Primary cutaneous B-cell lymphomas (PCBCL) are rare and constitute approximately 5–10% of all cutaneous lymphomas. In the literature, conflicting data exist on the optimal treatment modality ...regarding the efficacy and the relapse rate after radiotherapy (RT) or polychemotherapy. To evaluate the efficacy of RT, patient data from two centers were analyzed and compared with recent reports in the literature.
Between April 1984 and June 2001, 35 patients with PCBCL, 17 men and 18 women ages 27–86 years, were treated with RT alone (29/35 patients) or postoperative RT (6/35 patients). According to the European Organization for Research and Treatment of Cancer classification for PCBCL, this study group included 21 patients (60%) with primary cutaneous follicle center–cell lymphoma, 7 (20%) with primary cutaneous immunocytoma, 4 (11%) with primary cutaneous large B-cell lymphoma (PCLBCL) of the leg, and 3 (9%) provisional types.
A total of 34/35 patients achieved an initial complete response after RT. In one additional patient, RT was interrupted after 16 Gy because of fulminant pneumonia. A total of 11/35 (31%) patients developed cutaneous relapse after a median of 11 months. Three patients developed an in-field response and 8 patients an out-field relapse. After a median follow-up of 52 months, 27/35 patients are alive, whereas 8/35 patients died (three deaths resulting from PCBCL and five unrelated to PCBCL). The 5-year overall survival rate was 75% (95% CI: 55–95%). The 5-year relapse-free survival was 50% (95% CI: 32–68%). Univariate and multivariate analysis revealed disseminated primary lesions in at least two noncontiguous anatomic sites and the histologic subtype PCLBCL as unfavorable prognostic factors.
RT of all visible skin lesions is an effective treatment for localized PCBCL. In patients with cutaneous relapses, RT is an effective treatment option as well.
We found that betaCaMKII, the predominant CaMKII isoform of the cerebellum, is important for controlling the direction of plasticity at the parallel fiber-Purkinje cell synapse; a protocol that ...induced synaptic depression in wild-type mice resulted in synaptic potentiation in Camk2b knockout mice and vice versa. These findings provide us with unique experimental insight into the mechanisms that transduce graded calcium signals into either synaptic depression or potentiation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Recombination is an efficient mechanism of HIV-1 to generate genetic variability. Some of the recombinant forms of HIV-1 that have been described are of epidemic importance, and they are referred to ...as circulating recombinant forms (CRFs). In this study, we characterized four HIV-1 isolates from Cameroon that had previously been classified as subtype J in the protease gene and as subtype A in the env C2-V5 region. Analyses of the nearly complete genomes revealed that two of the samples (95CM-1816 and 96CM-4496) had the same recombinant structure as CRF11-cpx. The two remaining samples (96CM-1849 and 96CM-4164) constituted a new recombinant virus variant with genomic regions identified as subtypes A, G, J, and CRF01-AE. This mosaic virus structure was found in two individuals who had no direct epidemiological relationship, and may thus represent a new CRF. The fragments that were classified as subtype J in the new recombinant form were more related to subtype J regions of the CRF11-cpx sequences than to the reference strains of subtype J. The complex structures of CRF11-cpx and our new recombinant form, which are both the result of at least four recombination events, exemplify the coming difficulties in characterizing the internal relationships and origins of future recombinant HIV-1 strains. The new recombinant structure has been designated CRF13-cpx in the Los Alamos HIV Sequence Database.
The dystonias are a common group of movement disorders, which are mechanistically poorly understood. Rapid-onset dystonia-parkinsonism (RDP) is a hereditary movement disorder without ...neurodegeneration resulting from mutations in the ATP1A3 gene encoding the α3-isoform of the Na+/K+ ATPase. RDP patients are generally asymptomatic until a stressful life event triggers disease onset. Basal Ganglia dysfunction has previously been implicated in RDP aaetiology. To investigate the neuronal pathology in RDP we have generated patient-specific induced pluripotent stem cell (iPS) lines and derived mature midbrain dopaminergic neurons. Using functional live- cell imaging, we have shown that RDP neurons show higher intracellular Na+ levels at rest and smaller Na+ signals in response to stimulation by glutamate or KCl. Consistent with this, resting membrane potential in RDP neurons was chronically elevated and cells failed to return to resting potential after stressful depolarisation. Interestingly, spontaneous spiking activity in the absence of stress was normal. Apart from abnormalities in sodium homeostasis, there was reduced uptake of calcium from the cytosol by mitochondria in RDP neurons probably due to a reversal of the mitochondrial sodium/calcium exchanger in response to elevated intracellular calcium levels. Furthermore mitochondrial pathology in RDP included depolarised mitochondrial membrane potential, reduced oxidative phosphorylation and increase ROS production. Stressful depolarisation induced a sharp increase in ROS production. There was a compensatory increase in Krebs cycle activity to counteract energy depletion due to reduced oxidative phosphorylation and marked upregulation in levels of glutathione, an endogenous antioxidant. This high level of compensation may explain the absence of neurodegeneration in RDP. Based on our findings, we suggest antioxidant therapy as a potential treatment to improve neuronal function in RDP patients.
The dystonias are a common group of movement disorders, which are mechanistically poorly understood. Rapid-onset dystonia-parkinsonism (RDP) is a hereditary movement disorder without ...neurodegeneration resulting from mutations in the ATP1A3 gene encoding the α3-isoform of the Na+/K+ ATPase. RDP patients are generally asymptomatic until a stressful life event triggers disease onset. Basal Ganglia dysfunction has previously been implicated in RDP aaetiology. To investigate the neuronal pathology in RDP we have generated patient-specific induced pluripotent stem cell (iPS) lines and derived mature midbrain dopaminergic neurons. Using functional live- cell imaging, we have shown that RDP neurons show higher intracellular Na+ levels at rest and smaller Na+ signals in response to stimulation by glutamate or KCl. Consistent with this, resting membrane potential in RDP neurons was chronically elevated and cells failed to return to resting potential after stressful depolarisation. Interestingly, spontaneous spiking activity in the absence of stress was normal. Apart from abnormalities in sodium homeostasis, there was reduced uptake of calcium from the cytosol by mitochondria in RDP neurons probably due to a reversal of the mitochondrial sodium/calcium exchanger in response to elevated intracellular calcium levels. Furthermore mitochondrial pathology in RDP included depolarised mitochondrial membrane potential, reduced oxidative phosphorylation and increase ROS production. Stressful depolarisation induced a sharp increase in ROS production. There was a compensatory increase in Krebs cycle activity to counteract energy depletion due to reduced oxidative phosphorylation and marked upregulation in levels of glutathione, an endogenous antioxidant. This high level of compensation may explain the absence of neurodegeneration in RDP. Based on our findings, we suggest antioxidant therapy as a potential treatment to improve neuronal function in RDP patients.
Objectives: Human herpesvirus 8 (HHV-8) infection is common among men who have sex with men (MSM), especially those infected with HIV, and is frequently detected in saliva. We sought to determine ...whether oral or anogenital contact with HIV discordant, or unknown serostatus sexual partners is associated with HHV-8 seroprevalence among HIV negative MSM. Methods: HIV negative MSM participating in a behavioural intervention trial for the prevention of HIV infection (the EXPLORE study) were recruited from the Seattle and Denver areas for participation in this cross sectional study. Participants completed detailed questionnaires regarding sexual behaviour, focusing on activities with possible exposure to the oropharynx. Serum samples from study enrolment were tested for the presence of HHV-8 antibodies using whole virus enzyme immunoassay and immunofluorescence assay to latent and lytic proteins. Results: 198/819 MSM (24.3%) were HHV-8 antibody positive. Exposure to saliva with HIV positive and HIV unknown serostatus sex partners was reported by 83% and 90% of all men, respectively. In a multivariate model, reporting more than the median number of lifetime sex partners (OR 2.2, p = 0.03) or lifetime sex partners of unknown HIV status (OR 1.7, p = 0.03), and the performance of oro-anal sex (“rimming”) on partners whose HIV status is unknown (OR 2.7, p = 0.04) were independently associated with HHV-8 infection. Conclusions: The oropharynx may be an important anatomical site in HHV-8 acquisition, and contact with HIV serodiscordant or unknown sex partners is associated with higher HHV-8 seroprevalence among HIV negative MSM.
BICD2 is one of the two mammalian homologues of the Drosophila Bicaudal D, an evolutionarily conserved adaptor between microtubule motors and their cargo that was previously shown to link vesicles ...and mRNP complexes to the dynein motor. Here, we identified a G2-specific role for BICD2 in the relative positioning of the nucleus and centrosomes in dividing cells. By combining mass spectrometry, biochemical and cell biological approaches, we show that the nuclear pore complex (NPC) component RanBP2 directly binds to BICD2 and recruits it to NPCs specifically in G2 phase of the cell cycle. BICD2, in turn, recruits dynein-dynactin to NPCs and as such is needed to keep centrosomes closely tethered to the nucleus prior to mitotic entry. When dynein function is suppressed by RNA interference-mediated depletion or antibody microinjection, centrosomes and nuclei are actively pushed apart in late G2 and we show that this is due to the action of kinesin-1. Surprisingly, depletion of BICD2 inhibits both dynein and kinesin-1-dependent movements of the nucleus and cytoplasmic NPCs, demonstrating that BICD2 is needed not only for the dynein function at the nuclear pores but also for the antagonistic activity of kinesin-1. Our study demonstrates that the nucleus is subject to opposing activities of dynein and kinesin-1 motors and that BICD2 contributes to nuclear and centrosomal positioning prior to mitotic entry through regulation of both dynein and kinesin-1.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Kaposi sarcoma-associated herpesvirus (KSHV) has been identified as the etiologic agent of Kaposi sarcoma (KS). Although KSHV is required for the development of KS, immune dysfunction is a common and ...important cofactor in the development of KS, as illustrated by the presence of KS in association with HIV infection or immunosuppressive-drug treatment after transplantation. Because neutralizing antibodies (NAb) constitute an important component of an antiviral immune response, we examined the functionality of the humoral immune response associated with KS, by measuring KSHV NAb titers in 3 groups of subjects. Group 1 included subjects who were KSHV positive, KS positive, and human immunodeficiency virus (HIV) positive; group 2 included subjects who were KSHV positive, KS negative, and HIV positive; and group 3 included subjects who were KSHV positive, KS negative, and HIV negative. NAb titers were significantly lower among subjects with KS, compared with subjects who were infected with KSHV but who did not have clinical evidence of KS, in a multivariate model adjusted for HIV infection and CD4 T cell count. The data from the present study suggest that NAb may play a role in the control of KSHV infection and the prevention of progression of KSHV infection to KS.
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