Spine trauma due to diving: main features and short-term neurological outcome.

STUDY DESIGN: This is a retrospective study. OBJECTIVES: The aim of this study is to examine the main features and short-term neurological outcomes associated with injuries to the spine due to diving into water in a Latin American country. SETTING: Salvador, Brazil. PATIENT SAMPLE: A total of 1324 subjects were admitted with spinal trauma between 1991 and 2006 (inclusive). Subjects aged between 14 and 65 years who sustained diving injuries corresponded to 10.6% (N=140) of the cases. OUTCOME MEASURES: Neurological status was determined by the Frankel Functional Scale (FFS) on admission and discharge. The FFS was secondarily converted to the American Spinal Injury Association impairment scale. METHODS: This study is a patient record database review that examines demographic and injury-related characteristics, details of hospital treatment and neurological status at the time of discharge. RESULTS: Males (N=129) outnumbered females (N=11) in a proportion of 12:1 (mean age: 28.62 years). The cervical spine region was the most affected area (92.1%) and 45% of the cases presented with tetraplegia. On admission, neurologically complete lesions accounted for 32.1% of the overall cases and 45.7% were neurologically intact. The mean length of stay (7.7 weeks) did not differ with regard to treatment option (P=0.83). During hospitalization, patients with incomplete neurological impairment had shorter lengths of stay and showed more neurological improvement than those with complete lesions (P=0.26 and 64.5 versus 2.2%, P<0.0001). CONCLUSION: Diving spine injuries have a high tetraplegia rate. Neurological recovery and shorter length of stay are associated with incomplete lesions.

Drug development from natural products: exploiting synergistic effects.

Drug development in phytomedicine has been focused in the past on the discovery and analysis of new structures from natural products. The search aimed at the determination of the single "active principle" in plants, based on the assumption that a plant has one or a few ingredients which determine its therapeutic effects. But traditional systems of medicines like Ayurveda, traditional Chinese medicine or the European phytotherapy generally assume that a synergy of all ingredients of the plants will bring about the maximum of therapeutic efficacy. This approach has for long been impossible to investigate since adequate methods to standardize complex plant mixtures as well as to rationalize complex mode of actions were lacking. The introduction of high throughput technologies provides the opportunity to determine profiles of plants and to systematically explore the mode of action of combinatory drug regimes. The present review highlights the concept of synergy and gives examples of synergistic effects of plant constituents. It elaborates on how the high throughput technologies can be used in drug development from natural products with the aim of creating evidence-based plant medications in prevention and treatment of different diseases in the form of new single treatments or new combinatory drug regimes while exploiting synergy-effects.

[Parameters of quality for aortic valve replacement]. / Qualitätsparameter für den Aortenklappenersatz.

Advantages and disadvantages of mechanical or biological heart valve prostheses in combination with complications during long-term follow-up are responsible for the quality of aortic valve replacement. Anatomical conditions like narrow aortic root, concomitant coronary artery disease or reduced left ventricular function impair the quite good surgical results necessitating surgical intervention or the use of stentless valve implants.

New perspectives for synergy research with the "omic"-technologies.

Synergistic effects, understood as true overadditive effects, are often observed in experimental and clinical studies using phytopharmaceuticals. The introduction of the "omic"-technologies is now opening new perspectives in rationalizing these effects and making use of them in the development of a new generation of phytopharmaceuticals. This review describes possible mechanism of synergistic actions of herbal drugs by mono- and multitargeting and by the activation of signal cascades. It examines the possibilities of the standardization of single and multi component plant extracts and the prediction and assessment of the toxicity and safety of plant extracts with the support of the "omic"-technologies. It further discusses the use of phytopharmaceuticals in the context of an "individualized medicine". It makes proposals how to use the "omic"-technologies to rationalize and develop combination therapies of phytopharmaceuticals and synthetic drugs to minimize adverse reactions (ARs) or improve the therapeutic efficacy. Examples of clinical studies are given which explore already the potential of such co-medications. Modern medical therapy has acknowledged for quite some time the usefulness of combination therapies in the treatment of multifactorial diseases like cancer, cardiovascular or rheumatic diseases. The term "synergy" is rarely used in this context, the combinatory mechanisms of actions seldom completely understood and the potentially occurring adverse reactions feared. A systematic exploitation of synergy effects of phytomedical interventions alone or in combination with synthetic drugs should lead in a long term perspective to the discovery and development of more rational evidence-based interventions in the prevention and therapy of multifactorial diseases and should thereby enrich modern pharmacotherapy.

A novel stop mutation truncating critical regions of the cardiac transcription factor NKX2-5 in a large family with autosomal-dominant inherited congenital heart disease.

We report on a familial screen of five female members in three generations affected by an autosomal-dominant inherited atrioventricular (AV) conduction block associated with atrial septal defects (ASD) and other congenital cardiovascular diseases (CCVD), such as pulmonary artery stenosis (PAS), patent foramen ovale (PFO) and ventricular septal defect (VSD). We tested the cardiac transcription factor NKX2-5 which is known to cause CCVD with variable phenotype and penetrance by direct sequencing of the two NKX2-5 coding exons in the index patient and identified a novel heterozygous c.325G> T mutation in exon 1 of the gene. This mutation co-segregated with the disease in the family and was present in all five affected family members, but not in 100 control chromosomes. The c.325G > T mutation is predicted to introduce a stop codon at amino-acid position 109 (p.E109X). The truncated protein lacks all of the functionally important domains of the cardiac transcription factor. Therefore, it is very likely that this novel mutation causes a complete loss of NKX2-5 function and haploinsufficiency is the pathophysiological mechanism underlying the disease in the family.

Effect of medical honey on wounds colonised or infected with MRSA.

Full healing was achieved in seven consecutive patients whose wounds were either infected or colonised with methicillin-resistant Staphylococcus aureus. Antiseptics and antibiotics had previously failed to irradicate the clinical signs of infection.

Differential diagnoses of suspected Lyme borreliosis or post-Lyme-disease syndrome.

The symptoms of Lyme borreliosis are similar to those of a variety of autoimmune musculoskeletal diseases. Persistence of complaints is frequently interpreted as unsuccessful antibiotic treatment of Borrelia-associated infections. However, such refractory cases are rare, and re-evaluation of differential diagnoses helps to avoid the substantial risk of long-term antibiotic therapy. In this study, we analyzed patients who presented to our rheumatology unit with previous suspected or diagnosed Lyme borreliosis. Eighty-six patients from a 3.5-year period were evaluated. The mean age of patients was 49.2 +/- 17.2 years; 60% (n = 52) reported a tick bite and 33% (n = 28) an erythema. Forty-seven percent (n = 39) had positive enzyme-linked immunoassay results and Western blots (Mikrogen, Martinsried, Germany). All but 12 patients had already received antibiotic treatment previously. Nine percent (n = 8) had ongoing or recent Lyme borreliosis. Twenty-nine percent (n = 25) showed clinical symptoms and radiographic changes compatible with degenerative disorders of the cervical and/or lumbar spine. These patients were significantly older when compared to the other patients (59.3 +/- 13.7 years vs 46.1 +/- 17.2 years, p = 0.001). Seventeen percent (n = 16) had arthropathies related to psoriasis or rheumatoid arthritis. Twelve percent (n = 10) were positive for the HLA B27 antigen. Other diseases were less frequent. Six patients (7%) could not be diagnosed conclusively, and four of these patients had negative Borrelia immunoassay results. In conclusion, Borrelia-associated diseases were rare in this study. Differential diagnoses helped to initiate a successful disease-specific therapeutic strategy.

[Effect of candesartan cilexetil with hydrochlorothiazide on blood pressure and ST-segment depression in patients with arterial hypertension]. / Blutdruck- und ST-Streckenanalyse bei Patienten mit arterieller Hypertonie: Einfluss von Candesartan/Hydrochlorothiazid.

OBJECTIVE: To examine the effect of candesartan cilexetil with hydrochlorothiazide (6 mg and 12.5 mg, respectively) on blood pressure and ST-segment depression during daily life of patients with treated but not controlled arterial hypertension (blood pressure taken at doctor's practice (3)140/90 mmHg, despite being on at least two antihypertensive drugs) PATIENTS AND METHODS: 51 patients (45 men, 17 women) with treated but reportedly uncontrolled hypertension were placed on self-measurement of blood pressure for 4 weeks of a run-in period and 8 weeks as a follow-up period. Combined 24-hour automatic blood pressure measurement (ABPM) and electrocardiography were done at the end of the run-in and the follow-up periods. Ten patients proved to be normotensive according to the self-measurement and ABPM after the run-in period (group A), while 41 were still uncontrolled according to both methods (group B). In group B the least efficacious component of the antihypertensive medication was replaced by candesartan with hydrochlorothiazide (C + HCT) and any changes in blood pressure and ST-segment depression analysed after 8 weeks of follow-up in both groups. RESULTS: In group A no significant blood pressure change was observed between run-in- and follow-up periods. But in group B (n=41) the self-measured systolic blood pressure had significantly decreased (155/84 mmHg compared with [vs] 147/81 mmHg; p<0.0073) as had the systolic 24-h ABPM (148/81 mmHg vs 137/753 mmHg; p<0.0015) after C + HCT had replaced the previous noneffective medication. After the run-in period 15 patients of group B had ST-segment depression (1 mm of horizontal or descending depression for at least 1 minute). In 16 other patients of group B and in all patients of group A no ST depressions were recorded. At the end of the follow-up period significant reduction of mean ischemic burden per patient (106 vs 72 minutes), of total ischemic events (228 vs 153) and of mean duration of ST depression (372 vs 210 seconds) had occurred. CONCLUSIONS: Replacing candesartan + hydrochlorothiazide for previously ineffective antihypertensive drugs in patients with uncontrolled arterial hypertension significantly reduced both blood pressure and ST-segment depression during daily life.

Application of the "-Omic-" technologies in phytomedicine.

The proof of efficacy of phytopreparations and the determination of their mode of action are permanent challenges for an evidence-based phytotherapy. The technology platform of genomics, proteomics and metabolomics ("-omic-" technologies) are high-throughput technologies. They increase substantially the number of proteins/genes that can be detected simultaneously and have the potential to relate complex mixtures to complex effects in the form of gene/protein expression profiles. Provided that phytopreparation-specific signatures in the form of gene/protein expression profiles can be developed, these technologies will be useful for the chemical and pharmacological standardization and the proof of the toxicological potential of a plant extract. Over a long-term perspective they may economize the proof of efficacy, the determination of the mode of action of phytomedicines and allow to investigate herbal extracts without prominent active principle(s). The application of this genomics revealed already that gene expression profiles induced by single drugs and the ones induced by the combination of the same drugs can be entirely different. These results make the information of the mode of action of isolated "active principles/lead substances" of phytopreparations questionable. The application of the "-omic-" technologies may lead to a change of paradigms towards the application of complex mixtures in medicine and open the new field of phytogenomics, -proteomics and -metabolomics.

Toll-like receptor (TLR) 4 polymorphisms are associated with a chronic course of sarcoidosis.

The aetiology of sarcoidosis, an inflammatory granulomatous multi-system disorder, is unclear. It is thought to be the product of an unknown exogenous antigenic stimulus and an endogenous genetic susceptibility. Toll-like receptors (TLR) are signal molecules essential for the cellular response to bacterial cell wall components. Lipopolysaccharide (LPS), for example, binds to TLR 4. Two different polymorphisms for the TLR4 gene (Asp299Gly and Thr399Ile) have been described recently. This leads to a change in the extracellular matrix function of TLR4 and to impaired LPS signal transduction. We genotyped a total of 141 Caucasian patients with sarcoidosis and 141 healthy unrelated controls for the Asp299Gly and Thr399Ile polymorphisms in the TLR4 gene. The mutations were identified with polymerase chain reaction followed by restriction fragment length polymorphism (RFLP) analysis. Among sarcoidosis patients the prevalence for each Asp299Gly and Thr399Ile mutant allele was 15.6% (22/141). In the control group the prevalence was 5.67% (8/141) (P = 0.07). In the subgroup of patients with acute sarcoidosis there was no difference in the control group (P = 0.93), but there was a highly significant association between patients with a chronic course of sarcoidosis and TLR4 gene polymorphisms (P = 0.01).

[The modified Bonn Malmö protocol (MBMP) in the treatment of acquired haemophilia A]. / Das modifizierte Bonn-Malmö-Protokoll in der Behandlung der erworbenen Hemmkörperhämophilie -- Eine multimodale Therapiestrategie.

BACKGROUND AND OBJECTIVE: Autoantibodies directed against clotting factors can induce life threatening bleeding with a mortality rate up to 22%. Although the incidence of the disease is low (1-4 x 10(-6)), costs of treatment due to long-term clotting factor substitution can be enormous. Aim of an optimal treatment strategy should be to control bleedings by a rapid and safe elimination of the inhibitor and reinducing long-term immune tolerance. PATIENTS AND METHODS: Treatment of 48 patients with acquired haemophilia A (m=20, f =28, age 61.3 (SD 16.4)), the largest patient collective world-wide, was monitored for a mean of 48 months. Three patients received only conservative treatment. 45 patients were treated intensively by a multimodal strategy including: 1. immunoadsorption for antibody elimination; 2. FVIII substitution; 3. intravenous immunoglobulin substitution and 4. immunosuppression. The times required for inhibitor elimination, factor VIII substitution and the duration of the MBMP were documented. RESULTS: In 45 patients with a high titre critical bleeding was controlled immediately after the initiation of MBMP. There were no deaths from bleeding or the treatment. Inhibitor levels decreased to undetectable levels within a median of 3 days (95% CI, 3-7 days), factor substitution was terminated within a median of 13 days (95% CI, 10-16 days) and the treatment was completed within a median of 15 days (95% CI, 13-17 days). The overall response rate for complete remission (CR) was 91%. When cancer patients were excluded, the CR rate was 97%. CONCLUSION: Considering the short duration and amount of factor VIII substitution, the short time of hospitalization and the long-term median follow up of 48 months without bleeding events, the MBMP appears to have a modifying effect on the immunological response.

Comparison of in vitro-activity of commonly used topical glucocorticoids on cytokine- and phospholipase inhibition.

BACKGROUND AND OBJECTIVES: Topical glucocorticoids (GCs) are potent inhibitors of cellular inflammatory mediator production. Differences in receptor binding activities are believed to correlate with inhibition of mediator release and anti-inflammatory efficacy in vivo. To further assess this hypothesis we compared in cultured human monocytes the inhibitory activity of classic synthetic GCs on leukotriene B4 (LTB4), prostaglandin E2 (PGE2), interleukin 1 beta (IL-1beta) and c-phospholipase A 2 activity (cPLA2). METHODS: Normal human monocytes (10(5) /ml) were tested for 20 hrs with increasing concentrations (range 10(-12) -10(-5) M) of triamcinolone acetonide (TAA) compared to beclomethasone dipropionate (BDP), budesonide (BUD), dexamethasone (DEX), or the ethanol diluent together with 10 microg/ml of lipopolysaccharide (LPS). Mediator production and spontaneous cPLA subset 2-activity was determined by direct enzyme immunoassay methods. RESULTS: TAA at therapeutically relevant concentration (10(-8) M) inhibited significantly (p<0.01, n = 9) mediator production of TNF-alpha > IL-1beta > TxB2 > LTB subset 4 in a dose dependent manner by 75%, 65%, 41%, and 33%. IL-1beta inhibition at 10(-8) M by TAA (65%)> BDP (52%)> BUD (47%) was not different (ANOVA, p>0.2). Also spontaneous cPLA2-activity at 10(-8) M was inhibited to a similar degree (ANOVA, p> 0.6) by BUD (17.3%) > TAA (11.4%) > BDP (8.6%). In the same culture conditions spontaneous PGE2-secretion was inhibited by BDP (28.8%) > BUD (24.2%) > TAA (11.4%) with no significant effect for TAA. CONCLUSION: Clinically well established GCs have a similar inhibitory capacity on monocyte cytokine production and surprisingly only weak effects on AA-metabolism. Small receptor binding activity may account for the lack of cytokine inhibition by subtherapeutic (<10(-8) M) airway concentrations of TAA and BDP. Partial mediator inhibition by GCs at therapeutically known airway concentrations may be relevant to control bursts of airway inflammation during acute exacerbation but unfavourable to effectively delay progression of chronic airway inflammation.

Different mechanisms of action of beta2-adrenergic receptor agonists: a comparison of reproterol, fenoterol and salbutamol on monocyte cyclic-AMP and leukotriene B4 production in vitro.

BACKGROUND: Beta2-adrenergic receptor agonists have several effects on airway function, most of which are mediated in a variety of cell types resulting in increased c-AMP-production and inhibition of inflammatory mediator production. However, their stimulating effects on cAMP-production became known to be inversed by increasing phosphodiesterase (PDE) activity and degradation of cAMP. Therefore, in this study we have evaluated the efficacy of reproterol, a dual acting beta2-adrenoceptor agonist and PDE-inhibitor, as compared to salbutamol and fenoterol with respect to production of cAMP and LTB4 in cultured monocytes. METHODS: Isolated human monocytes (10(5)/ml) were incubated (n = 9) in suspension with beta2-adrenoceptor agonists (10(-10) -10(-4) M) for 30 minutes with and without IBMX. Then, cAMP production was determined following treatment with Triton-X100. Production of LTB4 was measured following incubation of beta2-adrenoceptor agonists for 4 hrs in the presence of LPS (10 mg/ml). cAMP and LTB subset 4 were measured in culture supernatants by enzyme immunoassay. RESULTS: At 10(-5) M, production of cAMP was significantly stimulated by reproterol > fenoterol > salbutamol in a dose-dependent manner to an extent of *128%, *65%, 13% (*p<0.04) respectively. In contrast, LTB4-production was inhibited significantly to a similar degree by salbutamol and reproterol in a dose-dependent manner by 59% and 49% (10(-5) M, p<0.03), respectively, with decreasing inhibition (15%) after fenoterol. Following co-incubation with IBMX, cAMP production only increased significantly (p<0.002) after fenoterol (+110%) compared to salbutamol (+29%) and reproterol (+50%) (ANOVA, p<0.001). CONCLUSION: These data suggest effects of the theophylline constituent of reproterol to inhibit adenylyl cyclase induced phosphodiesterase activity. The advantageous synergistic effects of reproterol on cAMP-production need to be further explored in trials.