[Medical care situation of patients with ankylosing spondylitis and psoriatic arthritis in Germany : Medical care situation of patients with spondyloarthritis (SpA): ankylosing spondylitis (AS) and psoriatic arthritis (PsA) from the perspective of rheumatologists in private practice and hospitals in Germany-Results of the research project "SpA Loop-Life of Outpatients"]. / Versorgungssituation von Patienten mit ankylosierender Spondylitis und Psoriasisarthritis in Deutschland : Versorgungssituation von Patienten mit Spondyloarthritis (SpA): Ankylosierende Spondylitis (AS) und Psoriasisarthritis (PsA) aus der Sicht von niedergelassenen und in Kliniken tätigen Rheumatologen in Deutschland ­ Ergebnisse des Forschungsprojekts "SpA Loop ­ Life of Outpatients".

BACKGROUND: The prevalence of spondyloarthritis (SpA) in Germany is approximately 1-1.4% and includes predominantly axial SpA (axSpA) and predominantly peripheral SpA. Ankylosing spondylitis (AS) belongs to the group of axial SpA but also exhibits peripheral manifestations. Psoriatic arthritis (PsA) can show purely peripheral or also axial manifestations. The total prevalence of SpA in Germany is approximately 1­1.4%, the prevalence of AS is ca. 0.5% and PsA 0.2-1.4%. Patients with AS are mainly treated by internal medical rheumatologists but in many places also basically treated by general practitioners and orthopedists. Patients with PsA are mainly diagnosed and treated by rheumatologists and dermatologists working in private practice or in clinical settings. Besides the control of inflammatory activity and prevention or slowing down of the characteristic disease progression, including irreversible structural changes, the main objectives of patients as well as treating physicians are particularly freedom from pain and a quality of life comparable to non-affected persons. Decisive for successful treatment are an early diagnosis and initiation of adequate therapy as well as regular monitoring of disease activity including treatment adjustment taking the needs of the patient into consideration; however, it is unknown how often this is actually successful in routine daily practice in Germany. OBJECTIVE: The aim of the SpA Loop research project was to display the current medical care situation of patients with AS and PsA treated in private practices and hospitals for rheumatology in Germany focusing on patient/physician profiles as well as the diagnostics and treatment. MATERIAL AND METHODS: The instrument for the survey was a standardized questionnaire with 29 multiple choice and perception questions that was distributed to medical specialists in the field of internal medicine and rheumatology. RESULTS: A high accordance between rheumatologists in private practice and in hospitals was observed with respect to the presentation and perception of the current medical care situation for patients with AS and PsA in Germany. Differences were only occasionally found. CONCLUSION: The results of this research project reflect the current status of the medical care situation of AS and PsA patients in Germany. They provide information on which areas of the medical care situation can selectively be improved as well as on interesting aspects and points of discussion with respect to the patient population treated.

Sp100A is a tumor suppressor that activates p53-dependent transcription and counteracts E1A/E1B-55K-mediated transformation.

Human adenoviruses (HAdV) are used as a model system to investigate tumorigenic processes in mammalian cells where the viral oncoproteins E1A and E1B-55K are absolutely required for oncogenic transformation, because they simultaneously accelerate cell cycle progression and inhibit tumor suppressor proteins such as p53, although the underlying mechanism is still not understood in detail. In our present study, we provide evidence that E1B-55K binding to the PML-NB component Sp100A apparently has an essential role in regulating adenovirus-mediated transformation processes. Specifically, when this E1B-55K/Sp100A complex recruits p53, Sp100A-induced activation of p53 transcriptional activity is effectively abolished. Hence, Sp100A exhibits tumor-suppressive activity, not only by stabilizing p53 transactivation but also by depressing E1A/E1B-55K-mediated transformation. E1B-55K counteracts this suppressive activity, inducing Sp100A SUMOylation and sequestering the modified cellular factor into the insoluble matrix of the nucleus or into cytoplasmic inclusions. These observations provide novel insights into how E1B-55K modulates cellular determinants to maintain growth-promoting activity during oncogenic processes and lytic infection.

PML isoforms IV and V contribute to adenovirus-mediated oncogenic transformation by functionally inhibiting the tumor-suppressor p53.

Although modulation of the cellular tumor-suppressor p53 is considered to have the major role in E1A/E1B-55K-mediated tumorigenesis, other promyelocytic leukemia nuclear body (PML-NB)/PML oncogenic domain (POD)-associated factors including SUMO, Mre11, Daxx, as well as the integrity of these nuclear bodies contribute to the transformation process. However, the biochemical consequences and oncogenic alterations of PML-associated E1B-55K by SUMO-dependent PML-IV and PML-V interaction have so far remained elusive. We performed mutational analysis to define a PML interaction motif within the E1B-55K polypeptide. Our results showed that E1B-55K/PML binding is not required for p53, Mre11 and Daxx interaction. We also observed that E1B-55K lacking subnuclear PML localization because of either PML-IV or PML-V-binding deficiency was no longer capable of mediating E1B-55K-dependent SUMOylation of p53, inhibition of p53-mediated transactivation or efficiently transforming primary rodent cells. These results together with the observation that E1B-55K-dependent SUMOylation of p53 is required for efficient cell transformation, provides evidence for the idea that the SUMO ligase activity of the E1B-55K viral oncoprotein is intimately linked to its growth-promoting oncogenic activities.

Cross-talk between phosphorylation and SUMOylation regulates transforming activities of an adenoviral oncoprotein.

Since the discovery of post-translational modification (PTM) by the small ubiquitin-related modifiers (SUMOs), a multitude of proteins have been described to be reversibly modified, resulting in the alteration of several cellular pathways. Interestingly, various pathogens gain access to this modification system, although the molecular mechanisms and functional consequences are barely understood. We show here that the adenoviral oncoprotein E1B-55K is a substrate of the SUMO conjugation system, which is directly linked to its C-terminal phosphorylation. This regulative connection is indispensable for modulation of the tumor suppressor p53/chromatin-remodeling factor Daxx by E1B-55K and, consequently, its oncogenic potential in primary mammalian cells. In virus infection, E1B-55K PTMs are necessary for localization to viral transcription/replication sites. Furthermore, we identify the E2 enzyme Ubc9 as an interaction partner of E1B-55K, providing a possible molecular explanation for SUMO-dependent modulation of cellular target proteins. In conclusion, these results for the first time provide evidence how E1B-55K PTMs are regulated and subsequently facilitate exploitation of the host cell SUMOylation machinery.

Austrian clinical practice with anidulafungin in 2008: a multicenter survey.

Anidulafungin had demonstrated favorable efficacy versus fluconazole in a randomized trial on invasive Candida infections. Since patient characteristics in the post-approval use of antifungals likely deviate from clinical trials, we surveyed the use of anidulafungin in clinical routine. We performed a retrospective survey of the post-approval use of anidulafungin in 9 Austrian clinical centers. Anidulafungin was used in 129 critically ill patients with severe comorbidities and multiple risk factors. Indications were suspected invasive fungal infections (IFI) (61%), proven candidemia (19%), and at risk for IFI (prophylaxis, 20%). Candida colonization in conjunction with other risk factors prompted treatment in many patients. predominant pathogens were C. albicans, C. glabrata and C. krusei. Anidulafungin was mostly used for pre-emptive (69%) and first-line treatment (17%) of invasive candidiasis. Treatment response, i.e. complete response/stabilization as determined by investigators (89% in the overall population; 87% for documented candidemia) and survival rates (81% and 75%, respectively) were similar to previous trial data. No breakthrough IFI and few adverse events were reported. Overall, favorable clinical experiences were documented with anidulafungin in the clinical routine setting.

SUMO modification of E1B-55K oncoprotein regulates isoform-specific binding to the tumour suppressor protein PML.

The E1B-55K product from human adenovirus is a substrate of the small ubiquitin-related modifier (SUMO)-conjugation system. SUMOylation of E1B-55K is required to transform primary mammalian cells in cooperation with adenovirus E1A and to repress p53 tumour suppressor functions. The biochemical consequences of SUMO1 conjugation of 55K have so far remained elusive. Here, we report that E1B-55K physically interacts with different isoforms of the tumour suppressor protein promyelocytic leukaemia (PML). We show that E1B-55K binds to PML isoforms IV and V in a SUMO1-dependent and -independent manner. Interaction with PML-IV promotes the localization of 55K to PML-containing subnuclear structures (PML-NBs). In virus-infected cells, this process is negatively regulated by other viral proteins, indicating that binding to PML is controlled through reversible SUMOylation in a timely coordinated manner. These results together with earlier work are consistent with the idea that SUMOylation regulates targeting of E1B-55K to PML-NBs, known to control transcriptional regulation, tumour suppression, DNA repair and apoptosis. Furthermore, they suggest that SUMO1-dependent modulation of p53-dependent growth suppression through E1B-55K PML-IV interaction has a key role in adenovirus-mediated cell transformation.

Open pelvic fractures. A multicenter retrospective analysis.

A marked discrepancy exists in the reported mortality rates in patients with open pelvic fractures, ranging from 4.8% to 50%. A retrospective review of patients with open pelvic fractures was performed at three centers. Thirty-nine patients with open pelvic fractures were identified; the average age was 32. The average injury-severity score was 29 (13-75). There were 10 (26%) deaths. Factors that correlated with mortality and morbidity were instability of the pelvic fracture and the presence of a rectal injury. Delay in performing diverting colostomy correlated with a poor outcome. Previously described methods of treatment are still valid; however, there is a need for re-emphasis of early diverting colostomy in the patient with a rectal or perineal injury. A classification system for open pelvic fractures is proposed in this article.

Fatal vascular catastrophe in Ehlers-Danlos syndrome: a case report and review.

The Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue disorders that are characterized by abnormalities of the skin, joints, and a diversity of other phenotypic manifestations. An awareness of the disease is vital for optimal outcome in this rare group of patients who may present with a variety of life-threatening illnesses. Ehlers-Danlos type IV has been associated with vascular catastrophes, perforated viscous, ruptured uterus, and pneumothorax (1-4). We present a case of aneurysmal formation and spontaneous rupture of the great vessels in a 15-year-old male with EDS type IV, who remained undiagnosed until the time of autopsy.

A precision tester for studies of holographic optical storage materials and recording physics.

The design and the realization of an advanced precision optical test stand for evaluating materials and developing tools and techniques for holographic digital data storage are described. This apparatus allows studies of holographic recording materials and recording physics to be performed in the context of practical data storage. The system concept, its implementation, and its performance are described, and examples of holographic storage in photorefractive materials are discussed.

Association of antidepressants and other medications with mortality in the residential-care elderly.

To explore the extent to which treatment of depression affects survival, we evaluated the association between use of antidepressant medications and death rates among the residents of a large residential-care facility for the elderly using a retrospective record-review study (N = 624). One year survival, among those taking antidepressants (10.9%), was 11.8% compared to 11.1% among the remainder of the population. A second study followed a group of 32 patients in the same institution who had participated in a therapeutic trial of nortriptyline treatment for major depression. Patients who experienced adverse medical events during treatment exhibited significantly increased mortality; among treatment completers, there was no significant relationship between mortality and therapeutic response. These findings suggest that the inability to tolerate treatment with an antidepressant can be considered a manifestation of physiologic frailty and increased vulnerability to mortality from disease. The previously reported decrease in survival among residential-care patients with major depression is not paralleled by a similar effect in those taking antidepressants. This may reflect selection factors with respect to the ability to tolerate antidepressants, rather an effect of treatment.

Failure to thrive in the elderly: exploration of the concept and delineation of psychiatric components.

Findings from an exploratory study of the relationships between routine clinical laboratory tests and the clinical status of elderly patients living in a nursing home or congregate housing facility demonstrate that low albumin and anemia are associated with decreased survival and with self-care deficits, cognitive impairment, depression, and summary measures of the severity of medical illness. The interrelationships observed among these variables support the usefulness of the concept of failure to thrive. Although albumin can serve as a nutritional marker, findings on its relationship with sedimentation rate, triiodothyronine uptake, fasting plasma amino acids, and retinol-binding protein levels suggest that the low albumin related to failure to thrive is not a simple reflection of steady-state deficits in protein-calorie nutrition; it appears to be sensitive to more direct effects of disease and inflammation or to the interactions between nutrition and illness.

Development of the cardiovascular system: an interactive video computer program.

The major aim of this project is to provide interactive video computer based courseware that can be used by the medical student and others to supplement his or her learning of this very important aspect of basic biomedical education. Embryology is a science that depends on the ability of the student to visualize dynamic changes in structure which occur in four dimensions--X, Y, Z, and time. Traditional didactic methods, including lectures employing photographic slides and laboratories employing histological sections, are limited to two dimensions--X and Y. The third spatial dimension and the dimension of time cannot be readily illustrated using these methods. Computer based learning, particularly when used in conjunction with interactive video, can be used effectively to illustrate developmental processes in all four dimensions. This methodology can also be used to foster the critical skills of independent learning and problem solving.

Gender differences in neurotransmitter expression in the rat superior cervical ganglion.

Sexual dimorphism of neuron number has been observed in several areas in the central and peripheral nervous system. In many of these areas enhanced neuron survival exists in males during the period of naturally occurring cell death. This has been attributed to high levels of circulating testosterone in the perinatal period. The superior cervical ganglion (SCG) of the rat exhibits this sexual dimorphism. The difference in neuron numbers is established by two weeks postnatally and precedes the differences in body weight and sympathetic target mass between the sexes. At this two week time point, fewer SCG neurons in the female rat must supply neurotransmitter to the same mass of sympathetic target as in the male. The present study examined some of the mechanisms used by neurons in the SCGs of male and female rats to compensate in supplying neurotransmitter to their targets. At birth, the SCGs of male and female rats contain equal numbers of neurons. There is also no sex difference at this time in the content of norepinephrine (NE) in these neurons or in the enzyme activity of tyrosine hydroxylase (TH). However, a sex difference does exist in the expression of TH-mRNA, with SCG neurons in female expressing more TH-mRNA than males. At this time, there is no sex difference in either the total body weight of males and females or in the mass of sympathetic target organs. During the first two postnatal weeks, natural neuron death in the SCG results in the loss of significantly more neurons in females than in males. At the end of the period of cell death, neurons in females continue to express more TH-mRNA, and at this time both TH enzyme activity and NE content per neuron are also higher in females. Since the adult sex difference in body weight and sympathetic target mass has not yet been established, the same amount of target mass is innervated by fewer neurons in females. In the adult, the sex difference in SCG neuron number is maintained. However, both overall body weight and sympathetic target mass are significantly greater in males. At this time expression of TH-mRNA is greater in SCG neurons of males, while both TH enzyme activity and NE content per neuron are equal in males and females. One of the challenges presented to the developing nervous system is to match a population of neurons with its targets.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent regulation of neurotransmitter metabolism in perikarya and terminals of developing sympathetic neurons.

Steady-state levels and turnover of the neurotransmitter, norepinephrine (NE), were measured in sympathetic perikarya and in two sympathetic target organs in the rat at various times during postnatal development. NE content in sympathetic perikarya in the superior cervical ganglion (SCG) increases 15-fold from birth to reach adult levels by 60 days. This increase in NE content parallels the increase in total protein in the ganglion. The rate of turnover of NE in the sympathetic perikarya increases slightly from birth to adulthood. Since the perikarya in the SCG project to a variety of different targets in the head and neck, NE metabolism was also examined in two terminal sympathetic plexuses, in the iris and in the submandibular gland (SMG). The terminal noradrenergic plexuses within these target organs do not mature with the same time course. In the iris, levels of NE increase 24-fold from birth until 90 days postnatally. Turnover of NE in sympathetic terminals in the iris at the time of birth is equivalent to that in the adult. In contrast, both the content and turnover of NE in sympathetic terminals in the SMG are very low at birth, and increase dramatically in the first month postnatally. Deafferentation of the SCG at birth impairs the development of normal levels of NE in sympathetic perikarya by approximately 40%, and total ganglionic protein is similarly affected. NE turnover in sympathetic perikarya deafferented at birth is only slight reduced from normal. The response to neonatal deafferentation differs in the two terminal sympathetic plexuses. In neurons that project to the iris, no detectable NE turnover could be measured, although the content of transmitter attains 64% of control values after deafferentation.(ABSTRACT TRUNCATED AT 250 WORDS)

Dendritic development in the rat superior cervical ganglion.

Previous studies from our laboratory have shown that synaptogenesis in the superior cervical sympathetic ganglion (SCG) of the rat occurs predominantly during the first weeks after birth. The purpose of the present study was to examine the normal development of dendrites of the ganglion neurons, and to assess the importance of the afferent input in shaping this development. Two independent methods for examining dendritic morphology were used. One was to label neurons in the SCG by injecting a conjugate of horseradish peroxidase and wheat germ agglutinin (HRP-WGA) into a target of the SCG neurons (the submandibular gland). This procedure results in a 'Golgi-like' filling of the retrogradely labelled cell bodies and their dendrites. The second method was stereologic analysis (point-counting) of electron micrographs of sections of the SCG. At birth, the ganglion neurons give rise to an average of 2.4 primary dendrites and 1.2 secondary branches. No tertiary branches are observed at this age. The total dendritic length is 15.3 microns. Electron microscopic stereology reveals that the mean volume occupied by dendrites in the newborn SCG is 0.0093 mm3. In the adult, there is an average of 5.2 primary, 6.3 secondary, 4.8 tertiary and 1.9 quaternary dendrites. The total dendritic length is increased 23-fold to 347 microns. The mean volume occupied by dendrites is 0.0771 mm3, representing an 8-fold increase. In ganglia from adult rats which were deafferented at birth, an essentially normal dendritic form is attained. There are 4.5 primary, 6.2 secondary, 2.8 tertiary and 2.2 quaternary dendrites, and the total dendritic length is 297 microns. The mean volume of dendrites is 0.0571 micron3.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurotransmitter synthesis, storage, and turnover in neonatally deafferented sympathetic neurons.

In the superior cervical sympathetic ganglion (SCG) of the rat, a significant amount of morphological and biochemical maturation occurs in the first few postnatal weeks. The specific activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of norepinephrine (NE), increases during this time and is subject to transsynaptic regulation by the preganglionic inputs. In the present study, we examined the normal postnatal development of NE stores in sympathetic neurons and the transsynaptic regulation of this development. NE content undergoes an 8-fold increase from the time of birth, and stabilizes at adult levels at one month. Following neonatal deafferentation, there is a temporary stunting of NE accumulation in sympathetic neurons and a permanent reduction in the activity of TH, whether or not regeneration of the afferents occurs. When regeneration is prevented, the turnover of NE is significantly reduced, while NE levels rise to near normal levels. When regeneration is permitted, however, both the stored amount and turnover of NE attain normal levels. These data suggest that there is a critical period during the first two postnatal weeks when transsynaptic influences from afferents are necessary for the induction of TH in sympathetic neurons. Levels and turnover of transmitter do not have this critical period, but appear to depend solely on the functional integrity of the system.

[Determination of thyroxine in serum by a heterogeneous enzyme immunoassay: results of a joint trial]. / Bestimmung von Thyroxin im Serum mit einem heterogenen Enzymimmunoassay: Ergebnisse einer gemeinsamen Erprobung.

This paper describes the evaluation of a heterologous enzyme immunoassay for the determination of total thyroxine in serum by a group of seven clinical chemical laboratories. The test follows the principles of the enzyme linked immunosorbent assay (ELISA) and uses peroxidase as a marker. The evaluation of analytical reliability yielded the following results within the analytical range from 39 unto 322 nmol/l: 1. Within-batch precision ranged from 3.1 unto 10.4% (coefficient of variation) with single analyses. 2. Between-batch precision ranged from 3.7 unto 20.4% with single analyses. 3. Between-laboratories precision ranged from 5.4 unto 6.8%. 4. Pure thyroxine, added to serum or thyroxine-free serum, gave recoveries between 93 and 120%. 5. Analysis of control sera gave results essentially comparable to the assigned values based upon radioimmunoassays. 6. Analysis of 288 clinical sera gave slightly higher results by the enzyme immunoassay than by the analogous radioimmunoassay from the same manufacturer. 7. Comparison with other methods of analysis (radioimmunoassays, competitive protein ligand assays, hormonal iodine assay) yielded partly comparable, partly higher results. 8. Comparison with the homogenous enzyme immunoassay (EMIT) led to comparable results. 9. Interference due to hyperlipemia or hemolysis was not observed. 10. There might be an interference in hyperbilirubinaemic sera, due to an as yet unknown factor. With respect to practicability the ELISA-test compares favourably with the analogous solid phase radioimmunoassay. The main differences are the absence of radioactive material and a longer shelf-live of reagents. Following the manual procedure the time taken to perform the enzyme immunoassay is slightly longer than for the analogous radioimmunoassay.

[Clinical trial of a combination preparation of clonidine and cyclothiazide (author's transl)]. / Klinische Prüfung eines Kombinations-präparates von Clonidin und Cyclothiazid.

Three dosage combinations of clonidine and cyclothiazide were tested in at least 20 patients each, under clinical (4 weeks) and oupatients (longterm) conditions, in order to find a suitable combination with fewer side effects than the single drugs with at least equal efficacy for the longterm treatment of hypertension. The combination of 150 mcg clonidine and 2.5 mg cyclothiazide (Dimapres) in the form of a scored oblong sugar-coated tablet seems to satisfy these demands best and to be an optimal combination of clonidine and cyclothiazide. It is an antihypertensive agent which has shown particularly good results in mild and moderate hypertension, as demonstrated by daily measurement of blood pressure and ergometric tests.