Initial assessment of α-synuclein structure in platelets

Journal of Thrombosis and Thrombolysis - Over the last few years data from our group have indicated that α-synuclein is important in development of immune cells as well as potentially...     

Proof of systemic safety of a lidocaine ointment in the treatment of patients with anorectal pain

OBJECTIVE: The aim of the study was to demonstrate that repeated anorectal administration of a 5% lidocaine ointment (CAS 137-58-6; LidoPosterine Salbe, Posterisan akut Rektalsalbe) in the treatment of patients with acute anorectal pain does not result in systemically efficacious plasma concentrations of lidocaine. PATIENTS AND METHODS: In an open single-center study 24 male or female patients with anorectal pain due to hemorrhoids, anal fissures, fistulas or proctitis administered lidocaine ointment as a single anorectal dose (2.5 g ointment corresponding to 125 mg lidocaine) followed by repeated administration (2.5 g ointment t.i.d.) for 4 days. Safety evaluation was performed with respect to plasma concentrations of lidocaine, vital signs, electrocardiogram (ECG), physical findings and adverse events. Blood samples were drawn prior to the first single administration and at 13 time points over the first 24 h in order to create a pharmacokinetic profile. Blood samples were also drawn prior to administration of the last dose on day 5 and thereafter using the identical time points for blood sampling as on day 1. Vital signs and ECG were recorded immediately before and 1 and 4 h after the first and last administration, respectively. Adverse events and skin tolerability were also recorded at predefined times during the study period. RESULTS: After a single dose of 125 mg lidocaine the average extent of exposure in terms of the AUC(tau,sd) during a 6 h dosage interval amounted to 397.7 ng/ml x h (geometric mean). C(max,sd) reached a mean value of 131.8 ng/ml (geometric mean). Only a minor accumulation of the lidocaine plasma concentrations was observed after multiple dose application. The geometric mean of the AUC(tau,md) (503.8 ng/ml x h, tau = 6 h) and the geometric mean of C(max,md) (145.9 ng/ml) were slightly higher than the corresponding single dose values. The AUC accumulation ratio was calculated as 127% (90% CI: 108-148%) and the C(max) accumulation ratio reached 120% (90% CI: 101-139%). Plasma peak concentrations of lidocaine in all subjects remained with a sufficient safety margin below the minimal effective therapeutic plasma concentration (1.5 microg/ml) as well as by an order of magnitude below toxic concentrations (5 microg/ml). There were neither unexpected, serious nor severe adverse events. There were no clinically relevant findings with respect to vital signs and ECG. CONCLUSIONS: Repeated anorectal administration of a 5% lidocaine ointment proved to be safe with respect to systemic plasma concentrations of lidocaine and vital signs.     

CD11c (LEU-M5) expression characterizes a B-cell chronic lymphoproliferative disorder with features of both chronic lymphocytic leukemia and hairy cell leukemia.

Chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL) are two common chronic lymphoproliferative disorders, each having characteristic clinical, morphologic, and immunologic features. Phenotypically, CD5 reactivity in CLL and CD11c (Leu-M5) reactivity in HCL have characterized these two leukemias among B-cell disorders. In this study, we report 14 cases of a novel chronic lymphoproliferative disorder characterized by lymphocytosis and CD11c expression, but morphologically similar to CLL. The patients' ages ranged from 46 to 81 years (median 62). Eleven had palpable splenomegaly, five with markedly enlarged spleens; only one patient had generalized lymphadenopathy. The white blood cell count ranged from 5.2 to 131.0 x 10(9)/L (median 20.8). The morphologic diagnosis in all cases was CLL, with the cells usually having abundant cytoplasm. No morphologic features, of hairy cells were evident; tartrate-resistant acid phosphatase cytochemistry was negative in all cases. Bone marrow biopsies were available in 8 of 14. Four showed focal nodular infiltrates and two had diffuse infiltrates similar to CLL; two showed only minimal interstitial involvement. All cases expressed multiple B-cell markers, and 12 of 14 had monoclonal surface immunoglobulin. The leukemic cells of all cases strongly expressed CD11c, while CD5 was expressed in 7 of 14; only 1 of the 14 cases expressed the lymph node homing receptor, Leu-8. This unique group of leukemias appears to represent the malignant transformation of lymphocytes arising from a stage of lymphocyte differentiation between that found in typical cases of CLL and that of HCL. CD11c is known to have an important function in cellular adhesion and may be important in determining the pattern of lymphocyte tissue distribution found in this group of patients.     

Satisfaction with primary health care and confidence in general practitioners: an exploratory comparison of US and UK students.

This paper explores attitudes of university students towards two differently organised health services, ie the National Health Service in the UK and the more market oriented system in the US and analyses the level of confidence placed in primary care providers (GPs/family physicians) in both systems. Although major differences in the perception of the two health care systems are identified, hardly any differences emerge between the two countries in terms of the confidence patients place in their primary care providers.     

Mutagenic activity of acetonitrile and fumaronitrile in three short term assays with special reference to autoinduction

Two aliphatic nitriles, acetonitrile and fumaronitrile were tested for their genotoxic potential in three mutagenicity test systems: the Salmonella/microsome-assay, an assay using Saccharomyces cerevisiae (strain D7), and the bone marrow micronucleus test. Both compounds were tested with and without metabolic activation in the yeast and the bacterial test systems using S9 preparations from phenobarbitone-pretreated and autoinduced rats. Autoinduction was performed by chronic (7 days) application of a dose equivalent to a 5% oral LD50-value of the respective compound. With yeast strain D7 both nitriles induced low levels of gene conversion in the presence of phenobarbitone-induced liver homogenate. An increase in the number of ile+-revertants was not detectable under any condition. Neither of the compounds showed mutagenic activity in the Ames test with or without metabolic activation. A weak positive effect of acetonitrile could be detected in the micronucleus test 24 h after i.p.-injection of the compound using a dose of 60% LD50. Fumaronitrile showed positive results with a 50% LD50 dose 48 h after administration to mice not preinduced. After 1 week of autoinduction these effects did not appear anymore, with the exception of acetonitrile 72 h after application of a dose amounting to 60% of the oral LD50-value.     

Mother-child attachment in later middle childhood: assessment approaches and associations with mood and emotion regulation

This study examined the overlap and validity of several measures of mother - child attachment developed for preadolescents. Validity was assessed in part by examining how attachment is related to children's mood and emotion regulation. Mother - child attachment was assessed in a sample of 9 to 11 year-old children using a story stem interview technique and questionnaires. Positive and negative mood were scored from daily logs completed by children. Emotion regulation was assessed with mothers' reports of constructive coping and teacher reports of children's ability to tolerate frustration. Interview and questionnaire measures of attachment were not consistently related to one another, although both were related to mood and emotion regulation. As expected, secure attachment and maternal secure base support were related to higher levels of positive mood, more constructive coping, and better regulation of emotion in the classroom, with effects stronger for emotion regulation than for mood. Children classified Disorganized or Ambivalent displayed the most negative mood. All effects remained significant after controlling for child temperament.     

Spectral characteristics of light sources for S-cone stimulation

Purpose: Electrophysiological investigations of the short-wavelength sensitive pathway of the human eye require the use of a suitable light source as a S-cone stimulator. Different light sources with their spectral distribution properties were investigated and compared with the ideal S-cone stimulator. Methods: First, the theoretical background of the calculation of relative cone energy absorption from the spectral distribution function of the light source is summarized. From the results of the calculation, the photometric properties of the ideal S-cone stimulator will be derived. The calculation procedure was applied to virtual light sources (computer generated spectral distribution functions with different medium wavelengths and spectrum widths) and to real light sources (blue and green light emitting diodes, blue phosphor of CRT-monitor, multimedia projector, LCD monitor and notebook display). The calculated relative cone absorbencies are compared to the conditions of an ideal S-cone stimulator. Results: Monochromatic light sources with wavelengths of less than 456 nm are close to the conditions of an ideal S-cone stimulator. Spectrum widths up to 21 nm do not affect the S-cone activation significantly (S-cone activation change < 0.2%). Blue light emitting diodes with peak wavelength at 448 nm and spectrum bandwidth of 25 nm are very useful for S-cone stimulation (S-cone activation 95%). A suitable display for S-cone stimulation is the Trinitron computer monitor (S-cone activation 87%). The multimedia projector has a S-cone activation up to 91%, but their spectral distribution properties depends on the selected intensity. LCD monitor and notebook displays have a lower S-cone activation ( 74%). Conclusion: Carefully selecting the blue light source for S-cone stimulation can reduce the unwanted L- and M-cone activation down to 4% for M-cones and 1.5% for L-cones.     

Decremental conduction properties in overt and concealed atrioventricular accessory pathways.

AIM: Most atrioventricular accessory pathways (AV-APs) exhibit Kent bundle physiology characterized by fast and non-decremental conduction properties. In contrast, atriofascicular APs, which are only capable of reaching slow levels of long antegrade decremental conduction, are uncommon. The aim of this study was to describe antegrade and/or retrograde AV-APs with unusual decremental properties. METHODS AND RESULTS: Five patients with unusual decremental AV-APs underwent electrophysiological evaluation and radiofrequency catheter ablation for symptomatic tachycardias. Three were found to have structural heart disease, and three latent decremental AV-APs in the anterograde and/or retrograde direction that could not be demonstrated by routine electrophysiological testing. In Case 1, a right posteroseptal AV-AP with bidirectionally latent decremental conduction was associated with clinical antidromic circus movement tachycardia (CMT) mimicking ventricular tachycardia and orthodromic CMT, the latter inducible only with isoprenaline. In Case 2, incessant orthodromic CMT was due to a latent retrograde left posterolateral AV-AP. In both cases, double atrial responses to a single paced ventricular beat, initiating orthodromic CMT, were observed. In Case 3 with latent preexcitation unmasked by adenosine and atrial pacing, retrograde latent decremental conduction over a right posteroseptal AV-AP could be shown only with isoprenaline. This patient and the remaining two with overt preexcitation demonstrated anterograde decremental AP conduction that was discontinuous over a right posteroseptal AV-AP in Cases 3 and 4 and was continuous over a midseptal AV-AP in Case 5. In the latter case, the site of decremental conduction could be localized at the proximal AP origin. All five AV-APs were successfully ablated at the annulus level. CONCLUSION: AV-APs with unusual decremental properties that are either latent, demonstrable only during CMT or overt, exhibiting functional longitudinal dissociation are described. These APs could be identified and successfully ablated after detailed electrophysiological analysis.