[Investigation of a fetal heart-rate pattern that shows a reduced oscillation amplitude]. / Silentes CTG--Hypoxie oder Intoxikation?

A fetal heart-rate pattern that has a reduced oscillation amplitude may indicate a physiological fetal dormant period but could also be an indication of fetal hypoxemia. In some rare cases such a fetal heart rate-pattern can be an indicator of cerebral or cardial fetal malformation or of an intoxication caused by sedative drugs. Our patient is a 32-year-old Para III in the phase of 29 weeks and 3 days gestation. Upon admission to the clinic, the fetal heart-rate pattern showed a reduced oscillation amplitude, and there were no signs of fetal movement. The ultrasound examination gave us no reason to suspect fetal malformation, and the results of the Doppler ultrasonography were also normal. However, although the patient had denied taking any medication at all, the results of an toxicological blood test confirmed our suspicion of benzodiazepine intoxication. Throughout the night the fetal heart-rate pattern was continuously measured, and in the early hours of the morning, after breaking down of the oxazepam medication, a normalization of the fetal heart-rate pattern was observed. This case report definitively demonstrates that Doppler ultrasonography is a valuable method for assessing any uncertainty regarding a fetal heart-rate pattern.

Laboratory simulation of charge exchange-produced X-ray emission from comets.

In laboratory experiments using the engineering spare microcalorimeter detector from the ASTRO-E satellite mission, we recorded the x-ray emission of highly charged ions of carbon, nitrogen, and oxygen, which simulates charge exchange reactions between heavy ions in the solar wind and neutral gases in cometary comae. The spectra are complex and do not readily match predictions. We developed a charge exchange emission model that successfully reproduces the soft x-ray spectrum of comet Linear C/1999 S4, observed with the Chandra X-ray Observatory.

Problems of the Glasgow Coma Scale with early intubated patients.

The Glasgow Coma Scale is probably the most common grading scale in neurotraumatology all over the world. Its validity concerning severity and prognosis of the injury has been established in the Anglo-American literature. Data derived from the German rescue system, however is different from the Anglo-American in some respects. The analysis of a well-defined group of German trauma patients with moderate and severe head injuries (n = 299) shows that low Glasgow Coma Scores (GCS 3-6) established during the first two posttraumatic days must not correspond directly to the outcome after one year. Especially for the best Glasgow Coma Score during the day after the injury, GCS 4 had a poorer collective long-term prognosis than GCS 3. Therefore, German data from head injury studies based on the Glasgow Coma Scoring are difficult to compare to those cited in the Anglo-American literature. Any statistical analysis of a so called "ranking scale" which does not satisfy its own claims under special conditions is difficult.

An epidermal growth factor receptor promoter construct selectively expresses in the thymus and spleen of transgenic mice.

To determine the range of tissues in which the human epidermal growth factor (EGF) receptor promoter is active, we created 12 independently derived lines of mice expressing a transgene consisting of human EGF receptor promoter and enhancer sequences fused to the bacterial chloramphenicol acetyltransferase (CAT) gene. Analysis for the presence of CAT activity in these transgenic mice revealed that the human EGF receptor promoter construct was consistently active in the thymus and spleen. Thymocytes separated from thymic stromal cells of EGF receptor-CAT mice demonstrated no CAT activity suggesting that expression in the thymus is confined to the thymic stroma, which consists mainly of epithelial cells. Thus, it should be possible to use the EGF receptor promoter construct described in this study to direct expression of a variety of foreign genes to the nonlymphocytic cells of the thymus and spleen so that the effect of these genes on the maturation and proliferation of thymocytes may be addressed.

Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands.

Expression of the int-3 locus is activated in mouse mammary tumors as a consequence of insertional mutagenesis by the mouse mammary tumor virus (MMTV). Integration of the MMTV provirus into the int-3 locus promotes the transcription and translation of flanking cellular int-3 sequences sharing significant homology with the intracellular domain of the neurogenic Notch gene of Drosophila, and with the yeast cell cycle regulatory genes cdc10 and SWI6. To determine the in vivo consequences of activated int-3 expression, transgenic mice were generated harboring a genomic tumor DNA fragment consisting of the MMTV LTR and the flanking cellular int-3 sequences. All six int-3 founder transgenic mice and the progeny of one established line exhibited similar dramatic phenotypic abnormalities in tissues in which the transgene was expressed. Focal and often multiple poorly differentiated mammary and salivary adenocarcinomas appeared in the majority of transgenic mice between 2 and 7 months of age. Significantly, mammary glands were arrested in development and were lactation deficient in all female int-3 mice. The salivary glands, glands of the nasal mucosa and maxillary sinus, the extraorbital lacrimal glands, and the Harderian glands of juvenile and adult transgenic mice all contained proliferating immature ductule cells and were incompletely differentiated. In addition, all male int-3 transgenic mice were sterile, apparently the result of severe hyperplasia of the epididymis. These findings demonstrate in vivo that expression of the activated Notch-related int-3 gene causes deregulation of normal developmental controls and hyperproliferation of glandular epithelia.

Transplantation of bone marrow cells from transgenic mice expressing the human MDR1 gene results in long-term protection against the myelosuppressive effect of chemotherapy in mice.

Many human cancers that are initially responsive to chemotherapy eventually fail to respond to treatment. For some drugs, dose escalation that may be required for a cure cannot be achieved because sensitive tissues such as bone marrow (BM) limit cytotoxic therapy. Approaches to prevent or circumvent BM toxicity are therefore a high priority of research on dose escalation protocols. In this study, we have transplanted BM cells from transgenic mice that constitutively express physiologic amounts of a functional human multidrug resistance (MDR1) cDNA to lethally irradiated C57BL/6 x SJL F1 mice (n = 36). From 6 weeks to 10 months after the transplant, all animals contained MDR1 DNA in spleen and BM specimens as indicated by Southern blot analysis, and expressed MDR1 messenger RNA in BM samples as detected by slot blot analysis. In addition, these animals were resistant to the myelosuppressive effect of doxorubicin, daunomycin, taxol, vinblastine, vincristine, etoposide, and actinomycin D, whereas control animals that were reconstituted with normal BM were drug sensitive. Finally, the chemoprotection afforded by the MDR1 gene could readily be reversed by adding chemosensitizers such as cyclosporin A and R-verapamil to chemotherapy. Hence, it appears that BM cells expressing the human MDR1 gene maintain this function after transplantation to host animals for a minimum of 10 months, and confer multidrug resistance to these BM recipients. This selective advantage conferred by expression of the MDR1 cDNA suggests a strategy for the use of MDR1 gene therapy in cancer chemotherapy and for the introduction of otherwise nonselectable genes into BM.

Inactivation of a sperm motility gene by insertion of an epidermal growth factor receptor transgene whose product is overexpressed and compartmentalized during spermatogenesis.

Transgenic mice were generated with a human epidermal growth factor (EGF) receptor cDNA driven by the chicken beta-actin gene promoter. One line (AE24) that exhibited a unique expression pattern in which dramatically elevated levels of EGF receptor RNA were found only in the testis was established, suggesting that the beta-actin promoter was being influenced by an adjacent testis-specific enhancer. EGF receptor RNA was detected in primary spermatocytes, whereas the synthesis of receptor protein was restricted to elongate spermatids, indicating that transgene expression was under translational control. At spermiation, the EGF receptor was sequestered in residual bodies and excluded from mature sperm by a compartmentalization mechanism. About half of AE24 homozygous males were sterile because of sperm paralysis, whereas heterozygous males and females of either genotype were completely fertile. Electron microscopic analysis of sperm flagella from sterile AE24 homozygotes revealed an aberrant axonemal structure in which outer doublet microtubules were missing from the middle piece, resembling changes observed in the sperm of some infertile humans. Flagellar axonemal disassembly was observed in the vas deferens and epididymis but not in the testis, suggesting that outer doublets were assembled in a grossly normal manner but possessed a latent instability. These results demonstrate that in the AE24 mouse line the EGF receptor transgene was integrated into and inactivated an endogenous autosomal gene, causing sperm flagellar axonemal disruption and male sterility.

TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas.

To define the role of TGF alpha in normal tissue function and in pathogenesis, transgenic mice have been generated bearing a fusion gene consisting of the mouse metallothionein 1 promoter and a human TGF alpha cDNA. In these mice, human TGF alpha RNA and protein are abundant in many tissues and TGF alpha is detectable in blood and urine. The effects of TGF alpha overproduction in transgenic mice are pleiotropic and tissue specific. The liver frequently contains multifocal, well-differentiated hepatocellular carcinomas that express enhanced levels of human TGF alpha RNA. The mammary gland exhibits impeded morphogenetic penetration of epithelial duct cells into the stromal fat pad. The pancreas shows progressive interstitial fibrosis and a florid acinoductular metaplasia, during which acinar cells appear to degranulate, dedifferentiate, and assume characteristics of intercalated or centroacinar duct cells. TGF alpha therefore plays an important role in cellular proliferation, organogenesis, and neoplastic transformation.

Incidence of Ménière's disease.

The incidence of Ménière's disease in Sweden for the year 1973 has been calculated as one case in a population of 2,163. This gives an overall incidence of 46/100,000. Extrapolating the Swedish incidence data to the population of the United States, there should have been 97,000 cases of Ménière's disease treated as inpatients or outpatients during the year 1973. The incidence in the United States of Ménière's disease, cochlear type, is considered to be even higher. In addition, the Swedish statistic for some other disorders, including otosclerosis, are reported. For otosclerosis, the yearly incidence in Sweden is 12/100,000 or one case in a population of 8,414. This could be extrapolated to 25,000 patients with clinical otosclerosis in the United States for the year 1973. By comparison, Ménière's disease, by stringent diagnostic criteria, is approximately four times as common as clinical otosclerosis. It is also more common than all laryngeal carcinomas, all salivary gland tumors, both benign and malignant, as well as acute epiglottitis and acute nephritis.