[Akinetic mutism due to fulminant multilocular cerebral venous thrombosis, including the vein of Galen]. / Akinetischer Mutismus bei fulminanter multilokulärer Sinus- und Venenthrombose einschließlich der Vena Galeni.

Cerebral venous thrombosis may present with multifaceted symptoms and therefore be difficult to diagnose. Only few evidence-based data exist with respect to therapy and prognosis, especially concerning the deep cerebral venous system. A thrombosis of the vein of Galen is deemed to have a poorer prognosis. Our case report describes the local combined neuro-interventional therapy as an individual attempt to cure a patient with a fulminant disease course.

Treatment of post-implantation aneurysm growth by laparoscopic sac fenestration: long-term results.

OBJECTIVES: Sac growth after endovascular aneurysm repair (EVAR) is an important finding, which may influence prognosis. In case of a type II endoleak or endotension, clipping of side branches and subsequent sac fenestration has been presented as a therapeutic alternative. The long-term clinical efficacy of this procedure is unknown. METHODS: The study included eight patients who underwent laparoscopic aortic collateral clipping and sac fenestration for enlarging aneurysms following EVAR. Secondary interventions and clinical outcome were retrieved from hospital records. Sac behaviour was evaluated measuring volumes on periodical computed tomography angiography (CTA) imaging using dedicated software. RESULTS: Follow-up had a median length of 6.6 (range 0.6-8.6) years. During this time, only three patients successfully achieved durable aneurysm shrinkage (n = 2) or stability (n = 1). The remaining patients suffered persistent (n = 2) or recurrent sac growth (n = 3), all regarded as failure of fenestration. A total of six additional interventions were performed, comprising open conversion (n = 2), relining (n = 1) and implantation of iliac extensions (n = 3). All additional interventions were successful at arresting further sac growth during the remainder of follow-up. CONCLUSIONS: Despite being a less invasive alternative to conversion and open repair, the long-term outcome of sac fenestration is unpredictable and additional major procedures were often necessary to arrest sac growth.

[Actual state and prospects of acute stroke treatment in the Grand-Duchy of Luxemburg]. / Aktueller Stand und Perspektiven der Akutbehandlung des Schlaganfalls im Grossherzogtum Luxemburg 2011.

Stroke is a neurological emergency condition that warrants immediate hospitalisation on a stroke unit, where a dedicated team offers state-of-the-art diagnostic and therapeutic measures. Stroke units have shown to reduce mortality and handicap especially if thrombolysis is possible. A critical mass of stroke patients with standardised, simplified and automated processes is required to achieve good results. Stroke teams are no alternative to a stroke unit as a geographic unit. A turnover of less than 200-250 strokes per year is associated with a worse patient outcome and the treatment effect of a stroke unit may be abolished. The situation in Luxembourg offers the possibility to create units of this size and performance if all the concerned physicians and hospitals, health insurance and health administration join their efforts.

Decision-making in type-B dissection: current evidence and future perspectives.

Aortic dissection is a devastating cardiovascular condition with an incidence of 3,5:100 000. It is classified according to anatomic extent, mechanism of lesion, duration from index event and course (uncomplicated vs. complicated). Intramural hematoma and penetrating aortic ulcers share many of the features of classic dissections, but tend to occur in older patients with advanced atherosclerosis. In uncomplicated type-B dissection, conservative treatment with tight blood pressure and heart rate control is safe and effective. Early stent-graft implantation may, however, result in more favorable aortic remodeling and reduced late complications. For acute complicated cases intervention is usually required. Stent-graft coverage of the entry tear frequently resolves malperfusion, but the role of the false lumen in organ perfusion must be assessed and endovascular revascularization performed if necessary. In chronic type-B dissections, coverage of the entry tear likely results in continued pressurization of the false lumen due to rigidity of the dissecting membrane and distal fenestrations. Better understanding of the different disease mechanisms involved, imaging advances and introduction of dedicated stent-grafts are expected to further improve patient outcomes in the future. Primary and secondary pharmacological prevention, stricter follow-up protocols and screening of family members may also prove valuable. Better patient selection will allow preventive treatment with low morbidity for those at higher risk of complications.

Device-specific outcomes after endovascular abdominal aortic aneurysm repair.

Over the last decade, endovascular aneurysm repair (EVAR) has been used extensively for the elective treatment of infra-renal abdominal aneurysms. However, it remains unclear how specific devices perform and how they compare to others. We provide an overview of currently used endografts, and discuss the current evidence regarding device-specific outcomes. Published literature confirms differences in results according to endograft selection. These differences were more pronounced with older generations of devices, in comparison to newer models. Contemporary results are generally good and one should remember that no randomized data exist regarding individual device performance. Moreover, by the time there is enough follow-up to draw conclusions, the data is relatively obsolete due to constant improvements in endograft technology and design. Results from EVAR have been steadily improving and individualized device selection has shown to be valuable. It appears that patients with favorable anatomy do well with most modern endografts. Those with challenging anatomies may benefit more from a particular design, delivery and deployment feature requiring greater knowledge and experience for adequate device selection.

Structure, mapping, and expression of erp, a growth factor-inducible gene encoding a nontransmembrane protein tyrosine phosphatase, and effect of ERP on cell growth.

We have characterized a growth factor-inducible gene, erp, and demonstrated that it encodes a 367-amino-acid nontransmembrane tyrosine phosphatase protein with significant similarity to the vaccinia virus H1 protein. Immunoprecipitation analyses show that the erp protein, ERP, is rapidly induced following serum stimulation of quiescent fibroblasts. ERP has been expressed as a fusion protein with glutathione S-transferase and shown to have tyrosine as well as serine protein phosphatase activity. The enzymatic activity of ERP depends on the presence of reducing agents such as dithiothreitol, and its tyrosine phosphatase activity is inhibited by sodium vanadate, a potent inhibitor of protein tyrosine phosphatases. The number of stable NIH 3T3 clones obtained after transfection with a vector expressing the complete ERP protein is reduced more than 90% compared with that after transfection with a vector expressing a mutated inactive ERP protein. The remaining ERP-expressing clones present a significant increase in the proportion of bi- and multinucleated cells and a decrease in proliferation rate. Studies on the genomic structure reveal that the erp transcription unit is 2.8 kbp long and split into four exons. The erp gene maps to the 17A2-17C region of the murine genome. Our results demonstrate that the protein product of the immediate-early gene erp has a negative effect on cell proliferation.

c-Fos-induced activation of a TATA-box-containing promoter involves direct contact with TATA-box-binding protein.

Transcriptional activation in eukaryotes involves protein-protein interactions between regulatory transcription factors and components of the basal transcription machinery. Here we show that c-Fos, but not a related protein, Fra-1, can bind the TATA-box-binding protein (TBP) both in vitro and in vivo and that c-Fos can also interact with the transcription factor IID complex. High-affinity binding to TBP requires c-Fos activation modules which cooperate to activate transcription. One of these activation modules contains a TBP-binding motif (TBM) which was identified through its homology to TBP-binding viral activators. This motif is required for transcriptional activation, as well as TBP binding. Domain swap experiments indicate that a domain containing the TBM can confer TBP binding on Fra-1 both in vitro and in vivo. In vivo activation experiments indicate that a GAL4-Fos fusion can activate a promoter bearing a GAL4 site linked to a TATA box but that this activity does not occur at high concentrations of GAL4-Fos. This inhibition (squelching) of c-Fos activity is relieved by the presence of excess TBP, indicating that TBP is a direct functional target of c-Fos. Removing the TBM from c-Fos severely abrogates activation of a promoter containing a TATA box but does not affect activation of a promoter driven only by an initiator element. Collectively, these results suggest that c-Fos is able to activate via two distinct mechanisms, only one of which requires contact with TBP. Since TBP binding is not exhibited by Fra-1, TBP-mediated activation may be one characteristic that discriminates the function of Fos-related proteins.

Emerging trends in health and productivity management.

Many large U.S. employers have generally embraced a Health and Productivity Management (HPM) perspective to guide their multiple employee health management efforts. In looking ahead there are a number of emerging trends that are helping to shape these efforts. As health promotion professionals assess the implications of these trends on their respective role and function within the worksite, it may provide a very useful process for refining strategies for programming and professional development. The identified trends also have a variety of implications for health promotion vendors and the growth of the health management marketplace.

The helix-loop-helix protein rE12 and the C/EBP-related factor rNFIL-6 bind to neighboring sites within the c-fos serum response element.

We show that members of two major families of transcription factors, the helix-loop-helix and C/EBP families, interact with the c-fos serum response element (SRE). Two cDNA clones encoding SRE binding factors (clones 9 and 21) were isolated by the direct screening of a PC12 lambda gt11 cDNA library using SRE oligonucleotide sequences as probes. Clone 9 encodes the rat homolog of the human HLH transcription factor, E12 (called here rE12). Clone 21 encodes a b-zip domain polypeptide that is related to the liver transcription factor C/EBP, and is homologous to the human NFIL-6 transcription factor (called here rNFIL-6). Using in vitro-translated products we show that rNFIL-6 recognizes a 'CCAATT' motif which overlaps the c-fos dyad symmetry element (DSE), the binding site for serum regulatory factor (SRF). Factor rE12 binds to an E-box enhancer sequence, 'CATCTG', immediately adjacent to the rNFIL-6 site, within the SRE. Antibodies specific to rE12 and rNFIL-6 disrupt nucleoprotein complexes with these DNA-binding sites, confirming the interaction of native in vivo factors. We present evidence that rNFIL-6 and SRF binding are mutually exclusive, consistent with the overlap of their binding sites. The demonstration that rE12 and rNFIL-6 bind to the SRE at sites adjacent to the major c-fos regulatory element, the DSE, raises the possibility that helix-loop-helix and C/EBP families regulate the SRE and provide a new basis for the multifunctional properties of the SRE, including possible tissue specificity of expression.

Regulation of Fra-1 and Fra-2 phosphorylation differs during the cell cycle of fibroblasts and phosphorylation in vitro by MAP kinase affects DNA binding activity.

The Fos family of transcription factors, c-Fos, FosB, Fra-1 and Fra-2, are rapidly induced in quiescent fibroblasts following serum or growth factor stimulation. The Fos proteins show distinct patterns of expression during cell growth with only Fra-1 and Fra-2 maintained at significant levels in growing cells, suggesting that the different family members direct unique functions for cell growth. Post-translational modification of Fos proteins has been observed following serum stimulation, which may allow an additional level of regulation. Our studies show that the synthesis and post-translational modification of Fra-1 and Fra-2 in Swiss 3T3 cells is serum-dependent during G1 following the transition from G0 and during asynchronous growth but is serum-independent during S phase and mitosis. Post-translational modification of Fra-1 and Fra-2 causes a significant shift in their gel mobility which is eliminated by alkaline phosphatase treatment. Several kinases can phosphorylate Fra-1 and Fra-2 in vitro, including cAMP-dependent kinase (PKA), protein kinase C (PKC), cyclin-dependent kinase 1-cdc2 (cdc2), and mitogen activated protein (MAP) kinase. From these, MAP kinase is the only one that causes a shift in gel mobility similar to that observed in vivo. One dimensional phosphopeptide maps of Fra-1 and Fra-2 phosphorylated by MAP kinase in vitro are similar to those of in vivo labeled Fra-1 and Fra-2, suggesting that MAP kinase may also phosphorylate Fra-1 and Fra-2 in vivo. We have also determined that phosphorylation of Fra-1 and Fra-2 by MAP kinase increases their DNA binding activity.

A randomized double-blind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy.

Seventy-five breast cancer patients scheduled to receive a first course (in a new cycle) of cyclophosphamide, fluorouracil, and doxorubicin (FAC) or epirubicin (FEC) participated in a double-blind crossover study to compare the antiemetic efficacy and safety of ondansetron (GR38032), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, and metoclopramide. Ondansetron was given as an 8 mg loading dose (4 mg intravenously [IV] plus 4 mg orally) before chemotherapy followed by 8 mg every 8 hours orally for 3 to 5 days. Metoclopramide was given as an 80 mg loading dose (60 mg IV plus 20 mg orally) before chemotherapy followed by 20 mg every 8 hours orally for 3 to 5 days. A "period" interaction in the analysis of emetic response in the first 24 hours necessitated a parallel group analysis of first treatments only, 68 patients being assessable for this parameter. In the first 24 hours, complete or major control (zero to two emetic episodes) of emesis was achieved in 30 of 35 (86%) patients receiving ondansetron and in 14 of 33 (42%) patients receiving metoclopramide (P less than .001). Ondansetron was also more effective in reducing acute nausea. On days 2 to 3, the complete or major responses were significantly better with ondansetron (81% v 65%; P = .033), but there was no statistical difference in the control of nausea. There was a significant patient preference for ondansetron (63% v 26%; P = .001). Extrapyramidal reactions were observed in two metoclopramide treatments; both treatments were otherwise well tolerated. These results are consistent with serotonin (5-HT), being a significant neurotransmitter of cyclophosphamide/doxorubicin- or epirubicin/fluorouracil-induced emesis.

Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration.

PURPOSE: To determine the long-term impact on disease-free survival (DFS) and overall survival (OS) of adjuvant anthracycline-based chemotherapy, when prospectively compared by random allocation with standard cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive (N+) breast cancer patients. PATIENTS AND METHODS: Two hundred forty-nine patients with N+ breast cancer, recruited from eight French cancer centers, were randomized to receive 12 monthly cycles of adjuvant chemotherapy, either CMF (n = 112) or doxorubicin, vincristine, cyclophosphamide, and fluorouracil (AVCF) (n = 136). All had a negative metastatic work-up before inclusion, which was stratified by accrual center, tumor stage (International Union Against Cancer [UICC]), and menopausal status. RESULTS: No severe adverse effect related to grade 4 (World Health Organization [WHO]) toxicity was observed. There was no difference in second primary tumor incidence between the two arms. The treatment given was 88% of planned for AVCF and 75% for CMF in both premenopausal and menopausal patients. With a median follow-up time of 16 years (range, 13 to 17), the OS and DFS rates are significantly longer in the AVCF arm (56% v 41% [P = .01] for OS, and 53% v 36% [P = .006] for DFS). These differences are significant, irrespective of tumor stage (T1 to T2 v T3 to T4), and remain positive in patients with or without postoperative locoregional radiotherapy (55% of cohort). When analyzed according to menopausal status, the differences remain significant only for premenopausal patients. CONCLUSION: This set of mature controlled data confirms the added value of anthracycline-based combination adjuvant therapy for N+ breast cancer patients when compared with CMF, with both regimens given for 1 year.

Comparative analysis of individuals with and without chiropractic coverage: patient characteristics, utilization, and costs.

BACKGROUND: Back pain accounts for more than $100 billion in annual US health care costs and is the second leading cause of physician visits and hospitalizations. This study ascertains the effect of systematic access to chiropractic care on the overall and neuromusculoskeletal-specific consumption of health care resources within a large managed-care system. METHODS: A 4-year retrospective claims data analysis comparing more than 700 000 health plan members with an additional chiropractic coverage benefit and 1 million members of the same health plan without the chiropractic benefit. RESULTS: Members with chiropractic insurance coverage, compared with those without coverage, had lower annual total health care expenditures ($1463 vs $1671 per member per year, P<.001). Having chiropractic coverage was associated with a 1.6% decrease (P = .001) in total annual health care costs at the health plan level. Back pain patients with chiropractic coverage, compared with those without coverage, had lower utilization (per 1000 episodes) of plain radiographs (17.5 vs 22.7, P<.001), low back surgery (3.3 vs 4.8, P<.001), hospitalizations (9.3 vs 15.6, P<.001), and magnetic resonance imaging (43.2 vs 68.9, P<.001). Patients with chiropractic coverage, compared with those without coverage, also had lower average back pain episode-related costs ($289 vs $399, P<.001). CONCLUSIONS: Access to managed chiropractic care may reduce overall health care expenditures through several effects, including (1) positive risk selection; (2) substitution of chiropractic for traditional medical care, particularly for spine conditions; (3) more conservative, less invasive treatment profiles; and (4) lower health service costs associated with managed chiropractic care. Systematic access to managed chiropractic care not only may prove to be clinically beneficial but also may reduce overall health care costs.

Effects of a managed chiropractic benefit on the use of specific diagnostic and therapeutic procedures in the treatment of low back and neck pain.

OBJECTIVE: The aim of this study was to measure the effects of a managed chiropractic benefit on the rates of specific diagnostic and therapeutic procedures for the treatment of back pain and neck pain. DESIGN: This study is a retrospective analysis of claims data from a managed-care health plan over a 4-year period. The use rates of advanced imaging, surgery, inpatient care, and plain-film radiographs were compared between employer groups with and without a chiropractic benefit. RESULTS: For patients with low back pain, the use rates of all 4 studied procedures were lower in the group with chiropractic coverage. On a per-episode basis, the rates in the group with coverage were reduced by the following: surgery (-32.1%); computed tomography (CT)/magnetic resonance imaging (MRI) (-37.2%); plain-film radiography (-23.1%); and inpatient care (-40.1%). On a per-patient basis, the rates were reduced by the following: surgery (-13.7%); CT/MRI (-20.3%); plain-film radiography (-2.2%); and inpatient care (-24.8%). For patients with neck pain, the use rates were reduced per episode in the group with chiropractic coverage as follows: surgery (-49.4%); CT/MRI (-45.6%); plain-film radiography (-36.0%); and inpatient care (-49.5%). Per patient, the rates were surgery (-31.1%); CT/MRI (-25.7%); plain-film radiography (-12.5%); and inpatient care (31.1%). All group differences were statistically significant. CONCLUSION: For the treatment of low back and neck pain, the inclusion of a chiropractic benefit resulted in a reduction in the rates of surgery, advanced imaging, inpatient care, and plain-film radiographs. This effect was greater on a per-episode basis than on a per-patient basis.

The selection effects of the inclusion of a chiropractic benefit on the patient population of a managed health care organization.

OBJECTIVE: The aim of this study is to measure the selection effects of the inclusion of a chiropractic benefit on a managed care health plan. DESIGN: An analysis of enrollment data from a managed care health plan over a 4-year period was conducted. Employers could select the managed care plan with or without a chiropractic care benefit. Comparisons of demographic and comorbid characteristics were made between employees who had the chiropractic benefit and those who did not, and between individuals who self-selected chiropractic care and those who self-selected medical care. RESULTS: The cohort with chiropractic coverage was younger with fewer subjects in the older age group (>65 years; 6.5% vs 9.6%) and more subjects in the younger age group (0-17 years; 31.9% vs 26.2%). The mean age of the group with coverage was 32.9 compared with 35.5 in the group without coverage. Comparing self-selected chiropractic patients to self-selected medical patients, there were fewer subjects older than 65 years in the chiropractic group (4.9% vs 9.2%) and fewer subjects aged 0 to 17 years (9.4% vs 19.4%). In 6 of the 8 comorbid conditions studied, the rates were lower in the cohort with chiropractic coverage compared with the group without coverage. The rates of comorbid conditions in self-selected chiropractic patients were lower in all 8 categories compared with self-selected medical patients. CONCLUSION: The inclusion of a chiropractic benefit in a health plan produces a modest favorable selection processes resulting in a slightly younger patient population with fewer comorbidities. At the level of patient self-selection, chiropractic patients are considerably younger and healthier than comparable medical patients.

Chiropractic as spine care: a model for the profession.

BACKGROUND: More than 100 years after its inception the chiropractic profession has failed to define itself in a way that is understandable, credible and scientifically coherent. This failure has prevented the profession from establishing its cultural authority over any specific domain of health care. OBJECTIVE: To present a model for the chiropractic profession to establish cultural authority and increase market share of the public seeking chiropractic care. DISCUSSION: The continued failure by the chiropractic profession to remedy this state of affairs will pose a distinct threat to the future viability of the profession. Three specific characteristics of the profession are identified as impediments to the creation of a credible definition of chiropractic: Departures from accepted standards of professional ethics; reliance upon obsolete principles of chiropractic philosophy; and the promotion of chiropractors as primary care providers. A chiropractic professional identity should be based on spinal care as the defining clinical purpose of chiropractic, chiropractic as an integrated part of the healthcare mainstream, the rigorous implementation of accepted standards of professional ethics, chiropractors as portal-of-entry providers, the acceptance and promotion of evidence-based health care, and a conservative clinical approach. CONCLUSION: This paper presents the spine care model as a means of developing chiropractic cultural authority and relevancy. The model is based on principles that would help integrate chiropractic care into the mainstream delivery system while still retaining self-identity for the profession.

Flocculation and loss of potency of human NPH insulin.

In late 1986, several vials of Humulin N (NPH human insulin, recombinant DNA origin) came to our attention because of a clumped, white coating on the inside of the vials. To determine the frequency of this phenomenon, we surveyed 100 consecutive patients who used Humulin N. Ten patients had encountered 21 vials of flocculated insulin in the previous 12 mo, reflecting an incidence of 1 per 72 vials. Insulin drawn from affected vials was markedly reduced in potency: 20.9 +/- 3.4 U/ml vs. the labeled potency of 100 U/ml. Several patients reporting flocculated insulin, including one hospitalized with ketoacidosis, experienced unusual and unexplained elevation in blood glucose concentration for several days before flocculation was observed. Patients who use NPH human insulin should be aware of this phenomenon and carefully inspect their vials for evidence of insulin precipitation before each injection.

Phase II study of pirarubicin (THP) in patients with cervical, endometrial and ovarian cancer: study of the Clinical Screening Group of the European Organization for Research and Treatment of Cancer (EORTC).

From 1986 to 1990, a multicentric phase II study was conducted with pirarubicin, a new semi-synthetic anthracyclin[4'-O-tetrahydropyranyl-adriamycin (THP)]. 87 patients with advanced gynaecological cancers were treated: epidermoid cervical carcinoma (n = 31), adenocarcinoma of the endometrium (n = 28) and ovarian adenocarcinoma (n = 28). THP was administered by short intravenous infusion, for 3 consecutive days, every 3 weeks. The initial dose of THP was 25 mg/m2 day (25% of patients) which was then reduced to 20 mg/m2 day. The average number of courses was 3.7 (range 1-10). The cumulative THP dose was 180 mg/m2 (range 56-594) in cervix and endometrial tumours and 121 mg/m2 (range 58-425) in ovarian tumours. Myelosuppression was the major observed toxicity with grade 3-4 leukopenia and thrombocytopenia in 62 and 19% of the patients, respectively. Severe general complications occurred in 6% of the patients with three fatalities due to infections. Gastro-intestinal side-effects were frequent and usually mild (7% of grade 3 vomiting). 48% of the patients showed alopecia, which was complete in 9 cases (10%). 3 patients experienced cardiac events. No significant antitumoral activity was observed in patients who had failed to respond to previous chemotherapy. Promising antitumoral activity was noticed in untreated cervico-uterine carcinomas with 19% partial responses and 12% complete responses (CR). THP activity was lower in endometrial carcinomas (9.5% CR). Results were found to be negligible in ovarian cancer patients, most of them being refractory to previous chemotherapy containing an anthracyclin compound. On the basis of these results, the definite role of THP in gynaecological cancers deserves to be studied in more favourable programmes (e.g. in combined protocols as first-line chemotherapy).

Tetracosactrin vs. methylprednisolone in the prevention of emesis in patients receiving FEC regimen for breast cancer.

0.5 mg tetracosactrin is considered to be equivalent to 40 mg methylprednisolone with regard to the induced cortisol secretion. 97 female breast cancer patients who received their first two FEC courses (epirubicin 50-75 mg/m2, 5-fluorouracil 500 mg/m2, cyclophosphamide 500 mg/m2) entered this randomised crossover study (76 had previously received an adjuvant treatment); tetracosactrin was administered intramuscularly and methylprednisolone intravenously immediately before chemotherapy administration. The tolerability was evaluated using a diary card during 5 days and patients were asked for their preference at the end of the two cycles. There was no difference either for vomiting (dry heaves were included) or nausea between the two treatments (the analysis was performed on day 1, the worse day of days 2 and 3 and the worse day of days 4 and 5). At day 1, 49% of the patients experienced no or mild nausea after tetracosactrin and 62% after methylprednisolone (not significant) (first period analysis); a complete control of vomiting (including dry heaves) was observed in 49% of the patients after tetracosactrin and 53% after methylprednisolone (not significant). No difference was observed between patients with or without previous chemotherapy. However, slightly more patients preferred tetracosactrin (P = 0.048).

Autonomic dysfunction in systemic sclerosis: sympathetic overactivity and instability.

PURPOSE: This study was designed to assess the prevalence and nature of autonomic dysfunction (AD) in 34 patients with systemic sclerosis (SSc). PATIENTS AND METHODS: Patients were questioned for current symptoms possibly related to AD. Five noninvasive cardiovascular autonomic function tests and sequential plasma catecholamine estimations at rest, during standing, and during sustained handgrip were performed. Seven patients with manometrically documented esophageal involvement and high resting plasma adrenaline levels were treated with clonidine (75 to 375 micrograms/d). One month later, resting plasma catecholamine estimations and esophageal motility studies were repeated. RESULTS: Autonomic testing revealed AD in each patient, while symptoms were experienced by 33 of them. Findings on two of the three heart rate tests and both blood pressure tests were significantly impaired as compared with those in 25 matched control subjects. Mean resting plasma adrenaline levels were 18 times higher than in 10 matched controls (p less than 0.001). Plasma catecholamine (adrenaline, noradrenaline, and dopamine) concentrations and mean arterial blood pressures fluctuated inappropriately during standing and sustained handgrip in 28 (82%) of the patients. The presence of headaches correlated significantly with sympathetic overactivity and instability (p less than 0.05). Resting plasma adrenaline concentrations correlated inversely with disease duration (p less than 0.05). Significant suppression of sympathetic overactivity and increases in resting lower esophageal sphincter pressures were observed in the seven patients treated with clonidine. CONCLUSION: AD is extremely common in SSc. It is characterized by parasympathetic impairment and marked sympathetic overactivity, particularly in early disease. The potential role of AD in the pathogenesis of SSc deserves further study.