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The broadening of the classification systems for manic-depressive illness towards a spectrum of bipolar disorders implicates a more differentiated use of pharmacotherapies. However, many questions still remain open. This implies that all consensus guidelines and recommendations have to be considered as preliminary. On the other hand, research in the last decade has developed many new treatment alternatives, both for mood stabilizers and antidepressants as well as antipsychotics. These recommendations, which have been developed in the process of two consensus meetings, try to consider the broadening of the concept of bipolar disorder by differentiating between subgroups according to acute symptomatology and characteristics of the long-term course, e.g., rapid cycling. In particular, the emerging role and new indications of mood stabilizing antiepileptic drugs, atypical antipsychotics, and new antidepressants will be discussed.

Aims: Data concerning the relative risk of amputations in diabetic patients compared with the general population are scarce. Therefore, we carried out a case control study to quantify the relationship between diabetes and amputations., Methods: In 20 hospitals in seven German cities and counties we obtained complete lists of non-traumatic lower limb amputations performed in 1990 and 1991. CONTROLS were selected from patients of the same surgical departments operated on in the same years. We drew a random sample of patients with procedures not likely to be associated with diabetes. Diabetic status was determined from patients' records in both cases and controls. We calculated age- and sex-specific and, using logistic regression, adjusted odds ratios (OR) and attributable risks., Results: N = 2400, mean age 61.7 (SD 16.3) years., Cases: n = 729; 486 (66.7%) of them had diabetes., Controls: n = 1671; 127 (7.6%) of them had diabetes. Adjusted OR: 18.2 (confidence interval (CI) 14.2-23.6). Adjusted attributable risk among exposed (ARE): 0.95 (CI 0.93-0.96). Adjusted population attributable risk (PAR): 0.62 (CI 0.57-0.66)., Conclusions: This study has demonstrated a strong association between the risk of amputation and diabetes. The odds ratios and attributable risks for diabetic individuals are higher in the younger than in the older age groups. Population attributable risks are great. We conclude that the reduction of amputations in the general population will be achieved by improving foot care in people with diabetes.

Due to progress in transplantation medicine and especially thanks to the possibility of transplantation of a liver lobe from a living donor - usually one parent - even very small children with end-stage liver diseases are transplanted nowadays. But there is little research on how parents cope with this specific situation facing the death of their baby without transplantation during the period of transition to parenthood, how family-relationships and bonding develop after transplantation, how the infants develop mentally and emotionally and what specific psychosocial help these families would need to prevent future problems. Stimulated by clinical experiences with families with liver-transplanted infants, a pilot study with families before liver-transplantation was conducted. The aim of the study was to determine methods of infant research suitable for this clinical population. Based on case-vignettes of the interviews and the clinical work with these families, questions as to transition to parenthood, bonding and liver-transplantation by donation of a lobe of one parent's liver are discussed.

The authors report the correction of an ulnar club-hand in a 16 year-old boy who complained of recurrent wrist pain after a fracture of both bones of his left forearm treated by internal fixation at the age of nine years. Correction was achieved by progressive ulnar lengthening, using Ilizarov's method, without radius osteotomy or bone grafting. Union was achieved 2 months post-operatively. Functional outcome and cosmetic appearance were satisfying.

During neutrophil activation, the properties of the cell are rapidly altered by increases in the surface expression of functionally important receptors and adherence molecules. At the same time, endocytic and phagocytic activities increase. These alterations require precise regulation of membrane and protein movement, which is achieved, at least in part, by bidirectional movement of small transport vesicles. GTP-binding proteins, including Rabs and ADP-ribosylation factors (ARFs), play critical roles in regulating vesicle trafficking in other types of cells. The ability to immunoisolate the "secretory" vesicle subpopulation in which complement receptor type 1 (CR1) is stored allowed us to determine which types of low-molecular-weight GTP-binding proteins interact with these vesicles and under what conditions. CR1-containing vesicles from resting human neutrophils constitutively copurify with Rabs 3a, 4, and 5a, and reversibly bind an ARF, likely ARF1. ARF binding is dependent on free Mg(2+) and is enhanced by GTPgammaS. Mg(2+) at 0.4 microM is necessary for half-maximal binding of ARFs to CR1 storage vesicles. Artificial phospholipid vesicles and primary and secondary granules from human neutrophils do not bind ARFs themselves and do not compete for recruitment of ARFs to CR1 vesicles, suggesting that specific membrane environments and/or proteins on these vesicles stabilize the ARF-GTP-Mg(2+) complex. Free Ca(2+) at 300 nM does not inhibit ARF binding to CR1 storage vesicles, but 10 mM Ca(2+) does reduce such binding. These findings suggest that ARF-GTP specifically and reversibly interacts with CR1 storage vesicles in human polymorphonuclear leukocytes and may play a role in regulating their transport.

A new magnetic separation idea utilizing several ideas from microfabrication and nanomagnetics is presented. The basic idea comes from our earlier work using asymmetry in obstacles and Brownian motion to effect separation of objetcs [10] by moving them in streams whose angle to the hydrodynamic average velocity is a function of the diffusion coefficient of the object. The device we propose here is not technically a Brownian ratchet device but uses the idea of force which acts at angle to the hydrodynamic flow. In our case, the force is generated by a magnetic field gradient which comes from an array of magnetized wires which lie at an angle 0 to a hydrodynamic field flow. The sum of the hydrodynamic force and the magnetic force create a new vector which as in the case of the Brownian ratchet moves the cell out of the main stream direction.

Depressive disorders are of high clinical and economic relevance in outpatient and inpatient care. For the treatment of depression effective measures are available. However, these methods often are not used because depressive disorders are underdetected or underestimated in their severity. To improve diagnostic and therapeutic processes in the last years different national and international organizations developed guidelines for diagnosis and treatment of depressive disorders (e. g. AHCPR, APA, German Association of Psychiatrists). These guidelines differ substantially in their goals, content, size, specifically in their methodological quality. The Association of the Scientific Medical Societies in Germany (AWMF) and the German Agency for Quality in Medicine (AQUMED) developed a checklist to evaluate the methodological quality of guidelines. This manual was used to describe and analyze the most relevant and actual six guidelines for diagnosis and treatment of depressive disorders. Recommendations for further improvement and implementation of these guidelines are given.

The p53 protein is subject to Mdm2-mediated degradation by the ubiquitin-proteasome pathway. This degradation requires interaction between p53 and Mdm2 and the subsequent ubiquitination and nuclear export of p53. Exposure of cells to DNA damage results in the stabilization of the p53 protein in the nucleus. However, the underlying mechanism of this effect is poorly defined. Here we demonstrate a key role for c-Abl in the nuclear accumulation of endogenous p53 in cells exposed to DNA damage. This effect of c-Abl is achieved by preventing the ubiquitination and nuclear export of p53 by Mdm2, or by human papillomavirus E6. c-Abl null cells fail to accumulate p53 efficiently following DNA damage. Reconstitution of these cells with physiological levels of c-Abl is sufficient to promote the normal response of p53 to DNA damage via nuclear retention. Our results help to explain how p53 is accumulated in the nucleus in response to DNA damage.

Malocclusion of the canines, which in dogs is frequent and often has a congenital pattern, remains a challenge to treat. Steeply positioned lower jaw canines are corrected by means of a specifically designed orthodontic intervention. The case at hand was characterized by a combination of a slight skeletal distal bite and compensatory distal tilt of the entire premaxilla (retrusion, caudal tilt) with a mesial tilt of the canines in the upper jaw (rostral and anterior tilt). An individual solution was found which resulted in a functional adjustment of both upper and lower jaws. A model cast device which included both appropriately tilted areas and screws to ensure distal adjustment solved the problem.

Since the pathogenesis of allergic diseases is associated with elevated levels of immunoglobulin E (IgE), we developed a high throughput reporter gene assay in a human B-cell line to screen for low molecular weight IgE inhibitory compounds. Monitoring the IL-4 driven IgE-germline promoter activity (IgE-GLP), we discovered 4-(1-phenylethylamino)qinazolines as potent inhibitors of IgE-germline gene expression. Testing of the individual enantiomers (1, 2) revealed that only the S(+) enantiomer 1 was active. A cell viability assay done in the same cell line in parallel discriminated the dose-dependent inhibition from a general antiproliferative effect. The observed correlation of the inhibitory potencies found in the reporter gene assay with those measured by IgE-ELISA in primary human splenocytes provided evidence that the blockade of IgE synthesis is the direct consequence of IgE-germline gene inhibition, thereby validating the reporter gene assay. Parallel synthesis in solution rapidly provided a series of analogues of compound 1 with modifications in the phenethylamine side chain and the quinazoline core for SAR studies. Increasing the lipophilicity of the arylalkylamine moiety yielded S(+)-4-(1-(2-naphthyl)ethylamino)quinazoline (6) as the most potent inhibitor (IC(50) of 14 nM) while the R(-) enantiomer was again found to be inactive. Within the set of S enantiomers, quantum mechanical calculations revealed that the IgE inhibitory activity can be quantitatively described by the charge at N-1 of the heterocyclic core and to a lesser extent by the molar refractivity. These results demonstrate the importance of electron-deficient fused 4-aminopyrimidines and lipophilic side chains for biological activity. The strong preference for the S configuration of the phenethylamine side chain is remarkable insofar as biological activity for fused 4-(1-phenylethylamino)pyrimidines has been published for the R enantiomers only (EGFR tyrosine kinase inhibition).

Monopolar electrosurgery is querried because of the availability of new preparation-techniques in laparoscopic cholecystectomy. The advantage of simple handling, cheap application and high efficiency has to be set against the danger of tissue lesions e. g. the damage of the bile duct as demonstrated by four own cases. Especially the bipolar preparation-method and ultrasonic dissection are safer, but expensive and not as fast and effective as monopolar technique. Laser-heated instruments exist but are not in wide clinical use. The danger of tissue-lesions can be reduced by accurate preparation-principles and caution in dissection of the Calot-triangle.

Certain microbial substances, e.g., LPS, can activate neutrophils or prime them to enhance their response to other activating agents, e.g., fMLP. We investigated the role of the Mycobacterium tuberculosis (MTB) 19-kDa lipoprotein in activation of human neutrophils. MTB 19-kDa lipoprotein initiated phenotypic changes characteristic of neutrophil activation, including down-regulation of CD62 ligand (L-selectin) and up-regulation of CD35 (CR1) and CD11b/CD18 (CR3, Mac-1). In addition, exposure of neutrophils to MTB 19-kDa lipoprotein enhanced the subsequent oxidative burst in response to fMLP as assessed by oxidation of dihydrorhodamine 123 (determined by flow cytometry). LPS also produced these effects with similar kinetics, but an oligodeoxynucleotide containing a CpG motif failed to induce any priming or activation response. Although the effects of LPS required the presence of serum, neutrophil activation by MTB 19-kDa lipoprotein occurred independently of serum factors, suggesting the involvement of different receptors and signaling mechanisms for LPS and MTB 19-kDa lipoprotein. Thus, MTB 19-kDa lipoprotein serves as a pathogen-associated molecular pattern that promotes neutrophil priming and activation.

Disturbances of sleep are typical for most depressed patients and belong to the core symptoms of the disorder. Polysomnographic sleep research has demonstrated that besides disturbances of sleep continuity, in depression sleep is characterized by a reduction of slow wave sleep and a disinhibition of REM sleep, with a shortening of REM latency, a prolongation of the first REM period and increased REM density. These findings have stimulated many sleep studies in depressive patients and patients with other psychiatric disorders. In the meantime, several theoretical models, originating from basic research, have been developed to explain sleep abnormalities of depression, like the two-process-model of sleep and sleep regulation, the GRF/CRF imbalance model and the reciprocal interaction model of non-REM and REM sleep regulation. Interestingly, most of the effective antidepressant agents suppress REM sleep. Furthermore, manipulations of the sleep-wake cycle, like sleep deprivation or a phase advance of the sleep period, alleviate depressive symptoms. These data indicate a strong bi-directional relationship between sleep, sleep alterations and depression.

Forty-eight-hour rapid cycling is a rare subclass of affective disorders and entails a regular periodic change of moods. The following case study describes the symptoms, therapy, and outcome of a patient suffering from daily switching between mania and depression along with neurobiological findings correlated to the affective cycles. We found alternating reduction and prolongation of sleep duration during manic and depressive days as well as differences in the amount of REM sleep. Cortisol secretion was regularly increased during depressive days. Regarding thyroid-stimulating hormone (TSH) secretion, the circadian rhythm was absent on depressive days. However, the glucose metabolic rate as measured by positron emission tomography (PET) did not differ on manic and depressive days. The patient reached almost complete remission under treatment with lithium.

Rebound effects after withdrawal from hypnotics are believed to trigger their chronic use and to enhance the risk of tolerance and dependence. It was the purpose of this study to investigate the acute polysomnographic withdrawal effects after a 4 week treatment with standard doses of the non-benzodiazepine hypnotics zopiclone and zolpidem compared with triazolam and placebo. Healthy male subjects between 22 and 35 years of age participated in a parallel study design. They received either zopiclone 7.5 mg (n=11), zolpidem 10 mg (n=11), triazolam 0.25 mg (n=10) or placebo (n=7) over 4 weeks in randomized and double-blind order. Sleep EEG was registered during 2 nights before treatment under placebo, on days 1, 27 and 28 of treatment and on days 29,30,41 and 42 under placebo. Total sleep time and sleep efficiency were lower in the 1st night after discontinuation of triazolam (p < 0.05, t-test). After withdrawal from zopiclone or zolpidem slight but not significant rebound effects concerning sleep continuity were observed. Self-rating scales showed minimal rebound insomnia after discontinuation of all three hypnotics. In the placebo group no changes of sleep parameters were observed. Assuming that rebound insomnia is part of a withdrawal reaction, this study indicates that the risks of tolerance and dependency are low when administering zopiclone or zolpidem at the recommended doses.

Background: Over recent years, the use of antidepressants for the symptomatic treatment of insomnia has grown substantially, but controlled studies are still lacking. Our study is the first investigation to prove objective efficacy and tolerability of low doses of a sedating antidepressant in a randomized, double-blind, and placebo-controlled manner in patients with primary insomnia., Method: Forty-seven drug-free patients meeting DSM-IV criteria for primary insomnia (mean +/- SD duration of complaints = 11.2+/-9.7 years) received either 25-50 mg of the tricyclic antidepressant doxepin or placebo for 4 weeks followed by 2 weeks of placebo withdrawal. Sleep was measured by polysomnography at baseline and the first night of application, at 4 weeks of treatment and the first to third night of withdrawal, and after 2 weeks of withdrawal., Results: In the doxepin-treated patients who completed the study (N = 20, 47.6+/-11.3), medication significantly increased sleep efficiency after acute (night 1, p < or = .001) and subchronic (night 28, p < or = .05) intake compared with the patients who received placebo (N = 20, 47.4+/-16.8 years of age). Latency to sleep onset was not affected since the patients had normal baseline sleep latencies. Investigators found doxepin to cause significantly (p < or = .05) better global improvement at the first day of treatment. Patients rated sleep quality (p < or = .001) and working ability (p < or = .005) to be significantly improved by doxepin during the whole treatment period. Overall rebound in sleep parameters was not observed, but patients with severe rebound insomnia were significantly more frequent in the doxepin group (night 29, p < .01, night 30, p < or = .01; night 31, p < or = .05). No significant group differences in side effects were found, but 2 doxepin-treated patients dropped out of the study due to specific side effects (increased liver enzymes, leukopenia, and thrombopenia)., Conclusion: The results support the effectiveness of low doses of doxepin to improve sleep and working ability in chronic primary insomniacs, although subjective effects were light to moderate, and in some patients, rebound insomnia and specific side effects have to be considered.

Kainic acid (KA), a potent neurotoxin and excitatory amino acid, leads to derangements and modulation of brain proteins. No global brain protein expression pattern induced by KA-treatment has been reported yet. We therefore studied the effect of systemic KA administration on the levels of brain proteins. Rats were injected placebo or KA intraperitoneally and brain was taken after one week. The mitochondrial and cytosolic fractions of the brain proteins were analyzed by proteomics technologies and the levels of selected proteins were quantified using specific software. Heat shock protein HSP 27 was exclusively detected in brains of animals treated with KA, whereas the glucose regulated protein GRP 78 was downregulated. The levels of neurofilaments and alpha-internexin were significantly decreased and a fragment of tubulin alpha-1 chain was manifold increased in KA-brains. The mitochondrial enzymes dihydrolipoamide dehydrogenase, ATP synthase beta chain and isocitrate dehydrogenase were reduced and pyruvate kinase M1 was increased following KA treatment. We conclude that the concomitant determination of the brain proteins indicates altered regulation of heat shock proteins, neuronal death, cytoskeletal disruption, and mitochondrial derangement by systemic KA administration. This report confirms and extends previous studies on the effect of KA on the expression of brain proteins and suggests that our analytical system can serve as a model for neurotoxicological, neurobiological, and neuropathological proteome studies.

Low-abundance gene products are of interest in proteomic studies, because they are probably involved in disease-related changes and their altered levels or modifications may carry significant biological information. Detection of low-abundance proteins of a proteome is one of the major limitations of proteomics and a scientific challenge. We investigated the changes in the levels of low-abundance rat brain cytosolic proteins after administration of kainic acid, a potent neurotoxin and excitatory amino acid. The cytosolic proteins from controls and animals treated with kainic acid were fractionated on an ion-exchange column. The fractions collected were analyzed by 2D electrophoresis, and the proteins with altered levels were identified by matrix-assisted laser desorption ionization or ion-spray MS. We found a manifold decrease in annexin VII, heat-shock cofactor HOP/p60 and SP-22 and a manifold increase in heparin-binding protein p30. The results suggest, respectively, the involvement of an apoptotic pathway, recruitment of the heat-shock protein machinery, generation of an antioxidant response, and, probably, induction of repair mechanisms. Three of the four proteins with altered levels had not been previously detected in the cytosolic fraction, and detection of the altered levels was possible only after the protein-enriching step.

Varicella-zoster virus (VZV), a member of the human herpesvirus family, causes childhood chickenpox (varicella), becomes latent in sensory ganglia, and reactivates years later in immunocompromised and elderly persons to produce shingles (herpes zoster). Early in the AIDS epidemic, zoster was noted in adults and children infected with HIV. Severe and debilitating zoster-associated dermatological, ophthalmic, and neurological complications may occur in patients infected with HIV. Antiviral therapy can modify the duration of zoster and alleviate its attendant complications. Varicella vaccine may boost the immunity and prevent virus reactivation. VZV immune globulin (VZIG) prevents or modifies clinical illness in persons who have been exposed to varicella or zoster.

Background: The 5-hydroxytryptamine(1B/1D) agonists, or triptans, are the newest class of drugs to become available for the acute treatment of migraine. The class currently includes sumatriptan, zolmitriptan, naratriptan, and rizatriptan. The efficacy of rizatriptan in the acute treatment of migraine has been established against placebo and other oral triptans in controlled comparative trials., Objective: The US Migraine Assessment Protocol (USMAP) collected data on the use of rizatriptan in a naturalistic setting reflecting clinical practice. This paper presents results for patients enrolled in the USMAP study who had never taken a triptan before the study., Methods: At enrollment, 216 patients completed a questionnaire describing their responses to their current nontriptan medications. They were then given specially packaged samples of 4 standard 10-mg rizatriptan tablets and 4 orally disintegrating 10-mg rizatriptan tablets (wafers) and were asked to take a different formulation for each of their next 2 attacks, the sequence to be at their discretion. Within approximately 24 hours after taking rizatriptan, patients were to call a toll-free number to report their responses to rizatriptan using an interactive voice-response system., Results: Within 2 hours after initial dosing of rizatriptan, significantly more patients taking either the rizatriptan tablet or the rizatriptan wafer reported onset of pain relief, had become largely symptom free, and were able to resume usual activities compared with their baseline responses to nontriptans (P < 0.05). In addition, compared with their baseline responses to nontriptans, significantly more patients taking either rizatriptan formulation had mild or no pain 2 hours after dosing (P < 0.05). More than twice as many patients taking the rizatriptan tablets or wafers were either somewhat or very satisfied with the medication compared with their satisfaction with nontriptans (P < 0.05)., Conclusions: In the naturalistic setting of this study, migraineurs who had not previously taken a triptan medication reported more rapid relief of pain, more effective pain relief, and more rapid resumption of normal activities when taking rizatriptan tablets or wafers than when taking a nontriptan medication. Patients dissatisfied with their current nontriptan migraine therapy may benefit from treatment with rizatriptan.

Sleep Disorders are one of the most common complaints of patients seen by general practitioners. Prevalences vary considerably--depending on the kind of research and the definition of sleep disorders--between 4 and 40%. In 2000 the first grand nationwide survey was carried out in primary care settings [1]. 12.3% of the 17,928 questioned stated sleep disorders as the main reason for their consultation, the prevalence of all kinds of sleep disorders being 29%. Like seen in other studies sleep complaints increased with age and predominated significantly in women. In one-third of the sample the differential diagnosis was primary or non-organic insomnia [1] while treatment was mainly conducted by the general practitioner. In two-thirds of the patients sleep disorders existed for more than 12 months while 41%--by their own account--took sleep agents at least once a week. This article gives an overview of the causes and treatment of sleep disorders, particularly therapy of non-organic insomnia.

The fast but short-lasting improvement of depressive symptoms by sleep deprivation (SD) in about 60% of patients with a major depressive disorder is well established, but the mechanisms of action are still not clear. Recent studies suggest that changes in non rapid eye movement (NREM) sleep, especially in slow wave activity (SWA), could be associated with the therapeutic outcome of SD. In the current study, spectral analysis of NREM sleep EEG directly prior to SD was performed to determine if automatically derived sleep parameters predict SD response. Sixteen pair matched and drug free patients with a major depressive disorder, 8 SD responders and 8 non-responders (response criterion: 50% reduction on the 6-item HAMD score), were included. Average EEG spectral power was calculated for the whole night before SD and for single NREM episodes. While whole-night averages of spectral power did not differ significantly between subgroups, SD responders showed a steady decrease of SWA across successive NREM episodes, whereas in non-responders an increase from the first to the second episode was observed. The different distribution of SWA was significantly expressed in the delta sleep ratio (quotient of SWA in the first to the second NREM episode). In conclusion, a high delta sleep ratio is a positive predictor for SD response. Referred to psycho- and pharmacotherapeutic results it is hypothesized that low and high values of the delta sleep ratio characterize subgroups of depressed patients with different neurobiological alterations, which could be relevant for further scientific and therapeutic approaches.

Cancer cells express particular genes, part of which are normally active during the embryonic development. On the other hand, young embryos are able to differentiate teratocarcinoma or leukemia cells, likely by producing differentiation factors. In this work, rat and mouse embryo cell nuclei extracts were tested on hepatoma carcinoma cells LFCl2A: they inhibit the cell growth in culture and increase the survival of syngeneic rats injected with hepatoma cells incubated with these extracts. This inhibition is correlated with a decrease of DNA synthesis without toxic effect: It seems to be due to the mixture of tight binding DNA proteins, possibly transcriptional factors.

Background: Although controlled-rate freezing and storage in liquid nitrogen are the standard procedure for peripheral blood progenitor cell (PBPC) cryopreservation, uncontrolled-rate freezing and storage at -80 degrees C have been reported., Study Design and Methods: The prospective evaluation of 109 autologous PBPC transplantations after uncontrolled-rate freezing and storage at -80 degrees C of apheresis products is reported. The cryoprotectant solution contained final concentrations of 1-percent human serum albumin, 2.5-percent hydroxyethyl starch, and 3.5-percent DMSO., Results: With in vitro assays, the median recoveries of nucleated cells (NCs), CD34+ cells, CFU-GM, and BFU-E were 60.8 percent (range, 11.2-107.1%), 79.6 percent (6.3-158.1%), 35.6 percent (0.3-149.5%), and 32.6 percent (1.7-151.1%), respectively. The median length of storage was 7 weeks (range, 1-98). The median cell dose, per kg of body weight, given to patients after the preparative regimen was 6.34 x 10(8) NCs (range, 0.02-38.3), 3.77 x 10(6) CD34+ cells (0.23-58.5), and 66.04 x 10(4) CFU-GM (1.38-405.7). The median time to reach 0.5 x 10(9) granulocytes per L, 20 x 10(9) platelets per L, and 50 x 10(9) reticulocytes per L was 11 (range, 0-37), 11 (0-129), and 17 (0-200) days, respectively. Hematopoietic reconstitution did not differ in patients undergoing myeloablative or nonmyeloablative conditioning regimens before transplantation., Conclusion: This simple and less expensive cryopreservation procedure can produce successful engraftment, comparable to that obtained with the standard storage procedure.

The psychometric properties of the PTSD Symptom Scale (PSS) were evaluated in a clinical sample of severely injured in-patients after a traffic accident (n = 123). The PSS contains 17 items which were derived from the DSM-III-R criteria of posttraumatic stress disorder (PTSD). The results indicate that the PSS has satisfactory reliability and validity (internal and external). The results are in correspondence with the results of Foa et al. using a sample of rape and non-sexual-assault patients., (Copyright 2001 S. Karger AG, Basel)

Objective: A reduction of diabetes-related amputations by at least one-half within 5 years was declared a primary objective for Europe (St. Vincent Declaration, 1989). We collected data about incidence rates of amputations in one German city (Leverkusen, with a population of approximately 160,000 inhabitants) between 1990 and 1998 to ascertain a potential change in rates of incidence., Research Design and Methods: From all three hospitals in Leverkusen, we obtained complete lists of lower-limb amputations. From each patient record, diabetic status was determined. Only the first observed amputation was counted for the analysis. We estimated incidence rates of amputations in the entire population, the diabetic population, and the nondiabetic population. To test for time trend, we fitted Poisson regression models, adjusting for age and sex., Results: During, the defined period (the years 1990, 1991, and 1994-1998), 339 patients (all residents of Leverkusen) without previous amputations had nontraumatic lower-limb amputations. Of all subjects. 46% were female. Moreover, 76% of the subjects were known to have diabetes. Mean age was 71.3 years. Incidence rates in the diabetic population (standardized to the estimated German diabetic population, per 100,000 person-years) were as follows: 1990, 549; 1991, 356; 1994, 544; 1995, 386; 1996, 426; 1997, 433; and 1998, 463. The Poisson models showed no significant change of incident amputations over time in the diabetic population or in the nondiabetic population., Conclusions: Beyond random variation, no change of incidence rates could be observed over the past 9 years. More specific interventions are needed to achieve a substantial reduction of diabetes-related amputations.

Ependymoma occurs most frequently within the central nervous system of children and young adults. We determined relative chromosomal copy-number aberrations in 44 ependymomas using comparative genomic hybridization. The study included 24 intracranial and 20 spinal cord tumors from pediatric and adult patients. Frequent chromosomal aberrations in intracranial tumors were gain of 1q and losses on 6q, 9, and 13. Gain of 1q and loss on 9 were preferentially associated with histological grade 3 tumors. On the other hand, gain on chromosome 7 was recognized almost exclusively in spinal cord tumors, and was associated with various other chromosomal aberrations including frequent loss of 22q. We conclude that cytogenetic analysis of ependymomas may help to classify these tumors and provide leads concerning their initiation and progression. The relationship of these aberrations to patient outcome needs to be addressed.

The effects of trimipramine, a tricyclic antidepressant (TCA) with atypical pharmacological properties, and fluoxetine, a selective serotonine reuptake inhibitor (SSRI), were compared in an exploratory analysis using mood and polysomnographic parameters during a six-week double-blind trial in 19 depressed geriatric patients. In sleep EEG measures, trimipramine demonstrated clear-cut effects on sleep measures resulting in higher values for sleep efficiency, total sleep time, stage 2 sleep, and shorter wake time. Under fluoxetine treatment, the proportion of REM sleep was decreased and REM latency was lengthened, whereas no change in REM sleep parameters was observed in the trimipramine group. The present data suggest that early antidepressant effects of medication occur independently of drug-induced changes in objective measures of sleep, i.e. suppression of REM sleep.

Background: Measures of patient satisfaction or dissatisfaction with treatment are increasingly being used as indicators of quality of care. As these measures become more widely used, it is important to know if patient dissatisfaction is associated with important processes or outcomes of medical care., Methods: Survey of patient-reported asthma management issues using the Asthma Therapy Assessment Questionnaire in a large health maintenance organization in the Pacific Northwest. Associations between patient dissatisfaction with asthma treatment and patient-reported measures of asthma control, patient-provider communication, and belief in asthma medications (self-efficacy) were examined., Results: Of the 5181 adult members with asthma enrolled in the health maintenance organization, 30% indicated dissatisfaction with current treatment. Dissatisfaction was higher among patients with a higher number of asthma control problems, patient-provider communication problems, or belief in medication problems (eg, failure to believe their medications are useful and inability to take asthma medications as directed). The odds of dissatisfaction with treatment were 2.8 (95% confidence interval [CI], 2.4-3.3; P<.001) for asthma control problems, 2.0 (95% CI, 1.6-2.6; P<.001) for communication problems, and 8.0 (95% CI, 6.7-9.5; P<.001) for belief in medication problems compared with patients without these perceived problems., Conclusion: Patient dissatisfaction with treatment may be related to important asthma disease management issues.

The p53 protein plays a key role in the cellular response to stress by inducing cell growth arrest or apoptosis. The polyproline region of p53 has been shown to be important for its growth suppression activity. p53 protein lacking the polyproline region has impaired apoptotic activity and altered specificity for certain apoptotic target genes. Here we describe the role of this region in the regulation of p53 by its inhibitor Mdm2. p53 lacking the polyproline region was identified to be more susceptible to inhibition by Mdm2. Furthermore, the absence of this region renders p53 more accessible to ubiquitination, nuclear export, and Mdm2-mediated degradation. This increased sensitivity to Mdm2 results from an enhanced affinity of Mdm2 toward p53 lacking the polyproline region. Our results provide a new explanation for the impaired growth suppression activity of p53 lacking this region. The polyproline region is proposed to be important in the modulation of the inhibitory effects of Mdm2 on p53 activities and stability.

Aims/hypothesis: A reduction of diabetes-related blindness by at least one third was declared a primary objective for Europe in 1989 (St. Vincent Declaration). To ascertain a potential change of incidence rates, we collected data on blindness in a German district (population: about 5 million) over 9 years., Methods: We obtained complete lists of newly registered blindness-allowance recipients between 1990 and 1998 and population data on Württemberg-Hohenzollern, Germany. We estimated incidence rates of blindness in the general population and the diabetic population. To ascertain any time trend, we applied Poisson regression models., Results: There were 6371 newly registered blindness allowance recipients (1990-1998). Of these 67% were women and 27 % had diabetes. Mean age was 71.7 years. Standardised results in the diabetic population (incidence rates per 100,000 person-years; standard: diabetic population; 95 % CI): 1990: 72 (61;82); 1991: 88 (76;100); 1992: 77 (67;88); 1993: 82 (71;93); 1994: 62 (53;72); 1995: 82 (71;93); 1996: 70 (60;80); 1997: 69 (59;79); 1998: 59 (49;68). The Poisson model estimated a 3 % decrease of incident blindness in the diabetic population for each year (Relative risk per year 0.97; CI: 0.95; 0.99). No significant change could be observed in the non-diabetic population (Relative risk: 0.99; CI: 0.98; 1.00). Relative risks for each year varied between sub-groups according to sex, diabetic status and cause of blindness between 0.94 and 1.01., Conclusion/interpretation: A slight reduction of incident blindness could be shown but a reduction by one third has not been reached. Several possible sources of bias in the data have to be considered.

Background/aims: The objective, but noninvasive, assessment of the nail plate and nail matrix is of interest in dermatology, and cosmetics as well. These cutaneous structures were investigated with 20 MHz ultrasound. This study was performed to obtain data on normal nails in adults of different age groups, with a left-right comparison, and to investigate nail changes in selected dermatologic diseases., Methods: Healthy controls (n = 34) and patients with dermatologic complaints and nail disease (n = 37) were included after informed consent. In the control group, 18 woman and 16 men with a mean age of 37.2 years (range 15 to 82 years) were investigated for age- and gender-related differences. Patients with one of the following disorders were investigated: systemic lupus erythematosus (SLE; n = 11), systemic sclerosis (PSS; n = 8), psoriasis (n = 9), chronic hand eczema (n = 5), and others (n = 4). Measurements of length and width of the nail plate and the lunulae were performed with a micrometer device. Sonography was performed with a 20 MHz probe in B-scan mode., Results: The mean nail thickness of healthy controls varied between 0.481 mm (right thumb) and 0.397 mm (left fifth finger). The nail volume and the matrix volume disclosed a positive, but mostly nonsignificant, correlation for all controls. Age-specific differences were investigated for both genders. In men and women, the matrix volume increased significantly with age. The nail and matrix volume was higher in men than in women, independent of age. The left-right comparison disclosed a trend to higher nail and matrix volumes on the right hand. In patients with SLE there was an increase in nail thickness and in matrix volume. Patients with PSS showed a significant decrease in nail thickness and matrix volume. In other diseases the measurements disclosed no confident differences to healthy controls., Conclusion: The 20 MHz ultrasound offers a noninvasive method to calculate nail thickness, nail volume and matrix volume in healthy volunteers and in nail disease. Skin diseases show characteristic quantitative changes in these parameters.

The first two steps in mammalian biosynthesis of N-acetylneuraminic acid, an important carbohydrate moiety in biological recognition systems, are performed by the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. A subclone of the human B lymphoma cell line BJA-B K20, lacking UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase mRNA as well as epimerase activity, displayed hyposialylated, functionally impaired cell surface glycoconjugates. Here we show that this cell line surprisingly still retains N-acetylmannosamine kinase activity. A gel filtration analysis of BJA-B K88 control cells, which express UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, revealed two N-acetylmannosamine kinase activity peaks, one co-eluting with UDP-N-acetylglucosamine 2-epimerase activity and one co-eluting with N-acetylglucosamine kinase. For this enzyme previous studies already showed a ManNAc kinase activity in vitro. In contrast, the hyposialylated BJA-B K20 subclone displayed only the N-acetylmannosamine kinase peak, co-migrating with N-acetylglucosamine kinase. The CMP-N-acetylneuraminic acid content of both K88 and K20 cells and the sialylation of cell surface glycoconjugates of K20 cells could be significantly increased by supplementing the medium with N-acetylmannosamine. This N-acetylmannosamine-induced increase was drastically reduced by co-supplementation with N-acetylglucosamine only in K20 cells. We therefore propose the phosphorylation of N-acetylmannosamine as a hitherto unrecognized role of N-acetylglucosamine kinase in living cells.

The MVDP (mouse vas deferens protein) gene encodes an aldose reductase-like protein (AKR1B7) highly expressed in vas deferens epithelium and zona fasciculata of the adrenal cortex. Recombinant MVDP showed kinetic properties distinct from those of aldose reductase, including its spectrum of substrates, cofactor preference and sensitivity to inhibitors. We demonstrate that in adrenocortical cells, MVDP, rather than aldose reductase, is the principal reductase for isocaproaldehyde (a product of side-chain cleavage of cholesterol) and 4-hydroxynonenal (a lipid peroxidation product). In steroidogenic tissues MVDP expression is regulated by pituitary trophic hormones, namely ACTH in adrenals, FSH in ovaries, and LH in testicular Leydig cells.

The role of sildenafil in the treatment of erectile dysfunction is discussed. Especially in primary care there is a necessity to weigh the individual cost-benefit-ratio. Functional analysis of erectile dysfunction, exclusion of psychiatric and organic comorbidity, identification of sexual deviance and couple counseling about the advantages and disadvantages of sildenafil prescription are the core prerequisites of sildenafil application in primary care. The counseling model of PLIS-SIT is proposed as a guideline for counseling process. Current approaches of education for general practitioners are reviewed and the integration in a recently developed training for management of psychiatry and psychosomatic illness in general medical settings is proposed. Finally open questions for research and quality management are discussed.

The goal of this study was to determine whether presurgical metabolite levels measured by 3D MR Spectroscopic Imaging (MRSI) can accurately detect viable cancer within human brain tumor masses. A total of 31 patients (33 exams, 39 pathology correlations) with brain tumors were studied prior to surgical biopsy and/or resection. The 3D MRSI was obtained with a spatial resolution of 0.2 to 1 cc throughout the majority of the mass and adjacent brain tissue using PRESS-CSI localization. Levels of choline, creatine and NAA were estimated from the locations of the resected tissue and normalized to normal appearing brain tissue. The data were correlated with subsequent histologic analysis of the biopsy tissue samples. Although there were large variations in the metabolite ratios, all regions of confirmed cancer demonstrated significant choline levels and a mean choline/NAA ratio of 5.84 + 2.58 with the lowest value being 1.3. This lowest value is greater than 4 standard deviations above the mean (0.52 +/- 0.13) found in 8 normal volunteers. The choline signal intensities in confirmed cancers were significantly elevated compared to normal appearing brain tissue with a mean ratio of 1.71 +/- 0.69. Spectra with no significant metabolite levels were observed in the non-enhancing necrotic core of the tumor masses. The results of this study indicate that 3D MRSI of brain tumors can detect abnormal metabolite levels in regions of viable cancer and grades and can differentiate cancer from necrosis and/or normal brain tissue.

The psychostimulant theory of antidepressive sleep deprivation (SD) proposes a contribution of dopamine D3 receptors (DRD3) in the limbic system to the antidepressant effects of SD. Neuroendocrinological studies suggest a positive correlation of clinical response to SD and cortisol secretion. We hypothesized that the clinical response to SD and amount of cortisol secretion upon SD is associated with the 1-1 genotype of the Bal1 polymorphism of DRD3 on exon 1. In this study, aiming at evaluating the feasibility of screening large patient samples, 52 inpatients (19 males/33 females) with unipolar depression and a score of 18 or more on the 21-item Hamilton Depression Rating Scale were treated with 1 night of total SD. We found that 31% of our patients responded to SD. There was no association between response to SD and the genotype of the DRD3 Bal1 polymorphism (p < 0.879). There was also no association between increase in cortisol secretion after SD and DRD3 genotypes (p < 1.000) in a subgroup of patients. Statistical power analysis ruled out a major effect of the DRD3 Bal1 polymorphism on clinical response to SD. These results suggest that the DRD3 Bal1 polymorphism is not a promising lead to be followed up in larger patient samples., (Copyright 2001 S. Karger AG, Basel)

Patient education in diabetes has been successful in training and motivating patients to assume a more active and independent role in monitoring and treating their disease resulting in an improvement of patient-orientated outcomes. Traditionally, diabetes education has mainly aimed at increasing patient compliance to physician-defined therapeutic goals and treatment strategies. To strengthen their rights and autonomy, patients need to become more involved in medical decision making with respect to their individual therapeutic goals, such as HbA1c and blood pressure, body weight, etc., as well as choosing whether they pursue these goals. The importance of patient participatation is particularly relevant to Type 2 diabetes. Even perfect, long-term therapeutic co-operation will not eliminate diabetic complications, only reduce the risk of developing them. The benefits, lack of benefits and unwanted effects of various interventions need to be communicated to the patient in an unbiased manner, so that he/she can make an informed choice with regard to different therapeutic goals and strategies. In diabetes, ways of presenting patients with unbiased information to enable them to make such informed decisions are not yet available. We present ways of how this might be achieved using data provided by the UKPDS. The concept of patient participation in medical decision making represents a fundamental challenge for the future development of diabetes care.

Mobilization of peripheral blood stem cells (PBSC) by granulocyte colony-stimulating factor (G-CSF), at 10 micrograms/kg/day vs. 20 micrograms/kg/day (in 42 and 29 patients, respectively), was compared in children with solid tumors or leukemias. During mobilization, differences were noted in the peak values of CD34+ cells in peripheral blood (PB) in these two groups (median 28 x 10(6)/L for 10 micrograms/kg/day vs. 61 x 10(6)/L for 20 micrograms/kg/day; p = 0.025). Similar numbers of progenitor cells were harvested for the two concentrations of G-CSF. However, similar CD34+ cell levels in the leukapheresis product were obtained after only the third dose of G-CSF at 20 micrograms/kg/day compared with the fourth dose of G-CSF at 10 micrograms/kg/day (1.7 and 1.2 x 10(6) CD34+ cells/kg/one patient's blood volume processed, respectively). Of note is the impact of diagnosis on PB CD34+ cell levels. We conclude that, in children, mobilization with G-CSF at 20 micrograms/kg/day could minimize the duration of priming but not reduce the number of leukaphereses. Thus, the impact on outcome, clinical practice, bed utilization, and health economics is uncertain.

Aims: To assess predictors of mortality and end-stage diabetic complications in patients with Type 1 diabetes mellitus on intensified insulin therapy., Methods: A cohort of 3,674 patients (insulin treatment before age 31) who had participated in a 5-day in-patient group treatment and teaching programme for intensification of insulin therapy between 9/1978 and 12/1994 were reassessed after 10 +/- 3 (mean +/- SD) years., Results: Vital status and data on blindness, amputations, and renal replacement therapy were documented for 97% patients; 7% patients had died, 1.3% had become blind, 2% had amputations and 4.6% started renal replacement therapy. Using the Cox proportional hazards model, the following risk factors of mortality as assessed at baseline were identified: nephropathy (at least macroproteinuria), hazard ratio 3.8 (95% confidence interval 2.6-5.6); smoking, 1.9 (1.4-2.6); diabetes duration, 1.5 (1.2-1.8) for a difference of 10 years; serum cholesterol, 1.1 (1.0-1.2) for a difference of 1 mmol/l; lower social status, 1.4 (1.1-1.8) for a difference of 1 out of 3 levels; age, 1.3 (1.1-1.6) for a difference of 10 years; male sex, 1.4 (1.1-1.9); systolic blood pressure, 1.1 (1-1.2) for a difference of 10 mmHg. For the combined endpoint - blindness or amputations or renal replacement therapy - predictors were: nephropathy, foot complications, HbA1c, smoking, cholesterol, systolic blood pressure, retinopathy, hypertension, and social status., Conclusion: In Type 1 diabetic patients who start intensified insulin therapy, nephropathy remains the strongest predictor of mortality and end-stage complications. Glycosylated haemoglobin is a risk factor of end-stage complications but not of mortality. Conventional risk factors comparable to the general population, particularly smoking become operative as predictors of both mortality and end-stage complications.

Objective: To study the prognosis of persons with type 1 diabetes in relation to the degree of nephropathy at initiation of intensified insulin therapy., Design: Ten years follow-up of a cohort of 3674 patients who had participated in a 5-day group treatment and teaching programme for intensification of insulin therapy between September 1978 and December 1994., Setting: Ten diabetes centres in Germany., Subjects: A total of 3674 patients (insulin treatment before age 31), age at baseline 27 +/- 10 years, with a diabetes duration of 11 +/- 9 years. Patients were divided into three groups according to baseline renal parameters (group I, normal proteinuria, n = 1829; group II, microproteinuria, n = 1257; group III, at least macroproteinuria, n = 367)., Main Outcome Measures: End-stage diabetic complications (blindness, amputations, renal replacement therapy, standardized mortality ratios (SMR) and causes of death., Results: Outcome measures were documented for 97% of patients; 251 (7%) had died. During follow-up, 1% of patients in group I, 4% in group II and 47% in group III had at least one end-stage diabetic complication. SMR for men: nephropathy group I, 2.2 (95% CI = 1.5-3); group II, 3.2 (2.3-4.3); group III, 11.5 (8.8-14.7). SMR for women: group I, 2.5 (1.5-3.8); group II, 3.5 (2.2-5.3); group III, 27 (19.8-35.9). Causes of death for men and women combined: group I (total 58 deaths)--cardiovascular, 21 (36%); hypoglycaemia, 1; ketoacidosis, 3; violent deaths, 17 (29%); others, 16; group II (66 deaths)--cardiovascular, 25 (38%); hypoglycaemia, 2; ketoacidosis, 2; violent deaths, 14 (21%); others, 23; group III (114 deaths)--cardiovascular, 68 (60%); hypoglycaemia, 2; ketoacidosis, 5; infections, 15 (13%); violent deaths, 5 (4%); others, 19., Conclusions: Patients with microproteinuria have only a slightly worse prognosis than patients with normal proteinuria during the first 10 years after initiation of intensified insulin therapy. Excess mortality amongst patients who started intensified insulin therapy is mainly due to those with manifest clinical nephropathy.

In humans and rabbits, the TPT1 gene encoding the translationally controlled tumour protein TCTP generates two mRNAs (TCTP mRNA1 and TCTP mRNA2) which differ in the length of their 3' untranslated regions. The distribution of these mRNAs was investigated in 10 rabbit and 50 human tissues. They were transcribed in all tissues investigated, but differed considerably in their quantity and ratio of expression. This indicates an extensive transcriptional control and involvement of tissue-specific factors. In the rabbit genome numerous processed, intronless pseudogenes were detected. Four, corresponding to both types of mRNAs, were sequenced and analysed in detail; all displayed only few mutations and were either preserved completely in the original amino acid sequence of the intron containing gene, or contained only minor mutations in the coding region which did not interrupt the open reading frame. In the mRNA population of rabbit reticulocytes two additional TCTP RNAs of the TCTP mRNA2 type were detected, which have the characteristics of pseudogene transcripts. Pseudogene transcription was supported further by CAT reporter gene assays showing substantial promoter activity of 5'-flanking regions of two TPT1 pseudogenes.

Preclinical investigations suggest that the neuropeptide substance P might be involved in the etiopathology of pain, depression, and anxiety. In a recent study, the substance P receptor antagonist MK-869 showed antidepressant and anxiolytic activity in depressed outpatients which was comparable to a standard SSRI. The MK-869 was well tolerated. Although these findings are promising, further studies are necessary to prove the hypothesis that substance P receptor antagonists represent a new class of antidepressants or anxiolytics. Respective studies are currently underway.