Forebrain glutamatergic, but not GABAergic, neurons mediate anxiogenic effects of the glucocorticoid receptor.

Anxiety disorders constitute a major disease and social burden worldwide; however, many questions concerning the underlying molecular mechanisms still remain open. Besides the involvement of the major excitatory (glutamate) and inhibitory (gamma aminobutyric acid (GABA)) neurotransmitter circuits in anxiety disorders, the stress system has been directly implicated in the pathophysiology of these complex mental illnesses. The glucocorticoid receptor (GR) is the major receptor for the stress hormone cortisol (corticosterone in rodents) and is widely expressed in excitatory and inhibitory neurons, as well as in glial cells. However, currently it is unknown which of these cell populations mediate GR actions that eventually regulate fear- and anxiety-related behaviors. In order to address this question, we generated mice lacking the receptor specifically in forebrain glutamatergic or GABAergic neurons by breeding GRflox/flox mice to Nex-Cre or Dlx5/6-Cre mice, respectively. GR deletion specifically in glutamatergic, but not in GABAergic, neurons induced hypothalamic-pituitary-adrenal axis hyperactivity and reduced fear- and anxiety-related behavior. This was paralleled by reduced GR-dependent electrophysiological responses in the basolateral amygdala (BLA). Importantly, viral-mediated GR deletion additionally showed that fear expression, but not anxiety, is regulated by GRs in glutamatergic neurons of the BLA. This suggests that pathological anxiety likely results from altered GR signaling in glutamatergic circuits of several forebrain regions, while modulation of fear-related behavior can largely be ascribed to GR signaling in glutamatergic neurons of the BLA. Collectively, our results reveal a major contribution of GRs in the brain's key excitatory, but not inhibitory, neurotransmitter system in the regulation of fear and anxiety behaviors, which is crucial to our understanding of the molecular mechanisms underlying anxiety disorders.

A new arbutin derivative from the herb of Myrothamnus flabellifolia Welw.

The ethyl acetate soluble fraction of an acetone/water extract of the air-dried aerial parts from Myrothamnus flabellifolia Welw. (Myrothamnaceae) was fractionated by a combination of CC on Sephadex LH-20, MPLC on RP-18 material and LPLC on MCI-gel. This procedure has led to the isolation of 2,3-di-O-galloylarbutin, a new representative of the rare 2,3-diacylated glucopyranosides. The structure was elucidated with the help of 2D-NMR and ESI-MS experiments. Conformation of D-glucose was established by CZE (capillary zone electrophoresis).

Cytology and mRNA expression analysis of fine needle aspirates of thyroid nodules in an East German region with borderline iodine deficiency.

Fine needle aspiration cytology (FNAC) is widely recommended as an important tool for pre-operative identification of malignancy in patients with nodular thyroid disease. To assess the diagnostic contribution of FNAC and the potential of quantitative mRNA analysis in fine needle aspirates in daily practice, we conducted a prospective study in thyroid clinics (n=2) and endocrine practices (n=3), respectively in an East German region with borderline iodine deficiency. Two-hundred and forty-four consecutive FNACs were obtained over a period of 2 years (2002-2004) from euthyroid patients presenting for first evaluation of a solitary thyroid nodule. The mean nodule size for FNAC was 27 mm (range: 10-79 mm). In 55% of patients FNAC was performed after scintiscan detection of a cold or normal functioning thyroid nodule (CTN), while in the remainder FNAC was performed as a primary investigation. FNAC outcomes were: 57.8% benign, 22.1% indeterminate, 2.5% suspicious for malignancy, 17.6% non-diagnostic. Messenger RNA levels for a house keeping gene (beta-actin) and a thyroid specific marker (thyroglobulin, Tg) were studied as basic molecular markers using real-time PCR. Both in the IN VIVO and EX VIVO FNA series, beta-actin and Tg mRNA levels were positively correlated with the thyrocyte cell yield/respective FNA smear. However, subgroup analysis showed that FNAC with histologically confirmed follicular thyroid cancer and/or microfollicular adenoma exhibited significantly lower Tg mRNA expression despite high beta-actin levels. Sufficient mRNA quantities were obtained in >90% of FNA specimen to allow quantitative mRNA analysis of at least 5 further genes. In conclusion, quantitative mRNA analysis is feasible in FNA on a routine basis and provides a perspective for a molecular distinction of thyroid nodules, once specific marker genes have been defined for benign and malignant thyroid tumours respectively.

Evaluation of insulin-like growth factor II, cyclooxygenase-2, ets-1 and thyroid-specific thyroglobulin mRNA expression in benign and malignant thyroid tumours.

OBJECTIVE: We evaluated three markers (insulin-like growth factor II (IGF-II), cyclooxygenase-2 (COX-2) and ets-1) of thyroid growth stimulation and cell transformation together with a thyroid-specific marker (thyroglobulin (Tg)) for their potential to differentiate benign and malignant follicular thyroid neoplasia (FN). DESIGN AND METHODS: mRNA expression levels were determined by real-time PCR in 100 snap-frozen thyroid samples: 36 benign thyroid nodules with different histology and function (19 cold (CTN) and 17 toxic thyroid nodules (TTN)), 36 corresponding normal thyroid tissues of the same patients, eight Graves' disease (GD) thyroids, 10 follicular thyroid carcinomas (FTC) and 10 papillary thyroid carcinomas (PTC). RESULTS: Mean IGF-II and COX-2 levels were not significantly altered between benign and malignant thyroid nodules (IGF-II) or nodular (FTC, TTN, CTN) and normal thyroid tissues (COX-2). In contrast, eight- to tenfold upregulation of ets-1 was observed in PTC and three- to fourfold upregulation of ets-1 was observed in FTC (and GD) compared with benign thyroid nodules and normal thyroid tissues. In addition, thyroglobulin mRNA expression was markedly downregulated (50- to 100-fold) in FTC, PTC and GD samples compared with benign nodular and normal thyroid tissues. Hence an ets-1/Tg ratio >20 distinguished differentiated thyroid cancer from benign nodular or normal thyroid tissue. We then studied ets1- and Tg mRNA expression levels in fine needle aspiration cytology (FNAC) samples. However, in a consecutive series of 40 FNAC samples only equivocal results were obtained on 38 benign and two malignant (FTC) thyroid tumour samples. CONCLUSIONS: Upregulation of ets-1 and downregulation of Tg mRNA expression occur in differentiated thyroid cancer and may facilitate pre-operative identification of thyroid malignancy depending on further evaluation of these potentially promising markers in a larger series of benign and malignant thyroid tumours and their FNAC samples.

The direct economic costs of insomnia in the United States for 1995.

STUDY OBJECTIVES: To assess the direct economic costs of insomnia in the United States in 1995. METHODS: The costs of prescription medications were based on 1995 data compiled by IMS America, Ltd. (Plymouth Meeting, PA). Non-prescription medication expenditures were provided by Information Resources, Inc. (Chicago, IL). The costs of physician visits related to insomnia were estimated from unpublished data of the 1994 National Ambulatory Medical Care Survey conducted by the National Center for Health Statistics and from the America Medical Association Center for Health Policy Research. Several other sources were used for other cost estimates. RESULTS: Total cost for substances used to treat insomnia was $1.97 billion, less than half of which was for prescription medication. Health care services for insomnia totaled $11.96 billion, 91% of which is attributable to nursing home care. The total direct costs in the United States for insomnia in 1995 were estimated to be $13.9 billion. CONCLUSIONS: Increased efforts are needed in several domains to offset the cost of insomnia including clinical research on the consequences of untreated and treated insomnia, development and implementation of curricula to provide knowledge about sleep and sleep disorders for medical students, physicians, and other health professionals, education to increase public awareness of insomnia and sleep disorders, and more support for basic research on neural mechanisms involved in healthy and disordered sleep.

Increased blood cobalt and chromium after total hip replacement.

OBJECTIVE: To determine metal concentrations in blood and urine of patients who received cobalt-chromium-alloy metal on metal hip implants. METHODS: Cobalt and chromium were determined in blood and urine of 76 patients and 26 controls by electrothermal atomic absorption spectroscopy. RESULTS: A significant postoperative elevation of the metal concentrations was observed for total hip replacement patients in contrast to the control group. Twenty-nine patients exceeded the EKA (Expositionäquivalente für Krebserzeugende Arbeitsstoffe) threshold limits for cobalt in blood and for cobalt and chromium in urine. We obtained a significant correlation between cobalt in blood and cobalt in urine (r = 0.79; p < 0.005), chromium in blood and chromium in urine (r = 0.79; p < 0.005), cobalt in blood and chromium in blood (r = 0.69; p = 0.008), and cobalt in urine and chromium in urine (r = 0.95; p = 0.004). CONCLUSION: Our findings suggest that in total hip replacements using metal-metal pairings, metal ions of the alloys are released. This release may lead to significantly elevated metal concentrations in biological fluids. Long-term studies are needed to determine the risk of metal-metal implants as a potential cause of cobalt and chromium toxicity.

[Observation of an increase in "aggressive tumor forms" in increasing incidence of breast carcinoma]. / Beobachtung einer Zunahme "aggressiver Tumorformen" bei ansteigender Häufigkeit des Mammakarzinoms.

Between 1986 and 1990 23% more patients with carcinomas of the breast were treated in the Gynaecological Hospital of the Municipal Hospital (Städt. Krankenanstalten) of Krefeld than during the comparative period between 1976 and 1980. Simultaneously, an increase of carcinomas metastasising the further course of the disease were observed. When analysing the possible reasons it can be noticed that in the first group (1986 to 1990) compared to the second group (1976 to 1980) multifocal and lobular carcinomas were observed more frequently with regard to their statistical significance. The same applies to the metastatic involvement of axillary and infraclavicular lymphodes. It was noticed that in the first group, lymphangiosis and hemangiosis carcinomatosa were seen more frequently than in the second group. The collected data suggest that in case of an increase in carcinomas of the breast, a larger number of tumours with prognostically unfavourable tumour criteria is seen.

Trends in the pharmacologic treatment of insomnia.

Data from the National Disease and Therapeutic Index for the time period 1987-1991 (IMS, America) were examined for recent trends in the pharmacologic treatment of insomnia. All medications given with the desired action of promoting sleep or sedation at night were categorized as benzodiazepine hypnotics, benzodiazepine nonhypnotics, antidepressants, or other. From 1987 to 1991, the following trends were found: (1) overall pharmacologic treatment for insomnia decreased by approximately 10%, (2) use of benzodiazepine hypnotics fell about 30% during this time period, (3) use of antidepressants for insomnia increased by 100%, and (4) the noted changes were somewhat stronger for institutionalized patients than for ambulatory patients. These changes in the pharmacologic treatment of insomnia may be related to widespread media attention and are not supported by scientific data.

[Precancerous conditions and cancer of the endometrium]. / Präneoplasien und Karzinome des Endometriums.

In recent years the incidence in endometrial cancer is rising. The relation of cervical to endometrial cancer has shifted to almost 1:1. The peak of age distribution is between 50 and 60 years of age. Accompanying diseases are obesity, diabetes and hypertension. The endometrial cancer has its precancerous stages. The pertinent estrogenic stimulus is probably significant for the development of precancerous lesions: adenomatous hyperplasia of the endometrium without atypias is known as an optional, that with atypia as an obligatory precancerous lesion. The range of morphologic variation extends from mature endometrial adenocarcinoma with favorable prognosis to immature neoplasias with unfavorable outcome. Besides various other parameters of neoplastic disease the depths of infiltration into the myometrium is known to be significant. The leading sign of endometrial cancer is uterine bleeding. The histological diagnosis is established by the examination of the tissue produced by curettage from the cervical canal and from the uterine cavity. A true early diagnosis--in comparison to the early detection of cervical cancer--does still not exist for endometrial cancer. Exfoliative cytology from the uterine cavity or ultrasonography does still not allow the final and definite diagnosis. Among the therapeutic alternatives abdominal hysterectomy in combination with bilateral adnexectomy plays the most important role. Depending from more specific morphologic criteria of a given case additional pelvic and paraaortic lymphnode-dissection is advised. Surgical therapy in general accounts for a 10 to 20 percent better survival. In patients who cannot surgically be treated because of the local extension of the tumor or due to a general high risk situation the primary therapy is pelvic irradiation both by packing and percutaneously. Disseminated neoplasms, adenocarcinomas in particular, respond well to large dosages of progestins, whereas combinations of cytostatics have failed to show favorable results, perhaps with the exception of those containing adriamycin. All endometrial cancer patients need special posttreatment care, because early recurrences still have a certain chance of survival when recognized and appropriately treated.

Systemic recombinant alpha-2 interferon therapy in relapsing multiple sclerosis.

This report describes the first use of recombinant-DNA-produced human interferon in patients with multiple sclerosis (MS). Ninety-eight patients who were clinically definite for MS with two or more documented exacerbations during the preceding two years were admitted to this placebo-controlled double-blind randomized trial. Although both groups were similar, placebo patients had later MS onset. Patients injected themselves with 2 X 10(6) IU of alpha-2 interferon or placebo three times each week for up to 52 weeks. This dose of interferon was well tolerated in that side effects were minimal. During the trial, the exacerbation rate was sharply reduced in both groups. In the three-month follow-up period after stopping treatment, more patients who were receiving interferon than placebo became worse neurologically. More patients who were receiving interferon than placebo changed from exacerbating MS to progressive MS during the trial. Thus, no clear therapeutic benefit of alpha-2 interferon for MS was detected.

An evaluation of the Guest method for determining erythrocyte sedimentation rate.

The Guest method for determining erythrocyte sedimentation rate was compared with the standard Westergren method. The Guest method consists of disposable plastic tubes with a method of filling with potentially infectious blood to avoid contact between the technician and the sample. Erythrocyte sedimentation rates were determined for samples containing normal and elevated fibrinogen levels. On the basis of the results of this study, the Guest method performed as well as the Westergren method in the population of healthy volunteers with normal fibrinogen levels and in the population of diseased individuals whose serum fibrinogen levels were elevated.