[Otorhinolaryngological diseases in pregnancy-which drugs are approved?] / HNO-ärztliche Krankheitsbilder in der Schwangerschaft ­ welche Medikamente sind zulässig?

Between 1958 and 1961 approximately 10,000 children with severe deformities of extremities were born, whose mothers had taken the sedative thalidomide. Since then, drugs in pregnancy are applied with legitimate caution by the pharmaceutical industry, physicians and patients, although often accompanied by irrational panic. The pharmaceutical industry takes a legally safe position noting "contraindication" or at least "strict indication" in the consumer information. This transfers responsibility to the prescribing doctor. Even without drug therapy, the spontaneous malformation rate is approx. 3 to 4%. Concerning expectant mothers, a therapeutic nihilism may lead to a dramatic deterioration of the maternal disease, thereby causing high risks in fetal development. The aim of the present work is to present a structured "Guideline for Practice" of medication that can be used during pregnancy for treating medical conditions of the ear, nose and throat.

[Pregnancy Rhinitis - an Update]. / Update Schwangerschaftsrhinitis.

Pregnancy rhinitis (PR), a common condition in pregnant women, is defined as long-lasting nasal congestion due to mucosal swelling and increased secretion without any signs of infection, allergy or tumor, starting at any time during pregnancy and disappearing within 2 weeks of delivery. Smoking and a sensitization to house dust mites are known risk factors. While a definitive pathophysiological concept for PR does not exist, hormonal influences are discussed. We present a stepwise therapeutic strategy for PR and an overview to the latest literature.

Hypotension due to spinal anesthesia influences fetal circulation in primary caesarean sections.

PURPOSE: Hypotension due to spinal anesthesia is a well-known side effect in pregnant women receiving caesarean section. Little is known about its impact on fetal blood circulation. METHODS: 40 women with uncomplicated singleton term pregnancies prepared for caesarean section were prospectively evaluated by Doppler sonography before and immediately after spinal anesthesia. RESULTS: In 90% of the women, blood pressure significantly decreased after spinal anesthesia and 42.5% of the patients suffered from severe hypotension. We found a significant negative correlation between maternal blood pressure change and the resistant index (RI) of the umbilical artery (rs = - 0.376, p = 0.017) and a significant positive correlation between maternal blood pressure and fetal middle cerebral artery. CONCLUSION: Healthy fetuses seem to compensate well in situations with decreased uteroplacental blood flow due to maternal hypotension measured by means of RI changes in the fetal umbilical and middle cerebral artery. This raises the question if growth-restricted and/or preterm fetuses are able to compensate similarly or if general anesthesia would be a method of choice.

[Pregnancy Rhinitis - an Update]. / Update Schwangerschaftsrhinitis.

Pregnancy rhinitis (PR), a common condition in pregnant women, is defined as long-lasting nasal congestion due to mucosal swelling and increased secretion without any signs of infection, allergy or tumor, starting at any time during pregnancy and disappearing within 2 weeks of delivery. Smoking and a sensitization to house dust mites are known risk factors. While a definitive pathophysiological concept for PR does not exist, hormonal influences are discussed. We present a stepwise therapeutic strategy for PR and an overview to the latest literature.

Response Evaluation in Head and Neck Oncology: Definition and Prediction.

Curative treatment of head and neck squamous cell carcinoma includes surgery and/or (chemo)radiation, whereas in the palliative setting, chemotherapy and/or immunotherapy represent(s) the standard approach. With regard to quality control, methods for determining treatment response are sorely needed. For surgical therapy, histopathology is the standard quality control. Established criteria for high-risk patients include resection margins of the primary tumor and extracapsular extension of lymph node metastases. After definitive chemoradiation, treatment response is generally evaluated by tomographic imaging combined with endoscopy including re-biopsy of the tumor region. Single-cycle induction chemotherapy may be used to determine the radiosensitivity of tumors, helping to define surgical and nonsurgical treatment options. Innovative approaches with implications for prognosis include the analysis of immune infiltrates, liquid biopsy, molecular characterization (proteomics, genomics), molecular and functional imaging (PET-CT, PET-MRI), as well as advanced imaging data analysis (radio[geno]mics/texture analysis). Human papilloma virus, as a prognostically relevant parameter, is currently being investigated for de-escalation strategies. With regard to the extended personalization of oncologic therapy, markers predicting treatment response are desirable and seem to be important, also from a socioeconomic perspective.

[Drug therapy of otorhinolaryngological diseases in pregnancy : An update]. / Medikamentöse Therapie HNO­ärztlicher Krankheitsbilder in der Schwangerschaft : Ein Update.

The majority of women take at least one form of medication during pregnancy. Due to often discrepant information about the risk assessment of pharmaceuticals during pregnancy, physicians are often beset by uncertainty with respect to prescription and the fear of medicolegal consequences is high. As prospective clinical trials on drug safety during pregnancy are prohibited due to ethical reasons and animal studies are of limited applicability to humans, drug recommendations often only rely on observational data. An objective examination of the topic not only contributes to effective treatment of illnesses in pregnancy but also prevents impairment of fetal outcome by omission of necessary maternal treatment. The aim of this article is to give a structured presentation of medications that can be used during pregnancy for treating medical conditions of the ear, nose and throat, in the sense of practical guidelines.

[The Wolf-Hirschhorn Syndrome]. / Das Wolf-Hirschhorn Syndrom.

Wolf-Hirschhorn syndrome (WHS) represents a complex developmental disorder characterized by craniofacial dysmorphism, short stature, hypotonia, psychomotor retardation and seizures caused by a terminal deletion of the short arm of chromosome 4. Depending on the extent of the deletion, variable midline defects, abnormalities of the skeletal or urogenital system as well as the central nervous system are observed. Approximately 1/3 of the infants will die in the first year of life even though survival for more than 30 years has been reported. Due to current high quality standards of ultrasonography, WHS can often be diagnosed prenatally. We present a clinical case and provide an overview of the current literature.

Selection of the in vitro culture media influences mRNA expression of Hedgehog genes, Il-6, and important genes regarding reactive oxygen species in single murine preimplantation embryos.

BACKGROUND: The aim of this paper was to determine the influence of different in vitro culture media on mRNA expression of Hedgehog genes, il-6, and important genes regarding reactive oxygen species in single mouse embryos. METHODS: Reverse transcription of single embryos either cultured in vitro from day 0.5 until 3.5 (COOK's Cleavage medium or Vitrolife's G-1 PLUS medium) or in vivo until day 3.5 post coitum. PCR was carried out for ß-actin followed by nested-PCR for shh, ihh, il-6, nox, gpx4, gpx1, and prdx2. RESULTS: The number of murine blastocysts cultured in COOK medium which expressed il-6, gpx4, gpx1, and prdx2 mRNA differed significantly compared to the in vivo group. Except for nox, the mRNA profile of the Vitrolife media group embryos varied significantly from the in vivo ones regarding the number of blastocysts expressing the mRNA of shh, ihh, il-6, gpx4, gpx1 and prdx2. CONCLUSIONS: The present study shows that different in vitro culture media lead to different mRNA expression profiles during early development. Even the newly developed in vitro culture media are not able to mimic the female reproductive tract. The question of long-term consequences for children due to assisted reproduction techniques needs to be addressed in larger studies.

[Breast cancer metastases in the head and neck region]. / Mammakarzinommetastasen im Kopf-Hals-Bereich.

Breast cancer metastases to the head and neck region are very rare and therefore represent a challenge for the clinician in terms of diagnosis and therapy. Recent advances in breast cancer treatment have achieved longer median survival times in affected patients. However, at the same time, the risk of a clinical manifestation of metastasis increases. Here we present the cases of two breast cancer patients who developed filiae into the petrous portion of the temporal bone and one very rare case of metastasis to the larynx. Diagnosis, therapy and distinctive features of metastasis to the head and neck region are discussed.Secondary to long-term endocrine hormone therapy, a reduction in estrogen receptor expression occurred in all three cases. We believe that the loss of steroid receptor expression contributed to tumor resistance to endocrine therapy. Moreover, this receptor loss hindered the pathologist from confirming the diagnosis of metastases at very unusual sites.

The influence of interleukin-1beta on oxytocin signalling in primary cells of human decidua.

OBJECTIVE: Oxytocin (OT) and its corresponding receptor (OTR), synthesized within the pregnant uterus, play a key role in the process of (preterm) labor as part of a paracrine system that regulates symmetrical contractility. In the setting of intrauterine infection, a major cause of preterm labour and birth, decidua serves as a major source of cytokine production. The present study evaluates the time-dependent effect [0-24 h] of the inflammatory cytokine Interleukin-1beta (IL-1beta) treatment on OT signalling and OT stimulated prostaglandin release in primary cultures of human decidua. STUDY DESIGN: Primary cultures of human decidua (n=6) were treated with IL-1beta [5 ng/ml] for 0-24h and or indomethacin [100 microM]--an inhibitor of the prostaglandin synthesis--for 0-24 h or for 24 h. OT peptide expression, OTR binding, Inositol triphosphate production (IP(3)), and arachidonic acid (AA) as well as prostaglandin (PGE(2)) release were measured. RESULTS: IL-1beta transiently reduced cytoplasmic OT peptide at 4-6 h of IL-1beta incubation, while its secretion into the media was increased after 6 h of stimulation. The later was completely blocked by indomethacin. A decrease in OTR mRNA expression and a loss of OTR binding were detected after 8 h and 16 h of IL-1beta treatment, respectively. IL-1beta also decreased IP(3) production and AA release, but significantly enhanced OT mediated PGE(2) production. This effect was completely suppressed by the cyclooxygenase-2 (COX-2) inhibitor NS-398. CONCLUSION: Our data suggest, that IL-1beta indirectly increases OT secretion in primary cultures of human decidua in a time dependent fashion through the production of prostaglandins through COX-2 and that this increase in OT peptide may secondarily down-regulate the OTR and its signalling cascade. These findings might explain the poor effectiveness of oxytocin receptor antagonists as tocolytic agents in the setting of intrauterine infection.

[Mona Lisa syndrome: idiopathic facial paralysis during pregnancy]. / Das Mona-Lisa-Syndrom--die periphere Fazialisparese in der Schwangerschaft.

Mona Lisa has been pregnant shortly before the famous painting of Leonardo da Vinci was created (1503-1506). Recently, it has been speculated that Mona Lisa's famous smile is caused by facial muscle contracture and/or synkinesis after Bell's palsy with incomplete nerval regeneration. During pregnancy the incidence of Bell's palsy is increased up to 3.3 times compared to nonpregnant women. The etiology, associated factors as well as various treatment options aiming at the prevention of associated complications and improving recovery of facial nerve function have intensively been evaluated over the past three decades. However, the preferred mode of therapy management, particularly in pregnant women, remains undecided. Corticosteroids may be beneficial if they are applied after the first trimester.

[Symptoms and therapy for pregnancy rhinitis]. / Klinik und Therapie der Schwangerschafts-Rhinopathie.

Pregnancy rhinitis is a common condition with long-lasting nasal congestion without signs of infection, allergy or tumor, starting at any time during pregnancy and disappearing completely within 2 weeks of delivery. Risk factors are smoking, sensitisation to house dust mites and chronic sinusitis. Hormonal influences are most likely; however, a definitive pathophysiological concept does not exist. Various treatment options are presented and a stepwise therapeutic strategy for pregnancy rhinitis is developed.

[The oxytocin signal cascade during premature labor]. / Die Oxytozin-Signalkaskade im Rahmen vorzeitiger Wehentätigkeit.

Since 30 years the rate of preterm deliveries of 7% remained unchanged. This is due to a lack of understanding of the underlying pathomechanisms of preterm labor. Oxytocin (OT) as well as its receptor (OTR) play a key role in the process of (preterm) labor as part of a paracrine system that regulates myometrial contractility. Binding of OT to its corresponding receptor, OTR, leads to activation of actin-myosin interactions and therewith myometrial contractions as well as production of intrauterine prostaglandins (PGE(2), PGF(2 alpha)) mainly in decidua and myometrium. Oxytocin expression increases significantly at time of parturition, as does the expression of its receptor. Both can be influenced by diverse cellular substrates. The focus of our research group is based on the exploration of the influence of cytokines on OTR signaling.

Preeclamptic women are deficient of interleukin-10 as assessed by cytokine release of trophoblast cells in vitro.

BACKGROUND: It is well known that the acceptance of the fetoplacental unit in human pregnancy requires maternal immune tolerance, which is thought to be regulated locally by the placenta. Therefore an anti-inflammatory cytokine such as IL-10 plays a critical role in different pregnancy disorders including preeclampsia. In the present study, we examined the expression of both proinflammatory (TNF-alpha, IL-1beta, IL-2) and immunoregulatory (IL-6, IL-10) cytokines from normal term and preeclamptic patients in human trophoblast cultures. METHODS: Eleven patients with preeclampsia and 11 patients with a normal pregnancy at term were included in the study. Trophoblast cells isolated from placentas were cultured up to 48 h under standard tissue culture conditions and cytokine release was determined by ELISA. IL-10 synthesis was significantly decreased in the third trimester in preeclamptic patients in comparison with the control group. RESULTS: There were no significant differences in IL-1beta, IL-2, IL-6 or TNF-alpha expression but a significant alteration in IL-10 release in trophoblast cultures in vitro in term placentas from preeclamptic patients compared with normal pregnancy. CONCLUSIONS: Because IL-10 is a potent regulator of anti-inflammatory immune response these abnormalities may be associated with the inadequate placental development in preeclampsia.

Role of prolactin receptor and CD25 in protection of circulating T lymphocytes from apoptosis in patients with breast cancer.

Prolactin (PRL) has been reported to inhibit apoptosis in various cell types and to serve as a cofactor in the upregulation of CD25 on T cells during activation. We investigated a possible relation between prolactin receptor (PRL-R) or IL-2 receptor alpha (IL-2Ralpha, CD25) expression on circulating T lymphocytes and their apoptosis in patients with breast cancer. Peripheral blood mononuclear cells obtained from 25 patients, 25 normal controls (NC) and three cord blood samples were evaluated for Annexin V binding and expression of CD95, CD25, and PRL-R on CD3(+) T cells by multicolour flow cytometry. Plasma levels of PRL, sCD95L, and sIL-2R were determined in patients and controls and related to T-cell apoptosis. The ability of PRL to protect T cells from apoptosis induced by various agents was also studied. Expression of PRL-R on the surface of T cells was comparable in patients with breast cancer and NC, but PRL plasma levels in patients were significantly lower (P<0.05). In patients, 18+/-11% (mean+/-s.d.) of CD3(+) cells bound Annexin V, compared to 9+/-6% in NC (P<0.0004). Percentages of CD3(+)Fas(+) and CD3(+)CD25(+) cells were higher in the peripheral circulation of patients than NC (P<0.0001 and <0.04, respectively). Levels of sFasL were lowest in plasma of the patients with the highest proportions of CD3(+)Fas(+) T cells. Most T cells undergoing apoptosis were CD3(+)CD25(-) in patients, and the proportion of CD3(+)CD25(-) Annexin V(+) cells was significantly increased in patients compared to NC (P<0.006). Ex vivo PRL protected T cells from starvation-induced or anti-CD3Ab-induced but not from Fas/FasL-dependent apoptosis. These results indicate that expression of CD25 but not of PRL-R on the surface of activated T lymphocytes appears to be involved in modulating Fas/Fas - ligand interactions, which are, in part, responsible for apoptosis of T lymphocytes and excessive turnover of immune cells in the circulation of patients with breast cancer.

Effect of IL-1beta and IL-6 on oxytocin secretion in human uterine smooth muscle cells.

PROBLEM: Infection-mediated preterm labor results in the production of inflammatory cytokines, including interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). Oxytocin (OT) plays a key role in the process of labor. This study investigates the effect of IL-1beta and IL-6 on intra-and extracellular OT in human smooth muscle cells and evaluates IL-1beta induced changes in IL-6 production. METHOD OF STUDY: Primary cultures of human myometrium, obtained from term pregnant women (n = 7) were incubated with either IL-1beta or IL-6 for 0-24 hr. Intra- and extracellular OT peptide concentrations were measured by radioimmunoassay and IL-6 mRNA and protein were evaluated by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Both, IL-1beta and IL-6 led to an increase in OT secretion, which was accompanied by a reduction of the intracellular OT peptide pool. IL-1beta significantly induced IL-6 mRNA expression and protein secretion, which did not further enhance IL-1beta induced OT secretion. CONCLUSIONS: The induction of OT secretion by proinflammatory cytokines in human myometrium in vitro, supports the concept of a thus regulated infection-triggered preterm labor process in vivo.

Interleukin-6 up-regulates the oxytocin receptor in cultured uterine smooth muscle cells.

PROBLEM: Intra-uterine infection results in the production of inflammatory cytokines, including interleukin-6 (IL-6). Increased oxytocin-receptor (OTR) concentrations are associated with the onset of preterm labor. We hypothesize that infection up-regulates OTR expression through IL-6-induced transcription factors. METHOD OF STUDY: Primary cultures of human myometrium were treated for various time periods or with different concentrations of IL-6 and OTR mRNA as well as OTR binding were measured by means of reverse transcription polymerase chain reaction and 125I-ornithine-vasotocin-binding assay. To study underlying mechanisms of OTR changes with IL-6 treated, cells were also incubated with genistein or H7 (tyrosine and serine phosphorylation inhibitors), respectively. RESULTS: OTR mRNA increased 2.5-fold after 4 hr of IL-6 treatment and OTR binding 1.4-fold after 8 hr of cytokine stimulation. The IL-6-induced increase in binding was blocked by genistein and H7. CONCLUSIONS: IL-6 up-regulates uterine OTR mRNA expression and binding capacity in cultured human myocytes most likely through tyrosine and serine phosphorylation pathways involving the nuclear factor STAT-3.

Competition of peptide-MHC class I tetrameric complexes with anti-CD3 provides evidence for specificity of peptide binding to the TCR complex.

BACKGROUND: Major histocompatibility complex (MHC)-peptide tetrameric complexes (tetramers) are valuable tools for detecting and characterizing peptide-specific T cells. Because the frequency of these cells is generally very low, it may be difficult to discriminate between nonspecific and specific tetramer binding. METHODS: A four-color flow cytometric assay that simultaneously measures tetramer, CD3, CD8, and CD14 was used to investigate the sensitivity and specificity of MHC class I tetramer staining. This was accomplished by using the influenza virus matrix protein peptide, GILGFVFTL (FLU), as a model recall antigen and the human immunodeficiency virus (HIV) reverse transcriptase peptide, ILKEPVHGV (HIV), as a model novel antigen. Peripheral blood mononuclear cells (PBMC) from 31 HLA-A2.1(+) and 10 HLA-A2.1(-) healthy individuals were stained with the tetramers. RESULTS: The lower limit of detection was established at approximately 1/8,000. In HLA-A2(+) PMBC, frequencies of tetramer-positive CD8(+) T cells were log normally distributed and were high for FLU (1/910) but low for HIV (1/6,067). A novel competition assay, in which tetramer binding was shown to diminish subsequent staining with anti-CD3 antibody, was used to confirm the specificity of tetramer binding to the T-cell receptor (TCR) complex. The competition assay was validated by evaluating several anti-CD3 antibodies and showing that in PBMC from HLA-A2(-) subjects, spurious tetramer-positive events (1/20,000) failed to compete with CD3 binding. For the "recall" FLU tetramer, the degree of competition was proportional to the frequency, suggesting a selection of high avidity cells. Although CD3 competition was also highly correlated with the intensity of tetramer staining, competition allowed the identification of false positive cases with relatively high tetramer staining intensity. CONCLUSION: The data indicate that competition of CD3 binding allows confirmation of the specificity of tetramer binding to the TCR, extending the usefulness of tetramers in the frequency analysis of peptide-specific T lymphocytes.

Candida albicans chorioamnionitis associated with preterm labor and sudden intrauterine demise of one twin. A case report.

BACKGROUND: Although cervicovaginal Candida infections occur in 20-25% of pregnancies, the incidence of ascending infection in these cases is only 0.8%, and such infection rarely causes chorioamnionitis. CASE: Sudden intrauterine fetal demise (IUFD) of twin A occurred in a diabetic primigravida presenting with a twin pregnancy and preterm labor at 33 weeks of gestation. Placental pathology and autopsy of the stillborn twin revealed extensive chorioamnionitis and fetal sepsis in the presence of Candida albicans. Twin B was unaffected. CONCLUSION: In this case, C albicans chorioamnionitis seemed to be associated with sudden IUFD.