postnatal days 11-20 (a stage of hippocampal development analogous to third trimester human ontogeny). As adults, the D-fenfluramine-treated offspring exhibited dose-related impairments of sequential and spatial learning and reference memory in the absence of sensorimotor impairments. Procedures to minimize stress and to control for other performance effects prior to testing for spatial learning demonstrated that nonspecific factors did not account for the selective effects of D-fenfluramine on learning and memory. Developmental D-fenfluramine-induced spatial and sequential learning deficits are similar to previous findings with developmental MDMA treatment. By contrast, recent findings with developmental D-methamphetamine treatment showed spatial learning deficits while sparing sequential learning. The spatial learning effects common to all three drugs suggest that they may share a common mechanism of action, however, the effects are not related to long-lasting changes in hippocampal 5-HT levels as no differences were found in adulthood. Whether the cognitive deficits are related to the effects of substituted amphetamines on corticosteroids, other aspects of the 5-HT system, or some unidentified neuronal substrates is not known, but the data demonstrate that these drugs are all capable of inducing long-term adverse effects on learning.

Medical management of missed abortion: a randomized clinical trial.

OBJECTIVE: To estimate the efficacy of vaginal misoprostol for medical management of missed abortion. METHODS: Fifty women with missed abortion were randomized to treatment with up to two 800 microg [DOSAGE ERROR CORRECTED] doses of misoprostol vaginally or a placebo. Participants were reviewed daily for 2 days, then again at 1 week. A blood sample for hemoglobin and serum beta-human chorionic gonadotropin (beta hCG) was obtained on day 1 and the hemoglobin level checked again on day 7. Complete abortion was defined as expulsion of the products of conception without dilation and curettage (D&C) and a negative follow-up urine beta hCG test after 4 weeks, or as no products of conception obtained at D&C in cases of suspected incomplete abortion. RESULTS: The rate of complete abortion was 80% (20 of 25) in the misoprostol group and 16% (four of 25) in the placebo group, relative risk 0.20 (0.08, 0.50), P <.001. The rate of D&C was 28% (seven of 25) in the misoprostol group and 84% (21 of 25) in the placebo group, relative risk 0.33 (0.17, 0.64), P <.001. One participant in the misoprostol group had an emergency D&C for heavy bleeding. No participants required blood transfusion. The mean reduction in hemoglobin from day 1 to day 7 was 3.2 g/L in the misoprostol group versus 4.3 g/L in the placebo group, P = .72. Patient satisfaction with misoprostol treatment was high with 19 of 21 participants reporting they would try medical management again if they experienced another missed abortion. CONCLUSION: Medical management of missed abortion is effective, reduces the need for D&C, and is associated with high levels of patient satisfaction.

Shetland Sheepdog leukodystrophy.

Three litters of Shetland Sheepdog pups born to the same bitch and 2 different sires were studied because of uncontrollable seizures or progressive neurologic dysfunction. Four pups from the 1st litter, 1 from the 2nd litter, and 4 from the 3rd litter had severe diffuse spongy degeneration of the white matter of the brain and spinal cord. An inherited basis for this syndrome was suspected. The purpose of this study was to evaluate the pups with currently available screening tests for the metabolic, biochemical, infectious, and toxicologic causes of leukodystrophy seen in humans and animals. Computed tomography scans revealed diffuse hypomyelination in the affected pup. Complete postmortem examination, including histopathology and electron microscopy, delineated a leukodystrophy resembling human Canavan's disease, but amino acid and organic acid metabolism abnormalities were not detected. No etiology for Shetland Sheepdog leukodystrophy has been found, but this condition represents another familial disease in the purebred dog population.

Improved synchrony of estrus and ovulation with the addition of GnRH to a melengestrol acetate-prostaglandin F2alpha synchronization treatment in beef heifers.

The objective of this experiment was to determine the effect of a GnRH injection within a melengestrol acetate (MGA)-PGF2alpha (PGF) estrus synchronization protocol on follicular dynamics and synchronization of estrus. Pubertal crossbred beef heifers (n = 34) were randomly assigned to one of two treatments. Both treatment groups were fed MGA (0.5 mg x hd(-1) x d(-1)) for 14 d and injected (i.m.) with PGF (25 mg of Lutalyse) 19 d after MGA withdrawal. Melengestrol acetate was delivered in a feed supplement of 1.8 kg x hd(-1) x d(-1). Seventeen heifers received an injection of GnRH (100 microg Cystorelin) 12 d after MGA withdrawal and 7 d before PGF. The control group (n = 17) received only MGA-PGF. Estrus was detected four times/d for 7 d beginning on the day PGF was injected. Transrectal ultrasonography was performed daily on eight heifers from each treatment to monitor ovarian activity and characterize changes in follicular dynamics after MGA withdrawal and until ovulation after PGF. Each of the GnRH-treated heifers either ovulated or had a luteinized dominant follicle following GnRH and subsequently initiated a new follicular wave (8/8, 100%). All GnRH-treated heifers (17/17, 100%) and 94% of controls (16/17) exhibited estrus after PGF. Estrus was exhibited over a 132-h period (12 to 144 h) for control heifers compared with 60 h (48 to 108 h) for GnRH-treated heifers. The peak synchronized period for both treatments was between 48 and 72 h after PGF, during which time 76% (13/17) of the GnRH-treated heifers exhibited estrus compared with 63% (10/16) for controls. Seventy-one percent (12/17) of the GnRH-treated heifers exhibited estrus from 48 to 60 h after PGF, compared with 38% (6/16) for controls (P < 0.05). In summary, injection of GnRH within a 14- to 19-d MGA-PGF protocol increased the synchrony of estrus during the synchronized period and concentrated the period of detected estrus. This protocol may offer potential for the fixed-time insemination of replacement beef heifers.

Interaction of endophyte-infected fescue and heat stress on ovarian function in the beef heifer.

The objective of the experiment was to examine the interaction of endophyte-infected tall fescue and environmental temperature on follicular and luteal development and function in beef heifers. Heifers were fed endophyte-free or endophyte-infected tall fescue seed at thermoneutral or heat stress temperatures (n = 6/treatment) 4 wk before and 3 wk after synchronized ovulation. All heifers were subjected to thermoneutral conditions (19 degrees C, 50% relative humidity) from Days -7 to -2; temperature increased incrementally from Days -1 to 0 and cycled between 25 degrees C and 31 degrees C between Days 1 and 20 for heat-stressed heifers. Serum was collected and ovaries monitored every other day after induced luteolysis between Days 1 and 23 or until ovulation. Size and location of follicles >4 mm and corpora lutea were recorded. Serum concentrations of prolactin were reduced in heat-stressed heifers fed infected seed and both heat stress and infected seed decreased total cholesterol. Rectal temperature and respiration rate were greatest in heifers fed the infected seed when exposed to maximal temperatures. Heat stress led to reduced diameter of the corpus luteum and serum progesterone compared with thermoneutral conditions. Progesterone was reduced more so in heifers fed infected seed. The combination of infected seed and heat stress was associated with reduced diameter of the preovulatory dominant follicle, and consumption of infected seed led to fewer large follicles during the estrous cycle. Both stressors led to reduced serum estradiol. Impaired follicle function may explain reduced pregnancy rates commonly observed in heifers grazing infected tall fescue pasture.

3,4-methylenedioxymethamphetamine (ecstasy)-induced learning and memory impairments depend on the age of exposure during early development.

Use of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) has increased dramatically in recent years, yet little is known about its effects on the developing brain. Neonatal rats were administered MDMA on days 1-10 or 11-20 (analogous to early and late human third trimester brain development). MDMA exposure had no effect on survival but did affect body weight gain during treatment. After treatment, body weight largely recovered to 90-95% of controls. MDMA exposure on days 11-20 resulted in dose-related impairments of sequential learning and spatial learning and memory, whereas neonatal rats exposed on days 1-10 showed almost no effects. At neither stage of exposure did MDMA-treated offspring show effects on swimming ability or cued learning. Brain region-specific dopamine, serotonin, and norepinephrine changes were small and were not correlated to learning changes. These findings suggest that MDMA may pose a previously unrecognized risk to the developing brain by inducing long-term deleterious effects on learning and memory.

Elevations in plasmatic titers of corticosterone and aldosterone, in the absence of changes in ACTH, testosterone, or glial fibrillary acidic protein, 72 h following D,L-fenfluramine or D-fenfluramine administration to rats.

Studies in both humans and animals demonstrate that D,L- and D-fenfluramine (D,L-FEN and D-FEN, respectively) can activate the hypothalamic-pituitary-adrenal axis following an acute dose. No data exist showing a prolonged effect of either drug, although two studies have hinted at increased adrenal activity. There are also considerable differences in the literature pertaining to the neurotoxic effects of D,L- and D-FEN. Some possible explanations for these differences include: activation of different neurotransmitter systems, the temperature at which the animals were maintained during exposure, or the substance sampled in each study. We investigated the effects of either D,L-FEN or D-FEN on pituitary, adrenal, and gonadal hormones 72 h after drug exposure. Furthermore, using a dosing regimen adapted from studies on methamphetamine (e.g., four times every 2 h in a single day) known to produce elevations in glial fibrillary acidic protein (GFAP) under hyperthermic conditions, we examined the effects of D- and D,L-FEN (15 mg/kg, four times) on GFAP content when the animals were dosed at ambient temperatures of 21 or 32 degrees C. Approximately fivefold increases of corticosterone and threefold increases of aldosterone were found 72 h later under resting conditions following both D- and D,L-FEN. Nonetheless, when animals were dosed with D-FEN at 32 degrees C, no significant elevation in corticosterone was detected. No effect was observed for ACTH, testosterone, or GFAP following D- or D,L-FEN treatment. These data suggest that: (1) FEN treatment causes prolonged elevations in adrenal cortical hormones; (2) FEN-treated animals displayed hormonal characteristics similar to animals undergoing a chronic stressor as suggested by no difference in ACTH titers; (3) D,L-FEN treatment or D-FEN treatment (as reported previously) is not similar to other substituted amphetamines in that it does not increase GFAP, even under hyperthermic conditions.

Prediabetes and perinatal mortality.

OBJECTIVE: The association between gestational diabetes mellitus (GDM) and perinatal outcome is largely based on case series and retrospective studies that found an increased risk of perinatal mortality and stillbirth as the onset of diabetes approached. Our objective was to assess the relationship between latency to diabetes and perinatal outcome of prediabetic pregnancies in a contemporary population of women with adult-onset diabetes. RESEARCH DESIGN AND METHODS: A population of 403 diabetic women from two recruitment sites completed a pretested questionnaire. RESULTS: Details of 1,181 pregnancy outcomes were obtained. This comprised 1,024 live births, 22 stillbirths, and 8 early neonatal deaths. Crude analysis suggested a relationship between time to diabetes (latency) < or =20 years and both perinatal death and stillbirth: odds ratio (95% CI), 2.41 (1.17-4.95) and 2.15 (0.93-4.98). Generalized additive modeling revealed a nonlinear relationship between the variables time to diabetes, and maternal age and perinatal outcome. Final logistic regression analysis was then performed for the outcomes perinatal death and stillbirth, with maternal age as a second-degree polynomial, year of birth as a continuous variable, and time to diabetes dichotomized < or =20 years to diagnosis and >20 years. This final analysis documented a significant association between time to diabetes < or =20 years and both perinatal death (4.06 [1.79-9.36]) and stillbirth (3.35 [1.25-9.05]). CONCLUSIONS: There appeared to be an increased risk of perinatal death and stillbirth in pregnancies occurring in the last 20 years before the diagnosis of diabetes.

Preweaning treatment with methamphetamine induces increases in both corticosterone and ACTH in rats.

Treatment with methamphetamine (MA) on postnatal days P11-20 induces adult spatial learning and memory deficits without affecting monoamine levels in various brain regions. In this study, we examined the pituitary and adrenal response of animals administered MA four times daily on P11, P11-15, or from P11 to P20. Corticosterone (CORT) and adrenocorticotropin hormone (ACTH) levels were assessed over a 1-hour period following MA exposure. On P11, MA produced marked elevations of both CORT and ACTH; this is during the stress hyporesponsive period (SHRP). On P15 and P20, the maximal effect of MA on CORT titers was observed at 30 min, with lower, but still significantly increased, levels at 60 min compared to controls. Males receiving MA on P15 had higher levels of ACTH than did control males, while no differences were noted among females. On P20, MA treatment resulted in higher levels of ACTH relative to vehicle-injected controls, but levels were not different from controls that were only weighed at each drug administration. MA treatment inhibited body, but not brain weight gain, resulting in hippocampal weights that were heavier in the MA-treated animals when expressed as a percent of body weight. The elevations of adrenal steroids by MA, during late phases of hippocampal neurogenesis, may contribute to neuronal alterations that are later manifested in deficits of learning and memory.

Uterine rupture during induced trial of labor among women with previous cesarean delivery.

OBJECTIVE: This study was undertaken to compare the rates of uterine rupture during induced trials of labor after previous cesarean delivery with the rates during a spontaneous trial of labor. STUDY DESIGN: All deliveries between 1992 and 1998 among women with previous cesarean delivery were evaluated. Rates of uterine rupture were determined for spontaneous labor and different methods of induction. RESULTS: Of 2119 trials of labor, 575 (27%) were induced. The overall rate of uterine rupture was 0.71% (15/2119). The uterine rupture rate with induced trial of labor (8/575; 1.4%) was significantly higher than with a spontaneous trial of labor (7/1544; 0.45%; P =.0004). Uterine rupture rates associated with different methods of induction were compared with the rate seen with spontaneous labor and were as follows: prostaglandin E(2) gel, 2.9% (5/172; P =.004); intracervical Foley catheter, 0.76% (1/129; P =.47); and labor induction not requiring cervical ripening, 0.74% (2/274; P =.63). The uterine rupture rate associated with inductions other than with prostaglandin E(2) was 0.74% (3/474; P =.38). The relative risk of uterine rupture with prostaglandin E(2) use versus spontaneous trial of labor was 6.41 (95% confidence interval, 2. 06-19.98). CONCLUSION: Induction of labor was associated with an increased risk of uterine rupture among women with a previous cesarean delivery, and this association was highest when prostaglandin E(2) gel was used.