Implementation of a uniform nationwide medical licensing examination in general practice. A feasibility study.

Objective: A competency-based training of medical students that is adapted to the realities of care is required internationally and is being intended in Germany with the Master Plan for Medical Studies 2020. In order to test these competencies, the German National Institute for state examinations in Medicine, Pharmacy and Psychotherapy (IMPP) has developed a concept for the redesign of the final part of the medical licensing examination in Germany. It focuses on general and interprofessional healthcare in the examination with outpatients. The aim of this work is to assess the feasibility of the new final examination on the basis of pilot examinations in family practices and to derive further steps for the national implementation. Methods: Fourteen medical students in their internship year completed a full examination with patients aged 42 to 84 years. Examiners evaluated the examination performance using standardised evaluation forms. Feasibility was qualitatively assessed in terms of compliance with content and time limits, examination results, patient reflections, and implementation in the practice. Results: Students were able to complete all tasks within the given time frame. Based on the evaluation forms, the examiners assessed the performance of the students. Patients appreciated the structured course of the examination in the familiar location of their family practice. For the nationwide implementation of the examination, 2,500 examination practices are required for about 10,000 examinees per year. Four students can then be examined on two days per year in each practice. Conclusions: Oral-practical examinations with outpatients in general medical practices can be carried out successfully throughout the nation. An implementation of the examinations throughout Germany requires that medical studies are restructured and that this new curriculum is implemented as intended by the Master Plan for Medical Studies 2020. Furthermore, training and remuneration of examiners together with a legal framework for the new examination must be established.

N-acetylcysteine modulates effect of the iron isomaltoside on peritoneal mesothelial cells.

Intravenous (i.v.) iron supplementation is used in patients on chronic peritoneal dialysis (pd). Iron induced intraperitoneal inflammation observed in our previous studies with iron sucrose may deteriorate the function of the peritoneum as the dialysis membrane. We evaluated effect iron compound, iron-isomaltoside-100 (IIS) on the peritoneal mesothelial cells (MC). We studied the effect of iv treatment with IIS ± N-acetylcysteine (NAC) on the dialysate parameters and function of MC. In 7 uremic pd patients IIS 200 mg was infused i.v. ± NAC 600 mg. Afterward, a 4 hours exchange was performed with Dianeal 1.5%. As a control dialysate exchange preceding IIS treatment was used. Inflammatory parameters of the drained dialysates as well as the dialysates and IIS effects on MC were evaluated in ex vivo experiments. Intravenous infusion of IIS resulted in an increase of the dialysate Fe (+147%, P < 0.01). Concentrations of the dialysates inflammatory mediators were increased: interleukin-6 (IL-6) +39%, P < 0.02, monocyte chemoattractant protein-1(MCP1) +50%, P < 0.02, and hyaluronan (HA) +64%, P < 0.02. Simultaneous i.v. infusion of NAC prevented increase of the dialysate inflammatory mediators. Dialysates collected after IIS treatment induced oxidative stress in MC (+29%, P < 0.05) and stimulated IL-6 synthesis (+64%, P < 0.05) in MC; no such effect was seen in dialysates obtained after simultaneous IIS and NAC i.v. treatment. IIS used as the additive to culture medium stimulated synthesis in MC of IL6 (+76%, P < 0.001) and plasminogen activator inhibitor-1 (PAI-1) (28%, P < 0.001) whereas synthesis of tissue plasminogen activator (t-PA) was reduced (-16%, P < 0.001). These changes were prevented in the presence of NAC 1 mmol/L. Intravenous administration of IIS results in the mild stimulation of intraperitoneal inflammation. IIS changes MC phenotype to the inflammatory one with reduced fibrinolytic activity. These effects are prevented by NAC.

Sulodexide modulates the dialysate effect on the peritoneal mesothelium.

Peritoneal membrane damage during chronic peritoneal dialysis is the main cause of that treatment failure. Preservation of the mesothelial cells (MC) is important for the survival of the peritoneum. Evaluation of dialysates effect on the function of MC and potential modification of that effect by sulodexide (heparin 80% and dermatan sulfate 20%). Dialysate effluents, after the overnight exchange with dianeal 1.5% dextrose, were collected from 7 continuous ambulatory peritoneal dialysis (CAPD) patients, and their effect ± sulodexide 0.5 LRU/mL on genes expression, secretory activity and protein synthesis in MC was studied. Exposure of MC to the studied dialysates caused intracellular oxidative stress and significantly increased expression of the genes regulating the synthesis of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-beta (TGF-ß), vascular cell adhesion molecule 1 (VCAM-1) and vascular endothelial growth factor (VEGF). Secretion of the studied molecules from MC treated with dialysates was increased: by 96% for IL-6 (P < 0.01), 34% for MCP-1(P < 0.01), 24% for TGF-ß (P < 0.01), 27% for VCAM-1 (P < 0.01), and by 15% for VEGF (P < 0.01). Sulodexide reduced the stimulatory effect of the dialysates on the intracellular generation of free radicals, genes expression and secretory activity of MC. These cells exposed to the dialysates showed increased synthesis of total protein (by 216%, P < 0.005) and collagen (by 264%, P < 0.005), as compared to standard culture medium. Supplementation of the dialysates with sulodexide resulted in weaker stimulation of collagen synthesis (-21% versus dialysate). We concluded that peritoneal dialysate changes the genes expression and phenotype of MC to a proinflammatory, profibrotic and proangiogenic one. Sulodexide reduces these negative effects of the dialysate.

Sulodexide suppresses inflammation in patients with chronic venous insufficiency.

AIM: According to previously performed studies, inflammation plays a crucial role in vein wall and leg tissue injury related to chronic venous insufficiency (CVI) development. Sulodexide (SUL) is a balanced mix of glycosaminoglycans with potential anticoagulant and profibrinolytic activity, also protecting endothelial cells and suppressing inflammatory reactions in various vascular disease-related conditions. The goal of the present study was to evaluate the anti-inflammatory action of SUL in patients with CVI. METHODS: The study was performed on a group of 11 patients with chronic venous disease (stage C5 according to CEAP classification). The mean age of the patients was 58.4±7.7 years, and none of them were diabetic. The patients were treated for 8 weeks with orally-administered SUL (2 x 500 LSU/day). Blood samples were collected at the start and at the end of the study for measurement of MMP-9, IL-6 and monocyte chemoattractant protein-1 (MCP-1). Additionally, the effect of the obtained serum samples on the function of human venous endothelial cells (HVEC) in in-vitro culture was evaluated. RESULTS: After treatment with SUL, the serum concentration of MMP-9 (ng/mL) decreased from 6.50±3.48 to 5.41±1.36, P<0.05, and the concentration of IL-6 (pg/mL) decreased from 11.5±3.4 to 10.1±2.3, P<0.005. There was also a trend of decreased serum MCP-1 (pg/mL) from 31.3±23.0 before treatment to 27.1±10.7 at the end. Intracellular generation of oxygen-derived free radicals in HVEC maintained in in-vitro culture was lower in the serum samples collected after treatment with SUL: 3.09±0.35 abs/µg protein vs. 3.63±0.32 abs/µg protein, at the start, P<0.05. Synthesis of IL-6 was lower in HVEC exposed in vitro to serum collected at the end of SUL treatment: 1.02±0.31 ng/µg cell protein vs. 1.32±0.41 ng/µg cell protein before SUL treatment. The proliferation rate of HVEC was similar in serum collected at the beginning and at the end of SUL treatment. CONCLUSION: We conclude that treatment with SUL in patients with CVI reduces intravascular inflammation and is protective for the endothelial cells and for the extracellular matrix changes related to metalloproteinase expression.

N-Acetylglucosamine modulates function of the skin fibroblasts.

BACKGROUND: Fibroblasts are an important component of the skin determining its properties. N-Acetylglucosamine (NAG) is the substrate for hyaluronan synthesis, and it also has anti-inflammatory and anti-senescent activity in mesothelial cells. METHODS: We tested in in vitro-cultured human skin fibroblasts how supplementation of culture medium with NAG 10 mmol L(-1) changes properties of these cells. RESULTS: Fibroblasts cultured in presence of NAG produced more proteins and that was mainly due to increased synthesis of collagen (+33% vs. control, P < 0.05). Hyaluronan synthesis was increased (+107% vs. control, P < 0.001), but interleukin-6 synthesis was reduced (-22% vs. control, P < 0.05). Fibroblasts cultured in medium with NAG 10 mmol L(-1) demonstrated improved ability to heal the injured layer of cells (+34% vs. control, P < 0.05). Additionally senescence of fibroblasts undergoing replicative ageing in the presence of NAG was less pronounced, as reflected by smaller increase in the population doubling time (-70% vs. control, P < 0.05). CONCLUSION: We conclude that NAG induced changes in the skin fibroblasts' properties maybe important for prevention of the age-dependent changes in its structure and function.

Sulodexide modifies intravascular homeostasis what affects function of the endothelium.

PURPOSE: Sulodexide is a mixture of heparin and dermatan sulphate which has an antithrombotic action. It was shown that it has also direct effect on the endothelial cells. We tested the effect of sulodexide on the intravascular homeostasis in patients with peripheral vascular disease. METHODS: Sulodexide was infused iv. at a dose of 1200 Lipoprotein Lipase Releasing Units (LRU) in 10 patients with peripheral vascular disease. Blood samples were collected before the infusion and 1, 6 and 24 hours after the infusion. Inflammatory and fibrinolytic parameters were studied in the collected serum samples. Additionally, ex-vivo effect of the serum samples on in vitro function of the endothelial cells was studied. RESULTS: Infusion of sulodexide caused acute and transient peak of the Hepatocyte Growth Factor (HGF) concentration in blood and decrease of the Vascular Endothelial Growth Factor (VEGF) level, what, as we found in in vitro experiments, was due to adsorption of VEGF to endothelium. We found that HGF enhanced in vitro stimulating effect of VEGF on proliferation of the endothelial cells. Serum level of interleukin-6 was gradually decreased, whereas fibrinolytic activity of serum, reflected by t-PA/PAI-1 ratio, increased. Serum samples obtained from the studied patients suppressed oxidative stress and release of interleukin-6 in endothelial cells maintained in in vitro culture. CONCLUSION: Sulodexide reduces intravascular inflammation and suppresses inflammatory reaction in the endothelial cells; both effects are desirable in patients with peripheral vascular disease.

High-speed phosphor thermometry.

Phosphor thermometry is a semi-invasive surface temperature measurement technique utilising the luminescence properties of doped ceramic materials. Typically, these phosphor materials are coated onto the object of interest and are excited by a short UV laser pulse. Up to now, primarily Q-switched laser systems with repetition rates of 10 Hz were employed for excitation. Accordingly, this diagnostic tool was not applicable to resolve correlated temperature transients at time scales shorter than 100 ms. This contribution reports on the first realisation of a high-speed phosphor thermometry system employing a highly repetitive laser in the kHz regime and a fast decaying phosphor. A suitable material was characterised regarding its temperature lifetime characteristic and its measurement precision. Additionally, the influence of laser power on the phosphor coating was investigated in terms of heating effects. A demonstration of this high-speed technique has been conducted inside the thermally highly transient system of an optically accessible internal combustion engine. Temperatures have been measured with a repetition rate of 6 kHz corresponding to one sample per crank angle degree at 1000 rpm.

Longitudinal study of the socioeconomic burden of Parkinson's disease in Germany.

OBJECTIVE: To determine the health economic burden on patients with Parkinson's disease (PD) in Germany over a 12-month observation period and provide a comprehensive analysis of cost-driving factors. METHODS AND PATIENTS: Patients with PD (n = 145) were recruited from two clinical departments, two office-based neurologists and 12 GPs. Clinical evaluations were performed at baseline, 3, 6 and 12 months. Disease severity was measured using the Unified Parkinson's Disease Rating Scale (UPDRS). Cost data were assessed based on a patient diary and via personal structured interviews at the respective time-points. Costs were calculated from the societal perspective (2009 euro). Cost-driving factors were identified by multivariate regression analysis. RESULTS: Mean annual costs totalled euro20 095 per patient. Amongst direct costs, the highest expenditures (euro13 158) were for drugs (euro3526) and inpatient care including nursing homes (euro3789). Indirect costs accounted for 34.5% (euro6937) of total costs. Costs of home care provided by family accounted for 20% of direct costs. Cost-driving factors were identified for total costs (UPDRS, fluctuations, dyskinesia and younger age), direct costs (UPDRS, fluctuations), patient expenditures (UPDRS, depression) and drug costs (younger age). CONCLUSION: Parkinson's disease has a chronic course with growing disability and considerable socioeconomic burden. Disease progression leads to an increasing number of patients who require costly institutionalized care. Home care is a major factor influencing patients' families. Healthcare programmes aimed at reducing the burden of PD on society and individuals should consider cost-driving factors of PD.

Composition-function relationships during IL-1-induced cartilage degradation and recovery.

OBJECTIVE: To examine the relationships between biochemical composition and mechanical properties of articular cartilage explants during interleukin-1 (IL-1)-induced degradation and post-exposure recovery. DESIGN: Bovine articular cartilage explants were cultured for up to 32 days with or without 20 ng/mL IL-1. The dynamic shear modulus |G*(dyn)| and equilibrium and dynamic unconfined compression moduli (E(equil) and |E*(dyn)|) were measured at intervals throughout the culture period. In a subsequent recovery study, explants were cultured for 4 days with or without 20ng/mL IL-1 and for an additional 16 days in control media. The dynamic moduli |E*(dyn)| and |G*(dyn)| were measured at intervals during degeneration and recovery. Conditioned media and explant digests were assayed for sulfated glycosaminoglycans (sGAG) and collagen content. RESULTS: Continuous IL-1 stimulation triggered progressive decreases in E(equil), |E*(dyn)|, and |G*(dyn)| concomitant with the sequential release of sGAG and collagen from the explants. Brief IL-1 exposure resulted in a short release of sGAG but not collagen, followed by a gradual and incomplete repopulation of sGAG. The temporary sGAG depletion was associated with decreases in both |E*(dyn)| and |G*(dyn)| which also recovered after removal of IL-1. During IL-1-induced degradation and post-exposure recovery, explant mechanical properties correlated well with tissue sGAG concentration. CONCLUSIONS: As previously shown for developing cartilages and engineered cartilage constructs, cytokine-induced changes in sGAG concentration (i.e., fixed charge density) are coincident with changes in compressive and shear properties of articular cartilage. Further, recovery of cartilage mechanical properties can be achieved by relief from proinflammatory stimuli and subsequent restoration of tissue sGAG concentration.

Modification of neutrophil function by plasma of rheumatoid arthritis patients treated with infliximab.

OBJECTIVE: To examine whether the release of superoxide anions from neutrophils of healthy donors was affected when incubated with plasma from infliximab-treated rheumatoid arthritis (RA) patients. METHODS: Fifteen consecutive seropositive RA patients were treated with 3mg/kg infliximab on weeks 0, 2, 6, and 14. Disease activity was assessed by DAS28 score and by IL-6 level. Neutrophils from healthy donors were incubated with plasma drawn before each infliximab treatment. PMA-stimulated superoxide release was measured by the ferricytochrome C reduction method. RESULTS: 53% of the patients had a favorable clinical response. IL-6 levels showed a significant decline at week two, with a gradual increase thereafter. Treatment with infliximab did not change the superoxide production. However, when the group was divided retrospectively to responders (DeltaDAS28 > -1.2) and non-responders (DeltaDAS28 < -1.2), two different patterns were seen, although the pre-treatment levels were similar: Among the responders IL-6 remained low at its 2 weeks level till week 14, while in the non responders IL-6 increased 3 times (P < 0.03) from week 2 to 14. The responders showed mild, but continuous, reduction of superoxide release, while in the non-responders it increased significantly from week 2 on. CONCLUSION: The reduction in IL-6 in RA sera following anti-TNFalpha therapy has little influence on the capacity of these sera to stimulate healthy neutrophils to produce superoxide, suggesting the existence of non-TNFalpha non-IL-6 dependent neutrophil-stimulating mediators in RA sera. The increasing level of IL-6 among the non-responders after initial dramatic decline might represent an escape phenomenon, possibly caused by alternative mediator(s). Clinically, this IL-6 "escape" might be used as a tool for early identification of responders from non-responders.

[Food-drug interactions: an underestimated risk]. / Interaktionen zwischen Medikamenten und Ernährung. Verkannte Ursache von Nebenwirkungen und Therapieversagen.

With only few exceptions, administration of medicaments should, in principle, be independent of food intake (at least half an hour before or two hours after eating). This ensures uniform and assessable bioavailability. However, it also entails the risk that the patient is more likely to forget to take medication postponed to 2 hours after a meal, than when it is directly coupled to a meal. Certain foodstuffs or food constituents, such as, for example, grapefruit, Seville orange juice, red wine, alcoholic drinks in general, or large quantities of caffeine and garlic should be avoided during drug treatment. In addition, specific interactions with certain drugs must also be taken into account (e.g. MAO inhibitors and tyramine, curamine and vitamin K).

Human esophageal cancer is distinguished from adjacent esophageal tissue by tissue cysteine concentrations.

Recent studies have suggested that cysteine, in addition to glutathione, may play a role in the genesis, pathobiology, and treatment response of rodent and human cancers. We examined the relative concentrations of cysteine and glutathione in human esophageal cancer and adjacent, minimally involved esophageal tissue. Small biopsies from tumors and adjacent esophageal tissues were placed into cold acid to allow extraction of low-molecular-mass compounds and simultaneous precipitation of macromolecules. Supernatants were analyzed by high-performance liquid chromatography with electrochemical detection for thiol content. While there was no statistically significant difference between the glutathione content of tumor versus adjacent tissue (2.2 mM vs 2.1 mM, respectively), tumor tissue had significantly higher levels of cysteine than adjacent tissue (0.21 mM vs 0.13 mM, respectively). In conclusion, cysteine content distinguishes tumor from adjacent more normal tissue.

Clinical findings in patients presenting with sore throat. A study on inter-observer reliability.

BACKGROUND: Several clinical prediction scores have been developed to help practitioners assess the probability of streptococcal throat infection. Prior to this study, it was not known how reliably doctors assess the signs that contribute to these decision aids. OBJECTIVE: The aim of this study was to measure the inter-observer reliability of clinical findings related to sore throat. METHODS: Consecutive patients presenting with sore throat in five primary care practices in Germany took part (n = 126). Each patient was assessed independently by two doctors with regard to lymph nodes, pharynx, soft palate and tonsils. RESULTS: Agreement among practitioners was not satisfactory. CONCLUSIONS: Results suggest that the performance of clinical scoring systems can be improved by training on how to elicit relevant clinical signs. Our findings cast some doubt on the effectiveness of under- and post-graduate training in this area.

Identification and characterization of new inhibitors of the Escherichia coli MurA enzyme.

The bacterial enzyme MurA catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (PEP) to uridine diphospho-N-acetylglucosamine (UNAG), which is the first committed step of bacterial cell wall biosynthesis. From high-throughput screening of a chemical library, three novel inhibitors of the Escherichia coli MurA enzyme were identified: the cyclic disulfide RWJ-3981, the purine analog RWJ-140998, and the pyrazolopyrimidine RWJ-110192. When MurA was preincubated with inhibitor, followed by addition of UNAG and PEP, the 50% inhibitory concentrations (IC(50)s) were 0.2 to 0.9 microM, compared to 8.8 microM for the known MurA inhibitor, fosfomycin. The three compounds exhibited MICs of 4 to 32 microg/ml against Staphylococcus aureus; however, the inhibition of DNA, RNA, and protein synthesis in addition to peptidoglycan synthesis by all three inhibitors indicated that antibacterial activity was not due specifically to MurA inhibition. The presence of UNAG during the MurA and inhibitor preincubation lowered the IC(50) at least fivefold, suggesting that, like fosfomycin, the three compounds may interact with the enzyme in a specific fashion that is enhanced by UNAG. Ultrafiltration and mass spectrometry experiments suggested that the compounds were tightly, but not covalently, associated with MurA. Molecular modeling studies demonstrated that the compounds could fit into the site occupied by fosfomycin; exposure of MurA to each compound reduced the labeling of MurA by tritiated fosfomycin. Taken together, the evidence indicates that these inhibitors may bind noncovalently to the MurA enzyme, at or near the site where fosfomycin binds.

Characterization of an influenza A (H3N2) virus resistant to the cyclopentane neuraminidase inhibitor RWJ-270201.

The novel influenza virus neuraminidase (NA) inhibitor, (1S,2S,3R,4R)-3-[(1S)-(acetylamino)-2-ethylbutyl]-4-[(aminoiminomethyl)amino]-2-hydroxy-cyclopentanecarboxylic acid (RWJ-270201, BCX-1812), is a potent inhibitor of influenza A and B viruses in cell culture and in infected mice. A mouse-adapted strain of influenza A/Shangdong/09/93 (H3N2) virus was serially passaged in the presence of 1 microM compound. After the fourth passage, breakthrough of resistant virus occurred. By the tenth passage, a twice plaque purified isolate was obtained which could replicate in 10 microM inhibitor. The 50% effective concentration (EC(50)) values for RWJ-270201 against wild-type and resistant viruses, determined by using a cytopathic effect inhibition assay, were 0.007 and 23 microM, respectively. Cross-resistance to zanamivir and oseltamivir carboxylate was observed. The hemagglutinin (HA) and NA genes of the virus were sequenced to determine the mutation(s) which conferred drug resistance. No differences were found between the resistant and wild-type viruses in the NA gene. However, a point mutation resulting in a single amino acid change (Lys189Glu) was found in the resistant viral HA. The wild-type and resistant viruses were compared for virulence in BALB/c mice. The resistant virus was approximately tenfold less virulent than the wild-type virus based upon virus challenge dose. Mice infected with a lethal dose of the resistant virus could still be effectively treated with RWJ-270201. Thus, the HA mutation may allow for the spread of the virus in cell culture in the presence of the NA inhibitor, but not in mice.

[Ga18(SitBu3)8] and [Ga22(SitBu3)8]--syntheses and structural characterization of novel gallium cluster compounds.

The novel neutral gallium cluster compounds [Ga18R*8] (1) and [Ga22R*8] (2) are obtained by warming up a metastable solution of gallium(I) bromide in THF/C6H5CH3 after addition of equimolar amounts of supersilyl sodium NaR* from -78 degrees C to room temperature (R* = SitBu3 = supersilyl). From X-ray structure analyses, the observed arrangements of the 18 and 22 Ga atoms in 1 and 2, respectively, are comparable with an 18 atom section of the beta-Ga modification, or show at least some kind of relationship to a 22 atom section of the Ga-III modification. This allows a description of both the clusters as metalloid. The topology of the atoms in 2 is also well explained by the Wade-Mingos rules as an eightfold capped closo-Ga14 cluster, whereby the Ga atoms of Ga14 occupy the center and the corners of a cuboctahedron with one Ga3 face replaced by a Ga4 face. Some concepts are presented about the formation mechanism, the cluster growth, and the metalloid character of the two Ga cluster compounds.

Synthesis and characterization of an Al(69)(3-) cluster with 51 naked Al atoms: analogies and differences to the previously characterized Al(77)(2-) cluster.

A disproportionation process of a metastable AlCl solution with a simultaneous ligand exchange-Cl is substituted by N(SiMe(3))(2)-leads to a [Al(69)[N(SiMe(3))(2)](18)](3-) cluster compound that can be regarded as an intermediate on the way to bulk metal formation. The cluster was characterized by an X-ray crystal structural analysis. Regarding its structure and the packing within the crystal, this metalloid cluster with 4 times more Al atoms than ligands is compared to the [Al(77)N(SiMe(3))(2)](20)](2-) cluster that has been published four years ago. Although there is a similar packing density of the Al atoms in both clusters as well as in Al metal, the X-ray structural analysis shows significant differences in topology and distance proportions. The differences between these-at a first glance almost identical-Al clusters demonstrate that results of physical measuring, e.g., of nanostructured surfaces which carry supposedly identical cluster species, have to be interpreted with great caution.