Thalidomide potentiates etoposide-induced apoptosis in murine neuroblastoma through suppression of NF-κB activation.

PURPOSE: Treatment for high-risk neuroblastoma is still challenging. The purpose of the present study was to determine whether thalidomide suppresses etoposide-induced NF-κB activation and thus potentiates apoptosis in murine neuroblastoma. METHODS: A murine neuroblastoma cell line, C1300, and A/J mice were used in this study. We evaluated NF-κB activation after using etoposide with or without thalidomide by quantitative analysis of NF-κB by ELISA and by Western blot analysis of IκB phosphorylation in vitro and in vivo. Induction of apoptosis was evaluated by Western blot analysis of the apoptotic signals caspase-3, 8, and 9 in vitro and by TUNEL assays in vivo. We also evaluated the efficacy of the combination of etoposide and thalidomide by assessing tumor growth and mouse survival in vivo. RESULTS: Etoposide activated NF-κB in C1300 cells. This activation was suppressed by thalidomide and IκB was re-upregulated. The apoptotic signals were enhanced by the combination of thalidomide and etoposide compared with etoposide alone in vitro, which was consistent with TUNEL assays. The combination of etoposide and thalidomide also slowed tumor growth and mouse survival. CONCLUSION: Thalidomide potentiates etoposide-induced apoptosis in murine neuroblastoma by suppressing NF-κB.

Adaptive toothbrush handle: case report of a Thalidomide patient.

Thalidomide poisoning can result in malformation of limbs, specifically upper limbs, compromising manual dexterity. Although Thalidomide has long since been withdrawn for use in pregnant patients, its affects on those exposed pose significant challenges for patients' oral hygiene maintenance. This case reports a novel technique of adaptation to facilitate a Thalidomide poisoned patient in maintenance of oral hygiene via an adaptive toothbrush handle.

History of public health crises in Japan.

In Japan, a number of serious public health crises involving environmental pollution, food-borne diseases, and health hazards due to pharmaceuticals (i.e., "Yakugai") have occurred in the past 50 years. Based on the literature, we summarize the initial investigations and the subsequent measures. Some common points emerge: (1) prolonged cause identification, (2) lack of countermeasures after the cause was identified, and (3) discrimination against victims and they contributed to spreading the damage. We identify lack of corporate ethics and ill-timed disclosure of information as the principal problems in Japan's crisis-management systems. Defects in information gathering were common to all of the cases, thus we suggest necessary corrective measures, such as the establishment of a new reporting system for health hazard-related information.

Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review.

Autism is a complex developmental disorder without an established single etiology but with significant contributions from genetic studies, functional research, and neuropsychiatric and neuroradiologic investigations. The purpose of this paper is to review the findings in five studies involving individuals manifesting the characteristic findings of autism spectrum disorder associated with malformations and dysfunctions known to result from early embryogenic defects. These investigations include two associated with teratogens (thalidomide embryopathy, Mobius sequence with misoprostol) and three (most Mobius sequence cases, CHARGE association, Goldenhar syndrome) with no known etiology. These studies suggest that early embryonic development errors often involving cranial nerve palsies, internal and external ear malformations, ophthalmologic anomalies, and a variety of systemic malformations may be associated with autism spectrum disorders statistically more frequently than expected in a normal population. Although the exact time of developmental insult for each condition cannot be identified, the evidence is that it may occur as early as week 4 to 6+ of embryogenesis.

Thalidomide sensory neurotoxicity: a clinical and neurophysiologic study.

The clinical and neurophysiologic data from 65 patients taking thalidomide were reviewed. Thalidomide sensory neurotoxicity was found to be cumulative dose dependent but occurs only when the total dose is relatively high (>20 g). The risk of developing sensory neuropathy is around 10% below this threshold but increases with higher doses.

On the ability of birth defects monitoring to detect new teratogens.

Recent concerns have been raised about the ability of birth defects monitoring programs to detect increases in the incidence of birth defects following the introduction of new teratogens. The authors illustrate how most monitoring programs in the United States and Europe are limited in their ability to detect new teratogens because of a combination of parameters: the small population size, the low population frequency of exposure to the new teratogen, the weakness of many suspected teratogens (measured in terms of relative risk R), the low background rate, and the etiologic heterogeneity in the measured defects. In a system that monitors 25,000 births per year, it can be shown that although a new teratogen such as thalidomide (R = 175) can lead to a significant increase in the number of observed cases in 1-2 weeks of monitoring, even strong teratogens such as valproic acid and isotretinoin (R = 20-25) require more than 20 years of monitoring to show a significant increase in the number of cases because of low exposure frequency. Also, most mild to moderate teratogens (R = 2-5) can be totally missed. To improve the ability of birth defects monitoring programs to detect new teratogens, it is suggested that surveillance systems ought to examine subsegments of the population with maximal exposure potential, classify birth defects into more etiologically homogeneous groups, and expand the sample size of the monitored population.

Fetal ear malformations induced by maternal ingestion of thalidomide in the bonnet monkey (Macaca radiata).

Gross malformations of the external, middle, and internal ear were seen in fetal monkeys following maternal ingestion of thalidomide. Twenty-five pregnant bonnet monkeys (Macaca radiata) were each given a single oral dose of 10 mg/kg of thalidomide on day 24, 25, 26, 27, 28, or 29, or 30 mg/kg on day 25 or 28 of gestation. (Day of mating is assumed to be day zero of pregnancy). The skeletons, processed and stained with Alizarin Red S, were examined for changes in configuration and/or ossification of the ossicles and temporal bones. Bilateral temporal bones of one case, treated on day 24, were sectioned at 10 microns and examined histologically. Twelve fetuses collected at 70 +/- 3 days of gestation showed no gross ear defects, while 10 out of 13 fetuses collected at 100 +/- 3 days of gestation had structural anomalies similar to those observed in humans. All malformations were severe in fetuses treated on day 24 of gestation and lessened in degree of severity with treatments on days 25-28. Fetuses treated on day 29 were normal. External ear anomalies included microtia with meatal atresia or stenosis, and varying degrees of auricular hypoplasia. Defects of the middle ear were predominantly hypoplasia of malleus, incus, and tympanic ring. Fused ossicles and cochlear and vestibular window abnormalities were only seen in animals treated on day 24. The internal ear exhibited petrosal hypoplasia and delayed ossification of the lateral aspect of the lateral and posterior semicircular canals. Cochlear, vestibular, semicircular, and transcapsular canal defects were confirmed histologically in one case.