[Unemployment and Addiction: The SUNRISE Project]. / Arbeitslosigkeit und Sucht ­ Das SUNRISE-Projekt.

OBJECTIVES: In the SUNRISE-project, the unemployment benefit office refers long-term unemployed clients (25-49 years old) to medical and psychological specialists of an addiction clinic, if substance-related problems are suspected as an obstacle for job placement. The present study aims at characterizing these clients with respect to educational qualifications, vocational training, diagnosed addictive disorders, and other mental disorders. Of special interest is the temporal sequence of unemployment and addictive disorders. METHOD: Officials referred clients to medical examination if substance abuse was suspected. The examination was based on Europ-ASI, diagnosis of mental disorders based on SCID-I and SCID-II. RESULTS: In 87 out of the first 100 examined persons, an addictive disorder was diagnosed, most frequently alcohol-related disorders, and often multiple addictive disorders. These 87 clients were on average 40 years old (SD 8.5), and mostly male (73 out of 87 clients). About one-third had very low school qualification, and 55.2% had not completed vocational training. An additional psychiatric diagnosis was made in 51.7%. Addictive disorders had commenced during adolescence or early adulthood in most cases. The longest duration of continuous employment was 3 years (median). In only a few cases (7.4%), the current period of unemployment had started before regular substance use. CONCLUSION: Many long-term unemployed clients examined here showed deficits in schooling and vocational training, early onset of regular substance use, and additional mental disorders. In most cases, the addictive disorder did not emerge as a consequence of unemployment, but had existed before. Programs combining the efforts of unemployment benefit offices and the healthcare system are needed for these clients to help them gain access to the regular job market.

[Psychiatric interventions for the unemployed]. / Psychiatrische Interventionen für Arbeitslose.

Unemployment is related to a higher risk for psychological distress and mental disorders, which cause individual suffering and socioeconomic costs for society in general. This selective review surveys the relationship between unemployment and psychological well-being and mental disorders. The most important programs for the improvement of the mental health of the unemployed are summarized: 1. Interventions for the unemployed with the aim of improving coping strategies reduce the risk of developing depressive symptoms. 2. The SUPPORT liaison outpatient unit collaborates closely with the unemployment agency and offers a low-threshold screening for mental disorders for unemployed subjects as well as counseling for those in need of treatment. 3. A group training based on cognitive behavioral therapy improves the psychological well-being of unemployed participants. 4. Supported employment is an effective means of placing severely mentally ill patients in a work-place accompanied by an extensive professional support.

Influence of the 393T>C polymorphism of the GNAS1 gene on the intensity of opiate withdrawal.

There are high interindividual differences regarding the intensity of withdrawal symptoms. in opiate addicts. This study was carried out in order to test whether the intensity of withdrawal is influenced by the 393T>C polymorphism of the GNASI gene. Only patients addicted exclusively to opiates were included. Thirty-three out of 39 patients undergoing inpatient detoxification treatment achieved a drug-free state. During the most intense period of withdrawal (stop of methadone and following days) TT homozygotes (n=4) had a significantly higher pulse rate (primary outcome criterion) than C-allele carriers (n=29). This study and a previous study about GNB3 825C> T underline the possible role of G-protein polymorphisms in the interindividual variability of opiate withdrawal.

[Anticonvulsants in the treatment of alcoholism]. / Antikonvulsiva in der Behandlung der Alkoholabhängigkeit.

Because of promising data from animal studies the clinical trials on anticonvulsants for the treatment of alcohol disorder have been accumulating in the last 40 years. A comprehensive research of various data bases (MEDLINE, EMBASE, Cochrane) was performed. Here, we present the trials found together with an estimation of their evidence according to the guidelines of the "Arzneimittelkommission der deutschen Arzteschaft". We examined the clinical studies conducted for the treatment of alcohol withdrawal syndrome, for relapse prevention/consumption reduction as well as for the treatment of co-morbide psychiatric disorders. The study analysis has not resulted in any safe alternative to benzodiazepines, clomethiazole or carbamazepine in the treatment of the stronger alcohol withdrawal syndrome. The material is also insufficient with regard to relapse prevention/consumption reduction or to the treatment of co-morbide psychiatric disorders. The safest proof of effect is currently topiramate (consumption reduction) and valproate (alcohol dependence with bipolar disorder). However, first positive results must be confirmed in well controlled studies with a much longer duration. Baclofen und several anticonvulsants such as valproate, oxcarbazepine and gabapentin demonstrate a potential to aid in the treatment of alcohol disorder. Currently, there exists any published controlled study for levetiracetam, which would be well suited in the treatment of alcoholism due to its favorable safety profile and low pharmacological interaction potential.

Intensity of opiate withdrawal in relation to the 825C>T polymorphism of the G-protein beta 3 subunit gene.

OBJECTIVES: The intensity of withdrawal in opiate dependence shows a high inter-individual variability. The 825C>T polymorphism (rs5443) of the G-protein beta 3 (GNB3) subunit gene has a strong influence on clinical signs of sympathetic activity in cardiac research. This study was carried out in order to test the hypothesis that carriers of the T allele have an increased sympathetic activity in opiate withdrawal. METHODS: Thirty-nine monovalent opiate addicted patients consecutively admitted to a detoxification ward were investigated. The main parameter for sympathetic activity was the pulse rate in the first 3 days after the regular end of gradual methadone reduction. RESULTS: Thirty-three out of 39 patients achieved a drug-free state: 22 carried a T allele (TT, CT), 11 belonged to the CC genotype group. The pulse rate was significantly (p<0.05) raised in the T allele group compared to the CC genotype group on the first 2 days after stopping methadone administration. In addition, about a third of the T allele carriers needed clonidine treatment on the respective days, but only one patient among the 11 CC homozygotes. There was no significant difference between groups in systolic and diastolic blood pressures as well as in subjective withdrawal ratings. CONCLUSION: A group difference regarding pulse rate could be observed in a small sample and despite a higher degree of concomitant clonidine medication in T allele carriers. The failure to detect group differences in blood pressure and self-rated withdrawal symptoms may be attributed to the more complex regulation of blood pressure and the known weak correlation between objective and subjective withdrawal symptoms.

[Unhealthy alcohol use in the elderly--current screening and treatment strategies]. / Alkoholbezogene Störungen im Alter--Aktueller Stand zu Diagnostik und Therapie.

Due to demographic trends and an aging cohort, which has higher rates of substance abuse than any previous generation, an increase in numbers of elderly alcohol abusers is predicted. The number of older alcohol dependent adults in Germany has been estimated to 400 000, the prevalence of risky use up to 2 million. Despite this reported high prevalence, patients over age 60 are seldom seen attending in- or outpatient treatment programs for alcohol dependence. In addition, little is known about this growing population of older adults with alcohol-related disease, e. g. regarding course of alcohol addiction, consumption patterns, somatic and mental comorbid disorders. This article shows the state of research in this area and reviews clinically-relevant concepts related to identifying, assessing and treating older adults with alcohol-related disability. Emphasis will be placed on the psychotherapy-methods of brief interventions and cognitive-behavioral therapy and on the pharmacological approaches for treating alcohol dependence with disulfiram, acamprosate and naltrexone.

Structures of two molluscan hemocyanin genes: significance for gene evolution.

We present here the description of genes coding for molluscan hemocyanins. Two distantly related mollusks, Haliotis tuberculata and Octopus dofleini, were studied. The typical architecture of a molluscan hemocyanin subunit, which is a string of seven or eight globular functional units (FUs, designated a to h, about 50 kDa each), is reflected by the gene organization: a series of eight structurally related coding regions in Haliotis, corresponding to FU-a to FU-h, with seven highly variable linker introns of 174 to 3,198 bp length (all in phase 1). In Octopus seven coding regions (FU-a to FU-g) are found, separated by phase 1 introns varying in length from 100 bp to 910 bp. Both genes exhibit typical signal (export) sequences, and in both cases these are interrupted by an additional intron. Each gene also contains an intron between signal peptide and FU-a and in the 3' untranslated region. Of special relevance for evolutionary considerations are introns interrupting those regions that encode a discrete functional unit. We found that five of the eight FUs in Haliotis each are encoded by a single exon, whereas FU-f, FU-g, and FU-a are encoded by two, three and four exons, respectively. Similarly, in Octopus four of the FUs each correspond to an uninterrupted exon, whereas FU-b, FU-e, and FU-f each contain a single intron. Although the positioning of the introns between FUs is highly conserved in the two mollusks, the introns within FUs show no relationship either in location nor phase. It is proposed that the introns between FUs were generated as the eight-unit polypeptide evolved from a monomeric precursor, and that the internal introns have been added later. A hypothesis for evolution of the ring-like quaternary structure of molluscan hemocyanins is presented.

Marine tumor vaccine carriers: structure of the molluscan hemocyanins KLH and htH.

Keyhole limpet hemocyanin (KLH) is a well-established immune stimulant and hapten carrier, and Haliotis tuberculata hemocyanin (HtH) is a related product. Biologically, KLH and HtH are blue copper proteins which serve as oxygen carriers in the blood of the keyhole limpet Megathura crenulata and the abalone H. tuberculata, respectively, two marine gastropods. Both hemocyanins occur as two distinct isoforms, termed KLH1 KLH2, HtH1, and HtH2. Each of these molecules is based on a very large polypeptide chain, the subunit (molecular mass ca 400 kDa), which is folded into a series of eight globular functional units (molecular mass ca 50 kDa each). Twenty copies of this subunit form a cylindrical quaternary structure (molecular mass ca 8 MDa). This article reviews the recent data on the biosynthesis, quaternary structure, subunit architecture, amino acid sequence, gene structure, and recombinant production of KLH and HtH.

The sequence of a gastropod hemocyanin (HtH1 from Haliotis tuberculata).

The eight functional units (FUs), a-h, of the hemocyanin isoform HtH1 from Haliotis tuberculata (Prosobranchia, Archaeogastropoda) have been sequenced via cDNA, which provides the first complete primary structure of a gastropod hemocyanin subunit. With 3404 amino acids (392 kDa) it is the largest polypeptide sequence ever obtained for a respiratory protein. The cDNA comprises 10,758 base pairs and includes the coding regions for a short signal peptide, the eight different functional units, a 3'-untranslated region of 478 base pairs, and a poly(A) tail. The predicted protein contains 13 potential sites for N-linked carbohydrates (one for HtH1-a, none for HtH1-c, and two each for the other six functional units). Multiple sequence alignments show that the fragment HtH1-abcdefg is structurally equivalent to the seven-FU subunit from Octopus hemocyanin, which is fundamental to our understanding of the quaternary structures of both hemocyanins. Using the fossil record of the gastropod-cephalopod split to calibrate a molecular clock, the origin of the molluscan hemocyanin from a single-FU protein was calculated as 753 +/- 68 million years ago. This fits recent paleontological evidence for the existence of rather large mollusc-like species in the late Precambrian.

Subunit organization of the abalone Haliotis tuberculata hemocyanin type 2 (HtH2), and the cDNA sequence encoding its functional units d, e, f, g and h.

We have developed a HPLC procedure to isolate the two different hemocyanin types (HtH1 and HtH2) of the European abalone Haliotis tuberculata. On the basis of limited proteolytic cleavage, two-dimensional immunoelectrophoresis, PAGE, N-terminal protein sequencing and cDNA sequencing, we have identified eight different 40-60-kDa functional units (FUs) in HtH2, termed HtH2-a to HtH2-h, and determined their linear arrangement within the elongated 400-kDa subunit. From a Haliotis cDNA library, we have isolated and sequenced a cDNA clone which encodes the five C-terminal FUs d, e, f, g and h of HtH2. As shown by multiple sequence alignments, defg of HtH2 correspond structurally to defg from Octopus dofleini hemocyanin. HtH2-e is the first FU of a gastropod hemocyanin to be sequenced. The new Haliotis hemocyanin sequences are compared to their counterparts in Octopus, Helix pomatia and HtH1 (from the latter, the sequences of FU-f, FU-g and FU-h have recently been determined) and discussed in relation to the recent 2.3 A X-ray structure of FU-g from Octopus hemocyanin and the 15 A three-dimensional reconstruction of the Megathura crenulata hemocyanin didecamer from electron micrographs. This data allows, for the first time, an insight into the evolution of the two functionally different hemocyanin isoforms found in marine gastropods. It appears that they evolved several hundred million years ago within the Prosobranchia, after separation of the latter from the branch leading to the Pulmonata. Moreover, as a structural explanation for the inefficiency of the type 1 hemocyanin to form multidecamers in vivo, the additional N-glycosylation sites in HtH1 compared to HtH2 are discussed.

Tracing keratin evolution: catalog, expression patterns and primary structure of shark (Scyliorhinus stellaris) keratins.

We have studied individual keratins of an elasmobranch, the shark Scyliorhinus stellaris (the lesser-spotted dogfish). From various shark tissues, notably skin and stomach, cytoskeletal proteins were isolated and then separated by two-dimensional polyacrylamide gel electrophoresis. Using complementary keratin blot-binding assays and immunoblotting, among these proteins we identified a variety of type I and type II keratins. According to their tissue-specific expression, we distinguished Is and IIs keratins from IE and IIE keratins ("S" and "E" from "simple epithelial" and "epidermal", respectively). Guinea pig antibodies which in immunoblots specifically labeled the entire range of identified shark keratins, and a monoclonal antibody specific for IE keratins were used for immunofluorescence microscopy of a broad range of shark tissues. These experiments demonstrated that in this shark, keratin expression is largely restricted to epithelia and - in contrast to the situation in teleost fishes - is lacking in mesenchymally derived cells and tissues. Peptide mass mapping of the major electrophoretically separated shark keratin spots revealed that the identified Is, IIs and IIE polypeptides are modifications of a single genuine keratin, respectively, whereas there are two different IE keratins. It, therefore, appears that in this shark most (if not all) of the keratin cytoskeleton is constituted by only five different gene products (each present in various modifications): a heterologous pair of "S" and three different "E" keratins. We sequenced three of them (Is, IIs and IIE) via cDNA cloning. Sequence alignments showed that the shark Is keratin (termed SstK18) is an ortholog of human K18, whereas the IIs keratin (termed SstK8) corresponds to human K8. In contrast, the shark IIE keratin (termed SstK1; it is the first known primary structure of a fish IIE keratin) apparently has no direct equivalent in human. On the basis of a phylogenetic tree constructed from 37 aligned keratin sequences, these results are discussed with respect to the evolution of keratin diversity in vertebrates.

Identification of a novel mRNA-associated protein in oocytes of Pleurodeles waltl and Xenopus laevis.

Amphibian oocytes accumulate a large pool of mRNA molecules for future embryonic development. Due to their association with specific proteins the stored maternal RNAs are translationally repressed. The identification of these RNA-binding proteins and the characterization of their functional domains may contribute to the understanding of the translational repression mechanisms and the subsequent activation processes during early embryogenesis. Here we present the complete Pleurodeles cDNA sequence of a cytoplasmic protein which is present in oocytes, eggs, and very early cleavage stage embryos but undetectable in postcleavage embryo and adult tissues. The predicted molecular mass of the protein is 55 kDa and the apparent molecular mass as determined by SDS-PAGE, 68 kDa. The deduced amino acid sequence reveals proline- and serine-rich domains in the aminoterminal part as well as two RGG boxes which represent characteristic motifs of several RNA-binding proteins. No distinct homologies to the consensus RNA recognition motif were found. The 55-kDa protein was recovered in cytoplasmic ribonucleoprotein (RNP) particles containing poly(A)+ RNA. It was therefore termed RAP55 for mRNA-associated protein of 55 kDa. However, a direct interaction of RAP55 with mRNA could not be demonstrated by UV-crosslinking experiments, indicating that it is bound to mRNP complexes via protein-protein interactions. RAP55 is evolutionarily conserved since antibodies raised against a recombinant Pleurodeles RAP55 fragment recognize the protein from Pleurodeles and Xenopus. The expression pattern and intracellular distribution of RAP55 suggest that it is part of those mRNP particles which are translationally repressed during oogenesis and become activated upon progesterone-induced oocyte maturation.

Duction ranges in normal probands and patients with Graves' ophthalmopathy, determined using the Goldmann perimeter.

BACKGROUND: We examined whether the Goldmann perimeter is suitable for measuring the range of monocular ductions, especially in the follow-up of patients with Graves' ophthalmopathy. METHODS: Using the Goldmann perimeter, the range of monocular ductions was determined in one eye of 100 normal probands (aged between 21 and 70 years) and of 36 patients (aged between 29 and 66 years) with a motility disturbance due to Graves' ophthalmopathy. Subjects were asked to follow target I/4e which was slowly moved by the examiner in the vertical and the horizontal meridian. The end-point of the pursuit movement observed by the examiner was taken as the duction limit. Subjects were measured twice, in half of the cases by the same, in the other half by two different examiners. RESULTS: In the 100 normal probands, the mean ranges of ductions were: elevation 37.6 degrees, depression 58.0 degrees, adduction 51.6 degrees, abduction 48.7 degrees. There was a slight age-related decline. The intraobserver and interobserver mean coefficients of variation ranged between 1.5% and 3.8%. In the 36 patients with Graves' ophthalmopathy the coefficients were between 0.7% and 2.3%. In both the normal probands and the Graves' ophthalmopathy patients, the coefficients were smaller for the total vertical and horizontal duction ranges than for adduction, abduction, elevation and depression alone. CONCLUSIONS: Measurements of the range of monocular ductions with the Goldmann perimeter are highly reproducible and appear to be suitable for follow-up studies in patients with Graves' ophthalmopathy.

Localization of a high molecular weight form of DNA topoisomerase I in amphibian oocytes.

Xenopus oocytes express a 165 kDa variant of DNA topoisomerase I (topo I) as opposed to the canonical 110 kDa form of somatic cells (Richard and Bogenhagen, Dev. Biol. 146: 4-11, 1991). By immunofluorescence microscopy using variant-specific antibodies we show that this high molecular weight form is associated with lampbrush chromosome loops and the inner regions of the amplified nucleoli. Inhibition of topo I-activity by either Camptothecin-treatment or microinjection of neutralizing antibodies resulted in loop retraction and the condensation of chromosomes and amplified nucleoli. These data indicate that the oocyte-specific 165 kDa form of topo I is involved in transcriptional processes mediated by RNA polymerase I and II and is therefore functionally equivalent to the somatic cell 110 kDa counterpart.

A monoclonal antibody against DNA topoisomerase II labels the axial granules of Pleurodeles lampbrush chromosomes.

By immunizing Balb/c mice with oocyte nuclei of Pleurodeles waltl we obtained a monoclonal antibody, mAb 4A6, that labels distinct globular domains of the lampbrush chromosomal axes of Pleurodeles. These domains are found at corresponding sites of homologous chromosomes, often at telomeric and putative centromeric regions, and appear to be devoid of DNA. Because of these characteristic features it is most likely that the mAb 4A6-positive domains correspond to the central part of the "axial granules" of urodelan lampbrush chromosomes. In immunoblotting analyses mAb 4A6 reacts with a nuclear antigen of approximately Mr 180000 and a structurally nonrelated cytoplasmic protein of Mr 98000, which was not characterized any further. Comparative immunofluorescence and immunoblotting studies with mAb 4A6 and an antiserum against DNA topoisomerase II (topo II) as well as immunodepletion experiments demonstrated that the nuclear 4A6 antigen is topo II. Our results indicate that topo II is not a constituent of a continuous, loop-anchoring scaffold in lampbrush chromosomes of Pleurodeles but, rather, is restricted to the axial granules.

[Motility and binocular function after radial episcleral buckle]. / Motilität und Binokularfunktion nach radiärer episkleraler Plombe.

BACKGROUND: The incidence of motility disturbances induced by episkleral buckle operations for retinal detachment has been reported to range between 7 and 77%. We anticipated a relation between the buckle size and the incidence and extent of motility disturbances. PATIENTS AND METHODS: We examined 45 patients 2 to 4 years after successful retinal detachment surgery with a radial buckle. The buckle diameter was 3-11 mm. Patients were examined for diplopia and heterophoria in the primary position and in 20 degrees secondary and tertiary gaze deviations. Stereopsis was determined using the TNO plates. Refractive error and visual acuity were also measured. RESULTS: Heterophoria measurements in the various directions of gaze revealed a hypermotility in 22/45 cases. A hypomotility was encountered only in one of the 45 cases. In 40 of the 45 cases the field of binocular single vision had a radius of at least 20 degrees. 39 of the 45 patients had stereopsis (after macular detachment 17/22, without macular detachment 22/23). 7/32 patients with a buckle of > or = 5 mm reported on diplopia, but none of the 13 patients with a buckle of < or = 4 mm. Heterotropia in the primary position was found in one of the 45 cases. He had three buckles, a 10.5 mm buckle under the superior rectus muscle of one eye and a 4 and 7.5 mm buckle under the inferior oblique and rectus muscles of the other eye. The resulting vertical deviation was successfully treated with prisms. Motility disturbances in the upper field of gaze were found in 2 of 45 cases with buckles of 5 and 7.5 mm. Diplopia was not permanent in these cases. DISCUSSION: Hypermotility towards the position of the buckle may be explained by a deviation of the adjacent rectus muscles, after sharp preparation and shrinkage of the intermuscular septum. CONCLUSION: Since motility disturbances were encountered only with buckles of > or = 5 mm, small buckles (< or = 4 mm) should be applied whenever possible.

Original papers Binocular vision in children with unilateral traumatic aphakia.

Twelve consecutive children under the age of ten years who were referred to the authors' hospital between 1990 and 1993 with a combined perforating injury of the cornea and the lens were treated as follows: lensectomy, corneal suture (in 11 of them) and, shortly after surgery, correction of the refractive error with a contact lens and a bifocal glass. The other eye was occluded only if there was a manifest strabismus and if binocular single vision appeared unattainable. In nine children visual acuity was ≥ 20/ 40, eight children had orthotropia with binocular single vision. Compared with other reports in the literature the percentage of children with orthotropia and binocular single vision was high. The authors suggest that two factors explain the favourable results: (I) early correction of the refractive error for far and near vision and (2) restriction of occlusion therapy to cases with a manifest strabismus.

[Peripheral retinal correspondence after retinal detachment]. / Periphere Netzhautkorrespondenz nach Amotio retinae.

BACKGROUND: Occasionally, patients who underwent surgery for complicated retinal detachment report spatial distortions. This may be due to a translocation of photoreceptors when they become reattached to the pigment epithelium. We wanted to find out if, and to what extent, similar translocations occur after a simple buckling operation. METHODS: Binocular retinal correspondence was used as an indicator of photoreceptor translocation. Correspondence was measured in the peripheral visual field at eccentricities of 5, 10 and 20 degrees, using a mirror haploscope. We examined two normal observers, one patient having had surgery for complicated retinal detachment including retinotomy, and 23 patients who had simple radial buckling operations. RESULTS: The patient who had received complicated detachment surgery including retinotomy revealed a tremendous shift in correspondence. Of the 23 patients who had simple radial buckle operations, only 10 were able to sustain central fixation while being tested in the periphery. Of these 10 patients, 2 showed distortions of peripheral retinal correspondence in the area of previous retinal detachment. However, only one of them remembered some spatial distortion after surgery. CONCLUSION: As a rule, photoreceptors become correctly reattached after radial buckle operations for retinal detachment. Rarely, vertical or horizontal translocations of about 1 to 2 degrees occur, but this does not usually lead to metamorphopsia.