Results From a Large,Multicenter, Retrospective Analysis On Radium223 Use in Metastatic Castration-resistant Prostate Cancer (mCRPC) in the Triveneto Italian Region

Background

Radium 223 was introduced for metastatic castration-resistant prostate cancer based on the results of a randomized controlled trial showing risk reduction for death and skeletal events. Our aim was to evaluate the outcome of patients receiving radium 223 in a real-world setting.

Positive and negative interactions in the behavioural expression of D1 and D2 receptor stimulation in a model of Parkinsonism: role of priming.

Previous exposure to a dopaminergic agonist (priming) strongly potentiates contralateral turning behaviour in response to D1 and D2 agonists in unilaterally 6-hydroxydopamine-lesioned rats. In order to study the influence of priming on the behavioural interaction of D1 and D2 receptors, we examined the effect of selective D1 and D2 receptor blockade on the contralateral turning induced by the mixed D2/D2 agonist apomorphine in drug-naive and primed 6-hydroxydopamine-lesioned rats. In drug-naive rats, apomorphine induced a dose-related, apparently monophasic rotation curve. Administration of selective D1 (SCH 23390) or D2 (raclopride) antagonists abolished the contralateral turning induced by 0.1 mg/kg of apomorphine and partially inhibited that induced by 0.5 mg/kg. In primed rats low doses of apomorphine (0.05 mg/kg) induced an apparently monophasic contralateral turning which was reduced by D1 receptor blockade and completely abolished by D2 receptor blockade; a higher dose of apomorphine (0.1 mg/kg) instead elicited a biphasic (two-peak) pattern of rotation. After this dose of the agonist, blockade of D1 or D2 receptors abolished the second peak of rotation but, while D1 blockade reduced the total number of turns, D2 blockade failed to do so. Quantitative analysis of the interaction between D1 and D2 receptors in the overall turning effect, as well as in the time-course of turning behaviour, indicates that D1 and D2 receptors interact not only positively but also negatively. After higher doses of apomorphine, both negative and positive interactions take place sequentially during the time-course of apomorphine action and provide a clue for explaining the two-peak pattern of rotation observed after apomorphine in rats previously exposed to the drug.     

Revisiting the prognostic role of gallium scintigraphy in low-grade Non-Hodgkin’s lymphoma

The purpose of this study was threefold: to evaluate the role of gallium-67 scintigraphy in the staging of low-grade non-Hodgkin’s lymphomas (LGNHL), to assess the relationship between the expression of CD71 on the surface of the neoplastic cells and the ⁶⁷Ga uptake by the tumour, and to establish the contribution of ⁶⁷Ga scan in defining the prognosis of LGNHL. Forty-eight patients with untreated LGNHL diagnosed in a single institution over a decade were reviewed. The end point of the study was survival of the patients according to the scintigraphic ⁶⁷Ga score at diagnosis. In addition to ⁶⁷Ga scan, other prognostic variables were studied, relating to the neoplastic burden, the biology of the tumour and the host. Univariate and multivariate analyses were used. ⁶⁷Ga scan identified only 116/286 (41%) nodes involved by lymphoma that were detected by clinical examination or computed tomography scan. A scintigraphic scoring system with an arbitrary cut-off value of 3 (high scan score) was able to predict patients with a dismal prognosis: with a mean follow-up of 47 months (range: 1–146 months) the median survival time was 28 months in patients with a high scan score and 74 months in patients with a low scan score (P=0.002). CD71 values were 27.4%±14.9% (mean ±SD) in the former and 8.9%±7.2% in the latter (P=0.0001). Only performance status and extranodal sites were significant variables for prognosis in multivariate analysis. It is concluded that ⁶⁷Ga scan is inaccurate in staging but might be very important in defining the prognosis in LGNHL, in association with other prognostic variables. Received 1 May and in revised form 6 August 1997     

Free copper and resting temporal EEG rhythms correlate across healthy, mild cognitive impairment, and Alzheimer's disease subjects.

OBJECTIVE: The present study tested the hypothesis that the serum copper abnormalities were correlated with alterations of resting electroencephalographic (EEG) rhythms across the continuum of healthy elderly (Hold), mild cognitive impairment (MCI), and AD subjects. METHODS: Resting eyes-closed EEG rhythms delta (2-4Hz), theta (4-8Hz), alpha 1 (8-10.5Hz), alpha 2 (10.5-13Hz), beta 1 (13-20Hz), beta 2 (20-30Hz), and gamma (30-40Hz), estimated by LORETA, were recorded in 17 Hold, 19 MCI, 27 AD- (MMSE< or =20), and 27 AD+ (MMSE20) individuals and correlated with copper biological variables. RESULTS: Across the continuum of Hold, MCI and AD subjects, alpha sources in parietal, occipital, and temporal areas were decreased, while the magnitude of the delta and theta EEG sources in parietal, occipital, and temporal areas was increased. The fraction of serum copper unbound to ceruloplasmin positively correlated with temporal and frontal delta sources, regardless of the effects of age, gender, and education. CONCLUSIONS: These results sustain the hypothesis of a toxic component of serum copper that is correlated with functional loss of AD, as revealed by EEG indexes. SIGNIFICANCE: The present study represents the first demonstration that the fraction of serum copper unbound to ceruloplasmin is correlated with cortical delta rhythms across Hold, MCI, and AD subjects, thus unveiling possible relationships among the biological parameter, advanced neurodegenerative processes, and synchronization mechanisms regulating the relative amplitude of selective EEG rhythms.     

Surgical synovectomy in the treatment of rheumatoid arthritis: the results obtained in a controlled study.

The authors report the long-term results obtained after 2 and 4 years in a controlled study conducted on surgical synovectomies performed in articular and extra-articular regions in rheumatoid arthritis. Out of a total of 157 patients submitted to surgery between 1977 and 1987 admitted to the study were 82 patients with bilateral symmetric localizations, but who had been submitted to synovectomy only unilaterally. The collection and interpretation of data showed that synovectomy is truly effective and that clinical improvements is not related to a spontaneous regression in the rheumatoid process. Surgery must be performed when the degree of osteocartilaginous deficit is absent or moderate. It does not avoid local recurrence, but it does obtain an antalgic effect, better joint excursion, and a slowing down in the destructive osteocartilaginous processes.     

Reversal by ribo- and deoxyribonucleosides of dehydroepiandrosterone-induced inhibition of enzyme altered foci in the liver of rats subjected to the initiation-selection process of experimental carcinogenesis

The effect of dehydroepiandrosterone (DHEA) on the activityof NADPH-producing enzymes and the development of enzyme-alteredfoci has been investigated in the liver of female Wistar ratssubjected to an initiating treatment (a necrogenic dose of diethylnitrosaimine)followed, 15 days later, by a selection treatment [a 15-dayfeeding of a diet containing 0.03% 2-acetylamlnofluorene (2-AAF),with a partial hepatectomy at the midpoint of this feeding].At the end of the selection treatment all rat groups received,for 15 days, a basal diet containing, when indicated, 0.05%phenobarbital (PB) and/or 0.6% DHEA. The effect of DHEA on theactivity of NADPH producing enzymes was also studied in normalrats fed, for 15 days, a diet containing 0.6% DHEA and in theirpair-fed controls. DHEA caused a 43–58% inhibition ofglucose-6-phosphate dehydrogenase (G6PD) and, respectively,338–420% and 21–24% increases in malic enzyme (ME)and isocitric dehydrogenase activities in all rat groups. Thiswas coupled with a great fall in the production of ribulose-5-phosphate,while no change in NADP⁺/NADPH ratio occurred. Hepatocytes,isolated from DHEA-treated rats, exhibited a very low activityof hexose monophosphate shunt (HMS), which was not stimulatedby methylene blue, an exogenous oxidizing agent that markedlystimulated HMS activity in control hepatocytes. DHEA causeda great fall in the percentage of liver occupied by -glutamyltranspeptidase(GGT)-positive foci, in the rats subjected to the initiation- selection treatments. PB enhanced the development of thesefoci, an effect which was completely overcome by DHEA. In addition,focal cells no longer expressed a G6PD activity higher thanthat of surrounding liver in DHEA-treated rats, but exhibiteda high histochemical reaction for ME. DHEA also caused a greatfall in labelling index of GGT-positive foci. Starting at theend of 2-AAF feeding, a mixture of ribonucleosides (RNs) ofadenine, cytosine, guanine and uracil and of deoxyribonucleosides(DRNs) of adenine, cytosine, guanine and thymine were injectedi.p. every 8 h for 12 days to the rats subjected to the initiation- selection treatments plus PB. Rats were killed 3 days afterthe end of RN and DRN treatments. These treatments completelyovercome the DHEA effect on the development of GGT-positivefoci and DNA synthesis by the focal cells, without affectingG6PD activity of both whole liver and putative preneoplasticfoci. Experiments with labeled nucleosides revealed that RNsand DRNs produced derivatives that were incorporated into liverDNA. These data indicate that liver of DHEA-treated rats produceenough NADPH for reduction of RNs to DRNs and growth. The antipromotingeffect of DHEA could depend on a relative deficiency of nudeosidesfor DNA synthesis, caused by a great fall in pentose phosphateproduction.     

Efficacy of intranasal administration of neostigmine in myasthenic patients

Summary The efficacy of intranasally administered neostigmine was tested in 22 patients with generalized myasthenia gravis (MG). Topical therapy to the highly vascularized oropharynx proved to be quickly effective in 5–15 min both clinically and electrophysiologically. Twenty-eight MG patients were then recruited from different centres and their morning doses of oral pyridostigmine were substituted with intranasal neostigmine over a period of 2 or 3 weeks. Intranasal neostigmine proved to be equally efficacious in this regimen. No side-effect was noted even in 4 patients treated in this way for 1 year. Intranasal administration of anti-acetylcholinesterase may be very beneficial: (1) for patients with irregular absorption of oral doses; (2) early in the morning and every time a fast and temporary effect is needed; (3) in bulbar impairment and emergencies, in which a handy atomizer may be life-saving.Presented in part at the XIV World Congress of Neurology, New Delhi, 22–27 October 1989     

Haplotype analysis of BRCA1 gene reveals a new gene rearrangement: characterization of a 19.9 KBP deletion

Germ-line mutations in the BRCA1 gene cause hereditary predisposition to breast and ovarian cancer. BRCA1 and BRCA2 mutations account for about 40% of high-risk families. Mutation-screening methods generally focus on genomic DNA and are usually PCR based; they enable the detection of sequence alterations such as point mutations and small deletions and insertions. However, they do not allow the detection of partial or entire exon(s) loss, because the presence of the homologous allele results in a positive PCR signal, giving rise to a false-negative result. Identification of unusual haplotypes in patient samples by an expectation maximization algorithm has recently been suggested as a method for identifying hemizygous regions caused by large intragenic deletions. Using a similar approach, we identified a novel BRCA1 genomic rearrangement in a breast/ovarian cancer family negative at the first mutation screening; we detected a deletion encompassing exons 14-19, probably due to replication slippage between Alu sequences.     

The small subset of CD56brightCD16- natural killer cells is selectively responsible for both cell proliferation and interferon-gamma production upon interaction with dendritic cells

The encounter of NK cells with dendritic cells (DC) undergoing maturation may result in the induction of NK cell proliferation. Whether such proliferation involves most NK cells or just a subset has yet to be determined. In the present study we analyzed the nature of such proliferating NK cells by combining carboxyfluorescein succinimidyl ester staining and double-fluorescence cytofluorimetric analysis. Freshly isolated peripheral blood NK cells cultured with LPS and immature DC underwent proliferation; however, proliferating cells were confined to a minor NK cell subset. This subset is characterized by the CD56(bright)CD16(-)NKG2A(+)KIR(-) surface phenotype (KIR, killer Ig-like receptor). This was further confirmed by the fact that, after cell sorting, only the CD56(bright) NK cells were able to proliferate in response to the DC stimulus, whereas the CD56(dull) were not. We also provide evidence that the CD56(bright) subset is the main source of IFN-gamma-producing NK cells, upon interaction with DC. The CD56(bright)CD16(-) NK cells express a panel of surface molecules including CD62L, CCR7 and CXCR3 that may allow their homing either to secondary lymphoid compartments or to inflamed tissues. This implies that, in vivo, the interactions between DC undergoing maturation and CD56(bright) NK cells may occur in different tissues and have different functional implications.     

Characterization of a minisatellite repeat locus in the chloroplast genome of Orchis palustris (Orchidaceae)

We describe the occurrence of a tandem repeat in the chloroplast genome of the marsh orchid, Orchis palustris. The repeat unit is an AT-rich, 16-bp sequence located in the chloroplast tRNALEU intron. Southern blot analysis confirmed that the O. palustris tRNALEU intron including the minisatellite locus has not been transferred to the nucleus, but is indeed located on the chloroplast genome. The 16-bp repeat unit was found to be present in all O. palustris accessions studied, as well as in the closely related O. laxiflora. Variation in repeat numbers among individuals was found in O. palustris from central and northern Italy; and this was consistently associated with a 13-bp sequence motif preceding the repeat. This motif was absent from O. palustris from southern Italy, Greece, and from O. laxiflora. In these accessions, no variation in repeat numbers was found. Our results suggest that the O. palustris chloroplast minisatellite locus evolved relatively recently, presumably in central Italy, and may represent a valuable marker for population genetic studies.