Changing antiepileptic drug use for seizures in US neonatal intensive care units from 2005 to 2014.

OBJECTIVE: Neonatal seizures are a common problem in the neonatal intensive care unit and are frequently treated with antiepileptic drugs. Limited data exist on current or changing antiepileptic drug use for seizures in the neonatal intensive care unit.We sought to describe trends of antiepileptic drug exposure in a large volume of US neonatal intensive care unit from 2005 to 2014 and we hypothesized increasing levetiracetam exposure over the 10-year study period. STUDY DESIGN: Retrospective cohort study of infants from the Pediatrix Medical Group Clinical Data Warehouse, a large, multicenter, deidentified data set. Data were analyzed for trends in 2-year time periods. Our cohort included infants with a diagnosis of seizures who received an antiepileptic drug that were discharged from the neonatal intensive care unit from 1 January 2005 to 31 December 2014. RESULTS: Among 778 395 infants from 341 facilities, we identified 9134 infants with a seizure diagnosis who received an antiepileptic drug. Phenobarbital was used in 98% of the cohort. From 2005-2006 to 2013-2014 phenobarbital exposure declined from 99 to 96% (P<0.001), phenytoin exposure decreased from 15 to 11% (P<0.001) and levetiracetam exposure increased 10-fold from 1.4 to 14% (P<0.001). Overall, <1% of infants were exposed to carbamazepine, lidocaine or topiramate. CONCLUSIONS: Infants with seizures were overwhelmingly exposed to phenobarbital, despite a significant increase in levetiracetam exposure. The use of phenytoin declined and has been surpassed by levetiracetam as the second most widely used antiepileptic in the neonatal intensive care unit. These changes in antiepileptic drug usage patterns have occurred in the absence of novel efficacy data in neonates.

Neuropeptide Y attenuates anxiety- and depression-like effects of cholecystokinin-4 in mice.

We investigated the involvement of neuropeptide Y (NPY) in the modulation of cholecystokinin-4 (CCK-4)-evoked anxiety and depression. Adult male mice were injected with vehicle, CCK-4, NPY, NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY or antagonist BIBP3226, via intracerebroventricular route, and subjected to social interaction or forced swim test (FST) for the evaluation of anxiety- and depression-like phenotypes, respectively. To assess the interactions between the two systems, if any, NPYergic agents were administered prior to CCK-4 and the animals were subjected to these behavioral tests. Treatment with CCK-4 or BIBP3226 dose-dependently reduced social interaction time, while NPY or [Leu(31), Pro(34)]-NPY produced opposite effect. CCK-4 treatment increased immobility time in FST. This effect was reversed by NPY and [Leu(31), Pro(34)]-NPY, although BIBP3226 per se did not alter the immobility time. In a combination study, the anxiogenic or depressive effects of CCK-4 were attenuated by NPY or [Leu(31), Pro(34)]-NPY and potentiated by BIBP3226. The brains of CCK-4 treated rats were processed for NPY immunohistochemistry. Following CCK-4 treatment, the nucleus accumbens shell (AcbSh), ventral part of lateral division of the bed nucleus of stria terminalis (BSTLV), hypothalamic paraventricular nucleus and locus coeruleus showed a reduction in NPY-immunoreactive fibers. Population of NPY-immunopositive cells was also decreased in the AcbSh, BSTLV, prefrontal cortex and hypothalamic arcuate nucleus (ARC). However, NPY-immunoreaction in the fibers of the ARC and cells of the central nucleus of amygdala was unchanged. We conclude that, inhibition of NPY signaling in the brain by CCK-4 might be causal to anxiety- and depression-like behaviors.

Ifosfamide/carboplatin/etoposide (ICE) for recurrent malignant solid tumors of childhood: a Pediatric Oncology Group Phase I/II study.

PURPOSE: The combination of ifosfamide (I) and etoposide (E) was useful in salvaging patients with recurrent/resistant malignant solid tumors of childhood. Carboplatin (C), active against a number of pediatric cancers, was added to I and E to form a three-drug combination called ICE to improve the response rate. PATIENTS AND METHODS: ICE, consisting of I 1.5 g/m2 plus E 100 mg/m2 i.v.q.d. x 3 plus C i.v. on day 3 only, was given in 21-28-day intervals. C was started at 300 mg/m2, and the dose was escalated in 25% increments, with three evaluable patients treated at each level. RESULTS: Ninety-two patients were enrolled in this phase I/II study between July 1990 and April 1993. A total of 331 courses of ICE was administered. Median courses of ICE received were three (range, 1-16). The maximum tolerated dose (MTD) for C when used in combination was found to be 635 mg/m2. The response rate for ICE at the MTD for C was complete response (CR) 26% and CR + partial response (PR) 53%. The response was even better in those who received C at the MTD: 32% achieving a CR and 63% a CR + PR. Pancytopenia was the dose-limiting toxicity. Thirteen episodes of bacterial infection were reported, none fatal. Only one patient developed a Fanconi-like syndrome. CONCLUSION: The MTD of C when used with I and E was found to be 635 mg/m2. The overall CR + PR rate for all patients treated at all C dose levels was 53%. Best responses were seen in non-Hodgkin's lymphoma, neuroblastoma, soft tissue sarcomas, and Wilms' tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of enhancing factor gene and its localization in mouse tissues.

Enhancing factor (EF), a 14 kDa protein, isolated from mouse small intestines, has been reported from this laboratory. Based on our earlier studies EF has been implicated in cell proliferation. Preliminary immunohistochemical studies have shown EF to be localized in the Paneth cells of small intestines. In this paper we report the tissue distribution of EF using conditions optimized for immunohistochemical staining. In addition, the data are supported by northern blot analysis using a nick translated cDNA probe specific for EF. The results indicate that EF gene is actively transcribed mainly in the intestines. The chief source of synthesis of EF appears to be the Paneth cells located at the base of the crypts of Lieberkühn.

Ontogeny of enhancing factor in mouse intestines and skin.

Enhancing Factor (EF) is a 14 kDa protein isolated from mouse small intestines, which enhances the binding of 125I-EGF to A431 cells. This observation as well as our earlier in vitro studies have indicated that EF is a modulator of EGF. In adult mice, localization of EF by immunohistochemistry shows it is present predominantly in the Paneth cells of the small intestines and to a lesser extent in the stomach and colon. This study of the ontogeny of EF shows that the appearance of the protein coincides with the appearance of mature Paneth cells. In new born mouse skin EF is localized in the hair follicles in the first hair cycle from day 2 to day 8. It is however absent in the adult skin. Thus EF is associated with tissues which have a high growth rate.

Management of Ontario children with acute lymphoblastic leukemia by the Dana-Farber Cancer Institute protocols.

There is ample evidence of the value of intensive therapeutic strategies in the management of acute lymphoblastic leukemia (ALL), the commonest form of malignant disease in children. Such a program, devised at the Dana-Farber Cancer Institute (DFCI), Boston, and incorporating high-dose L-asparaginase, was adopted in 1984 by the Children's Hospital at Chedoke-McMaster, Hamilton, Ont., and the Children's Hospital of Western Ontario, London. We describe the experience of these institutions in the treatment of 82 children with ALL, 19 of whom were switched to the DFCI protocols while in continuing first remission with other treatment programs to complete a minimum of 2 years of maintenance therapy; the remaining 63 children, who had recently diagnosed disease, were consecutively enrolled in the DFCI protocols. Each child was assigned at diagnosis to a category of risk for relapse and treated accordingly. There were no remission induction failures or deaths due to induction therapy among the patients with newly diagnosed disease. There were no differences in total or event-free survival rates between the patients in Hamilton and those in London or between those whose protocols were switched and those who were treated from the beginning with the DFCI protocols. With a median follow-up interval of 144 weeks the total survival rate was 95% and the event-free survival rate 88%. For patients at standard risk of relapse the event-free survival rate was 100%, for those at high risk the rate was 82%, and for those at very high risk the rate was 67%. If infants (all of whom suffered a relapse) are excluded from the last category the rate was 89%. These results were achieved with moderate toxic effects (except for two deaths, one of which was due to a therapeutic misadventure) and suggest that the prospect for cure in children with ALL. may now approximate 80%, a degree of success that demands that consideration be given to reducing total therapy, at least for children with standard-risk disease. Further follow-up will determine whether these high event-free survival rates will stabilize and meet the criteria for cure.

Diffuse panbronchiolitis preceding ulcerative colitis.

To expand the clinical spectrum of ulcerative colitis-associated lung disease, we describe a patient with panbronchiolitis associated with ulcerative colitis. In addition to his having a distinctive pulmonary manifestation of this bowel disease, other noteworthy aspects of this patient's course include the onset of pulmonary symptoms several years prior to bowel manifestations and the partial resolution of his pulmonary symptoms following colectomy.

Survival experience following Nd:YAG laser photoresection for primary bronchogenic carcinoma.

We followed the course of 47 consecutive patients with inoperable primary bronchogenic carcinoma who underwent palliative neodymium-yttrium-aluminum-garnet laser photoresection (YPR) between September 1983 and September 1986. Of these 47, 35 (74.5 percent) underwent both radiation therapy (XRT) and YPR. The survival of these 35 patients (median survival, 304 days) was compared with that of 58 who underwent only palliative palliative XRT (median survival, 253 days) from 1981 to 1983, when YPR was not yet available at our institution. There was no significant difference in overall survival (p = 0.17). A significant increase in survival (p = 0.04) was seen in 15 patients who underwent emergency palliative YPR as the initial therapeutic intervention compared with 11 patients who received emergency palliative XRT but would have received YPR had it been available at that time. A trend toward increased survival was also shown in patients who underwent endobronchial radiation therapy in addition to YPR and XRT.