Dose-escalation study evaluating pegylated interferon alpha-2a in patients with cutaneous T-cell lymphoma.

BACKGROUND: This open-label, multicenter, dose-escalation study evaluated the safety, tolerability, and efficacy of subcutaneous pegylated (40 kD) interferon α-2a (PEG-IFN α-2a) in patients with cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: PEG-IFN α-2a was administered subcutaneously at 180 (n = 4), 270 (n = 6), or 360 µg (n = 3) once weekly for 12 weeks. Efficacy was assessed by the proportion of patients with complete response (CR) or partial response (PR). RESULTS: PEG-IFN α-2a was generally well tolerated, with a moderate number of reductions or withholding of doses because of adverse events (AEs) (25% (n = 1), 66% (n = 4), and 0% (n = 0) in the 180-, 270-, and 360-µg/week groups, respectively). The only dose-limiting toxicity was a grade 3 elevation of liver enzymes in the 270-µg dose group. The most common AEs were fatigue, acute flu-like symptoms, and hepatic toxicity. The major response rate (CR or PR) was 50% in the 180-µg group (CR, 50%; PR, 0%), 83% in the 270-µg group (CR, 67%; PR, 17%), and 66% in the 360-µg group (CR, 33%; PR, 33%). CONCLUSION: PEG-IFN α-2a at doses up to 360 µg once weekly was well tolerated in patients with CTCL up to the highest dose group and showed good response rates. Due to their good tolerance even in high doses, they might be an option for patients not tolerating standard IFN-α preparations. However, for this purpose and to evaluate comparability between standard and PEG-IFN larger clinical trials are needed, alone and in combination with oral photochemotherapy (PUVA).

The effects of early or direct admission to a specialised spinal injury unit on outcomes after acute traumatic spinal cord injury.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: For acute traumatic spinal cord injury (ATSCI), this study aimed to determine differences in outcomes between patient groups stratified by admission time (⩽24 vs >24 h) to the Spinal Injury Unit (SIU) and by the nature of the admission (direct admission to the SIU vs indirect admission via another hospital). We also aimed to measure the effect on time to admission of a 'non-refusal' policy that triggered immediate acceptance of ATSCI cases to the SIU. SETTING: New South Wales, Australia. METHODS: Study population was all adult SCI patients admitted to the Prince of Wales SIU from 1 January 2001 to 31 December 2012. Patients admitted with chronic-stage SCI or with incomplete data for the duration of their stay were excluded. Comparison of outcomes was made between groups according to the setting of admission. Time to admission before and after initiation (2009) of the 'non-refusal' policy was compared. The prevalence of complications, lengths of stay (LOSs) and time to admission were compared by Mann-Whitney non-parametric methods. Count modelling was used to control for confounders of age and gender. RESULTS: A total of 460 cases were identified and 76 were excluded. The early group had fewer pressure areas (41.8% vs 63.2%; P<0.001) and shorter LOS (136 vs 172 days; P<0.001) than the late group. The direct group had fewer pressure areas (35.2% vs 54.9%, P<0.001), deep vein thrombosis (9.9% vs 24.6%, P=0.003) and shorter LOS (124 vs 158 days, P=0.007) than those admitted indirectly. Time to admission was reduced after introduction of the 'non-refusal' policy (1.53 vs 0.63 days; P=0.001). CONCLUSIONS: Early and direct admission to SIU reduced complication rates and LOS. A non-refusal policy reduced time to admission.

Unconventional apoptosis of polymorphonuclear neutrophils (PMN): staurosporine delays exposure of phosphatidylserine and prevents phagocytosis by MΦ-2 macrophages of PMN.

Apoptosis of polymorphonuclear neutrophils (PMN) and subsequent 'silent' removal represents an important check-point for the resolution of inflammation. Failure in PMN clearance resulting in secondary necrosis-driven tissue damage has been implicated in conditions of chronic inflammation and autoimmunity. Apoptotic PMN undergo profound biophysical changes that warrant their efficient recognition and uptake by phagocytes before fading to secondary necrosis. In this study, we demonstrate that staurosporine (STS), a non-selective but potent inhibitor of cyclin-dependent kinase and protein kinase C, exerts a drastic impact on PMN apoptosis. PMN treated with STS underwent an unconventional form of cell death characterized by a delayed exposure of aminophospholipids, including phosphatidylserine (PS) and phosphatidylethanolamine and an increased exposure of neo-glycans. STS caused an impaired cellular fragmentation and accelerated DNA fragmentation. Phagocytosis of STS-treated PMN lacking PS on their surfaces was decreased significantly, which highlights the importance of PS for the clearance of apoptotic PMN. Specific opsonization with immune complexes completely restored phagocytosis of STS-treated PMN, demonstrating the efficiency of back-up clearance pathways in the absence of PS exposure.

[Melanoma: introduction and special demands on radiology]. / Das Melanom: Einführung und besondere Anforderungen für die Radiologie.

CLINICAL ISSUE: The incidence of melanoma has rapidly increased in the last decades. Most relevant for patient prognosis is the tumor thickness, hence an early diagnosis is crucial. STANDARD TREATMENT: The basis of treatment is at the primary tumor stage and excision of regional metastases with curative intention. TREATMENT INNOVATIONS: Targeted therapies, such as BRAF and MEK inhibitors have the advantage of a rapid response even in highly advanced stages of the disease. DIAGNOSTIC WORK-UP: For routine diagnostics ultrasound, computed tomography (CT), fluorodeoxyglucose positron emission tomography CT (FDG-PET/CT) and magnetic resonance imaging (MRI) are used. PERFORMANCE AND ACHIEVEMENTS: In the treatment of distant metastases new treatment options are available which more than doubled patient survival rates. Especially immune therapies with immune checkpoint blockers, such as ipilimumab or PD-1 antibodies can lead to long-term survival of patients. In contrast to chemotherapy these new substances have characteristics which make new demands on radiologists related to the possibility of pseudoprogression in immune therapies, which make it necessary to use other response criteria. In addition, autoimmune phenomena, such as a sarcoid-like reactions may mimic new metastases and should be included in the differential diagnosis. BRAF inhibitors may lead to cystic conversions of metastases which again require an evaluation beyond the response evaluation criteria in solid tumors (RECIST), e.g. with the adapted Choi criteria. PRACTICAL RECOMMENDATIONS: Close interdisciplinary communication, functional imaging methods and adapted response criteria, such as the immune-related response criteria will optimize radiological evaluations of melanoma.

Nicotinic α4ß2 acetylcholine receptors and cognitive function in Parkinson's disease.

BACKGROUND: Idiopathic Parkinson's disease (IPD) is characterized by the clinical motor symptoms of hypokinesia, rigidity, and tremor. Apart from these motor symptoms, cognitive deficits often occur in IPD. The positive effect of cholinesterase inhibitors on cognitive deficits in IPD and findings of earlier molecular imaging studies suggest that the cholinergic system plays an important role in the origin of cognitive decline in IPD. METHODS: Twenty-five non-demented patients with IPD underwent a 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) SPECT to visualize α4ß2 nicotinic acetylcholine receptors (nAchR) and cognitive testing with the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) battery to identify domains of cognitive dysfunction. RESULTS: In the CERAD, the IPD patients exhibited deficits in non-verbal memory, attention, psychomotor velocity, visuoconstructive ability, and executive functions. After Bonferroni correction for multiple comparisons, we found significant correlations between performance of the CERAD subtests Boston Naming Test (a specific test for visual perception and for detection of word-finding difficulties) and Word List Intrusions (a specific test for learning capacity and memory for language information) vs binding of α4ß2 nAchR in cortical (the right superior parietal lobule) and subcortical areas (the left thalamus, the left posterior subcortical region, and the right posterior subcortical region). CONCLUSIONS: These significant correlations between the results of the CERAD subtests and the cerebral α4ß2 nAchR density, as assessed by 5-I-A-85380 SPECT, indicate that cerebral cholinergic pathways are relevant to cognitive processing in IPD.

Skin metastases in metastatic uveal melanoma: GNAQ/GNA11 mutational analysis as a valuable tool.

BACKGROUND: Uveal melanomas represent 3.1% of all melanomas, with a high potential of metastatic disease of up to 50%, where the median survival time is 6 months. Though liver metastases dominate as the primary site for metastasis, the existence of primary skin metastases is still under discussion but has been reported in only a few studies. OBJECTIVES: We present two cases in which patients with a known history of uveal melanoma developed melanoma skin metastases. METHODS: Mutational analysis was performed to clarify the origin of the metastases (uvea or skin). RESULTS: The analyses revealed GNA11 mutations, which are typical for uveal melanoma. These cases strongly suggest the skin to be the primary site of uveal melanoma. CONCLUSIONS: Knowledge about the mutational status of uveal melanomas opens the opportunity for future targeted therapies that directly interact with the mutation and its activated signal cascades. First trials in uveal melanoma have shown promising results with MEK inhibitors.

[Evaluation of intra-organisational effects after use of certification programmes in hospital]. / Evaluation einrichtungsinterner Effekte nach Durchführung eines Zertifizierungsverfahrens im Krankenhaus.

AIM: The introduction of quality management systems might be promoted by use of recognised certification programmes. Over the years, in health care organisations the certification model named KTQ has gained more and more importance. The aim of this study is to evaluate intra-organisational effects in a clinic after introduction of quality management on the basis of KTQ. METHODS: The evaluation was performed using a 2-step approach: first, before starting the implementation process of KTQ in the year 2008, and second, after the implementation process had become successful. Data were obtained by a systematic questionnaire survey. Hospital staff (physicians, nurses, and others like administration staff, technical and medical assistants) were asked to appraise the quality management, to give own preferences, and rate their overall satisfaction with the process. RESULTS: Response rates were 56% in the year 2008 and 50% in the year 2010. Subjects regarding the working atmosphere, leading of superiors, organisational issues, and pervasion of quality management predominantly were found to be improved, almost with high statistical significance. At the same time, higher satisfaction values could be determined. CONCLUSIONS: There might be high acceptance to the undergone changes from the staff members' point of view. It appears that the implementation process has led to higher satisfaction values. Moreover it can be concluded that certification programmes might be able to promote the needed pervasion of quality management throughout the institution.

Autoantibodies against galectin-2 peptides as biomarkers for the antiphospholipid syndrome.

Autoantibodies against opsonins of dying and dead cells mediate Fcγ receptor-dependent phagocytosis of autologous apoptotic and necrotic cells and hereby tend to elicit inflammation instead of silent clearance. We analysed sera of patients with chronic autoimmune diseases for the occurrence of IgG autoantibodies recognizing galectins. These pluripotent effectors can also bind to apoptotic or necrotic cells. Patients with antiphospholipid syndrome (APS; n = 104) and systemic lupus erythematosus (SLE; n = 62) were examined, healthy donors (n = 31) served as controls. Selected peptides of galectin (Gal)-2 were employed for peptide-based ELISAs. Levels of anti-Gal-2(PEP)-IgG were significantly increased in SLE and APS when compared with controls. In addition, patients with APS showed significantly higher levels of anti-Gal-2(PEP)-IgG compared with patients with SLE. Anti-Gal-2(PEP)-IgG may, therefore, be considered novel biomarkers for APS.

Comparison of pegylated interferon α-2b plus psoralen PUVA versus standard interferon α-2a plus PUVA in patients with cutaneous T-cell lymphoma.

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy profile of pegylated interferon α-2b (PEG-IFN α-2b) in combination with photochemotherapy (PUVA) in the treatment of cutaneous T-cell lymphoma (CTCL) in comparison with standard IFN α plus PUVA. DESIGN: Retrospective cohort study over a period of 7 years. PATIENTS AND INTERVENTIONS: A total of 17 consecutive CTCL patients (stage IA-IV) were retrospectively analysed for toxicity and response rates associated with PEG-IFN α-2b (1.5 µg/kg weekly) plus PUVA (n = 9) or standard IFN α-2a (9 MIU 3×/week) plus PUVA (n = 8). MAIN OUTCOME MEASURES: Differences of response rates (complete/partial remission), progression-free survival, discontinuation of therapy, safety and toxicity profiles according to World Health Organization - Common Terminology Criteria of Adverse Events (WHO-CTCAE). RESULTS: Myelosuppression and liver toxicity occured more frequently during PEG-IFN α-2b plus PUVA treatment than during standard IFN α-2a plus PUVA therapy [77.8 vs. 50% (odds ratio 1.477) and 77.8 vs. 50% (odds ratio 1.692), respectively]. By contrast, the occurence of constitutional side-effects (mainly fatigue) [100 vs.77.8% (odds ratio 0.889)] and more adverse events leading to study discontinuation was considerably higher in the standard IFN α-2a plus PUVA group. The overall response rate in the PEG-IFN α-2b plus PUVA group (89%) was significantly superior. CONCLUSIONS: In patients with cutaneous T-cell lymphoma PEG-IFN α-2b plus PUVA might become a promising treatment alternative as its higher rate of myelosuppression and liver toxicity is outweighed by its lower percentage of constitutional side-effects, and its significantly higher overall response. Due to the small number of participants at this retrospective study, a larger prospective study is essential to verify our results.

Economic burden of privately insured non-vertebral fracture patients with osteoporosis over a 2-year period in the US.

UNLABELLED: This study assesses the costs of non-vertebral osteoporosis-related fractures patients compared with osteoporosis patients without fractures, focusing on the second year following a fracture. Since fracture patients remained more costly in the second year, their economic burden extends beyond the year in which the fracture occurs. INTRODUCTION: The purpose of this study is to examine the comorbidity profile, resource use, and direct costs of patients who incur osteoporosis-related non-vertebral (NV) fractures in the United States during the 2 years following an incident fracture, focusing on the second year following a fracture. METHODS: Osteoporosis patients (ICD-9-CM: 733.0) with a NV fracture (hip, femur, pelvis, lower leg, upper arm, forearm, rib, and multiple sites) were selected from a privately insured health insurance claims database (>8 million lives, ages 18-64, 1999-2006). These NV fracture patients were randomly matched 1:1 on age, gender, employment status, and geographic region to controls with osteoporosis but without a fracture history. Year-by-year and month-by-month rates of comorbidities, resource use, and direct costs were calculated for the matched sample (N = 3,781). RESULTS: Comorbidity rates and resource use remained significantly higher among NV fracture patients during second year following an NV fracture compared with controls, although absolute rates of comorbidities and service utilization declined. Mean direct excess costs for NV fracture patients fell from $5,267 in the first year to $2,072 in the second year after a fracture, but remained statistically significant (p < 0.01). Patients with fractures of the pelvis, hip, and femur had the highest excess costs in the second year ($5,121, $3,930, and $3,828, respectively). Although hip fractures had highest excess costs over both years, non-vertebral, non-hip fracture patients made up a larger proportion of the sample and were significantly more costly than controls. CONCLUSIONS: Patients with osteoporosis-related NV fractures have substantial excess costs beyond the first year in which the fracture occurs.

Prevalence and costs of osteoporotic patients with subsequent non-vertebral fractures in the US.

UNLABELLED: This study assesses prevalence of subsequent fractures during the year after incident osteoporosis-related non-vertebral fractures among privately insured and Medicare populations and compares costs between patients with and without subsequent fractures. Many non-vertebral fracture patients incur subsequent fractures, and those who do are significantly more costly during the year after incident fracture. INTRODUCTION: To estimate the prevalence of subsequent osteoporosis-related non-vertebral (NV) fractures during the year following an incident NV fracture and compare costs between NV fracture patients with and without subsequent fractures. METHODS: Using insurance claims data (1999-2006), privately-insured (ages 18-64 years) and Medicare (ages 65+ years) patients with ≥1 subsequent osteoporosis-related NV fracture within a year of an incident osteoporosis-related NV fracture were matched to controls with incident NV fractures but no subsequent fractures. Subsequent fractures were identified as any claim for an NV fracture occurring >3 months after the incident NV fracture (>6 months were required for fractures occurring at the same site as the incident fracture). The study assessed prevalence of subsequent fractures and compared costs (from the payer's perspective) between patients with and without subsequent fractures over the year following an incident NV fracture. RESULTS: Among privately insured NV fracture patients, 14.1% had any subsequent NV fractures, 1.6% had subsequent hip fractures, and 13.0% had subsequent non-vertebral, non-hip (NVNH) fractures, while 22.6% of Medicare NV fracture patients had subsequent NV fractures, 9.4% had subsequent hip fractures, and 15.5% had subsequent NVNH fractures. Mean excess health care costs per privately insured subsequent fracture patient were $9,789 ($19,072 vs. $9,914, p < 0.01), while excess medical costs per Medicare subsequent fracture patient were $12,527 ($31,904 vs. $19,377, p < 0.01). CONCLUSIONS: NV fracture patients are at substantial risk for subsequent NV fractures within 1 year, and patients who incur subsequent fractures are significantly more costly than those who do not during the year following an incident fracture.

Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI): a modified outcome instrument for cutaneous lupus erythematosus.

BACKGROUND: In 2005, a scoring system (CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index) was developed for patients with cutaneous lupus erythematosus (CLE) to assess disease 'activity' and 'damage'. However, the CLASI does not give an accurate assessment of the severity in all disease subtypes. OBJECTIVES: The main objective of this study was to analyse critically the included parameters of the CLASI and to revise the activity and damage score taking into account various clinical features of the different subtypes of CLE. The revised CLASI (RCLASI) was also validated for use in clinical trials. Patients and methods A RCLASI was designed with regard to the anatomical region (i.e. face, chest, arms) and morphological aspects (i.e. erythema, scaling/hyperkeratosis, oedema/infiltration, scarring/atrophy) of skin lesions and evaluated by nine dermatologists who scored 12 patients with different subtypes of CLE to estimate inter- and intrarater reliability. RESULTS: Reliability studies demonstrated an intraclass correlation coefficient (ICC) for an inter-rater reliability of 0.89 for the activity score [95% confidence interval (CI) 0.79-0.96] and of 0.79 for the damage score (95% CI 0.62-0.92). The ICC for intrarater reliability for the activity score was 0.92 (95% CI 0.89-0.95) and the ICC for the damage score was 0.95 (95% CI 0.92-0.98). CONCLUSIONS: In the present study, a RCLASI was developed by experts, and reliability studies supported the validity and applicability of the revised scoring instrument for CLE. Thus, the RCLASI is a valuable instrument in multicentre studies and for the clinical evaluation of activity and damage in different disease subtypes.

[The role of incomplete clearance of apoptotic cells in the etiology and pathogenesis of SLE]. / Die Bedeutung einer unvollständigen Beseitigung apoptotischer Zellen für Atiologie und Pathogenese des SLE.

Systemic lupus erythematosus (SLE) is a complex prototypic autoimmune disease that is based on genetic factors (complement deficiencies) and is influenced by gender (female), environment (infections and UV irradiation), as well as random events (somatic mutations). The course of the disease is influenced by genes (e.g. FcgammaRIIA) and behaviour (sun-exposure). Inefficient clearance of dying cells and subsequent accumulation of apoptotic cell remnants is an intrinsic defect causing the permanent presence of cellular debris responsible for the initiation of autoimmunity. We favour the hypothesis that post-apoptotic debris accumulates in germinal centres, activates complement, and serves as a survival signal for B-cells that had stochastically become autoreactive in the process of somatic hypermutation (etiology). In the presence of autoantibodies against apoptotic cells or adaptor molecules the accumulation of post-apoptotic remnants (SNEC) causes immune complex formation and their pathological elimination, maintaining auto-inflammation. The SLE-type autoimmunity addresses nucleic acid-containing complex antigens (viromimetica). Autoantibody-protein-nucleic-acid complexes are likely to be mistaken for opsonised viruses. As a consequence, the immune system responds with the production of type-I interferons, a hallmark of SLE (pathogenesis). We conclude that the pathogenicity of autoantibodies is strongly increased if autoantigens are accessible and immune complexes are formed, which may be considered a binary pyrogen formed from less pro-inflammatory components. The accessibility of cognate autoantigens is likely to be related to impaired or delayed clearance of apoptotic cells.

Autoantigens are translocated into small apoptotic bodies during early stages of apoptosis.

A dysregulation of apoptosis or an ineffective clearance of apoptotic material is suspected to be involved in the pathogenesis of systemic lupus erythematodes. Subcellular fragments such as apoptotic bodies (ABs) have been recognized as modulators of intercellular communication and immune function. In this context, we have been interested whether nuclear and cytoplasmic antigens are relocated into ABs. In the present study, we characterized ABs isolated from apoptozing lymphoblasts. We found an accumulation of the linker-histone (histone 1) as well as the core-histones (histone 2A, histone 2B, histone 3, histone 4) in ABs. Further, they contained DNA, RNA and the ribonuclear protein La/SSB. Proteins such as cytochrome c, HSP 70, prohibitin, p53, nuclear matrix antigen or lamin B were excluded from ABs. The content of ABs differed from that observed in membrane microparticles isolated from viable cells. Formation of ABs occurred early during apoptosis. It was observed before DNA-degradation or phosphatidylserine exposure was detected. ABs were engulfed by monocyte-derived phagocytes. These findings suggest that immunogenic molecules are actively translocated into ABs followed by a rapid engulfment of the latter by environmental phagocytes. In autoimmune diseases, a defect in the clearance of ABs or AB formation may contribute to the development of autoimmunity.

Incremental build-up food challenge--a new diagnostic approach to evaluate pseudoallergic reactions in chronic urticaria: a pilot study: stepwise food challenge in chronic urticaria.

BACKGROUND: The remission rate of patients with chronic urticaria (CU) due to elimination diets varies between 31% and 71%. However, the diagnostic value of subsequent traditional oral provocation tests with food additives in capsules remains unsatisfactory. OBJECTIVES: A newly incremental build-up food challenge (IBUF) for patients with CU was designed and implemented in an open pilot study. Primary endpoint was the percentage of patients developing urticaria during at least one step of IBUF after an initial complete remission due to a pseudoallergen-free elimination diet. METHODS: In total, 153 patients with CU were submitted for 5 weeks to a pseudoallergen-free diet. All patients with remission were included to the 6-week IBUF protocol, containing pseudoallergen-rich foods in a systematic and additive manner. The recurrence and severity of CU was evaluated by urticaria score. Subjective disturbance and quality of life were evaluated by patients' diary, visual analogue scale and quality of life questionnaire (CU-Q2oL). Subsequently, patients were followed up for 3-24 months after IBUF by a telephone interview. RESULTS: A total of 104 patients completed the pseudoallergen-free diet, whereby 51% reported partial, 17% complete and 32% no remission due to the diet. All diet responders showed a decrease in subjective impairment, urticaria and quality of life score (P<0.001 each). Eighty-six percent (12/14) of the patients reaching complete remission, showed a recurrence of urticaria symptoms during the IBUF protocol. Fifty-eight percent (7/12) of these patients still remained free of symptoms due to avoidance of IBUF-identified foods at telephone follow-up. In patients with partial remission to pseudoallergen-free diet, however, IBUF did not provide information about the cause of urticaria symptoms. CONCLUSIONS: The newly developed IBUF protocol seemed to be a promising method for identifying individually incompatible foods in some CU patients. IBUF should be verified by randomized controlled trials to gain additional evidence for its diagnostic value.

Induction of integral membrane PAM expression in AtT-20 cells alters the storage and trafficking of POMC and PC1.

Peptidylglycine alpha-amidating monooxygenase (PAM) is an essential enzyme that catalyzes the COOH-terminal amidation of many neuroendocrine peptides. The bifunctional PAM protein contains an NH2-terminal monooxygenase (PHM) domain followed by a lyase (PAL) domain and a transmembrane domain. The cytosolic tail of PAM interacts with proteins that can affect cytoskeletal organization. A reverse tetracycline-regulated inducible expression system was used to construct an AtT-20 corticotrope cell line capable of inducible PAM-1 expression. Upon induction, cells displayed a time- and dose-dependent increase in enzyme activity, PAM mRNA, and protein. Induction of increased PAM-1 expression produced graded changes in PAM-1 metabolism. Increased expression of PAM-1 also caused decreased immunofluorescent staining for ACTH, a product of proopiomelanocortin (POMC), and prohormone convertase 1 (PC1) in granules at the tips of processes. Expression of PAM-1 resulted in decreased ACTH and PHM secretion in response to secretagogue stimulation, and decreased cleavage of PC1, POMC, and PAM. Increased expression of a soluble form of PAM did not alter POMC and PC1 localization and metabolism. Using the inducible cell line model, we show that expression of integral membrane PAM alters the organization of the actin cytoskeleton. Altered cytoskeletal organization may then influence the trafficking and cleavage of lumenal proteins and eliminate the ability of AtT-20 cells to secrete ACTH in response to a secretagogue.

FES-propelled cycling of SCI subjects with highly spastic leg musculature.

BACKGROUND: The presence of spasms precludes the use of artificial electrical activation of the muscles to restore mobility. The prospect of using an electrical stimulus that produces motor activation without causing unwanted reflex activation in patients with high levels of spasticity is an appealing one. OBJECTIVE: The purpose of the study was to determine the efficacy of modulated middle frequency alternating current (MFAC) muscle stimulation compared to the conventional method of standard low frequency rectangular pulse (LFRP) stimulation used in cycling of persons with spinal cord injury (SCI) and pronounced spasticity. METHODS: To evaluate cycling-relevant differences between stimulation modes, 13 subjects with SCI (ASIA-A), 11 of them with strong spasticity, underwent isometric and cycling measurements using both 20 Hz LFRP and 4 KHz modulated with 50 Hz MFAC. The isometric long-lasting reflex torque response in the quadriceps and hamstrings muscles, and the dynamic work during 1000 sec of ergometric cycling as well as the number of involuntary stops caused by hyperreflexia were recorded. RESULTS: The long-lasting reflex torque response was significantly lower when using MFAC than with LFRP stimulation. During MFAC stimulation work generated was on average 374% higher (p = 0.002) and the number of involuntary stops was on average 32% lower (p < 0.001) than during standard LFRP stimulation-propelled cycling. CONCLUSION: These findings suggest that MFAC-stimulated cycling of strongly spastic SCI subjects is more effective in terms of generated isometric torque and power than stimulation with LFRP. Thus, more health benefits, e.g., cardiovascular and muscular training and spasticity-decreasing effects, can be expected faster using MFAC instead of LFRP in stimulation-propelled cycling.

[Psychosocial issues in outpatient care of acne vulgaris]. / Psychosoziale Versorgungssituation in der ambulanten Akne-Behandlung.

OBJECTIVE: This survey aims to identify psychosocial issues in the outpatient care of acne vulgaris in dermatological and paediatric practices. The main object of the study lies on the impact of psychosocial stresses and strains, and offers of support in medical care. METHOD: Questionnaires were sent out to all dermatologists and paediatricians in private practice in Westphalia-Lippe (n=678) using a combined quantitative and qualitative approach. The average response rate was 41.0% (n=278), for paediatrics 43.7% (n=190) and dermatology 36.3% (n=88), respectively. Methods of descriptive statistics were applied. Qualitative data were analysed using a qualitative content analysis. RESULTS: From the physicians' point of view several needs of psychosocial care are seen, however, predominantly focussing on psychotherapeutic and inpatient medical care. Correspondingly, patients' demands for psychosocial care were also indicated. The responding physicians were not aware of low threshold offers of support such as self-help, support and advocacy organisations, social services or help-desks. These offers do not play an important role in outpatient care. Altogether only a minor group of respondents cooperates with these named institutions providing psychosocial care services. CONCLUSIONS: The integration of psychosocial care is not common practice in the outpatient care of acne vulgaris. On the one hand physicians are willing to cooperate with caring institutions inside and outside the health care system; on the other hand cooperation is limited by lots of structural and fiscal barriers. The mental and psychological stresses related to acne vulgaris are evident and important for social and emotional development of children and adolescents. Although this fact is actually being perceived, the implementation of psychosocial issues is medical practice remains inadequate.

[Evaluation of a multimodal pain therapy at the University Pain Centre Dresden]. / Evaluation einer multimodalen Schmerztherapie am UniversitätsSchmerzCentrum Dresden.

BACKGROUND: Data of a multimodal pain management program of the multidisciplinary pain management centre at the University Hospital of Dresden is presented. Over a period of 4 weeks, supplemented by an additional week 3 months later (booster week), patients with chronic pain of different origins are being treated in groups of 12. Based on the principles of the biopsychosocial pain model and the idea of functional restoration, the program is dedicated for pain patients where outpatient treatment was insufficient. METHODS: The program was evaluated on the basis of pain intensity (NRS), pain disability (PDI), fear and depression (HADS-D), catastrophizing (CSQ) and health-related quality of life and vitality (SF-36). The data were collected at the beginning and end of the initial 4 week treatment period, at the end of the booster period as well as 6 and 12 months after the end of active treatment. RESULTS: A total of 189 patients were included in the program in the period from January 2006 until August 2008. All outcome parameter showed statistically significant improvements with small to high effect sizes (ES 0.20-0.95). The results stayed stable even 1 year after the treatment. The highest effect sizes were found in catastrophizing (ES 0.86) and average pain intensity (ES 0.95). The primary pain diagnosis (e. g. low back pain versus headache) had no impact on treatment outcome. CONCLUSION: Significant and clinically relevant improvements could be achieved with the multimodal pain management program in groups of 12 patients. The results were stable over a time period of 1 year. Pain diagnosis had no impact on the outcome.

Hadean geodynamics inferred from time-varying 142Nd/144Nd in the early Earth rock record.

Tracking the secular evolution of 142Nd/144Nd anomalies is important towards understanding the crust-mantle dynamics in the early Earth. Excessive scatter in the published data, however, precludes identifying the fine structure of 142Nd/144Nd evolution as the expected variability is on the order of few parts per million. We report ultra-high precision 142Nd/144Nd data for Eoarchean and Palaeoarchean rocks from the Isua Supracrustal Belt (SW Greenland) that show a well-resolved 142Nd/144Nd temporal variability suggesting progressive convective homogenisation of the Hadean Isua depleted mantle. This temporally decreasing 142Nd/144Nd signal provides a direct measure of early mantle dynamics, defining a stirring timescale of <250 Myr consistent with vigorous convective stirring in the early mantle. The 142Nd/144Nd evolution suggests protracted crustal residence times of ~1000-2000 Myr, inconsistent with modern-style plate tectonics in the Archean. In contrast, a stagnant-lid regime punctuated by episodes of mantle overturns accounts for the long life-time estimated here for the Hadean proto-crust.