[Diagnostics and Eradication Therapy for MRSA Carriers in the Outpatient Sector: an Analysis of the Reimbursement Situation in the Light of Current Reimbursement Changes]. / Diagnostik und ambulante Eradikationstherapie von Trägern mit MRSA in der vertragsärztlichen Versorgung ­ Eine Analyse der Erstattungssituation im Kontext aktueller Vergütungsveränderungen.

Infection with methicillin-resistant Staphylococcus aureus (MRSA) occurs in both the inpatient and outpatient sector. The reimbursement for diagnostic services and eradication therapy in the outpatient sector was regulated for the first time on 01.04.2012 and after a 2-year test period, has been adopted into the standard range of care services. The aim of this retrospective study was to give an overview of the current situation in services and reimbursement in Germany and describe MRSA patients and their treatment in the outpatient sector. Secondary data, namely reimbursement data of the National Association of Statutory Health Insurance Physicians (KBV) und the Physicians' Association (KV) Mecklenburg-West Pomerania for the period 01/04/2012-31/03/2014 were analyzed. Results show that on the federal level, MRSA services amounting to € 3,235,870.18 have been reimbursed and that diagnostic costs exceed treatment costs. In Germany, 5,627 doctors invoiced services related to MRSA; 51,56% of these were general practitioners and 21,25% specialists in internal medicine working in general practice. In the KV Mecklenburg-Western Pomerania, patients were elderly (average age 69,13), cost for services were on average 27,76 €, and 76,85% of the patients were treated within one quarter. On the whole, there were regional differences in the identification and eradication of MRSA in the outpatient setting. In order to provide an extended base for a more efficient resource allocation in the health care sector, in addition to analysis of MRSA eradication from the medical point of view, attention needs to be paid to patient flow between the out- and inpatient sectors, as well as economic aspects.

Cost-analysis of PCR-guided pre-emptive antibiotic treatment of Staphylococcus aureus infections: an analytic decision model.

The aim of this study is to examine whether rapid polymerase chain reaction (PCR)-based screening is a cost-efficient tool to optimize pre-emptive antibiotic therapy of methicillin-resistant and methicillin-sensitive Staphylococcus aureus (MRSA and MSSA, respectively) infections. A decision analytic cost model was developed, based on data from the peer-reviewed literature. Sensitivity analyses were undertaken to investigate the impact of variation in the MRSA rate, cost ratio of the cost of inappropriate antibiotic therapy to the cost of appropriate antibiotic therapy, PCR test cost, and total hospital costs per case. At a current MRSA rate of 24.5 % in Germany, PCR-guided treatment regimens are cost-efficient compared to empirical strategies. The costs of alternative treatment strategies differ, on average, up to 1,780 per case. An empirical MRSA treatment strategy is least costly when the cost ratio is less than 1.06. When the total hospital cost per MRSA case is increased, pre-emptive MSSA treatment with PCR tests achieves the lowest average cost. Early verification and adaptation of an initial pre-emptive antibiotic treatment of S. aureus infections using PCR-based tests are advantageous in Germany and other European countries. PCR tests, accordingly, should be considered as elements in antimicrobial stewardship programs.

Expression of the Na-K-2Cl-cotransporter NKCC1 during mouse development.

Here we describe the expression pattern of the Na-K-2Cl-cotransporter NKKC1 during embryonal and early postnatal mouse development. During early stages hybridization signals were detected over single cells of the developing neuroepithelia, whereas the neuroepithelium of the basal telencephalon was labeled continuously. With ongoing differentiation a distinct pattern of hybridization became apparent, which switched from a neuronal to a more glial pattern in the adult. Outside the nervous system NKCC1 transcripts were present in many organs and were mostly confined to epithelia.

Ataxia with vitamin E deficiency: biochemical effects of malcompliance with vitamin E therapy.

To prevent neuronal damage, patients with ataxia with isolated vitamin E deficiency need lifelong supplementation with high doses of vitamin E. Short interruptions of therapy, such as occur in malcompliance, do not lead to clinical symptoms. However, the authors show that even short withdrawals may cause a prolonged decrease of the total radical trapping capacity of plasma; its major contributors, such as urate and sulfhydryl groups, fail to compensate for the missing vitamin E.

Urinary alpha-tocopherol metabolites in alpha-tocopherol transfer protein-deficient patients.

Patients with alpha-tocopherol transfer protein (alpha-TTP) defects experience neurological symptoms characteristic of vitamin E deficiency and depend on continuous high alpha-tocopherol supplements. We investigated the excretion of 2,5,7, 8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC), a urinary metabolite of alpha-tocopherol, as a putative marker for the alpha-tocopherol status of alpha-TTP-deficient patients and control subjects. In three patients vitamin E supplementation was stopped for short periods of time, during which plasma alpha-tocopherol concentrations and urinary alpha-CEHC excretion were measured. In the patients, plasma alpha-tocopherol decreased below normal (<5 micromol/l) but alpha-CEHC excretion remained above the range of unsupplemented control subjects (0.118-0.306 mg/day, n = 6). In healthy subjects, however, alpha-CEHC excretion was increased only after surpassing a plasma alpha-tocopherol threshold of 30-40 micromol/l. Such a threshold did not exist in patients. The general mechanism of alpha-tocopherol degradation did not appear to differ between patients and control subjects. The presumed mechanism of omega- and subsequent beta-oxidation was supported by the detection of alpha- CPHC, an alpha -CEHC homolog with a side chain longer by 3 carbon atoms, both in supplemented patients and in control subjects.

N-Methyl-D-aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain.

Morbidity and mortality from head trauma is highest among children. No animal model mimicking traumatic brain injury in children has yet been established, and the mechanisms of neuronal degeneration after traumatic injury to the developing brain are not understood. In infant rats subjected to percussion head trauma, two types of brain damage could be characterized. The first type or primary damage evolved within 4 hr and occurred by an excitotoxic mechanism. The second type or secondary damage evolved within 6-24 hr and occurred by an apoptotic mechanism. Primary damage remained localized to the parietal cortex at the site of impact. Secondary damage affected distant sites such as the cingulate/retrosplenial cortex, subiculum, frontal cortex, thalamus and striatum. Secondary apoptotic damage was more severe than primary excitotoxic damage. Morphometric analysis demonstrated that the N-methyl-D-aspartate receptor antagonists 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonate and dizocilpine protected against primary excitotoxic damage but increased severity of secondary apoptotic damage. 2-Sulfo-alpha-phenyl-N-tert-butyl-nitrone, a free radical scavenger, did not affect primary excitotoxic damage but mitigated apoptotic damage. These observations demonstrate that apoptosis and not excitotoxicity determine neuropathologic outcome after traumatic injury to the developing brain. Whereas free radical scavengers may prove useful in therapy of head trauma in children, N-methyl-D-aspartate antagonists should be avoided because of their propensity to increase severity of apoptotic damage.

Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency.

Dysfunction of the alpha-tocopherol transfer protein causes ataxia with isolated vitamin E deficiency. A 14-year-old male patient presented with ataxia and mental symptoms caused by a homozygous (552G-->A) alpha-tocopherol transfer protein mutation. After initiation of high-dosage alpha-tocopherol therapy, the organic mental syndrome disappeared and cognitive function improved rapidly. Neurologic recovery, however, was slow and incomplete.

Metabolic effects of adjuvant recombinant human growth hormone in patients with continuing sepsis receiving parenteral nutrition.

BACKGROUND: Adjuvant growth hormone is advocated for treating the catabolism of prolonged sepsis not corrected by parenteral nutrition alone. METHODS: An open study was performed in which eight patients whose postabsorptive resting energy expenditure was persistently elevated by a mean of 19% as a result of continuing sepsis were randomized to receive 0.03 or 0.06 mg/kg recombinant human growth hormone (rhGH) each evening for 7 days adjuvant to total parenteral nutrition. Plasma concentrations of growth hormone, insulin, insulin-like growth factors 1 and 2 (IGF-1 and -2) and their binding proteins IGFBP-1 and -3 were measured before and after rhGH, and their relationship with rates of whole-body protein turnover was determined in the morning in the postabsorptive state by using L-[1-13C]leucine. RESULTS AND CONCLUSIONS: Before rhGH, the patients were hyperinsulinemic (mean, 44.4 mU/L) but had growth hormone levels within the normal range (< 10 mU/L). After the seventh dose of rhGH, nocturnal growth hormone concentrations rose to a mean of 35.3 +/- 26.1 and 61.3 +/- 21.05 mU/L for the low and higher dose groups, respectively. Morning IGF-1 concentrations showed a small increase during treatment, rising from a mean of 241.3 +/- 99.0 to 301.7 +/- 167.3 ng/mL for the low-dose group and from 214.5 +/- 74.6 to 294.1 +/- 116.9 ng/mL for the higher-dose group. IGF-2 increased slightly by 89 +/- 39 and 75 +/- 49 ng/mL for the low and higher doses, respectively. IGFBP-1 and -3 and insulin did not change. The balance between nitrogen input and urinary urea nitrogen increased after rhGH by a mean of 5.3 g/d with no differences between the two dosage groups (4.74 +/- 1.56 g/d for the higher dose, 5.94 +/- 3.70 g/d for the lower). No significant changes were observed in whole-body protein turnover after a 1-week course of rhGH.

Effect of plasma alpha-tocopherol on leukotriene E4 excretion in genetic vitamin E deficiency.

Studying the biological effects of vitamin e in humans is difficult because conditions involving vitamin E deficiency are usually associated with chronic multiple pathology. Genetic vitamin E deficiency caused by a deficient alpha-tocopherol transport protein offers unique possibilities for study of vitamin E effects since the patients can be studied in good general health. In such a patient we manipulated plasma alpha-tocopherol levels in a wide range by varying oral alpha-tocopherol supplements and measured urinary leukotriene E4 (LTE4) concentrations. LTE4 excretion proved inversely correlated to plasma alpha-tocopherol levels. This strongly suggests that in genetic vitamin E deficiency, alpha-tocopherol influences formation of leukotrienes in vivo.

Prevention of pancreatic islet xenograft rejection by dietary vitamin E.

In pancreatic islet transplantation, the adhesion of activated leukocytes to endothelial cells and the loss of microvascular integrity represent the critical microcirculatory events, which promote loss of graft function due to rejection. With the view that oxygen radicals may contribute to graft rejection, we studied the effect of the antioxidant vitamin E on microvascular rejection of islet grafts. Islets were transplanted syngeneically and xenogeneically (rat) into dorsal skin-fold chambers of hamsters, which received a non-vitamin-E-supplemented laboratory chow. Treated animals with xenografts were fed with a diet supplemented with vitamin E in a low (150 mg/kg) and high (8000 mg/kg) concentration. Intravital fluorescence microscopy demonstrated complete vascularization of syngeneic grafts at day 10 after transplantation, intact islet microcirculation at day 20 with a functional capillary density of 653 +/- 6 cm-1, and only few leukocytes adherent to the endothelial lining of the islets' microvasculature (88 +/- 23 mm-2). Xenogeneic islets showed initial signs of rejection at day 6, including adhesion of leukocytes to the microvascular endothelium (610 +/- 110 mm-2) and loss of endothelial integrity. After 20 days, functional capillary density was significantly lower (173 +/- 68 cm-1) when compared with syngeneic grafts, indicating failure of graft acceptance. Supplementation of the diet with low and high concentrations of vitamin E resulted in a significant (P < 0.05) reduction of xenograft leukocyte-endothelium interaction (146 +/- 29 mm-2 and 109 +/- 42 mm-2) at day 6 after transplantation and and adequate development of functional capillary density at day 20 (478 +/- 36 cm-1 and 539 +/- 86 cm-1; P < 0.05), indicating prevention of microvascular rejection. We conclude that dietary supplementation of the lipophilic antioxidant vitamin E attenuates leukocyte-endothelial cell interactions, preserves microvascular integrity, and thus inhibits microvascular rejection in a dose-dependent fashion. Our study underscores the pivotal mediator role of reactive oxygen species in islet xenograft rejection and, furthermore, suggests that dietary vitamin E may act as an adjunct anti-rejection treatment in clinical islet transplantation.

Wheat kernel ingestion protects from progression of muscle weakness in mdx mice, an animal model of Duchenne muscular dystrophy.

A simple, reproducible test was used to quantify muscle weakness in mdx mice, an animal model of Duchenne muscular dystrophy. The effect of bedding on wheat kernels and of dietary supplementation of alpha-tocopherol on the progression of muscle weakness was investigated in mdx mice. When measured during the first 200 d of life, mdx mice developed muscle weakness, irrespective of bedding and diet. When kept on wood shavings and fed a conventional rodent diet, mdx mice showed progressive muscle weakness over the consecutive 200 d, and eventually showed a significant weight loss during the next 200-d observation period. Progression of muscle weakness and weight loss were almost completely prevented in mdx mice that were kept on wheat kernel bedding. In contrast, only incomplete maintenance of muscle strength and body weight was observed in mdx mice kept on wood shavings and fed the alpha-tocopherol-supplemented diet. It is concluded from these experiments that a component of wheat kernels other than alpha-tocopherol is essential to prevent the progression of muscle weakness in mdx mice.

Insulin-like growth factor-I and- II in combination inhibit the release of growth hormone-releasing hormone from the rat hypothalamus in vitro.

This study was designed to investigate the feedback loop between insulin-like growth factor-I (IGF-I) and IGF-II and the hypothalamic hormones growth hormone-releasing hormone (GHRH) and somatostatin (SS) using an in vitro rat hypothalamic model. IGF-I and, to lesser extent, IGF-II, both activate type 1 IGF receptors, while type 2 receptors are activated by IGF-II alone. IGF-I, IGF-II, their various specific analogues (Des[1-3]IGF-I, [Arg54/Arg55]IGF-II and [Leu27]IGF-II), insulin and the type 2 receptor antagonist beta-galactosidase were used on their own or in combination to study their effect on GHRH and SS release. Our results suggest that the simultaneous activation of type 1 and type 2 IGF receptors is needed for the negative feedback effect of IGFs on GHRH release in this in vitro system, in agreement with earlier findings in vivo. Somatostatin was not altered by any combination of peptides.

Deteriorating free radical-trapping capacity and antioxidant status in plasma during bone marrow transplantation.

Organ toxicity in BMT may in part be due to free radical damage. Therefore the 'Total Radical-trapping Antioxidant Parameter of plasma' (TRAP), individual plasma antioxidants, serum iron and linoleic acid, a main substrate of lipid peroxidation, were monitored before and after BMT, and they were compared with values obtained from healthy controls. Seven patients (3 AML, 3 CML, 1 multiple myeloma) receiving 16 mg/kg busulfan, 30-45 mg VP-16 and 120 mg/kg cyclophosphamide were investigated. TRAP values declined during chemotherapy by about 40% (day -9: 1019 +/- 245 mumol/l, mean +/- s.d.; day 0: 660 +/- 164 mumol/l; P < 0.05). The concentration of uric acid, one of the main antioxidants in plasma, decreased markedly (day -9: 339 +/- 108 mumol/l, day 0: 148 +/- 61 mumol/l; P < 0.05) and paralleled TRAP values. Vitamin E and bilirubin did not change from day -9 to 0 whereas vitamin C increased (day -9: 46 +/- 16 mumol/l, day 0: 89 +/- 44 mumol/l; P < 0.05). Serum iron rapidly increased within the pre-transplantation period, reaching values normally seen only in iron overload (day -9: 11.8 +/- 5.2 mumol/l, day 0: 40.6 +/- 6.5 mumol/l; P < 0.05). Linoleic acid levels were normal at the start and decreased substantially (27.0 +/- 1.6 wt% at day -9; 15.7 +/- 4.9 wt% at day 0; P < 0.05), indicating possible lipid peroxidation during high-dose chemotherapy. In conclusion, complex monitoring of the antioxidant status before and after BMT revealed a breakdown of plasma antioxidant defence and of radical-vulnerable lipids, which was associated with high circulating levels of iron.

Dietary fish oil reduces leukocyte/endothelium interaction following systemic administration of oxidatively modified low density lipoprotein.

BACKGROUND: In vitro and in vivo experiments have demonstrated the role of oxidatively modified low density lipoprotein (oxLDL) in eliciting leukocyte/endothelium interaction during early atherogenesis. METHODS AND RESULTS: In the present study we investigated the effect of dietary fish oil on oxLDL-induced leukocyte/endothelium interaction using intravital fluorescence microscopy in the dorsal skinfold chamber model in awake Syrian golden hamsters. Hamsters were fed for 4 weeks prior to the experiments with either standard laboratory chow or a diet supplemented with 5% of a fish oil concentrate (18% eicosapentaenoate, 12% docosahexaenoate). The efficacy of the fish oil diet was demonstrated by the incorporation of fish oil-derived omega-3 fatty acids into plasma, leukocyte, and erythrocyte lipids. In control hamsters (n = 7) and fish oil-fed hamsters (n = 7), leukocyte/endothelium interaction was assessed in the time course after intravenous injection of human LDL (4 mg/kg), oxidized by 7.5 microM Cu2+ (6 hours, 37 degrees C). In control hamsters, injection of oxLDL elicited the rolling and sticking of leukocytes to the endothelium of arterioles and postcapillary venules with a maximum 15 minutes after injection (arterioles: from 3 +/- 1 to 91 +/- 25 cells/mm2 at 15 minutes; venules: from 13 +/- 6 to 150 +/- 46 cells/mm2 at 15 minutes; mean +/- SD). This phenomenon was significantly reduced in fish oil-fed hamsters, where 15 minutes after injection of oxLDL leukocyte sticking reached a maximum of only 15 +/- 7 and 20 +/- 5 cells/mm2 in arterioles and postcapillary venules, respectively (p less than 0.01 versus control animals). CONCLUSIONS: The results of the present study suggest that inhibition of leukocyte/endothelium interaction may be one of the mechanisms by which dietary fish oil exerts its protective effects on experimental and clinical atherogenesis.

Dietary fish oil blocks the microcirculatory manifestations of ischemia-reperfusion injury in striated muscle in hamsters.

Epidemiologic observations and experimental studies have demonstrated a protective effect of dietary fish oil on the clinical manifestations of ischemia-reperfusion injury. To investigate the underlying mechanisms, we used the dorsal skinfold chamber model for intravital fluorescence microscopy of the microcirculation in striated muscle of awake hamsters. In control hamsters (n = 7), reperfusion after a 4-hr pressure-induced ischemia to the muscle tissue elicited the adhesion of fluorescently stained leukocytes to the endothelium of postcapillary venules, capillary obstruction, and the break-down of endothelial integrity. These microvascular manifestations of ischemia-reperfusion injury were significantly attenuated in animals (n = 7) when fed with a fish oil-enriched diet for 4 weeks prior to the experiments. In leukocyte total lipids, the fish oil diet resulted in a substantial displacement of arachidonic acid, the precursor of the potent adhesion-promoting leukotriene (LT) B4, by fish oil-derived eicosapentaenoic acid, the precursor of biologically less potent LTB5, emphasizing the mediator role of LTB4 in ischemia-reperfusion injury. These results suggest that the preservation of microvascular perfusion by dietary fish oil contributes to its protective effects on the clinical manifestations of ischemia-reperfusion injury.