Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR_1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR_1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR_1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR_1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow-up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR_1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.     

Localization of parathyroid enlargement: experience with technetium-99m methoxyisobutylisonitrile and thallium-201 scintigraphy,ultrasonography and computed tomography

Technetium-99m methoxyisobutylisonitrile (MIBI), like thallium-201, has recently been introduced as a myocardial perfusion agent and is now also showing very promising results in parathyroid scintigrapy. The results of ²⁰¹Tl/^99mTc-pertechnetate and ^99mTc-MIBI/^99mTc-pertechnetate subtraction scintigraphy, ultrasonography and computed tomography are presented in a series of 43 patients operated on for hyperparathyroidism. All four imaging modalities were confirmed to be reliable, scintigraphy being the most accurate. Sensitivities ranged from 81% to 95%, that of ^99mTc-MIBI being the highest. Moreover this tracer, which has more favourable physical and also biochemical properties, yielded images of superior quality. This allowed localization of the lesion by visual inspection only in as many as 86% of the patients with positive ^99mTc-MIBI/^99mTc-pertechnetate subtraction scintigraphy. We believe that the higher sensitivity, superior image quality and lower cost of ^99mTc-MIBI imaging will make ^99mTc-MIBI the new radiopharmaceutical of choice for parathyroid scintigraphy (when one takes into account the stability of labelling with large activities it is possible to perform three or four cardiac studies together with one parathyroid scintigraphic examination using one lyophililzed vial).     

Detection of Apoptosis in Peripheral Blood Cells of 31 Subjects Affected by Down Syndrome Before and After Zinc Therapy

Thirty-one patients affected by Down syndrome (DS) were investigated to study the presence of apoptosis in peripheral blood cells in relation to the plasma levels of zinc. Twelve patients had undergone therapy with ZnSO₄, while the remaining 19 were untreated. The presence of programmed cell death was evaluated by means of electron microscopy, in situ nick translation (NT), and agarose gel electrophoresis of DNA. These approaches evidenced the presence of apoptosis in peripheral blood cells of patients before therapy with ZnSO₄, while after zinc supplementation there was a reduction in the number of apoptotic cells. These results suggest that the process of programmed cell death in peripheral blood cells of patients with Down syndrome is related to the plasma levels of zinc ion.     

Protection of killer antiidiotypic antibodies against early invasive aspergillosis in a murine model of allogeneic T-cell-depleted bone marrow transplantation

Antiidiotypic monoclonal antibodies (MAbs) representing the internal image of a yeast killer toxin (KT) have therapeutic potential against several fungal infections. The efficacy of KT MAbs against Aspergillus fumigatus was investigated in a mouse model of T-cell-depleted allogeneic bone marrow transplantation (BMT) with invasive pulmonary aspergillosis. Mice were highly susceptible to infection at 3 days post-BMT, when profound neutropenia was observed both in the periphery and in the lungs. Treatment with KT MAbs protected the mice from infection, as judged by the long-term survival and decreased pathology associated with inhibition of fungal growth and hyphal development in the lungs. In vitro, similar to polymorphonuclear neutrophils, KT MAbs significantly inhibited the hyphal development and metabolic activity of germinated Aspergillus conidia. These results indicate that mimicking the action of neutrophils could be a strategy through which KT MAbs exert therapeutic efficacy in A. fumigatus infections.     

Absence of TREM2 polymorphisms in patients with Alzheimer's disease and Frontotemporal Lobar Degeneration

Triggering Receptor Expressed on Myeloid cells (TREM)2 deficiency originates a genetic syndrome characterized by bone cysts and presenile dementia, named Nasu-Hakola disease (NHD). Early onset dementia and marked involvement of frontal regions are features characterizing both NHD and other kinds of neurodegenerative disorders, such as Frontotemporal Lobar Degeneration (FTLD), and, in some cases, Alzheimer's disease (AD). Three Single Nucleotide Polymorphisms (SNPs) in TREM2 coding region were screened by allelic discrimination in a population of probable AD patients as well as FTLD patients as compared with age-matched controls. In addition, mutation scanning of the coding region of TREM2 gene was carried out in 7 patients with early onset AD (EOAD), 16 FTLD, and 20 controls. None of the SNPs analyzed was present, either in patients or controls. Moreover, mutation scanning of the five exons of TREM2 failed to detect the presence of novel polymorphisms. These data demonstrate that TREM2 coding region is highly conserved, implying a crucial role of this receptor. Further studies, including a functional analysis, are certainly required to clarify the role of TREM2 in neurodegenerative processes.     

Anaphylaxis: a 7-year follow-up survey of 46 children.

BACKGROUND: Little is known about the frequency of and the features associated with recurrent anaphylaxis in pediatric populations. During 1994 to 1996, we enrolled 76 children affected by anaphylaxis in a prospective study to analyze their clinical and allergic features. OBJECTIVE: To undertake a follow-up study of these children to ascertain how many experienced a recurrence of anaphylaxis. METHODS: After a mean interval of 7 years, a pediatric allergist conducted a telephone interview of patients who had been enrolled in our 1994-1996 study. RESULTS: A telephone interview was successfully completed in 46 (61%) of the 76 patients who had been enrolled in our 1994-1996 study. Of these 46 patients, 14 (30%) had experienced a recurrence of anaphylaxis. Children with atopic dermatitis either during 1994 to 1996 (64% vs 34%; P = .04) or at the time of the current study (43% vs 16%; P = .03) and those with urticaria-angioedema at the time of the current study (93% vs 31%; P = .0002) were found to be at a significantly higher risk for recurrent anaphylaxis. Furthermore, those children who were sensitive to at least 1 food allergen during 1994 to 1996 were more likely to have experienced a recurrence of anaphylaxis (93% vs 56%; P < .04). CONCLUSIONS: This study suggests that patients may have a greater risk of recurrence of anaphylaxis if they have atopic dermatitis, urticaria-angioedema, or at least 1 positive result of skin prick tests to food allergens.     

Clinical Features of Fatal Familial Insomnia: Phenotypic Variability in Relation to a Polymorphism at Codon 129 of the Prion Protein Gene

Fatal Familial Insomnia is a hereditary prion disease characterized by a mutation at codon 178 of the prion protein gene cosegregating with the methionine polymorphism at codon 129 of the mutated allele. It is characterized by disturbances of the wake-sleep cycle, dysautonomia and somatomotor manifestations (myoclonus, ataxia, dysarthria, spasticity). PET studies disclose severe thalamic and additionally cortical hypometabolism. Neuropathology shows marked neuronal loss and gliosis in the thalamus, especially the medio-dorsal and anterior-ventral nuclei, olivary hypertrophy and some spongiosis of the cerebral cortex. Detailed analysis of 14 cases from 5 unrelated families showed that patients ran either a short (9.1+ 1.1 months) or a prolonged (30.8 + 21.3 months) clinical course according to whether they were homozygote met/met or heterozygote met/val at codon 129. Moreover, homozygotes had more prominent oneiric episodes, insomnia and dysautonomia at onset, whereas heterozygotes showed ataxia and dysarthria at onset, earlier sphincter loss and epileptic Grand Mai seizures; they also displayed more extensive cortical involvement on PET and at postmortem examination. Our data suggest that the phenotype expression of Fatal Familial Insomnia is related, at least partly, to the polymorphism at codon 129 of the prion protein-gene.     

Cytomegalovirus infection after bone marrow transplantation in children

Cytomegalovirus (CMV) is a well-known cause of disease occurring after bone marrow transplantation (BMT). The manifestations of CMV range from asymptomatic infection, defined as active CMV replication in the blood in the absence of clinical manifestations or organ failure abnormalities, to CMV disease, characterized by CMV infection with clinical symptoms or organ function abnormalities. Diagnostic procedures to assess the viral load have improved greatly with the increased use of antigenemia, CMV DNA, and immediate early-messenger RNA. Many conditions concur in determining the risk of developing CMV reactivation or disease after bone marrow transplant with serologic status of donor and recipient, type of bone marrow transplant, presence of graft-versus-host disease being the most studied. However, time and quality of immune reconstitution seems to be the pivotal factors. Pneumonia and gastrointestinal involvement are the most frequently documented clinical pictures with late-onset CMV reactivation or disease representing a new challenge. CMV prophylaxis or pre-emptive therapy adopted during the last few years in allogeneic BMT recipients has changed the natural history of the disease, reducing the risk of CMV disease, CMV-associated death, transplant-related mortality, and has prolonged the period at risk. Specific studies on children are lacking, however, the clinical pictures and features seems to be similar both in children and adults.     

Effect of chemical structure and composition of the resin phase on mechanical strength and vinyl conversion of amorphous calcium phosphate-based composites

The mechanical properties of recently developed bioactive, antidemineralizing/remineralizing, amorphous calcium phosphate (ACP)-based composites need improvement. The objective of this study was to elucidate the effect of structure and composition of resins on the biaxial flexure strength (BFS) and the degree of conversion (DC) of composites attained after photo-polymerization. Two series of 2,2-bis[p-(2'-hydroxy-3'-methacryloxypropoxy)phenyl]propane (Bis-GMA)/triethylene glycol dimethacrylate (TEGDMA)/X (X being a neutral or acidic comonomer) ternary resins were prepared and mixed with a mass fraction of 40% of zirconia-hybridized ACP. Both unfilled copolymers and their composites were evaluated for BFS (dry and wet specimens after 2 weeks of immersion in buffered saline) and for DC (after 24 h at 23 degrees C). It was found that for the neutral X monomers, no correlation existed between the hydrophobic/hydrophilic character of the X monomer and the BFS values of the immersed composites. A flexible monomethacrylate yielded copolymers and composites with the highest DC. For the resins utilizing the acidic comonomers, methacrylic acid and mono-4-(methacryloyloxy) ethyltrimellitate (4MET), dry composites with improved BFS values were obtained. 4MET composites exhibited the least loss of strength of all the ternary resin ACP materials. The effect of acidic X on DC was most pronounced for maleic acid copolymers.