Effects of SSRI treatment on GABA and glutamate levels in an associative relearning paradigm.

Impaired cognitive flexibility represents a widespread symptom in psychiatric disorders, including major depressive disorder (MDD), a disease, characterized by an imbalance of neurotransmitter concentrations. While memory formation is mostly associated with glutamate, also gamma-Aminobutyric acid (GABA) and serotonin show attributions in a complex interplay between neurotransmitter systems. Treatment with selective serotonin reuptake inhibitors (SSRIs) does not solely affect the serotonergic system but shows downstream effects on GABA- and glutamatergic neurotransmission, potentially helping to restore cognitive function via neuroplastic effects. Hence, this study aims to elaborate the effects of associative relearning and SSRI treatment on GABAergic and glutamatergic function within and between five brain regions using magnetic resonance spectroscopy imaging (MRSI). In this study, healthy subjects were randomized into four groups which underwent three weeks of an associative relearning paradigm, with or without emotional connotation, under SSRI (10mg escitalopram) or placebo administration. MRSI measurements, using a spiral-encoded, 3D-GABA-edited MEGA-LASER sequence at 3T, were performed on the first and last day of relearning. Mean GABA+/tCr (GABA+ = GABA + macromolecules; tCr = total creatine) and Glx/tCr (Glx = glutamate + glutamine) ratios were quantified in a ROI-based approach for the hippocampus, insula, putamen, pallidum and thalamus, using LCModel. A total of 66 subjects ((37 female, mean age ± SD = 25.4±4.7) for Glx/tCr and 58 subjects (32 female, mean age ± SD = 25.1±4.7) for GABA+/tCr were included in the final analysis. A significant measurement by region and treatment (SSRI vs placebo) interaction on Glx/tCr ratios was found (pcor=0.017), with post hoc tests confirming differential effects on hippocampus and thalamus (pcor=0.046). Moreover, treatment by time comparison, for each ROI independently, showed a reduction of hippocampal Glx/tCr ratios after SSRI treatment (puncor=0.033). No significant treatment effects on GABA+/tCr ratios or effects of relearning condition on any neurotransmitter ratio could be found. Here, we showed a significant SSRI- and relearning-driven interaction effect of hippocampal and thalamic Glx/tCr levels, suggesting differential behavior based on different serotonin transporter and receptor densities. Moreover, an indication for Glx/tCr adaptions in the hippocampus after three weeks of SSRI treatment could be revealed. Our findings are in line with animal studies reporting glutamate adaptions in the hippocampus following chronic SSRI intake. Due to the complex interplay of serotonin and hippocampal function, involving multiple serotonin receptor subtypes on glutamatergic cells and GABAergic interneurons, the interpretation of underlying neurobiological actions remains challenging.

Facial emotion recognition in patients with subjective cognitive decline and mild cognitive impairment.

BACKGROUND: Deficits in facial emotion recognition (FER) have been shown to substantially impair several aspects in everyday life of affected individuals (e.g. social functioning). Presently, we aim at assessing differences in emotion recognition performance in three patient groups suffering from mild forms of cognitive impairment compared to healthy controls. METHODS: Performance on a concise emotion recognition test battery (VERT-K) of 68 patients with subjective cognitive decline (SCD), 44 non-amnestic (non-aMCI), and 25 amnestic patients (aMCI) with mild cognitive impairment (MCI) was compared with an age-equivalent sample of 138 healthy controls all of which were recruited within the framework of the Vienna Conversion to Dementia Study. Additionally, patients and controls underwent individual assessment using a comprehensive neuropsychological test battery examining attention, executive functioning, language, and memory (NTBV), the Beck Depression Inventory (BDI), and a measure of premorbid IQ (WST). RESULTS: Type of diagnosis showed a significant effect on emotion recognition performance, indicating progressively deteriorating results as severity of diagnosis increased. Between-groups effect sizes were substantial, showing non-trivial effects in all comparisons (Cohen's ds from -0.30 to -0.83) except for SCD versus controls. Moreover, emotion recognition performance was higher in women and positively associated with premorbid IQ. CONCLUSIONS: Our findings indicate substantial effects of progressive neurological damage on emotion recognition in patients. Importantly, emotion recognition deficits were observable in non-amnestic patients as well, thus conceivably suggesting associations between decreased recognition performance and global cognitive decline. Premorbid IQ appears to act as protective factor yielding lesser deficits in patients showing higher IQs.

[Screening for cancer]. / Screening für Krebserkrankungen.

A low birth rate in addition to an increasing life expectancy within the context of an aging population characterize the current demographic situation in Germany. Cancer is primarily a disease of old age and the frequency increases with an expanding older population. In 2013, cancer was the second most common cause of death in Germany. With the aid of screening examinations cancer should be detected in the early stages so that suitable therapeutic measures can be initiated. In Germany, screening is currently offered for breast, cervical, colorectal, skin and prostate cancer and is covered by the statutory health insurance. Mammography screening is the only organized screening program in Germany. Eligible women are regularly invited to attend this program, which is not the case for the other types of cancer screening. In accordance with the Cancer Screening and Registry Act (KFRG) of 2013, colorectal and cervical cancer screening will also be implemented as organized screening programs in the future. As is the case in the mammography screening program, those eligible to participate will receive an invitation letter and the new programs are to be continually monitored, documented and evaluated.

Subjective memory complaints, depressive symptoms and cognition in Parkinson's disease patients.

BACKGROUND AND PURPOSE: The goal of this study was to establish the prevalence of subjective memory complaints (SMCs) and depressive symptoms (DS)s and their relation to cognitive functioning in patients with Parkinson's disease (PD). METHODS: In all, 248 controls and 104 PD patients were included in the study. The PD group was subdivided into three PD subtypes with mild cognitive impairment (MCI) according to the Petersen criteria and three PD subtypes with MCI according to the Litvan criteria. RESULTS: Substantial SMCs were reported by 7.7% of controls and 16.3% of the PD patients (P < 0.001). A clinically relevant degree of DSs was evident in 16.6% of controls compared with 40.4% in the PD group (P < 0.001). An analysis of variance revealed a statistically significant difference for SMCs across all Petersen groups as well across all Litvan groups. Two-factor analyses of variance with the factors cognitive status (MCI subtype) and depressive state (depressed versus not depressed) and SMCs as dependent variable revealed significant results. CONCLUSIONS: Approximately 15% of PD patients seeking help in a movement disorder clinic report significant SMCs, with an increasing degree from cognitively healthy PD to PD-MCI. Significant DSs increase SMCs across all cognitive status groups.

[Early detection of cervical cancer in Germany: evidence and implementation]. / Früherkennung des Zervixkarzinoms in Deutschland : Evidenz und Umsetzung.

Cervical cancer is the third most common cancer among women worldwide, with an estimated 529,000 new cases in 2008. The incidence of cervical cancer in Germany is still among the highest in Western Europe. For more than 40 years women in Germany have had legal and free access to a conventional cytologic smear test starting at the age of 20 years. The introduction of the Pap smear subsequently led to a reduction in the incidence and mortality of cervical cancer. However, the low sensitivity of the Pap smear and the evidence regarding human papillomavirus (HPV) in the context of cervical cancer have led to a critical view of the existing early detection of cervical cancer. In the meantime, new screening methods have been developed and different HPV tests, liquid-based cytology, and novel biomarkers have become available. Several randomized studies have investigated HPV testing as a primary cervical cancer screening test, generating a large body of evidence. It is expected that a combination of HPV testing and cytology will improve cervical cancer screening. In the near future, the early detection of cervical cancer in Germany will be restructured on the basis of the German National Cancer Plan as well as the new Cancer Screening and Registers Act (KFRG). The European guidelines for quality assurance in cervical cancer screening will be taken into account, and an organized, population-based, and quality-assured cervical cancer screening program will be implemented.

Subjective memory complaints, depressive symptoms and cognition in patients attending a memory outpatient clinic.

BACKGROUND: The goals of this study were to establish prevalence of subjective memory complaints (SMC) and depressive symptoms (DS) and their relation to cognitive functioning and cognitive status in an outpatient memory clinic cohort. METHODS: Two hundred forty-eight cognitively healthy controls and 581 consecutive patients with cognitive complaints who fulfilled the inclusion criteria were included in the study. RESULTS: A statistically significant difference (p < 0.001) between control group and patient group regarding mean SMC was detected. 7.7% of controls reported a considerable degree of SMC, whereas 35.8% of patients reported considerable SMC. Additionally, a statistically significant difference (p < 0.001) between controls and patient group regarding Beck depression score was detected. 16.6% of controls showed a clinical relevant degree of DS, whereas 48.5% of patients showed DS. An analysis of variance revealed a statistically significant difference across all four groups (control group, SCI group, naMCI group, aMCI group) (p < 0.001). Whereas 8% of controls reported a considerable degree of SMC, 34% of the SCI group, 31% of the naMCI group, and 54% of the aMCI group reported considerable SMC. A two-factor analysis of variance with the factors cognitive status (controls, SCI group, naMCI group, aMCI group) and depressive status (depressed vs. not depressed) and SMC as dependent variable revealed that both factors were significant (p < 0.001), whereas the interaction was not (p = 0.820). CONCLUSIONS: A large proportion of patients seeking help in a memory outpatient clinic report considerable SMC, with an increasing degree from cognitively healthy elderly to aMCI. Depressive status increases SMC consistently across groups with different cognitive status.

Enteric neurons from postnatal Fgf2 knockout mice differ in neurite outgrowth responses.

The enteric nervous system (ENS) consists of several neuronal subclasses with distinct functional properties. The formation and maintenance of these distinct populations during development and aging is dependent on the support of appropriate neurotrophic factors. During early postnatal development, the ENS has to adept continuously to changing alimentation situations, which might also affect neuronal maturation and differentiation. There is evidence that basic-fibroblast-growth-factor (Fgf2) exerts neurotrophic effects in the ENS. In this study primary myenteric plexus cultures from both wild type and Fgf2-knockout mice were investigated under the influence of Fgf2 and glial-cell-line-derived-factor (GDNF). It could be demonstrated, that the influence of neurotrophic support is decreased in the Fgf2-knockouts, while the neuronal cultures of wild type revealed a more pronounced receptiveness for trophic support. These data show that Fgf2 plays a role in the development of the ENS.

HPV infection awareness and self-reported HPV vaccination coverage in female adolescent students in two German cities.

Low levels of human papillomavirus (HPV) awareness and knowledge have been observed in the few studies conducted among school-going adolescents. Such data are lacking in Germany. To assess awareness of HPV and of vaccination status among girls attending grades 8-13 in Bremen and Bremerhaven, two German cities. Participants completed a questionnaire in school including questions on demographic characteristics, about HPV awareness and on vaccination status. We analysed the relationship between awareness of HPV, of vaccination status and vaccine uptake and several variables including age and migrant background using univariate and multivariate logistic regression. Six hundred and thirty-two girls aged 12-20 years completed the questionnaire. 50 % had no awareness of HPV, 12 % reported being vaccinated against HPV and 57 % did not know whether or not they were vaccinated against HPV. In multivariate analyses, ever had sex was associated with awareness of HPV, and ever been to a gynaecologist with awareness of vaccination status. Our results may be an indication that female adolescents in Germany are not adequately informed and counselled about HPV and associated issues.

Effects of MDMA (ecstasy) and two of its metabolites on rat embryos in vitro.

MDMA consumers are young people of childbearing age. Consequently, developmental exposure to this drug is a potential public health concern. Several studies have addressed MDMA neurotoxicity in adults; however, knowledge of the effects of MDMA on developing embryos is limited. After administration, MDMA is metabolized species specifically via two main pathways. One leads to the formation of MDA and the other to the formation of HHMA. Here we evaluated the embryotoxic effects of MDMA, and also those of MDA, a main metabolite of MDMA in rats, and HHMA, a main metabolite in humans. For this purpose, we used the whole embryo culture (WEC). Our results show a concentration-dependent embryotoxic effect of MDMA, MDA and HHMA at a concentration range of 25-50µg/ml. The embryotoxic potential of the parent compound and the two metabolites was comparable in vitro.

[Comparison of ICD coding between mortality statistics and study-intern retrospective re-coding]. / Vergleich von ICD-Kodierungen zwischen Mortalitätsstatistik und studieninterner retrospektiver Nachkodierung.

OBJECTIVES: The aim of this study was to assess agreement between study-intern nosologist death certificate coding and official mortality statistics ICD codes. METHODS: During the follow-up of a historical cohort study conducted in Germany, original death certificates were obtained for deceased cohort members and ICD coded by a study-intern nosologist. Additionally, ICD codes for these study subjects were obtained from a state statistical office responsible for mortality statistics. A weighted inter-observer agreement for these two sources was calculated. RESULTS: In total, 406 ICD codes were available from both sources. 219 (53.9%) of these ICD codes completely agreed on the highest level possible (three- or four-digits). Agreement was found on the three-digit level with a difference at the fourth digit in 42 (10.3%) causes of death. Agreement within diagnosis groups or within chapters of disease was found in 21 (5.2%) and 49 (12.1%) causes of death, respectively. The weighted kappa for the overall inter-observer agreement was 0.67 [95% confidence interval (CI): 0.63-0.71]. Within chapters of disease, agreement was higher for neoplasms (kappa=0.88; 95% CI: 0.83-0.93) than for cardiovascular diseases (kappa=0.69; CI: 0.62-0.76). CONCLUSIONS: Overall level of agreement between the two coding sources was not very good. In Germany, the quality of coding has not improved substantially in the past two decades. The introduction of automatic coding systems, multicausal coding and a mortality register could improve the quality of ICD coding in Germany.

[Right-sided lower abdominal pain after appendectomy?]. / Rechtsseitige Unterbauchschmerzen nach Appendektomie?

A young male patient presented with right lower quadrant abdominal pain 3 years after laparoscopic appendectomy. Clinical and radiological findings were in keeping with acute appendicitis and the diagnosis of stump appendicitis could be confirmed by laparoscopy. This case serves as a reminder of this differential diagnosis and to discuss therapy and prevention of this rare condition.

[Significance of the ICD for the comparability of indicator sets]. / Bedeutung der ICD für Vergleiche von Indikatorensätzen.

Classifications and compliance with definitions and rules are necessary requirements for the construction of indicator sets. Many classification rules are included in the regulatory framework of the ICD and serve as a basis for the indicator sets of the federal states, the Federal Republic of Germany, WHO, the EU and OECD. Based on selected examples of population and mortality data, the authors of the following article analyse the compliance with and/or deviations from coding rules which make the comparability of indicator sets possible, sometimes however more difficult. All of analysed indicator sets adhere to international classification rules. The calculation of the average population data or of infant mortality in the WHO, EU and OECD indicator sets leads to deviating results of the country values. The calculation of the average population deviates from that in Germany or in the EU. Slight numeric deviations finally lead to differences in country data, both with regard to population and infant mortality data. Perinatal mortality on the country level is calculated based on criteria which differ from international indicator sets. Not to be underestimated are non-valid mortality data which are used for international studies. The comparability of indicators is not yet satisfactory; partly, uniform criteria are missing.

Whole embryo culture: an important tool in developmental toxicology today.

The number of candidate chemicals or drugs for registration and authorization is increasing at a fast rate and only few of the existing substances have been tested for teratogenicity to date. Therefore, there is high pressure on authorities to accept models like the whole embryo culture as a screening system for safety evaluation procedures. In view of this background the gradual development of the whole embryo culture into a standardized, scientifically validated tool for developmental toxicology during the last 70 years is summarized. The methodological development of the culture technique is described with the completion, improvement and refinement of the basic culture method as main intention. Special attention was paid to different culture techniques, culture media, gassing schedules, and evaluation strategies. Furthermore the importance of taking "in vitro pharmacokinetics" into consideration when a comparison of in vitro/in vivo results from embryotoxicity testing is intended, is stressed. Additionally, the demonstration of the broad spectrum of useful scientific applications when using this culture system in combination with sophisticated analytical techniques is demonstrated. Finally, an overview on different strategies for the validation of this culture system as an in vitro embryo toxicity test is provided and the officially accepted formal validation process for this application is summarized. The successful validation makes the whole embryo culture a complex in vitro embryotoxicity test with high accuracy and predictability. This robust in vitro system modelling the main phase of rodent organogenesis with a high reproducibility is valuable enough to attract special attention in related scientific fields.

[New research avenues in exploring causes of death in Germany via regional statistical offices as exemplified by a retrospective cohort study]. / Neue Möglichkeit der Recherche von Todesursachen in Deutschland über Statistische Landesämter am Beispiel einer retrospektiven Kohortenstudie.

In retrospective epidemiological cohort studies the mortality rate of a cohort exposed to certain agents under investigation is compared to the mortality rate of the general population. In Germany, vital status of the cohort is followed up via local population registries. Cause of death of deceased members of the cohort is obtained from death certificates by local health authorities. Since storage time for death certificates is short in some Federal German states, causes of death cannot be obtained if death occurred before storage deadline. Recently it became possible to obtain the cause of death from regional statistical offices. Initial co-operation has been established with the statistical offices of North Rhine Westphalia and Berlin. For a cohort study in the chemical industry, the initially low proportion of causes of death obtained from local health authorities (44.8 %) was increased by 30 % to 74.0 % after obtaining ICD coded causes of death from two regional statistical offices. Further advantages of this new data source are reduction in duration of inquiry time and of overall cost.

Effects of ethylene glycol and metabolites on in vitro development of rat embryos during organogenesis.

The aim of this study was to investigate in vitro the relative impact of ethylene glycol, a major industrial chemical, and its individual metabolites on the embryonic development of rats. Rat whole embryos were exposed for 48 h (day 9.5-11.5 of gestation) to ethylene glycol (EG) and its metabolites glycolaldehyde (GAl), glycolic acid (GA), glyoxylic acid (GXA), glyoxale (GXAl) and oxalic acid (OXA) at increasing concentrations. Embryotoxic concentrations were achieved within the following range: ethylene glycol (100-200 mM), glycolic acid (3 mM), glyoxal (6 mM), oxalic acid (1-3 mM), glyoxylic acid (0.3-1 mM), glycolaldehyde (0.1-0.2 mM). The pattern of dysmorphogenesis with all compounds including EG showed a general embryotoxicity with diffusely distributed cell necroses with no specific target tissues selectively affected. The results obtained in this study emphasize the hypothesis that the metabolites and not ethylene glycol itself are responsible for the embryotoxicity of ethylene glycol in rats.

HPV types and cofactors causing cervical cancer in Peru.

We conducted a hospital-based case-control study in Peru of 198 women with histologically confirmed cervical cancer (173 squamous cell carcinomas and 25 cases of adenocarcinoma/adenosquamous carcinoma) and 196 control women. Information on risk factors was obtained by personal interview. Using PCR-based assays on exfoliated cervical cells and biopsy specimens, HPV DNA was detected in 95.3% of women with squamous cell carcinoma and in 92.0% of women with adenocarcinoma/adenosquamous carcinoma compared with 17.7% in control women. The age-adjusted odds ratio was 116.0 (95% Cl = 48.6-276.0) for squamous cell carcinoma and 51.4 (95% Cl = 11.4-232.0) for adenocarcinoma/adenosquamous carcinoma. The commonest types in women with cervical cancer were HPV 16, 18, 31, 52 and 35. The association with the various HPV types was equally strong for the two most common types (HPV 16 and 18) as for the other less common types. In addition to HPV, long-term use of oral contraceptives and smoking were associated with an increased risk. HPV is the main cause of both squamous cell carcinoma and adenocarcinoma in Peruvian women.

TP53 polymorphism, HPV infection, and risk of cervical cancer.

The role of a polymorphism at position 72 of the tumor suppressor gene TP53 in the development of cervical cancer is not well established. The arginine variant of the p53 protein could be more susceptible to degradation by human papillomavirus (HPV) E6 protein than the protein containing proline. Recent studies show controversial results. We investigated a possible association between TP53 polymorphism and cervical cancer in a Peruvian population with high prevalence of HPV infection. HPV status and TP53 polymorphism were determined for 119 cases of invasive cervical cancer and 127 control women from Peru. HPV infection was detected by PCR of cervical cells or tumor biopsies. For determination of TP53 polymorphism, exon 4 of the TP53 gene was amplified by PCR, and DNA was subsequently subjected to restriction enzyme digest. Associations between TP53 polymorphism, HPV infection, and cervical cancer were assessed using logistic regression. Women homozygotes for arginine had a 2.2-fold increased risk (95% confidence interval: 0.6-7.6) for cervical cancer. The odds ratio for women heterozygotes for Arg/Pro was 3.5 (95% confidence interval: 0.9-14). Similarly increased risks were found when restricting analysis to HPV-positive women only. The distribution of TP53 genotypes in this Peruvian population was comparable with that found in Caucasians. Our results cannot rule out an association between the TP53 polymorphism at codon 72, HPV infection, and the etiology of cervical cancer.