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.

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.

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.

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.

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.

S49 cells endogenously express subtype 2 somatostatin receptors which couple to increase protein tyrosine phosphatase activity in membranes and down-regulate Raf-1 activity in situ.

S49 cells expressed type 2 somatostatin receptors (sstr2) by immunoblotting. Analysis by reverse transcription and polymerase chain reaction (RT-PCR) methodologies showed that S49 cells express predominantly sstr2A and sstr2B mRNAs; other subtypes were either not detected, in the case of sstr1, sstr3, sstr4, or variably detected, in the case of sstr5. No mutations were present in S49 cells at codon 12, 13, or 61 of the N-, K-, or H-ras genes. Nevertheless, randomly growing S49 cells contained Raf-1 activity by specific immune complex kinase assays. Treatment of S49 cells with somatostatin transiently inactivated the basal activity of Raf-1, but not that of B-Raf. Addition of somatostatin plus guanyl-5'-yl imidodiphosphate (GMPPNP) to S49 membranes stimulated PTPase activity. The concentration dependence for stimulation of PTPase activity correlated with high affinity binding of [125I-Tyr11]somatostatin-14. Both the effect of somatostatin to stimulate PTPase activity and to inactivate Raf-1 were abrogated by PTx. PTPase activity stimulated by somatostatin plus GMPPNP was recovered in a peak of high apparent M(r) (670,000) after solubilisation with Triton X-100 and Superose 6 chromatography. Furthermore, addition of activated, brain G alpha i/o subunits to fractions from control membranes stimulated PTPase activity in the high M(r) peak. Thus, S49 membranes contain a G-protein regulated PTPase (PTPase-G), and PTPase-G in these cells may reside in a high molecular weight complex.

Activation in vitro of somatostatin receptor subtypes 2, 3, or 4 stimulates protein tyrosine phosphatase activity in membranes from transfected Ras-transformed NIH 3T3 cells: coexpression with catalytically inactive SHP-2 blocks responsiveness.

Somatostatin receptors (sstr) subtypes 1-5 were transiently expressed in NIH 3T3 cells stably transformed with Ha-Ras(G12V) to assess the ability of each receptor to stimulate protein tyrosine phosphatase (PTPase) activity in vitro. Treatment of membranes from sstr2-, sstr3-, or sstr4-expressing cells with somatostatin-14 plus guanyl-5'-yl imidodiphosphate (GMPPNP) increased PTPase activity, and this stimulation was pertussis toxin-sensitive. Somatostatin alone, GMPPNP alone, or somatostatin plus GDP were ineffective under these conditions. sstr1 and sstr5 failed to increase PTPase activity although both receptors were expressed, as assessed by appearance of high-affinity binding sites for [125I-Tyr11]somatostatin-14. Somatostatin plus GMPPNP stimulated PTPase activity in vitro when sstr2 was coexpressed with wild type PTP1B or a Cys to Ser (C/S), catalytically inactive PTP1B or with wild type SH2-domain containing PTPase SHP-2. However, coexpression with catalytically inactive C/S SHP-2 abrogated this response. Thus, three of the five cloned sstr's can couple to activate PTPase in this cellular background. Abrogation of the response by C/S SHP-2 strongly suggests, but does not prove, a role for SHP-2 in the mechanism.

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.

Conduction of trans of impulses in uniform myelinated fibers: computed dependence on stimulus frequency.

The conduction of trains of action potentials in myelinated fibers was studied using computer simulations based on a modification of the Hodgkin-Huxley equations. Stimulation at short but regular interstimulus intervals caused some stimuli to fail to elicit propagated action potentials. Propagated impulse trains observed close to the stimulation site, elicited by high frequency stimulus trains, took the form of "clusters" of impulses, e.g. doublets or triplets. When these impulse trains were observed at distances farther from the stimulation site, interspike intervals were more uniform. For interstimulus intervals of less than 10 ms, distant intervals between impulses were relatively insensitive to the temporal patterning of impulses at the initiation zone and tended toward regular intervals corresponding to the average interstimulus intervals for propagated stimuli. This tendency toward uniform intervals between impulses was also observed for lower average frequency stimulus trains with irregular interstimulus intervals. Moreover, for the first two stimuli in a train, there was a very tendency toward impulse entrainment. These results indicate that intervals between impulses along unbranched myelinated axons are not fixed, but vary according to the site along the conduction pathway where they are observed. The tendency toward entrainment, and regularization of intervals, may represent a factor limiting the frequency with which interval-coded impulses are initiated.

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.

Evaluation of the twin peak or lambda sign in determining chorionicity in multiple pregnancy.

OBJECTIVE: To assess prospectively the diagnostic capabilities of ultrasound assessment, using the twin peak or lambda sign, in determining chorionicity in multiple pregnancy. METHODS: Fifty-five cases of multiple pregnancy were assessed. Real-time ultrasound scans of the origin of the inter-twin membrane for the presence or absence of the twin peak/lambda sign were performed and permanent images recorded. Chorionicity was determined by placental pathologic analysis. RESULTS: Presence or absence of the twin peak/lambda sign as determined by real-time ultrasound correctly predicted chorionicity in 34 of 36 dichorionic and seven of eight monochorionic twin pregnancies: sensitivity for dichorionicity 94%, specificity 88%, positive predictive value 97%, and negative predictive value 78%. Real-time assessment was superior to analysis of permanent films. CONCLUSION: Ultrasound assessment of chorionicity using the twin peak/lambda sign has high sensitivity and specificity, but accuracy may not be sufficient to guide clinical management in all cases.

Impulse conduction in inhomogeneous axons: effects of variation in voltage-sensitive ionic conductances on invasion of demyelinated axon segments and preterminal fibers.

Conduction in inhomogeneous axons may be blocked by several mechanisms. Conduction in demyelinated axons may fail since normal internodal membrane is inexcitable, because values of sodium conductance are too low to support impulse conduction. In addition, focal loss of myelin causes increased current leakage which slows or blocks invasion of impulses into the demyelinated zone due to inadequate current density. Similar considerations apply to the invasion of non-myelinated preterminal axons from myelinated parent fibers, where conduction can be blocked as a result of inadequate current density. A cable model of an axon is presented which allows myelinated regions, regions without myelin, and variable length transition zones of redistributed channel densities, to be studied. Action potentials and membrane currents were studied. Computer simulations using this model show that the safety factor for invasion is dependent on temperature. These studies also show that small changes in axon membrane properties, at the transition region between the myelinated zone and the region without myelin, may promote invasion of the region without myelin. In particular, increasing sodium conductance (gNa) or decreasing potassium conductance (gK) promotes invasion. Because of the non-linear behavior of excitable membranes the spatial distribution of channels is shown also to have significant effects on invasion. Thus, relatively small degrees of membrane reorganization may lead to functional changes with respect to the invasion of demyelinated axon regions. Similarly, the properties of the heminode at the distal part of the parent myelinated fiber may determine the invasion characteristics of non-myelinated terminal axons.

The multifunctional role of hormone-sensitive lipase in lipid metabolism.

Hormone sensitive lipase (HSL) is an enzyme of relatively broad specificity, having the ability to hydrolyze tri-, di- and mono-acylglycerols as well as cholesterol esters and small water-soluble substrates. This broad specificity allows HSL to perform a variety of functions in several tissues. A key feature of HSL is its ability to be activated via phosphorylation by cyclic AMP-dependent protein kinase. In addition it is phosphorylated at a second site by several kinases, notably AMP-activated protein kinase. Phosphorylation of this site apparently plays a role in rendering the enzyme hormone-insensitive, in that prior phosphorylation at site 2 prevents phosphorylation and activation at site 1 by cyclic AMP-dependent protein kinase. Investigation of the protein phosphatases responsible for dephosphorylation of these sites has indicated that phosphatase 2A plays a predominant role but also that protein phosphatase 2C is a significant phosphatase targeted against both phosphorylation sites. Evidence indicates that HSL has at least three functional domains which contain (a) the phosphorylation sites which control activity, (b) the active site responsible for the catalytic activity and (c) a lipid binding site responsible for anchoring the lipase at the water-lipid interface. Using limited proteolytic studies we have found that it is possible to cleave HSL into several fragments including a stable domain of M(r) approximately 17.6 kDa which contains the active site serine residue. Digestion under similar conditions also generates a stable domain of M(r) approximately 11.5 kDa containing both phosphorylation sites. Furthermore, under appropriate conditions it is possible to digest HSL and retain activity against water-soluble substrates but with the concomitant loss of activity against triacylglycerol, implying that a lipid binding domain is lost during this procedure. HSL is responsible for the neutral cholesterol esterase activity in macrophages and it may play a role in the accumulation of cholesterol esters which occur during the development of foam cells. HSL activity is reduced in macrophage foam cells, at least partly due to increased activity of a cytosolic HSL inhibitor protein. A finding unexplained for many years has been that, although lipolysis can be stimulated 50-100-fold in adipocytes by lipolytic hormones, HSL can apparently only be activated 2-3-fold via phosphorylation in vitro by cyclic AMP-dependent protein kinase. One possibility to explain this discrepancy is that an additional anchoring protein is missing from the in vitro system and indirect evidence is now accumulating for such a protein.

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.

Effects of prenatal cocaine on Morris and Barnes maze tests of spatial learning and memory in the offspring of C57BL/6J mice.

Cocaine was administered to gravid C57BL/6J mice on embryonic days E8-18 at doses of either 17.5 or 20 mg/kg x 2 per day; controls received equal volumes of vehicle. The two cocaine dose groups were indistinguishable in their effects on maternal weight gain, offspring survival or body weight; therefore, the two groups were combined. Offspring were assessed as adults in straight channel swimming, cued and spatial reference-memory and working memory versions of the Morris water maze (MWM), and in the Barnes spatial maze to escape from a light, tone and fan. Cocaine offspring had shorter latencies in the straight channel and increased cumulative distance from the platform and path length in the spatial version of the Morris maze, but only when the platform size was reduced, not under standard platform conditions. In the working memory test, cocaine offspring showed deficits in acquisition and, following random trials, on relearning during a final test phase. In the Barnes maze, cocaine offspring were delayed in utilizing more efficient search strategies and took longer to find the goal. Taken together, the data suggest that prenatal cocaine induces modest but significant long-term alterations in both reference and working memory-based spatial learning and memory.

Evaluation of neonatal exposure to cocaine on learning, activity, startle, scent marking, immobility, and plasma cocaine concentrations.

Prenatal cocaine treatment produces equivocal effects on spatial learning and memory; however, no data are available on neonatal treatment as a model of human third-trimester exposure. Sprague-Dawley rats were treated on postnatal days (P) 1-10 or 11-20 with cocaine (15 mg/kg x 4 per day at 2-h intervals) or saline (P1-P20) and evaluated as adults in the Morris water maze and on tests of activity, startle, scent marking, swimming immobility, and sequential learning. Neonatal cocaine had no effect on mortality; however, early treatment reduced body weight, whereas later treatment did not. Neonatal cocaine had no effects on exploratory activity, swimming ability, sequential learning, multiday activity rhythms, scent marking, or swimming immobility, but augmented acoustic startle amplitude in the early-treated group. Neonatal cocaine also produced an interaction on spatial learning in which the cocaine early-treated males performed slightly more efficiently than controls. Plasma cocaine concentrations were significantly higher in the early-treated group than the later-treated group despite receiving the same weight-adjusted doses. It was concluded that neonatal cocaine, when administered during a stage of brain development analogous to human third trimester, induces few behavioral effects based on the assessments used in this study.

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.