Subtyping of oligo-astrocytic tumours by comparative genomic hybridization

Oligo-astrocytic tumours (OAs) histologically show both oligodendroglial and astrocytic differentiation. Unequivocal criteria for delineation of OAs from pure oligodendroglial (Os) and astrocytic (As) tumours and for grading of OAs are lacking. Molecular genetic analysis may allow for a better characterization of OAs and thereby guide prognostic and therapeutic decisions. Comparative genomic hybridization (CGH) was performed on 39 gliomas with variable phenotypic expression of histological features characteristic of both astrocytic and oligodendroglial differentiation. The results show that OAs are genetically more heterogeneous than Os. In addition to the "-1p/-19q" and "+7/-10" subtypes that have been previously recognized, two additional genetic subtypes, "intermediate" and "other", were identified in the present study. "Intermediate" OAs likely represent progression from "-1p/-19q" tumours. The "other" subtype appears to represent an additional, heretofore unrecognized, genetic pathway(s). Application of rigorously "strict" histopathological criteria, as opposed to "relaxed" criteria, for the selection of oligo-astrocytic tumours resulted in a higher percentage of "-1p/-19q" tumours, but some "-1p/-19q" tumours might be missed. The results suggest that molecular genetic analysis is a useful and valid additional tool for the classification of gliomas, particularly for the significant subset of tumours in which subjective histopathological criteria are insufficient for an unequivocal distinction between Os, As, and mixed OAs.     

Correlation between localization,age, and chromosomal imbalances in ependymal tumours as detected by CGH

Ependymal tumours (ETs) are gliomas that arise from the ependymal lining of the cerebral ventricles and from the remnants of the central canal of the spinal cord. Both clinical and genetic studies suggest that distinct genetic subtypes of ETs exist, the subtypes being correlated with patient age and/or tumour site. In the present study, the tumour genome of 20 ETs (15 adult and five paediatric cases) was screened for chromosomal imbalances by comparative genomic hybridization (CGH). The most frequently detected imbalances were -22q (75%), -10q (65%), -21 (50%), -16p (50%), -1p (45%), +4q (45%), -10p (45%), -2q (40%), -6 (40%), -19 (40%), -2p (35%), -3p (35%), and -16q (35%). Comparison of the chromosomal imbalances detected in ETs with those previously reported in oligodendroglial and astrocytic tumours revealed that in this respect ETs show similarities to these other gliomas. By combining these results with those of a recent study of Zheng et al. and Hirose et al., it was found that although ETs from different sites and from adult and paediatric patients show overlap at the CGH level, some chromosomal imbalances occur predominantly in a certain category. In adult patients, spinal ETs relatively often showed +2, +7, +12, and -14q; infratentorial ETs -22; and supratentorial ETs -9. In addition, in posterior fossa ETs, -6 and +9 were much more frequent in adults than in children. It is concluded that the genetic background of ETs is complex and partly determined by tumour site, histopathological subtype, and age of the patient.     

Short-term alternating temperature enhances histamine-induced itch: a biphasic stimulus model

Itch is the major symptom of many allergic or inflammatory skin diseases; yet it is still difficult to measure objectively. Human studies on the physiology and pathophysiology of the itch sensation (e.g. functional magnetic resonance imaging studies) have been hampered by the lack of an efferent and manageable "on-off" stimulus. Here, a short-term temperature-modulated human histamine itch model is presented. In nine healthy right-handed male volunteers (age 29+/-2.6 years), 1% histamine dihydrochloride was used in the skin prick model as standard itch stimulus on the right forearm with subsequent thermal modulation of the target skin area using a Medoc TSA II NeuroSensory Analyzer thermode. Modulation occurred in rapid alternating order from 32 degrees C (neutral) to 25 degrees C (slight cold) and vice versa; each temperature block lasted 20 seconds. Subjective itch ratings were recorded using a computerized visual analog scale (VAS) and - for qualitative assessment - the Eppendorf Itch Questionnaire (EIQ). All subjects reported localized itch sensations without pain; mean VAS itch intensity was 50.6+/-3.5% during the 25 degrees C blocks and 33.8+/-3.9% during the 32 degrees C blocks (P<0.0001). Also, mean EIQ ratings were significantly higher related to the 25 degrees C blocks. In spite of the common knowledge that intensive cold can inhibit itch sensation, a reproducible, significant enhancement of histamine-induced itch by short-term moderate temperature decrease could be shown. This effect might be explained by peripheral and central adaptation processes triggered by alternating afferent activity patterns and might be used - owing to its "on/off" characteristics-in future itch physiology studies such as functional magnetic resonance imaging.     

Extended-Duration Dosing and Distribution of Dalbavancin into Bone and Articular Tissue

Dalbavancin is an intravenous lipoglycopeptide with activity against Gram-positive pathogens and an MIC₉₀ for Staphylococcus aureus of 0.06 μg/ml. With a terminal half-life of >14 days, dosing regimens with infrequent parenteral administration become available to treat infectious diseases such as osteomyelitis and endocarditis that otherwise require daily dosing for many weeks. In order to support a rationale for these novel regimens, the pharmacokinetics over an extended dosing interval and the distribution of dalbavancin into bone and articular tissue were studied in two phase I trials and pharmacokinetic modeling was performed. Intravenous administration of 1,000 mg of dalbavancin on day 1 followed by 500 mg weekly for seven additional weeks was well tolerated and did not demonstrate evidence of drug accumulation. In a separate study, dalbavancin concentrations in cortical bone 12 h after infusion of a single 1,000-mg intravenous infusion were 6.3 μg/g and 2 weeks later were 4.1 μg/g. A two-dose, once-weekly regimen that would provide tissue exposure over the dalbavancin MIC for Staphylococcus aureus for 8 weeks, maximizing the initial exposure to treatment while minimizing the frequency of intravenous therapy, is proposed.     

Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study

BACKGROUND: Adherence to highly active antiretroviral therapy (HAART) for human immunodeficiency syndrome type 1 (HIV-1) infection is essential to sustain viral suppression and prevent drug resistance. We investigated adherence to HAART among patients in a clinical cohort study. METHODS: Patients receiving HAART had their plasma concentrations of protease inhibitors or nevirapine measured and completed a questionnaire on adherence. We determined the percentage of patients who reported taking all antiretroviral medication on time and according to dietary instructions in the past week. Drug exposure was compared between patients reporting deviation from their regimen and fully adherent patients. Among patients who received HAART for at least 24 weeks, we assessed the association between adherence and virologic outcome. RESULTS: A total of 224 of 261 eligible patients completed a questionnaire. Forty-seven percent reported taking all antiretroviral medication on time and according to dietary instructions. Patients who reported deviation from their regimen showed lower drug exposure compared with fully adherent patients (median concentration ratio, 0.81 vs 1.07; P =.001). Among those receiving HAART for at least 24 weeks, patients reporting deviation from their regimen were less likely to have plasma HIV-1 RNA levels below 500 copies/mL (adjusted odds ratio, 4.0; 95% confidence interval, 1.4-11.6) compared with fully adherent patients. CONCLUSIONS: Only half of the patients took all antiretroviral medication in accordance with time and dietary instructions in the preceding week. Deviation from the antiretroviral regimen was associated with decreased drug exposure and a decreased likelihood of having suppressed plasma HIV-1 RNA loads. Patient adherence should remain a prime concern in the management of HIV-1 infection.     

Prognostic value of heart rate variability analysis in patients with carcinoid syndrome

BACKGROUND/AIMS: Recently, a decrease in heart rate variability measures was found in patients with carcinoid syndrome suffering from carcinoid heart disease compared to those without cardiac involvement of carcinoid syndrome. The prognostic relevance of this finding, however, was not clear. PATIENTS AND METHODS: Therefore, 35 patients with carcinoid syndrome (21 men, age 56 +/- 11 years), all of them suffering from metastatic carcinoid tumors, were followed prospectively at our institution. Digital 24-hour Holter monitoring, echocardiography, and serum serotonin and urine 5-hydroxyindole acetic acid (5-HIAA) samplings were performed in all study patients at baseline. Indices of time domain heart rate variability obtained from Holter recordings included the standard deviation of all normal RR intervals (SDNN) representing overall variability, the square root of the mean of the squared differences between adjacent normal RR intervals (rMSSD), and the percentage of the number of pairs of adjacent normal RR intervals differing by >50 ms (pNN50), both indices reflecting predominantly vagal influences on heart rate. RESULTS: During a mean follow-up of 18 +/- 7 months, 15 of 35 patients with carcinoid syndrome (43%) died. Patients with cardiac manifestation of the carcinoid syndrome showed a tendency towards an increased mortality in comparison to patients without cardiac involvement (p = 0.09). Patients with the combination of decreased heart rate variability (SDNN <100 ms) and presence of carcinoid heart disease had a significant worse prognosis (p = 0.04) compared to patients without carcinoid heart disease and preserved heart rate variability (SDNN > or =100 ms). CONCLUSIONS: The presence of carcinoid heart disease in combination with decreased heart rate variability is associated with the most adverse prognosis in the setting of carcinoid syndrome.