White Matter Disease and Outcomes of Mechanical Thrombectomy for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: The increased severity of white matter disease is associated with worse outcomes and an increased rate of intracerebral hemorrhage in patients with ischemic stroke undergoing thrombolytic treatment. However, whether white matter disease is associated with outcomes in patients undergoing endovascular treatment remains unclear. MATERIALS AND METHODS: In this prespecified exploratory analysis of our prospective multi-institutional study that enrolled consecutive adult patients with anterior circulation ischemic stroke undergoing endovascular treatment from November 2017 to September 2018, we compared the following outcomes between patients with none-to-minimal (van Swieten score, 0-2) and moderate-to-severe (van Swieten score, 3-4) white matter disease using logistic regression: 90-day mRS 3-6, death, intracerebral hemorrhage, successful recanalization, and early neurologic recovery. RESULTS: Of the 485 patients enrolled in the Blood Pressure after Endovascular Stroke Therapy (BEST) study, 389 had white matter disease graded (50% women; median age, 68 years; range, 58-79 years). A van Swieten score of 3-4 (n = 74/389, 19%) was associated with a higher rate of 90-day mRS of 3-6 (45% versus 18%; adjusted OR, 2.73; 95% CI, 1.34-5.93; P = .008). Although the death rate was higher in patients with van Swieten scores of 3-4 (26% versus 15%), the adjusted likelihood was not significantly different (adjusted OR, 1.14; 95% CI, 0.56-2.26; P = .710). Ordered regression revealed a shift toward worse mRS scores with increasing van Swieten scores (adjusted common OR, 3.04; 95% CI, 1.93-4.84; P < .001). No associations between white matter disease severity and intracerebral hemorrhage, successful recanalization, and early neurologic recovery were observed. CONCLUSIONS: Moderate-to-severe white matter disease is associated with worse outcomes in patients undergoing endovascular treatment without a significant increase in hemorrhagic complications. Studies comparing patients with and without endovascular treatment are necessary to determine whether the benefit of endovascular treatment is attenuated with greater white matter disease.

Leptin alters metabolic rates before acquisition of its anorectic effect in developing neonatal mice.

Leptin inhibits food intake and increases metabolic rates in adult mice. Neonatal mice need to maximize food intake and also maintain high thermoregulatory metabolic rates to optimize survival, suggesting that leptin may function differentially in neonatal versus adult animals. The efficacy of exogenous leptin to alter these two physiological functions during development was thus examined in C57BL/6J lean (+/+ or ob/+) and ob/ob (leptin-deficient) mice. Intraperitoneal leptin administration (1 mg/kg body wt) to lean and ob/ob pups from 7 to 10 days of age did not affect milk intake, oxygen consumption, body weight, or epididymal fat pad weights. Intracerebroventricular injection of 1 microg leptin to 9-day-old pups also failed to influence milk intake or oxygen consumption. Because neither lean nor ob/ob pups responded to exogenous leptin, high endogenous plasma leptin concentrations per se in these lean mice do not explain their resistance to leptin. Leptin administered intracerebroventricularly also failed to alter milk/food intakes of 17-day-old pups but markedly increased oxygen consumption of these older mice. By 28 days of age, intracerebroventricular leptin inhibited food intake. The well-defined actions of leptin to reduce food intake and enhance metabolic rates do not develop synchronously. The ability of leptin to accelerate metabolic rates is acquired early in life and independent of its anorectic action, which may promote survival of neonates.

Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice.

Leptin, the ob gene product, is released from adipose tissue and likely acts in the central nervous system, particularly within the hypothalamus, to exert many of its effects. Obesity in C57BL/6J ob/ob mice is caused by a mutation in the ob gene resulting in a lack of functional leptin. In this study, we first compared effects of a single intracerebroventricular (ICV) injection of 3 pmol (50 ng) or 60 pmol (1 microg) leptin on food intake and oxygen consumption of lean and ob/ob mice deprived of food for 4 h during the 48-h period postinjection. Injection of 3 pmol leptin minimally lowered food intake in these mice without influencing oxygen consumption. Injection of 60 pmol of leptin rapidly lowered food intake within 30 min in both lean and ob/ob mice, with effects persisting for 24 h. Lean and ob/ob mice treated with leptin consumed 40 and 60% less food, respectively, in 24 h than vehicle-treated controls. Injection of leptin (60 pmol ICV) suppressed food intake of adrenalectomized mice as well (by 25 and 40% in lean mice and by 20 and 68% in ob/ob mice at 3 and 24 h, respectively), indicating that glucocorticoids are not essential for leptin to suppress food intake. Leptin increased oxygen consumption in conditions in which diet-induced thermogenesis was low, i.e., in fed ob/ob mice and in food-deprived lean mice, but not in fed adrenalectomized ob/ob mice or in fed lean mice. ICV injection of 60 pmol leptin along with 230 pmol (2 microg) of neuropeptide Y (NPY) attenuated NPY-induced feeding in ob/ob, but not in lean mice, suggesting an enhanced potential for crosstalk between the leptin and NPY signaling systems in ob/ob mice lacking endogenous leptin. Leptin exerts rapid-onset actions within the central nervous system to coordinate control of food intake and metabolic rate.

Adrenalectomy reverses pre-existing obesity in adult genetically obese (ob/ob) mice.

OBJECTIVE: To determine if adrenalectomy would reverse the pre-existing gross obesity, characteristic of adult genetically obese (ob/ob) mice. DESIGN: Adult (12 week old) female ob/ob mice were adrenalectomized and fed a stock diet for 6 or 14 weeks. They were housed at 23-25 degrees C or 33 degrees C. Food intake and total body energy were determined. RESULTS: Adrenalectomy abolished the hyperphagia characteristic of ob/ob mice. Adrenalectomized ob/ob mice consumed 8-17% less food than intact lean mice. Adrenalectomized ob/ob mice housed at 23-25 degrees C lost 55% of their pre-existing body energy within 6 weeks after surgery and 75% of their body energy within 14 weeks after surgery. At 14 weeks after surgery, body weights and body energy content of the adrenalectomized ob/ob mice were comparable with values for intact lean mice. Intact ob/ob mice pair-fed to adrenalectomized ob/ob mice lost only half as much body energy as the adrenalectomized ob/ob mice did, indicating that adrenalectomy not only diminished food intake in ob/ob mice but also increased their energy expenditure per unit food consumed. Adrenalectomized ob/ob mice housed at 33 degrees C lost only half as much body energy in 6 weeks as did mice housed at 23-25 degrees C. CONCLUSION: Adrenalectomy reverses the gross obesity characteristic of adult ob/ob mice by abolishing their hyperphagia and increasing their energy expenditure per unit food consumed.

Consumption of a glucose diet enhances the sensitivity of pancreatic islets from adrenalectomized genetically obese (ob/ob) mice to glucose-induced insulin secretion.

Consumption of a glucose diet for 4 d markedly elevates plasma insulin concentrations in adrenalectomized ob/ob mice. The present study examined regulation of insulin secretion from perifused pancreatic islets of female adrenalectomized genetically obese (ob/ob) and lean mice fed a glucose diet for 4 d. These mice were fed a high carbohydrate commercial diet for 21 d, or the high carbohydrate commercial diet for 17 d and a purified high glucose diet for the last 4 d of the 21-d feeding period. Adrenalectomy equalized plasma insulin concentrations, pancreatic islet size, rates of insulin secretion in response to 20 mmol/L glucose and insulin mRNA relative abundance in ob/ob and lean mice fed the commercial diet, but the threshold for glucose-induced insulin secretion determined by a linear glucose gradient remained lower in islets from adrenalectomized ob/ob mice than in those from lean mice (3.8 +/- 0.1 vs. 4.9 +/- 0.2 mmol/L glucose), and addition of acetylcholine to the perifusate lowered the threshold to only 2.0 +/- 0.1 mmol/L glucose in islets from ob/ob mice vs. 3.3 +/- 0.1 mmol/L glucose in lean mice. Switching from the commercial diet to the glucose diet for 4 d increased plasma insulin concentrations -10-fold in islets from adrenalectomized ob/ob mice without affecting islet size, 20 mmol/L glucose-induced insulin secretion or insulin mRNA abundance. Consumption of the glucose diet did, however, markedly lower the threshold for glucose-induced insulin secretion in islets from adrenalectomized ob/ob mice to approximate the abnormally low glucose thresholds in intact ob/ob mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated neuronal c-Fos-like immunoreactivity and messenger ribonucleic acid (mRNA) in genetically obese (ob/ob) mice.

Adult genetically obese (ob/ob) mice display a number of metabolic alterations, the primary cause of which may be a defect in their central nervous system (CNS). The protein encoded by the protooncogene c-fos, c-Fos, functions as a nuclear transcription factor, and also serves as a marker of neuronal activity. The specific objectives of this study were (1) to use c-Fos immunohistochemistry to identify regions with altered neuronal activity in 6-7 week old male lean and ob/ob mice; (2) to examine c-fos relative mRNA abundance by northern blot analysis in brains of these mice and compare it with that of neuropeptide Y (NPY), a peptide well known to alter feeding and (3) determine changes in c-Fos immunoreactivity and mRNA caused by food deprivation. Fos-like immunoreactivity (FLI) tended to be higher in ad libitum fed ob/ob mice than in lean controls in most brain regions examined. The most prominent and consistent differences were in the paraventricular nuclei (PVN) where the numbers of Fos-positive nuclei were approximately 3 fold higher in ob/ob mice. Food deprivation for 24 h increased FLI in the PVN in lean mice but did not further augment FLI in the PVN of ob/ob mice. Arcuate nuclei of lean and ob/ob mice showed minimal FLI staining under ad libitum fed conditions. Food deprivation however, induced FLI in arcuate nuclei of both lean and ob/ob mice. The abundance of c-fos mRNA in whole brain of ob/ob mice averaged several fold higher than in leans under both fed and fasted conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Late pregnancy and rat choriocarcinoma cells inhibit nocturnal prolactin surges and serotonin-induced prolactin release.

The purpose of the present study was to determine the effect of hormonal secretion by trophoblast cells on serotonin-induced release of PRL in both pregnant and nonpregnant rats. In the first experiment, three compounds that effectively lead to stimulation of serotonin receptors were injected ip or intraarterially between 0900-1200 h on day 8 or 16 of pregnancy. These included the serotonin precursor 5-hydroxytryptophan (20 mg/kg BW); a releasor of serotonin, fenfluramine (10 mg/kg BW); and a serotonin S2 receptor agonist, DOI (2,5-dimethoxy-4-iodophenyl-2-aminopropane-HCl; 500 micrograms/kg BW). When injected on day 8, these treatments significantly (P less than 0.01) increased the level of plasma PRL within 30 min after the injection. However, on day 16 the same treatments could not induce any change in the plasma PRL level. In the second experiment, rat choriocarcinoma (Rcho) cells, which secrete placental lactogen I in vivo, were injected beneath the kidney capsule on day 1 of pregnancy. Control pregnant rats injected with the cell culture medium RPMI-1640 containing 20% FBS continued to have a nocturnal PRL surges on days 7, 8, and 9, with the peak value of plasma PRL occurring at 0400 h. Rats injected with the cells had Rcho tumors at the site of injection when analyzed on day 9. These rats also had significantly (P less than 0.05) reduced nocturnal PRL surges on days 7 and 8 of pregnancy compared to the control animals, and on day 9, the PRL surge was completely blocked. In another group of day 9 pregnant rats containing Rcho tumors, DOI-induced PRL release was blocked by Rcho cells, whereas in controls, plasma PRL increased from 5 to 47 ng/ml. The final experiment tested whether the presence of Rcho cells affected serotonergic- or TRH (1 microgram/rat)-induced PRL release in cyclic rats that were ovariectomized 1 day before drug injection. Injection of Rcho cells 8 days earlier completely inhibited 5-hydroxytryptophan- or DOI-induced PRL release, but did not affect TRH-induced PRL release. These results indicate that the absence of PRL surges after midpregnancy may be due in part to the inability of serotonin to stimulate PRL at this time compared to early pregnancy. Secretion of placental lactogens or other PRL-like peptides from the placenta in the pregnant rat may be antagonistic to the normal stimuli that cause the PRL surges of early pregnancy, resulting in a loss of surges.

Dopaminergic and serotonergic activity in the hypothalamus during early and late pregnancy.

Push-pull cannulae were implanted into the arcuate nucleus of pregnant or ovariectomized (OVX) rats, and the perfusate samples were analyzed for biogenic amines and their metabolites. Injection of pargyline, a monoamine oxidase inhibitor, resulted in a decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) levels in the samples, and detectable amounts of dopamine (DA) and serotonin (5-HT), which were usually not measurable prior to injection. Administration of 5-hydroxytryptophan resulted in a sharp increase in 5-HIAA and 5-HT levels in the perfusates, and no change in DOPAC levels. Push-pull perfusion was done between midnight and 06.00 h on day 8 and 16 of pregnancy. In those rats which showed a nocturnal prolactin (PRL) surge on day 8, 5-HIAA levels were very high compared to those that did not, or compared to those on day 16, which had chronic low PRL levels. DOPAC levels were not significantly different in the 3 groups. Perfusion of medial basal hypothalamic (MBH) fragments taken from mother rats on day 8 of pregnancy during the PRL surge spontaneously released more DA or 5-HT than did fragments taken on day 16 at the same time of day. These results suggest that serotonergic activity in the MBH is higher on day 8 of pregnancy, in parallel with the occurrence of PRL surges, than on day 16 when no surges are present. Dopaminergic activity, as measured by DOPAC levels in push-pull samples, does not appear to be different between the two days.

Serotonin synthesis inhibition or receptor antagonism reduces pregnancy-induced nocturnal prolactin secretion.

During early pregnancy, two surges of prolactin (PRL) designated as nocturnal (N) and diurnal (D) are displayed by the rat. We previously reported the positive influence of serotonin (5-HT) in regulating the D surge. Its role in the N surge remained inconclusive due to the contradictory results obtained with the 5-HT synthesis inhibitor parachlorophenylalanine (PCPA) and 5-HT2 receptor antagonists. This study further characterizes the involvement of 5-HT in regulating the N surge. The effectiveness of different doses of ketanserin (KET), a 5-HT2 receptor antagonist, to reduce plasma PRL levels during the surge was established. Sub-threshold (1 mg/kg BW) or just maximally effective (10 mg/kg BW) doses of KET were administered to rats that had been pre-treated with PCPA (250 mg/kg BW) for 24h. The lower dose of KET was ineffective in reducing the N surge even though less 5-HT was available due to PCPA treatment 24h earlier. The higher dose was effective in blocking the surge. Subsequently, the effect of one compared to two injections of PCPA 24 hours apart on plasma PRL levels and concentrations of 5-HT, dopamine (DA) and their respective metabolites 5-hydroxy-indoleacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC) in the medial basal hypothalamus (MBH) and the medial dorsal hypothalamus (MDH) was studied. Two injections of PCPA but not one abolished the N PRL surge. Levels of 5-HT and 5-HIAA were significantly (p less than .005) reduced following either one or two injections of PCPA. Nevertheless, there was a greater (50 fold) decrease in 5-HIAA following 2 injections compared to one injection (10 fold), resulting in lower 5-HT turnover as indicated by lower 5-HIAA/5-HT ratios. Levels of DA in the MBH were reduced significantly only following two injections of PCPA, suggesting that the lack of effect of PCPA after one injection on the N surge was not due to a decrease in DA.