Small molecule CXCR3 antagonist NIBR2130 has only a limited impact on type 1 diabetes in a virus-induced mouse model.

CXCL10 is one of the key chemokines involved in trafficking of autoaggressive T cells to the islets of Langerhans during the autoimmune destruction of beta cells in type 1 diabetes (T1D). Blockade of CXCL10 or genetic deletion of its receptor CXCR3 results in a reduction of T1D in animal models. As an alternative to the use of neutralizing monoclonal antibodies to CXCL10 or CXCR3 we evaluated the small molecule CXCR3 antagonist NIBR2130 in a virus-induced mouse model for T1D. We found that the overall frequency of T1D was not reduced in mice administered with NIBR2130. An initial slight delay of diabetes onset was not stable over time, because the mice turned diabetic upon removal of the antagonist. Accordingly, no significant differences were found in the islet infiltration rate and the frequency and activity of islet antigen-specific T cells between protected mice administered with NIBR2130 and control mice. Our data indicate that in contrast to direct inhibition of CXCL10, blockade of CXCR3 with the small molecule antagonist NIBR2130 has no impact on trafficking and/or activation of autoaggressive T cells and is not sufficient to prevent T1D.

Biomechanical analysis of a new 8-strand technique for flexor tendon repair.

We sought to compare the strength and rupture sites of a new 8-strand suture technique with those of an established 6-strand flexor tendon repair through biomechanical analysis. This new 8-strand suture pattern places minimal suture material in the remodeling zone and focuses on protecting the knot, a well-known weak point of the suture construct. The knot was buried within the tendon so as to not interfere with tendon gliding. In a biomechanical simulation, strength and rupture sites were compared with those of the 6-strand repair. We repaired a total of 54 porcine flexor tendons using one of the two techniques (n=27 each). Tensile strength at 2-mm gap formation and ultimate failure load were determined. Afterwards, we dissected the tendons to identify the rupture site of the suture material. The new 8-strand suture had a significant higher ultimate load to failure (87.7N) and 2-mm gap load (71.6N) compared to the 6-strand technique (57.7N and 45.9N) (P<0.001). Whereas the rupture site of the core suture in the 6-strand technique was mainly located next to the knot (81.5%), the suture seemed to fail independently from this weak spot in the 8-strand technique (11.1%). This new 8-strand technique achieves a strong flexor tendon repair in a biomechanical model. Additional cross-locking on either side of the knot seems to contribute to the repair's strength. The resulting higher ultimate failure load and 2-mm gap load may allow more aggressive active motion-based postoperative rehabilitation.

The utility of sural-sparing pattern in the electrodiagnosis of regional subtypes of Guillain-Barré Syndrome.

OBJECTIVE: We present an exemplar patient, illustrating utility of the sural-sparing pattern in diagnosis of Guillain-Barré Syndrome (GBS). We then present data that sheds light on the pathophysiology of sural-sparing. METHOD AND RESULTS: We describe a case of complex ophthalmoplegia that exemplifies the challenge of diagnosing regional subtypes of Guillain-Barré Syndrome, and the value of scrutinizing sensory nerve action potentials for the sural-sparing pattern. We also demonstrate, in a series of GBS patients, how serial nerve conduction studies can reveal "covert" sural-sparing in patients without sural-sparing on the initial study. Finally, by studying the median and radial sensory nerve action potentials at digit I in GBS patients, we demonstrate that the likely pathology of sural-sparing is related to the predilection of median nerve for subclinical entrapment; where the blood-nerve barrier is deficient and therefore more exposed to the immunopathology of GBS. CONCLUSION: Incorporating sural-sparing would improve the specificity of GBS electrodiagnosis; especially in difficult to diagnose regional subtypes of GBS.

Inhibition by interferon-gamma of human mononuclear cell-mediated low density lipoprotein oxidation. Participation of tryptophan metabolism along the kynurenine pathway.

In this study we examined the potential inhibition by interferon-gamma (IFN gamma) of the early stages of low density lipoprotein (LDL) oxidation mediated by human peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM) in Ham's F-10 medium supplemented with physiological amounts of L-tryptophan (Trp). We assessed LDL oxidation by measuring the consumption of LDL's major antioxidant (i.e., alpha-tocopherol) and targets for oxidation (cholesteryllinoleate and cholesterylarachidonate), together with the accumulation of cholesterylester hydroperoxides and the increase in relative electrophoretic mobility of the lipoprotein particle. Exposure of PBMC or MDM to IFN gamma induced the degradation of extracellular Trp with concomitant accumulation of kynurenine, anthranilic and 3-hydroxyanthranilic acid (3HAA) in the culture medium. Formation of 3HAA, but neither Trp degradation nor formation of kynurenine and anthranilic acid, was inhibited by low amounts of diphenylene iodonium (DPI) in a concentration-dependent manner. In contrast to oxidative Trp metabolism, exposure of human PBMC or MDM to IFN gamma failed to induce degradation of arginine, and nitrite was not detected in the cell supernatant, indicating that nitric oxide synthase was not induced under these conditions. Incubation of LDL in Trp-supplemented F-10 medium resulted in a time-dependent oxidation of the lipoprotein that was accelerated in the presence of PBMC or MDM but inhibited strongly in the presence of both cells and IFN gamma, i.e., when Trp degradation and formation of 3HAA were induced. In contrast, when IFN gamma was added to PBMC or MDM in F-10 medium that was virtually devoid of Trp, inhibition of cell-accelerated LDL oxidation was not observed. Exogenous 3HAA added to PBMC or purified monocytes in the absence of IFN gamma also strongly and in a concentration-dependent manner inhibited LDL oxidation. Selective inhibition of IFN gamma-induced formation of 3HAA by DPI caused reversion of the inhibitory action of this cytokine on both PBMC- and MDM-mediated LDL oxidation. These results show that IFN gamma treatment of human PBMC or MDM in vitro attenuates the extent of LDL oxidation caused by these cells, and indicate that Trp degradation with formation of 3HAA is a major contributing factor to this inhibitory activity.

Oxidative stress in brain during experimental bacterial meningitis: differential effects of alpha-phenyl-tert-butyl nitrone and N-acetylcysteine treatment.

Antioxidant treatment has previously been shown to be neuroprotective in experimental bacterial meningitis. To obtain quantitative evidence for oxidative stress in this disease, we measured the major brain antioxidants ascorbate and reduced glutathione, and the lipid peroxidation endproduct malondialdehyde in the cortex of infant rats infected with Streptococcus pneumoniae. Cortical levels of the two antioxidants were markedly decreased 22 h after infection, when animals were severely ill. Total pyridine nucleotide levels in the cortex were unaltered, suggesting that the loss of the two antioxidants was not due to cell necrosis. Bacterial meningitis was accompanied by a moderate, significant increase in cortical malondialdehyde. While treatment with either of the antioxidants alpha-phenyl-tert-butyl nitrone or N-acetylcysteine significantly inhibited this increase, only the former attenuated the loss of endogenous antioxidants. Cerebrospinal fluid bacterial titer, nitrite and nitrate levels, and myeloperoxidase activity at 18 h after infection were unaffected by antioxidant treatment, suggesting that they acted by mechanisms other than modulation of inflammation. The results demonstrate that bacterial meningitis is accompanied by oxidative stress in the brain parenchyma. Furthermore, increased cortical lipid peroxidation does not appear to be the result of parenchymal oxidative stress, because it was prevented by NAC, which had no effect on the loss of brain antioxidants.

Immunodetection of 3-nitrotyrosine in the liver of zymosan-treated rats with a new monoclonal antibody: comparison to analysis by HPLC.

Zymosan-induced peritonitis is associated with an increased production of reactive nitrogen oxides that may contribute to the often-observed failure of multiple organ systems in this model of acute inflammation. Quantitative biochemical evidence is provided for a marked 13-fold increase in protein-bound 3-nitrotyrosine (NTyr), a biomarker of reactive nitrogen oxides, in liver tissue of zymosan-treated rats. In order to investigate the localization of NTyr in this affected tissue, a monoclonal antibody, designated 39B6, was raised against 3-(4-hydroxy-3-nitrophenylacetamido) propionic acid-bovine serum albumin conjugate and its performance characterized. 39B6 was judged by competition ELISA to be approximately 2 orders of magnitude more sensitive than a commercial anti-NTyr monoclonal antibody. Binding characteristics of 39B6 were similar, but not identical, to that of a commercial affinity-purified polyclonal antibody in ELISA and immunohistochemical analyses. Western blot experiments revealed high specificity of 39B6 against NTyr and increased immunoreactivity of specific proteins from liver tissue homogenates of zymosan-treated rats. Immunohistochemical analysis of liver sections indicated a marked zymosan-induced increase in immunofluorescent staining, which was particularly intense in or adjacent to nonparenchymal cells, but not in the parenchymal cells of this tissue. Quantitative analysis of fractions enriched in these cell populations corroborated the immunofluorescent data, although the relative amounts detected in response to zymosan treatment was greatly reduced compared to whole liver tissue. These results demonstrate the high specificity of the newly developed antibody and its usefulness in Western blot and immunohistochemical analysis for NTyr, confirm the presence of NTyr by complementary methods, and suggest the possible involvement of reactive nitrogen oxides in hepatic vascular dysfunction.

gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention.

gamma-tocopherol is the major form of vitamin E in many plant seeds and in the US diet, but has drawn little attention compared with alpha-tocopherol, the predominant form of vitamin E in tissues and the primary form in supplements. However, recent studies indicate that gamma-tocopherol may be important to human health and that it possesses unique features that distinguish it from alpha-tocopherol. gamma-Tocopherol appears to be a more effective trap for lipophilic electrophiles than is alpha-tocopherol. gamma-Tocopherol is well absorbed and accumulates to a significant degree in some human tissues; it is metabolized, however, largely to 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), which is mainly excreted in the urine. gamma-CEHC, but not the corresponding metabolite derived from alpha-tocopherol, has natriuretic activity that may be of physiologic importance. Both gamma-tocopherol and gamma-CEHC, but not alpha-tocopherol, inhibit cyclooxygenase activity and, thus, possess antiinflammatory properties. Some human and animal studies indicate that plasma concentrations of gamma-tocopherol are inversely associated with the incidence of cardiovascular disease and prostate cancer. These distinguishing features of gamma-tocopherol and its metabolite suggest that gamma-tocopherol may contribute significantly to human health in ways not recognized previously. This possibility should be further evaluated, especially considering that high doses of alpha-tocopherol deplete plasma and tissue gamma-tocopherol, in contrast with supplementation with gamma-tocopherol, which increases both. We review current information on the bioavailability, metabolism, chemistry, and nonantioxidant activities of gamma-tocopherol and epidemiologic data concerning the relation between gamma-tocopherol and cardiovascular disease and cancer.

Ascorbate is depleted by smoking and repleted by moderate supplementation: a study in male smokers and nonsmokers with matched dietary antioxidant intakes.

BACKGROUND: Lack of reliable dietary data has hampered the ability to effectively distinguish between effects of smoking and diet on plasma antioxidant status. As confirmed by analyses of comprehensive food-frequency questionnaires, the total dietary intakes of fruit and vegetables and of dietary antioxidants were not significantly different between the study groups in the present study, thereby enabling isolation of the effect of smoking. OBJECTIVE: Our objective was to investigate the effect of smoking on plasma antioxidant status by measuring ascorbic acid, alpha-tocopherol, gamma-tocopherol, beta-carotene, and lycopene, and subsequently, to test the effect of a 3-mo dietary supplementation with a moderate-dose vitamin cocktail. DESIGN: In a double-blind, placebo-controlled design, the effect of a vitamin cocktail containing 272 mg vitamin C, 31 mg all-rac-alpha-tocopheryl acetate, and 400 microg folic acid on plasma antioxidants was determined in a population of smokers (n = 37) and nonsmokers (n = 38). The population was selected for a low intake of fruit and vegetables and recruited from the San Francisco Bay area. RESULTS: Only ascorbic acid was significantly depleted by smoking per se (P < 0.01). After the 3-mo supplementation period, ascorbic acid was efficiently repleted in smokers (P < 0.001). Plasma alpha-tocopherol and the ratio of alpha- to gamma-tocopherol increased significantly in both supplemented groups (P < 0.05). CONCLUSIONS: Our data suggest that previous reports of lower concentrations of plasma vitamin E and carotenoids in smokers than in nonsmokers may primarily have been caused by differences in dietary habits between study groups. Plasma ascorbic acid was depleted by smoking and repleted by moderate supplementation.

Marked elevation in cortical urate and xanthine oxidoreductase activity in experimental bacterial meningitis.

Experimental bacterial meningitis due to Streptococcus pneumoniae in infant rats was associated with a time-dependent increase in CSF and cortical urate that was approximately 30-fold elevated at 22 h after infection compared to baseline. This increase was mirrored by a 20-fold rise in cortical xanthine oxidoreductase activity. The relative proportion of the oxidant-producing xanthine oxidase to total activity did not increase, however. Blood plasma levels of urate also increased during infection, but part of this was as a consequence of dehydration, as reflected by elevated ascorbate concentrations in the plasma. Administration of the radical scavenger alpha-phenyl-tert-butyl nitrone, previously shown to be neuroprotective in the present model, did not significantly affect either xanthine dehydrogenase or xanthine oxidase activity, and increased even further cortical accumulation of urate. Treatment with the xanthine oxidoreductase inhibitor allopurinol inhibited CSF urate levels earlier than those in blood plasma, supporting the notion that urate was produced within the brain. However, this treatment did not prevent the loss of ascorbate and reduced glutathione in the cortex and CSF. Together with data from the literature, the results strongly suggest that xanthine oxidase is not a major cause of oxidative stress in bacterial meningitis and that urate formation due to induction of xanthine oxidoreductase in the brain may in fact represent a protective response.

Recurrent myocardial infarction caused by a giant coronary aneurysm.

We report on a patient with a giant aneurysm arising from the right coronary artery leading to infarction due to a steal phenomenon. Emergency coronary angiography was performed. The orifice of the aneurysm was occluded by balloon catheter restoring blood flow and resolving ischemia. Aneurysmectomie was done subsequently. The patient recovered very soon, and the following course was uneventful. This case illustrates that occasionally causes other than usual coronary atherosclerosis may lead to acute coronary syndromes.

A comparative study on schizophrenic patients with dual diagnosis.

As indicated in the literature, substance abuse is a significant yet complex variable in schizophrenic disorder. We evaluated hospital charts of 86 schizophrenic patients with comorbid substance use disorder and of 56 patients suffering from schizophrenia-only. We surmised that among the former group there will be a substantial proportion of patients abusing opiates and that there will be differences between schizophrenic patients abusing different drugs. Both hypotheses could be confirmed. Among our dual patients, 18 patients with alcohol, 18 patients with cannabis, and 50 patients with "hard drugs" (opiates, cocaine) use disorder were identified and several significant differences were found between the individual groups of patients in respect to basic sociodemographic and clinical variables; in particular, schizophrenic patients with alcohol use disorder (and patients suffering from schizophrenia-only) were older and better socially adjusted than schizophrenic patients with "illegal" drug use disorder. The particularities of schizophrenic patients suffering from different kinds of substance use disorder should be considered when creating individualized therapeutic programs.

[School type, school stress and health problems in 17-year-old Zurich middle school students]. / Schultypus, Schulstress und Gesundheitsstörungen bei 17jährigen Zürcher Mittelschülerinnen und -schülern.

In the present study a sample of 661 seventeen-year-old students of different undergraduate colleges of the Canton of Zurich were investigated by questionnaire. They were asked about various psychosocial variables, their consumer behavior, school-life and their physical and mental health. The aim of the study was to investigate whether students of different college types differ in regard to their psychosocial and morbidity characteristics: Out of the sample two subgroups were formed: Students of the traditional college type B (classical/modern languages) and C (mathematics and sciences) on the one hand, and students of the modern college type D (modern languages) and L (modern languages/fine arts) on the other. Regarding sociodemographic variables and social contact there were no differences for both sexes between the two college types. Female students of the modern colleges reported to drink alcohol more regularly. There was a significant difference, however, taking college type into account in regard to eating behavior, body image, and physical and mental complaints. Girls of the modern colleges showed more symptoms and disturbances on all applied check lists. Regardless the college type, the results indicated that low academic grades and stressfully assessed school life were accompanied with significantly higher symptom scores in female students. The findings of the study indicate that targeted concepts for prevention and health promotion should be advanced especially in the classes of the modern colleges.

Suicidal behavior in Swiss students: an 18-month follow-up survey.

Suicidal behavior and its relationship with other mental disturbances was assessed in an epidemiological study of 1937 Swiss adolescents aged 14 to 19 years. During the most recent 12 months, 27.5% of the females and 16.1% of the males reported suicidal ideation, while 3.3% of the girls and 1.0% of the boys reported suicidal ideation. Suicidality was significantly correlated with physical and mental impairment, alcohol and drug abuse. Of the total epidemiological sample, 475 students (24.5%) were reassessed 12 and 18 months later. Of this follow-up sample, 37 females (12.4%) and 10 males (5.6%) described suicidal ideation as a continuing problem. They revealed significantly more psychiatric symptoms than nonpersistent ideators. Three girls (1.0%) and one boy (0.6%) reported suicide attempts during the follow-up period of 18 months. Only one out of six of the ideators of both sexes received psychiatric treatment. The findings indicate that transient suicidal ideation is common in adolescents. Persistent suicidal behavior appears to be a sign of severe social and psychological disturbances and is associated with serious physical and mental impairment. There is a high risk of completed suicide for youths who demonstrate persistent suicidal ideation, and far more substantial prevention efforts should be designed and implemented to address the circumstances of these youths.

Specialising in radiology in Switzerland: still attractive for medical school graduates?

PURPOSE: To gain insight into the professional characteristics of radiologists in Switzerland and to determine how to enhance the attractiveness of radiology to medical graduates as a specialty. MATERIALS AND METHODS: Data from 262 members of the Swiss Society of Radiology (m:f = 76:24%) obtained in a questionnaire survey were analysed regarding socio-demographic variables, working status, specialty, main fields of interest, career success, mentoring and reasons for the shortage of radiologists. RESULTS: 35 (56.4%) female and 85 (45.5%) male radiologists were aged ≤ 45 years. 228 (87%) were board-certified; 44 (17.9%) had completed a sub-specialisation. Men worked part-time mostly just before retirement, while women worked part-time at a younger age. As reasons for specialty choice, the wide range of clinical work and the combination of technology and medicine were ranked highest. Women reported significantly less career success and support. To improve the attractiveness of radiology to graduates, radiology should be visible on medical school curricula. CONCLUSION: In Switzerland, more female radiologists work part-time than male ones, and there is less career success and support for women. In order to make radiology more attractive to medical graduates as a specialty, structured residency programmes and reliable gender-respecting career support are needed.

Improvement of the intrinsic time resolving power of the Cologne iron-free orange type electron spectrometers.

Conversion electron spectroscopy represents an important tool for nuclear structure analysis of medium and heavy nuclei. Two iron-free magnetic electron spectrometers of the orange type have been installed at the Institute for Nuclear Physics of the University of Cologne. The very large transmission of 15% and the very good energy resolution of 1% makes the iron-free orange spectrometer a powerful instrument. By means of fast timing techniques, lifetimes of nuclear excited states can be measured with an accuracy better than 20 ps. For the first time, the energy dependent centroid position of prompt events yielding the time-walk characteristics (the prompt curve) of the orange spectrometer fast timing setup has been measured using prompt secondary δ-electrons generated in a pulsed beam experiment. The prompt curve calibrated as a function of energy allows precise lifetime determination down to a few tens of picoseconds by the use of the centroid shift method.

Drug interactions and adverse events associated with antimycotic drugs used for invasive aspergillosis in hematopoietic SCT.

The aim of this study was to assess the frequency of potential drug-drug interactions (pDDIs) and adverse drug events (ADEs) associated with antimycotics in hospitalized patients with hematopoietic SCT (HSCT). Of the 120 HSCT recipients evaluated, 36 received antimycotics. A total of 124 ADEs were recorded in 32 of the 36 patients treated, with 54 ADEs being possibly and 9 probably related to antimycotics. Of the treatments with amphotericin B, 93% were associated with one or more possible and 36% with probable ADEs. The corresponding figures for lipid-based amphotericin B were 100% and 7%, for voriconazole 68% and 11% and for caspofungin 70% and 0%. A total of 57 potentially severe DDIs associated with antimycotics were detected in 31 of the 36 patients. Of these, 14 DDIs were a possible cause of an ADE and 5 (4 times a combination of voriconazole with CYA and once a combination of CYA with conventional amphotericin B) were probably related. Although the prevalence of pDDIs and ADEs is high in HSCT patients, ADEs related with a high probability to treatment with antimycotics are rare. Regarding the high prevalence of pDDIs, our findings underscore the importance of close monitoring of laboratory and clinical parameters, as well as dose adjustment for critical drugs, in patients with HSCT.

Comparison of infectious complications during induction/consolidation chemotherapy versus allogeneic hematopoietic stem cell transplantation.

Induction/consolidation chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies are associated with treatment-related risks such as infections. The predominant types of infections are blood stream infections (BSIs) and respiratory tract infections. We prospectively compared infectious complications after induction/consolidation chemotherapy versus allogeneic HSCT in a directly comparable setting with both groups being hospitalized on the same ward. From July 2003 until June 2008, 492 hospitalizations of 321 patients took place; 237 chemotherapies and 255 HSCTs were performed. We observed 49 (20.7%) BSIs, 70 (29.5%) pneumonias and 11 (4.6%) probable or proven invasive mould infections in the chemotherapy group. In the HSCT group we detected 70 (27.5%) BSIs, 71 (27.8%) pneumonias and 14 (5.4%) probable or proven invasive mould infections. There was a trend toward more transfers to the intensive care unit (OR 1.61; 95%CI 0.95-2.72; P=0.074) and BSIs (OR 1.45; 95%CI 0.95-2.22; P=0.079) after HSCT; 44 (13.7%) patients died. In-hospital mortality was significantly higher in the HSCT group (OR 2.39; 95%CI 1.22-4.68; P=0.010). We conclude that the risk of pneumonia and invasive mould infection is comparable after induction/consolidation chemotherapy and allogeneic HSCT. However, there was a trend for more BSIs and intensive care unit stays and a higher mortality in the latter.