[Alzheimer dementia: course and burden on caregivers : Data over 18 months from German participants of the GERAS study]. / Alzheimer-Demenz: Verlauf und Belastung der Pflegepersonen : 18-Monats-Daten der deutschen Teilnehmer der GERAS-Studie.

The GERAS study is an international observational study with dementia patients of the Alzheimer type (AD) and their caregivers in everyday care. The 18-month data recorded in Germany are presented. Disease progression, medical and psychosocial consequences for both patients and caregivers were recorded using commonly used tests in clinical care: the mini mental status examination (MMSE), Alzheimer's disease assessment scale (ADAS-Cog14), Alzheimer's disease cooperative study activities of daily living inventory (ADCS-ADL), neuropsychiatric inventory (NPI-12), resource utilization in dementia (RUD) and the Zarit burden interview (ZBI). Definition of AD severity level (MMSE): 21-26 mild (miAD), 15-20 moderate (moAD), <15 moderately severe to severe (m/sAD). For the 550 participants (mean age: 75.2 years, SD 7.6 years), miAD (41.5%), moAD (28.4%) and m/sAD (30.2%), the MMSE worsened: in miAD by -2.4 (CI -3.1/-1.7), in moAD by -3.9 (CI -5.0/-2.8) and in m/sAD by -2.5 (CI -3.5/-1.5) at 18 months and the ADAS-Cog14 by 6.2 (miAD-CI 4.6/7.8) and 7.1 points (moAD CI 3.9/10.3). Changes in overall ADCS-ADL amounted to -8.4 (CI -10.1/-6.2) for miAD, -12.9 (CI -15.3/-10.4) for moAD and -10.2 points (CI-12.8/-7.7) for m/sAD. Caregiver burden (NPI-12) rose in miAD by 1.2 points (CI -0.2/2.2), in moAD by 3.4 (CI 1.8/5.1) and in m/sAD by 1.5 points (CI 0.2/3.3). At study start, the total time required by caregivers (RUD) was 3.1 h/day (SD 5.4 h/day) for miAD, 6.6 (SD 7.5) for moAD and 12.7 (SD 9.3) for m/sAD. With 4.4 (SD 9.4) h/day, the increase after 18 months was highest in moAD. Caregiver burden (ZBI) increased most markedly in moAD with 7.2 (CI 4.2/9.7), 90.7% of the patients received antidementia drugs, while 26.6% received psychotropic medication.

Recent Developments in Pharmacotherapy of Alcoholism.

INTRODUCTION: Alcohol use disorders are common, but only a small minority of patients receive adequate treatment. Cognitive-behavioural therapies, motivational enhancement interviewing and brief interventions are established treatments, but few pharmacotherapies are available. AREAS COVERED: This narrative focuses on the neurobiological basis of alcohol use disorders and on emerging drugs that either have recently been approved or look likely to find their way into clinical practice. To date, acamprosate and the opioid antagonist naltrexone have been approved for treatment of alcohol dependence. Recently, the mu-opioid antagonist and partial kappa agonist nalmefene was approved by the European Medicines Agency for reduction of alcohol consumption. Novel clinical approaches include drugs established for other indications such as the GABA-B receptor agonist baclofen, anticonvulsants such as topiramate and gabapentin, the partial nicotine receptor agonist varenicline, and other drugs. Developments in pharmacogenetics are discussed. CONCLUSIONS: The development of pharmaceutical agents to treat alcohol use disorders has lagged behind that of depression and schizophrenic psychosis and is hampered by an incomplete understanding of the neurobiological background. Pharmacogenetics may improve treatment in the future.

[Mirtazapine and hyperemesis gravidarum]. / Mirtazapin bei Hyperemesis gravidarum.

The case of a 29-year-old patient in the 21st gestational week with severe hyperemesis gravidarum which did not respond to conventional antiemetic treatment is reported. Nausea and vomiting improved within 48 h after i.v. administration of 30 mg mirtazapine/day. The pathophysiological and therapeutic implications are discussed.

[Psychotic and non-psychotic denial of pregnancy]. / Psychotische und nicht psychotische Verleugnung der Schwangerschaft.

We report about two patients with denial of pregnancy. While the first patient was free of psychopathological symptoms besides denial of pregnancy until rupture of the membranes, and was able to accomodate the new born, the second patient with psychotic denial of pregnancy could not accomodate the child because of the schizophrenia, so that an adoption was necessary. On the basis of the two cases aetiological, epidemiological, clinical und prognostic implications of psychotic and non-psychotic denial of pregnancy are discussed.

Effects of alcohol consumption on iron metabolism.

BACKGROUND/OBJECTIVES: Patients with alcohol abuse frequently suffer from malnutrition which may result in insufficient iron distribution and iron overload or deficiency. Iron metabolism can be described by a combination of biochemical soluble transferrin receptor, ferritin, C-reactive protein (CRP), and hematological parameters. Here, vitamin B12 and folic acid state were assessed. Results on iron metabolism in patients with alcohol dependence in comparison with social drinkers are presented. MATERIALS/METHODS: Samples from 101 patients with dependent alcohol consumption were included. The control group comprised 115 social drinkers. Inclusion criteria for patients with chronic regular drinking/social drinkers were positive/negative score of the Alcohol Use Disorders Identification Test (AUDIT), and positive/negative score for alcohol abuse/dependence (DSM-IV criteria). RESULTS: Absolute values for ferritin and sTfR are increased in patients with alcohol dependence with current consumption (ALC) compared with social drinkers. No major differences are observed in the ratio of sTfR/log ferritin in comparison with social drinkers. Hemoglobin concentrations correlated between the two groups. Mean corpuscular volume (MCV) was significantly increased in the ALC collective compared to social drinkers. Eighty patients of the alcohol-dependent group had sufficient iron repletion, 11 had iron overload, 6 are suspicious for functional iron deficiency, and 4 are suspicious for reduced iron supply. No vitamin B12/folate deficiencies are observed in alcohol-dependent patients. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: No major abnormalities of iron metabolism are seen in patients with chronic alcohol ingestion besides the well-known macrocytic anemia. Iron overload is relatively frequent and observed in 9% of cases. No differences in vitamin B12 and folate levels were found between individuals with alcohol dependence and social drinkers.

Progressive encephalomyelitis with rigidity and myoclonus preceding otherwise asymptomatic Hodgkin's lymphoma.

Stiff-person syndrome (SPS), a rare neuroimmunological disorder, is characterized by symmetrical rigidity and muscle stiffness, particularly of axial and proximal limb muscles. Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a variant of SPS which includes additional clinical features (e.g. sensory symptoms, brain stem signs and pathological CSF findings). An association of both SPS and PERM with (solid) malignancies has been previously reported. Beyond this, there have been single reports of SPS in the setting of Hodgkin's lymphoma (HL). Here, we present a case of PERM associated with HL, with PERM preceding occurrence of lymphoma by more than seven months. Our observation has obvious implications for the management and, in particular, diagnostic evaluation of patients with PERM.

Imaging nanometre-sized hot spots on smooth au films with high-resolution tip-enhanced luminescence and Raman near-field optical microscopy.

A novel near-field optical microscope based on a parabolic mirror is used for recording high-resolution tip-enhanced photoluminescence (PL) and Raman images with unprecedented sensitivity and contrast. The measurements reveal small islands on the Au surface with dimensions of only a few nanometres with locally enhanced Au PL. These islands appear as nanometre-sized hot spots in tip-enhanced Raman microscopy when benzotriazole molecules adsorbed on the Au surface serve as local sensors for the optical field. The spectra show that localized plasmons are the cause of both the locally enhanced Au PL and enhanced Raman scattering. This finding suggests that the dispersive background in the surface-enhanced Raman spectra can be explained simply by the enhanced Au PL in the gap. Furthermore, our results show that the surface flatness must be better than 1 nm, to provide an optically homogeneous substrate for near-field enhanced PL and Raman spectroscopy.

A novel immobilization method for single protein spFRET studies.

We have developed a new method for immobilization of single proteins by utilizing streptavidin-biotin and protein L-antibody interactions on glass coverslips coated with polyethylene glycol. The method is particularly well suited for single-molecule fluorescence studies. A monomeric, detergent-solubilized bacterial transport protein, GlpT, and the dimeric cytoplasmic region of a mammalian transporter, cdAE1, were immobilized by our method with a high degree of specificity. The fluorescence from single molecules attached to the immobilized proteins was detected with a high signal/noise ratio. Single-pair fluorescence resonance energy transfer (spFRET) measurements on cdAE1 dimers indicate that the structure of the protein is not compromised and provide evidence that the cdAE1 protein can exist in at least two conformations under physiological conditions.

Probing highly confined optical fields in the focal region of a high NA parabolic mirror with subwavelength spatial resolution.

Parabolic mirrors with a high numerical aperture can be conveniently used to produce highly confined optical fields in the focal region. Furthermore, these fields can have interesting polarization behaviour due to the high numerical aperture. In particular, if the mirror is illuminated with a size matched radially polarized or azimuthally polarized doughnut mode, the electric field has in the focal region almost exclusively a longitudinal or a transverse polarization component. Such field distributions are interesting for applications in confocal or near-field optical microscopy. Here we present experimental results where we have probed some of these field distributions by raster scanning a fine gold tip in nanometer steps through the focal region and detecting the scattered light intensity. The measured intensity patterns are compared with corresponding vector-field calculations.

Interaction of MutS and Vsr: some dominant-negative mutS mutations that disable methyladenine-directed mismatch repair are active in very-short-patch repair.

In Escherichia coli and related bacteria, the very-short-patch (VSP) repair pathway uses an endonuclease, Vsr, to correct T-G mismatches that result from the deamination of 5-methylcytosines in DNA to C-G. The products of mutS and mutL, which are required for adenine methylation-directed mismatch repair (MMR), enhance VSP repair. Multicopy plasmids carrying mutS alleles that are dominant negative for MMR were tested for their effects on VSP repair. Some mutS mutations (class I) did not lower VSP repair in a mutS(+) background, and most class I mutations increased VSP repair in mutS cells more than plasmids containing mutS(+). Other plasmid-borne mutS mutations (class II) and mutS(+) decreased VSP repair in the mutS(+) background. Thus, MutS protein lacking functions required for MMR can still participate in VSP repair, and our results are consistent with a model in which MutS binds transiently to the mispair and then translocates away from the mispair to create a specialized structure that enhances the binding of Vsr.

A strategy for tumor-selective chemotherapy by enzymatic liberation of seco-duocarmycin SA-derivatives from nontoxic prodrugs.

Immuno-conjugates obtained by linking enzymes with appropriate monoclonal antibodies, which bind to tumor-associated antigens, can be employed in a tumor-selective antibody directed enzyme prodrug therapy (ADEPT). For this strategy the glycosides 17a--c were prepared as prodrugs of CI-TMI 14 which is a structurally simplified analogue of the highly potent antitumor agent duocarmycin SA 2. Exposure of 17a--c to cultured carcinoma cells of line A549 displayed a very low toxicity; however, after addition of the corresponding enzymes and exposure for 24 h at prodrug concentrations of <0.1 microM the proliferation of the carcinoma cells was inhibited almost completely with ED(50prodrug)/ED(50drug) of up to 270 in the presence and in the absence of the enzyme. The synthesis of 17a--c was achieved by transformation of nitroanisidine 6 into 12 which was glycosidated to give 16a--c. Removal of the silyl groups, introduction of a chlorine atom and solvolysis of the acetal groups led to 17a-c, of which 17a and 17c are promising candidates for further elaboration.

Nematic liquid crystals with a tetrafluoroethylene bridge in the mesogenic core structure.

A dramatic increase of the clearing temperatures of liquid crystals based on bis(cyclohexyl)ethane 1 by 50 to 70 K can be achieved by the perfluorination of the central ethylene link. Conformational analysis indicates that this effect is due to the increased rigidity of the mesogenic core structure and to the suppression of conformers with a bent shape. Materials based on bis(cylohexyl)tetrafluoroethane 2 might play a crucial role as materials for the next generation of active matrix LCDs with reduced power consumption.

A high numerical aperture parabolic mirror as imaging device for confocal microscopy.

We explore the diffraction limited focusing and confocal imaging properties of a high NA parabolic mirror for confocal imaging and spectroscopy of nanoparticles and single molecules. Vector field calculations of the electric fields near focus for both linear and radially polarized illumination are discussed and show that the optical field can be similar tightly focused as in the case of a high NA objective lens. Furthermore they show that a high NA parabolic mirror allows an easy orientation of the polarization of the illuminating light in all spatial directions. The simulation of confocal imaging of single molecules is discussed and yields, that the use of radially polarized excitation light gives an easy access to their orientations.

Confocal microscopy with a high numerical aperture parabolic mirror.

A novel high-resolution stage scanning confocal microscope for fluorescence microscopy and spatially resolved spectroscopy with a high numerical aperture (NA 1) parabolic mirror objective is investigated. A spatial resolution close to the diffraction limit is achieved. As microscopic fluorescent test objects, dye-loaded zeolite microcrystals (diameter approx. 0.4 microm) and single fluorescent molecules were used. Confocal fluorescence images show a spatial resolution of .x = 0.8 . both at room temperature and at 1.8 K. Imaging of a quasi-point light source and focusing by the parabolic mirror were investigated experimentally and theoretically. Deviations between the theoretical results for a perfect parabolic mirror and the experimental results can be attributed to small deviations of the mirror profile from an ideal parabola.

Why do people with anxiety disorders become depressed? A prospective-longitudinal community study.

OBJECTIVE: To examine the temporal relationships of anxiety and depressive disorders, their risk factors and to explore why people with anxiety develop depression. METHOD: Data from an original 4-5-year prospective-longitudinal community study (N= 3,021) of adolescents and young adults with DSM-IV anxiety and depressive disorders identified with the Composite International Diagnostic Interview are used to examine risk factors, as well as course and outcome. RESULTS: (i) Anxiety disorders, except for panic disorder, are almost always primary conditions. (ii) Over the follow-up period, rates of comorbid anxiety-depression increased substantially and resulted in increased impairment and disabilities. (iii) Predictors for first onset of 'pure' depressive and 'pure' anxiety disorders revealed recognizable differences. (iv) Baseline clinical characteristics of anxiety disorders were significantly associated with an increased risk to develop major depression over the follow-up period. CONCLUSION: Findings suggest that most anxiety disorders are primary disorders that substantially increase the risk for secondary depression.

SM-20 is a novel growth factor-responsive gene regulated during skeletal muscle development and differentiation.

SM-20 is a novel, evolutionarily conserved "early response" gene originally cloned from a rat aortic smooth muscle cell (SMC) cDNA library. SM-20 encodes a cytoplasmic protein, which is induced by platelet-derived growth factor and angiotensin II in cultured SMC and is upregulated in intimal SMC of atherosclerotic plaques and injured arteries. We have now examined SM-20 expression during differentiation of cultured skeletal myoblasts and during skeletal myogenesis in vivo. Low levels of SM-20 mRNA and protein were expressed in proliferating mouse C2C12 myoblasts. Differentiation by serum withdrawal was associated with a marked induction of SM-20 mRNA and the expression of high levels of SM-20 antigen in myotubes. The induction was partially inhibited by blocking differentiation with bFGF or TGFbeta. Similar results were obtained with the nonfusing mouse C25 myoblast line, suggesting that SM-20 upregulation is a consequence of biochemical differentiation and is fusion independent. During mouse embryogenesis, SM-20 was first observed at 8.5E in the dermomyotomal cells of the rostral somites. SM-20 expression progressed in a rostral to caudal pattern, with highest levels seen in the muscle primordia and mature muscles. SM-20 thus represents a novel intracellular protein that is regulated during skeletal muscle differentiation and development.

Preparation of cDNA libraries from vascular cells.

The vast majority of past and present efforts in the molecular cloning of expressed sequences involve isolation of clones from cDNA libraries constructed in bacteriophage lambda (1,2). As discussed in Chapter 6 , screening these cDNA libraries using labeled probes remains the most straightforward method to isolate full length cDNAs for which some partial sequence information is known. Although the availability of high quality reagents and kits over the past decade has made the process of library construction increasingly straightforward, generation of high-quality libraries is a task that still requires a fair amount of dedicated effort. Because alternative PCR-based cloning strategies have become increasingly popular alternatives to cDNA library screening, it is useful to consider the advantages and disadvantages of each strategy before embarking on a project to construct a cDNA library (Table 1). In our opinion, it is worthwhile to construct a cDNA library when the transcript of interest is not exceedingly rare (i.e., can readily be detected by Northern blot analysis of total RNA), when multiple cDNAs will need to be cloned over a period of time, and in situations where occasional mutations can not be tolerated (for example, if the cDNA is to be expressed in mammalian cells to examine function). In situations where the transcript of interest is expressed at exceedingly low levels, or when only a single cDNA needs to be cloned, a PCR-based strategy should be considered. When the tissue source is precious (such as a unique clinical specimen), successful construction of a phage library provides a resource that can be amplified and used for multiple cloning projects over many years, but runs the risk of consuming the available RNA if the library construction fails. Table 1 Comparison of Relative Advantages of cDNA Cloning from Lambda Phage Libraries by Plaque Hybridization Compared to Newer PCR- Based Strategies Lambda phage cDNA library PCR-based strategy Freedom from error ++ +/- Able to detect very rare transcripts - ++ Reusable ++ - Useful for rare/precious tissue samples - ++

Domino reactions for library synthesis of small molecules in combinatorial chemistry.

Domino reactions are highly efficient processes that allow the synthesis of complex molecules starting from simple substrates, in a straightforward fashion. The transformations are extremely useful for the design of small-molecule libraries by combinatorial chemistry if multicomponent domino reactions are employed. The reactions can be performed in solution, as well as on solid support, and give access to highly diverse molecules; in addition, their use in automated synthesis is possible.