Unraveling the complexity of anti-doping analysis: reassessing meldonium detection and doping verdicts in a case study.

BACKGROUND: The precision and accuracy of mass spectrometry (MS) made it a fundamental tool in anti-doping analysis. High-resolution (HR) mass spectrometers significantly improved compound identification. This study systematically analyzes data from an athlete (Subject 1) who tested positive for meldonium and compares it with data from a healthy volunteer (Subject 2) to examine the correctness of the doping verdict. CASE PRESENTATION: The documentation related to Subject 1 was thoroughly processed and analyzed. A study involving a volunteer (Subject 2) replicated Subject 1 regimen and urine sample collection for data alignment with anti-doping results, with Subject 2 reporting not using meldonium. The anti-doping agency's analysis of Subject 1 showed the presence of meldonium at a concentration close to the established cut-off level. However, a closer examination revealed that one specific ion, crucial for meldonium identification, was absent from the mass spectra. Analyzing Subject 2 data, using the same methodology, the absence of the specific ion was confirmed, even though the volunteer did not consume meldonium. The European directive and the method that was validated and cited by the anti-doping agency identified meldonium on at least four specific ions, whereas the anti-doping analysis used only three ions. This discrepancy compromises the specificity of meldonium identification. CONCLUSIONS: To enhance the analytical methodology, two strategic interventions are suggested: adjusting the meldonium cut-off value and expanding the analysis to include meldonium metabolites. By addressing these avenues, the precision of meldonium detection and doping verdicts can be improved. In conclusion, this study challenges the anti-doping agency's verdict and prompts a reevaluation of meldonium detection methodologies in anti-doping measures.

Morbidly adherent placenta: evaluation of ultrasound diagnostic criteria and differentiation of placenta accreta from percreta.

OBJECTIVES: To evaluate the diagnostic accuracy of two-dimensional (2D) gray-scale and color Doppler and three-dimensional (3D) power Doppler sonographic criteria for morbidly adherent placenta (MAP), and to identify criteria to help distinguish placenta accreta from placenta percreta. METHODS: We enrolled 187 patients with placenta previa and history of uterine surgery and performed transabdominal and transvaginal ultrasound examination for early detection of MAP. With 2D gray-scale transabdominal and transvaginal ultrasonography, we investigated loss/irregularity of the echolucent area between the uterus and the placenta ('clear space'), thinning or interruption of the hyperechoic interface between the uterine serosa and the bladder wall and the presence of turbulent placental lacunae with high-velocity flow (>15 cm/s). Using transabdominal 3D power Doppler, we evaluated the hypervascularity of the uterine serosa-bladder wall interface and irregular intraplacental vascularization. Ultrasound findings were reviewed against the final diagnosis made during Cesarean section (CS). RESULTS: MAP was detected on CS in 41 patients. All of them had an anterior placenta previa (34 major and seven minor) and had undergone at least one previous CS. The evaluated sonographic criteria showed good diagnostic performance; in MAP patients at least two out of five criteria were detected, with at most one of the criteria present in patients without MAP. Loss/irregularity of clear space used as a single criterion was responsible for the most false positives, demonstrating a low positive predictive value. Irregular intraplacental vascularization with tortuous confluent vessels affecting the entire width of the placenta, and hypervascularity of the entire uterine serosa-bladder wall interface, were only detected, on 3D power Doppler, in cases of placenta percreta. CONCLUSIONS: The reviewed ultrasound criteria may be useful for the prenatal diagnosis of MAP and to differentiate between placenta accreta and placenta percreta; 3D power Doppler techniques were an important aid in the diagnosis.

Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation.

OBJECTIVE: Large kindreds segregating familial Alzheimer disease (FAD) offer the opportunity of studying clinical variability as observed for presenilin 1 (PSEN1) mutations. Two early-onset FAD (EOFAD) Calabrian families with PSEN1 Met146Leu (ATG/CTG) mutation constitute a unique population descending from a remote common ancestor. Recently, several other EOFAD families with the same mutation have been described worldwide. METHODS: We searched for a common founder of the PSEN1 Met146Leu mutation in families with different geographic origins by genealogic and molecular analyses. We also investigated the phenotypic variability at onset in a group of 50 patients (mean age at onset 40.0 +/- 4.8 years) by clinical, neuropsychological, and molecular methodologies. RESULTS: EOFAD Met146Leu families from around the world resulted to be related and constitute a single kindred originating from Southern Italy before the 17th century. Phenotypic variability at onset is broad: 4 different clinical presentations may be recognized, 2 classic for AD (memory deficits and spatial and temporal disorientation), whereas the others are expressions of frontal impairment. The apathetic and dysexecutive subgroups could be related to orbital-medial prefrontal cortex and dorsolateral prefrontal cortex dysfunction. CONCLUSIONS: Genealogic and molecular findings provided evidence that the PSEN1 Met146Leu families from around the world analyzed in this study are related and represent a single kindred originating from Southern Italy. The marked phenotypic variability might reflect early involvement by the pathologic process of different cortical areas. Although the clinical phenotype is quite variable, the neuropathologic and biochemical characteristics of the lesions account for neurodegenerative processes unmistakably of Alzheimer nature.

De-repression of the p21 promoter in prostate cancer cells by an isothiocyanate via inhibition of HDACs and c-Myc.

Natural isothiocyanates from cruciferous vegetables have been described as important dietary factors for prostate cancer prevention. Phenethyl isothiocyanate (PEITC), found rich in watercress, induces growth arrest and apoptosis in prostate cancer cells, and also inhibits the testosterone-mediated growth of prostates by regulating the androgen receptor and cell cycle progression in rats. PEITC has been recently identified as an inhibitor of histone deacetylases (HDACs). Herein we describe the mechanism of PEITC-mediated growth attenuation in relation to HDAC inhibition in human prostate cancer cells. Exposure of androgen-dependent prostate cancer cells LNCaP to PEITC resulted in cell cycle arrest and a p53-independent up-regulation of the inhibitors of cyclin-dependent kinases, including p21WAF1 and p27. The mechanism of p21 activation was investigated. PEITC significantly enhanced histone acetylation and induced selective modification of histone methylation for chromatin remodeling. Chromatin immunoprecipitation revealed that the p21 gene was associated with the PEITC-induced hyperacetylated histones. As a result, the chromatin unfolding permitted the transcription activation of the p21 gene. PEITC also significantly reduced the expression of c-Myc which represses p21. Pull-down assays using Sp1 affinity oligo beads of the p21 promoter, showed decreased c-Myc binding to the Sp1 transcriptional complexes in the p21 promoter, resulting in reduced p21 repression. The quantity of PEITC (0.5-1 micro M) effective to mediate cell cycle arrest was less than that for inhibiting c-Myc (2-5 micro M), suggesting that the inhibition of HDACs may be the primary mechanism for p21 activation. The PEITC-mediated growth attenuation of prostate cancer cells includes an interactive mechanism involving HDAC and c-Myc inhibition.

Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation.

BACKGROUND: Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN). OBJECTIVE: To determine the frequency of GRN mutations in a cohort of Caucasian patients with FTD without mutations in known FTD genes. METHODS: GRN was sequenced in a series of 78 independent FTD patients including 23 familial subjects. A different Calabrian dataset (109 normal control subjects and 96 FTD patients) was used to establish the frequency of the GRN mutation. RESULTS: A novel truncating GRN mutation (c.1145insA) was detected in a proband of an extended consanguineous Calabrian kindred. Segregation analysis of 70 family members revealed 19 heterozygous mutation carriers including 9 patients affected by FTD. The absence of homozygous carriers in a highly consanguineous kindred may indicate that the loss of both GRN alleles might lead to embryonic lethality. An extremely variable age at onset in the mutation carriers (more than five decades apart) is not explained by APOE genotypes or the H1/H2 MAPT haplotypes. Intriguingly, the mutation was excluded in four FTD patients belonging to branches with an autosomal dominant mode of inheritance of FTD, suggesting that another novel FTD gene accounts for the disease in the phenocopies. It is difficult to clinically distinguish phenocopies from GRN mutation carriers, except that language in mutation carriers was more severely compromised. CONCLUSION: The current results imply further genetic heterogeneity of frontotemporal dementia, as we detected only one GRN-linked family (about 1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers.

The effects of APOE and tau gene variability on risk of frontotemporal dementia.

Frontotemporal dementia (FTD) is a complex dementing syndrome whose genetic/non genetic risk factors are mostly unknown. Aim of the present work was to investigate whether APOE and/or tau gene variability does affect the risk of FTD. A sample of FTD cases (sporadic: n = 54; familial: n = 46, one subject per family) was collected in a genetically homogeneous population (Calabria, southern Italy) and analyzed in comparison with an age- and sex-matched control group (n = 180) extracted from the same population. Logistic regression analysis showed that APOE gene variability affects the probability of disease, with allele epsilon4 increasing (exp(beta1) = 2.68 with [1.51-4.76] 95% confidence interval; p = 0.001) and allele epsilon2 decreasing (exp(beta1) = 0.28 with [0.12-0.66] 95% confidence interval; p = 0.003) the risk of FTD. On the contrary, tau gene variability was ineffectual (exp(beta1) non significantly different from 1 for either H1 or H2 haplotypes), although a small effect was observed by the H1 haplotype in increasing the protective effect of the epsilon2 allele (p = 0.007).

A large Calabrian kindred segregating frontotemporal dementia.

Frontotemporal dementia (FTD) displays significant neuropathological and genetic heterogeneity among and within affected families. An early diagnosis is often difficult because cognitive symptoms are manifest only at a late stage of the disease. We have been studying a large pedigree segregating frontotemporal dementia (FTD) to which belong 34 identified affected persons, 11 of whom were personally examined. The kindred has been genealogically reconstructed; all FTD patients have been linked to the same ancestors who lived in the early 18(th) century (11 generations before the present one). Autosomal dominant transmission was evident. Clinical features were uniform within the kindred and met the Lund-Manchester criteria. Personality changes with absence of insight, lack of empathy and of social awareness manifested up to 5 years before medical advice was sought. Loss of fluency was the earliest neuropsychological sign, in the absence of memory, orientation and praxis deficits, which evolved late, together with hyperorality. Akinesia was observed early, rigidity appeared late, tremor was absent. Two patients showed myoclonus late in their evolution. No ALS signs were observed in this kindred. Mutations of the MAPt gene, coding for the Tau protein, were not detected in affected family members. Linkage studies excluded chromosomes 3 and 9 and gave indeterminate results that were model dependent for chromosome 17.

Implicit theories of creativity: laypersons' perceptions of the creativity of adaptors and innovators.

Kirton has put forward a theory of creativity style in which he maintains that people with more adaptive or more innovative orientations possess equal creative potential. The purpose of this study was to compare Kirton's explicit theory with laypersons' implicit theories of creativity. Laypersons and students were asked to read descriptions of adaptors and innovators and then, using their own personal conceptions of creativity, rate adaptors and innovators on creativity. Analysis showed that the innovative style was perceived as significantly more creative. Furthermore, individuals who possessed a more innovative style were much more likely to rate the innovative orientation as more highly creative. Potential reasons for the implicit view that innovators are more creative are offered. In particular, cultural biases towards the innovative style are discussed.

The long gamma nail: indications and results.

The authors report their experience concerning the use of the long gamma nail in 18 cases with the following indications: double fractures of the proximal end and the diaphysis of the femur; subtrochanteric fractures and of the diaphysis with severe lesion of the medial cortical bone; subtrochanteric pathologic fractures. All of the fractures except one consolidated within 6 months and weight-bearing was allowed early. Breakage of the means of synthesis was the only major complication observed. The long gamma nail has proven to be an irreplaceable method for the treatment of associated fractures of the proximal end and of the femoral diaphysis.

Computerized analysis of eye movements as a function of age.

Vertical and horizontal saccadic (SEMv, SEMh) and smooth pursuit eye movements (SPEM) were recorded in 66 normal subjects of different ages using a computerized system. No difference was found in SEMh recordings for the right versus the left eye or for gaze direction. In contrast, SEMv recordings of upgaze vs. downgaze showed a significant difference in performance index (peak velocity) and delay. SEMh and SEMv performance index and delay were significantly slowed in elderly subjects, although accuracy was not affected. SPEM analysis also revealed a decrease in velocity in elderly people indicating diminished tracking ability as a result of the aging process. These data suggest that senescence may influence some SEM and SPEM parameters. We thus emphasize the usefulness of having reliable normative data corrected for age.

Person-environment fit: using commensurate scales to predict student stress.

The relationship between person-environment fit and stress was examined for two samples of university students (N = 55 and 79). The Kirton Adaption-Innovation Inventory (KAI) was modified to assess the students' perceptions of the adaptor-innovator style required by their course, the styles they exhibited in the course, and their ideal style preferences. To ascertain fit, the KAI total scores and subscale scores (Originality, Efficiency, and Rule/Group Conformity) were used to classify students on three dimensions: (1) perception of what style their course required, adaptive or innovative; (2) congruence between the style the course required and the style they exhibited in the course; and (3) the magnitude of the difference, if any, between the required style and the exhibited style. Points two and three are measures of fit. The dependent variable was stress. Also the students' ideal style scores, KAI total and subscales, were substituted for the exhibited scores and the classification and analyses were repeated. Analysis of the total scores revealed that a course requiring adaptive behaviours was perceived as more stressful than a course requiring innovative behaviours. Similarly, an analysis of the Rule/Group Conformity scores revealed that the greater the conformity required the greater the stress. Also the less originality demanded in the course the greater was the perceived stress. For the KAI total scores and Rule/Group Conformity scores, the two measures of fit (incongruity and magnitude of the incongruity) were not related to stress. However, analyses of the Originality and Efficiency subscales supported the importance of the P-E fit position. For both subscales, stress was associated with the magnitude of the difference between what was required in the course and what students exhibited in the course. Educational implications derived from these findings as well as recommendations for future research are discussed.

[A case of transitory Fanconi syndrome associated with acute renal insufficiency and hypoplasia of the bone marrow]. / Su un caso di sindrome di Fanconi transitoria associata ad insufficienza renale acuta e ad ipoplasia del midollo osseo.

The authors report a case of an eight-years old child, who presented with transient Fanconi syndrome, mild renal failure and hypoplastic bone marrow. No recognized etiology of the Fanconi syndrome was demonstrated in the patient. Laboratory data and clinical course are consistent with the hypothesis of a tubulo-interstitial lesion caused, directly or through an abnormal immune response, by an unknown etiologic agent.