CSF Tau proteins reduce misdiagnosis of sporadic Creutzfeldt-Jakob disease suspected cases with inconclusive 14-3-3 result

Cerebrospinal fluid (CSF) 14-3-3 protein supports sporadic Creutzfeldt-Jakob (sCJD) diagnosis, but often leads to weak-positive results and lacks standardization. In this study, we explored the added diagnostic value of Total Tau (t-Tau) and phosphorylated Tau (p-Tau) in sCJD diagnosis, particularly in the cases with inconclusive 14-3-3 result. 95 definite sCJD and 287 patients without prion disease (non-CJD) were included in this study. CSF samples were collected in routine clinical diagnosis and analysed for 14-3-3 detection by Western blot (WB). CSF t-Tau and p-Tau were quantified by commercial ELISA kits and PRNP and APOE genotyping assessed by PCR-RFLP. In a regression analysis of the whole cohort, 14-3-3 protein revealed an overall accuracy of 82 % (sensitivity = 96.7 %; specificity = 75.6 %) for sCJD. Regarding 14-3-3 clear positive results, we observed no added value either of t-Tau alone or p-Tau/t-Tau ratio in the model. On the other hand, considering 14-3-3 weak-positive cases, t-Tau protein increased the overall accuracy of 14-3-3 alone from 91 to 94 % and specificity from 74 to 93 % (p < 0.05), with no sensitivity improvement. However, inclusion of p-Tau/t-Tau ratio did not significantly improve the first model (p = 0.0595). Globally, t-Tau protein allowed a further discrimination of 65 % within 14-3-3 inconclusive results. Furthermore, PRNP MV genotype showed a trend to decrease 14-3-3 sensitivity (p = 0.051), but such effect was not seen on t-Tau protein. In light of these results, we suggest that t-Tau protein assay is of significant importance as a second marker in identifying 14-3-3 false-positive results among sCJD probable cases

Effect of physical exercise on lipid metabolism in the elderly

PURPOSE: To assess the effect of regular physical exercise on plasma lipids and apoproteins in an elderly group. MATERIAL AND METHODS: Sixty-three old people of both sexes, aged between 65 and 94, were randomly distributed between a test group (n = 31) and a control group (n = 32). The test group followed a program of physical exercise for eight months, with intensity of 60% to 80% of heart rate reserve, consisting of three weekly sessions, on alternate days, of 60 minutes each. Before the beginning of the program and eight months afterwards, blood samples were collected to assess total cholesterol, triglycerides, HDL-C, HDL2-C. HDL3-C, apo A1, apo B-100 and apo (a). The ratios total cholesterol/HDL-C, LDL-C/HDL-C, HDL2-C/HDL3-C and apo A1/apo B-100 were also calculated. RESULTS: In the test group total cholesterol, triglycerides, LDL-C, apo B-100, total cholesterol/HDL-C and LDL-C/HDL-C decreased significantly; HDL-C, HDL2-C, apo A1, HDL2-C/HDL3-C and apo A1/apo B-100 increased significantly; HDL3-C and apo (a) did not change. The control group did not present any significant alterations in any of the parameters assessed. CONCLUSIONS: Regular physical exercise decreases vascular risk and may help to reduce cardiovascular events in the elderly

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

The clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) is difficult, and reliable markers are highly desired. In this work we assess the value of several cerebrospinal fluid (CSF) markers for sCJD diagnosis. Within the framework of the Portuguese Epidemiological Surveillance Program for Human Prion Diseases, CSF samples from 71 patients with clinically suspected sCJD, 30 definite sCJD and 41 non-CJD patients, were analysed for the presence of 14-3-3 protein. CSF levels of tau (t-tau), and phosphorylated tau (p-tau181), S-100b and beta amyloid (Abeta42) proteins were determined. The influence of clinical and genetic characteristics on CSF markers sensitivity was also evaluated. Protein 14-3-3 was detected in 29/30 sCJD patients and 9/41 non-CJD patients. Extremely elevated t-tau and S-100b protein levels were found in sCJD patients, while p-tau181 levels were only slightly elevated and Abeta42 showed no differences compared to controls. 14-3-3 was the most sensitive parameter (97%), but its specificity was low (78%); sensitivity/specificity for other proteins were: S-100b-93/93%, t-tau-93/95%, with maximum accuracy being obtained by a combination of tests (14-3-3 combined with either t-tau or S-100b, or combining S-100b with t-tau/Abeta42 or p-tau/t-tau ratios). The sensitivity of 14-3-3, as well as of p-tau181/t-tau ratio, was decreased in younger patients with long disease duration, with the PrP-2 isotype and MV genotype. Both 14-3-3, t-tau and S-100b are sensitive markers for sCJD, but 14-3-3 specificity seems to be lower in this special clinical setting of rapidly progressing dementias. We propose that in cases with a 14-3-3 weak positive result, or in young patients with long disease duration, a second CSF marker would be valuable for the diagnosis of sCJD

The Evolution of the Manosphere across the Web

We present a large-scale characterization of the Manosphere, a conglomerate of Web-based misogynist movements focused on men's issues, which has prospered online. Analyzing 28.8M posts from 6 forums and 51 subreddits, we paint a comprehensive picture of its evolution across the Web, showing the links between its different communities over the years. We find that milder and older communities, such as Pick Up Artists and Men's Rights Activists, are giving way to more extreme ones like Incels and Men Going Their Own Way, with a substantial migration of active users. Moreover, our analysis suggests that these newer communities are more toxic and misogynistic than the older ones

Pseudohypoparathyroidism type I-b with neurological involvement is associated with a homozygous PTH1R mutation

Pseudohypoparathyroidism type 1b (PHP1b) is characterized by hypocalcemia, hyperphosphatemia, increased levels of circulating parathyroid hormone (PTH), and no skeletal or developmental abnormalities. The goal of this study was to perform a full characterization of a familial case of PHP1b with neurological involvement and to identify the genetic cause of disease. The initial laboratory profile of the proband showed severe hypocalcemia, hyperphosphatemia and normal levels of PTH, which was considered to be compatible with primary hypoparathyroidism. With disease progression the patient developed cognitive disturbance, PTH levels were found to be slightly elevated and a picture of PTH resistance syndrome seemed more probable. The diagnosis of PHP1b was established after the study of family members and blunted urinary cAMP results were obtained in a PTH stimulation test. Integration of whole genome genotyping and exome sequencing data supported this diagnosis by revealing a novel homozygous missense mutation in PTH1R (p.Arg186His) completely segregating with the disease. Here, we demonstrate segregation of a novel mutation in PTH1R with a phenotype of PHP1b presenting with neurological symptoms, but no bone defects. This case represents the extreme end of the spectrum of cognitive impairment in PTH dysfunction and defines a possible novel form of PHP1b resulting from the impaired interaction between PTH and PTH1R

Influence of PLLA/PCL/HA scaffold fiber orientation on mechanical properties and osteoblast behavior

Scaffolds based on aligned and non-aligned poly (L-lactic acid) (PLLA)/polycaprolactone (PCL) fibers obtained by electrospinning, associated to electrosprayed hydroxyapatite (HA) for tissue engineering applications were developed and their performance was compared in terms of their morphology and biological and mechanical behaviors. The morphological results assessed by scanning electron microscopy showed a mesh of PLLA/PCL fibers (random and perfectly aligned) associated with aggregates of nanophased HA. Fourier transform infrared spectrometry confirmed the homogeneity in the blends and the presence of nanoHA in the scaffold. As a result of fiber alignment a 15-fold increase in Young's Modulus and an 8-fold increase in tensile strength were observed when compared to non-aligned fibers. In PLLA/PCL/HA scaffolds, the introduction of nanoHA caused a remarkable improvement of the mechanical strength of this material acting as a reinforcement, enhancing the response of these constructs to tensile stress. In vitro testing was evaluated using osteoblast (MC3T3-E1) cells. The results showed that both fibrous scaffolds were able to support osteoblast cell adhesion and proliferation and that fiber alignment induced increased cellular metabolic activity. In addition, the adhesion and proliferation of Staphylococcus aureus were evaluated and a lower number of colony forming units (CFUs) was obtained in the scaffolds with aligned fibers.Project UID/BIM/04293/2019 by FCT/MCTES through Portuguese Funds

The Percentage of [−2]Pro–Prostate-Specific Antigen and the Prostate Health Index Outperform Prostate-Specific Antigen and the Percentage of Free Prostate-Specific Antigen in the Detection of Clinically Significant Prostate Cancer and Can Be Used as Reflex Tests

Context.—: There is a need to avoid the overdiagnosis of prostate cancer (PCa) and to find more specific biomarkers. Objective.—: To evaluate the clinical utility of [-2]pro-prostate-specific antigen ([-2]proPSA) derivatives in detecting clinically significant PCa (csPCa) and to compare it with prostate-specific antigen (PSA) and with the percentage of free PSA (%fPSA). Design.—: Two hundred thirty-seven men (PSA: 2-10 ng/mL) scheduled for a prostate biopsy were enrolled. Parametric and nonparametric tests, receiver operating characteristic curves, and logistic regression analysis were applied. Outcomes were csPCa and overall PCa. Results.—: Both [-2]proPSA derivatives were significantly higher in csPCa and overall PCa (P < .001). The areas under the curves for the prediction of csPCa were higher for the percentage of [-2]proPSA (%[-2]proPSA) (0.781) and the prostate health index (PHI) (0.814) than for PSA (0.651) and %fPSA (0.724). There was a gain of 11% in diagnostic accuracy when %[-2]proPSA or PHI were added to a base model with PSA and %fPSA. Twenty-five percent to 29% of biopsies could have been spared with %[-2]proPSA (cutoff: ≥1.25%) and PHI (cutoff: ≥27), missing 10% of csPCas. The same results could have been achieved by using [-2]proPSA as a reflex test, when %fPSA was 25% or less (cutoffs: ≥1.12% and ≥24 for %[-2]proPSA and PHI, respectively). Conclusions.—: The [-2]proPSA derivatives improve the diagnostic accuracy of csPCa when the PSA value is between 2 and 10 ng/mL, sparing unnecessary biopsies and selecting patients for active surveillance. [-2]proPSA can be used as a reflex test when %fPSA is 25% or less, without reducing the diagnostic accuracy for csPCa and the number of spared biopsies.info:eu-repo/semantics/publishedVersio

Mitochondrial-dependent apoptosis in Huntington's disease human cybrids

We investigated the involvement of mitochondrial-dependent apoptosis in Huntington's disease (HD) vs. control (CTR) cybrids, obtained from the fusion of human platelets with mitochondrial DNA-depleted NT2 cells, and further exposed to 3-nitropropionic acid (3-NP) or staurosporine (STS). Untreated HD cybrids did not exhibit significant modifications in the activity of mitochondrial respiratory chain complexes I-IV or in mtDNA sequence variations suggestive of a primary role in mitochondrial susceptibility in the subpopulation of HD carriers studied. However, a slight decrease in mitochondrial membrane potential and increased formation of intracellular hydroperoxides was observed in HD cybrids under basal conditions. Furthermore, apoptotic nuclei morphology and a moderate increase in caspase-3 activation, as well as increased levels of superoxide ions and hydroperoxides were observed in HD cybrids upon 3-NP or STS treatment. 3-NP-evoked apoptosis in HD cybrids involved cytochrome c and AIF release from mitochondria, which was associated with mitochondrial Bax translocation. CTR cybrids subjected to 3-NP showed increased mitochondrial Bax and Bim levels and the release of AIF, but not cytochrome c, suggesting a different mode of cell death, linked to the loss of membrane integrity. Additionally, increased mitochondrial Bim and Bak levels, and a slight release of cytochrome c in untreated HD cybrids may help to explain their moderate susceptibility to mitochondrial-dependent apoptosi

Recommended age groups and frequency of mammography screening : a systematic review

Esta revisão teve por objetivo avaliar a força de evidência do atual indicador de desempenho português relativo ao rastreio do Câncer da Mama através da mamografia, de modo a determinar o grupo etário e a periodicidade recomendadas. Foram pesquisados artigos nas principais bases de dados internacionais de literatura médica. Incluímos artigos publicados entre Janeiro de 2006 e Janeiro de 2012 que correspondiam aos objetivos da revisão. Foi utilizada a taxonomia SORT para a classificação dos resultados. Dos 253 artigos encontrados foram selecionados cinco que cumpriam os critérios de inclusão. Estes incluem três revisões sistemáticas (RS), uma meta-análise (MA) e uma norma de orientação clínica (NOC) baseada numa RS. Os artigos selecionados avaliaram a redução da mortalidade por câncer da mama através do rastreio com mamografia. A realização do rastreio mamográfico entre os 50 e os 69 anos é recomendado em todos os artigos que avaliam esta faixa etária. A NOC recomenda o rastreio bienal. Em suma, a mamografia deverá ser realizada entre os 50 e os 69 anos com uma periodicidade bienal. Estes resultados vão ao encontro do atual indicador de desempenho do rastreio do câncer da mama em Portugal.The scope of this review was to assess the strength of evidence for the current Portuguese performance indicator on breast cancer screening with mammography in order to determine the recommended age group and periodicity for screening. A search for articles was conducted in the main international databases of medical literature. Articles published between January 2006 and January 2012 addressing the objectives of this review were included. The SORT taxonomy was used to classify the results. Of the 253 articles, five articles met the inclusion criteria and were selected for review. These included three systematic reviews, one meta-analysis and one clinical guideline based on a systematic review. A reduction in breast cancer mortality with mamography screening was the outcome in all articles selected. Mammography screening between 50 and 69 years was recommended in all articles that assess this age group. The clinical guidelines recommended screening every two years. In conclusion, the current literature recommends mammography for women every two years between the ages of 50 and 69 years. This is consistent with the current performance indicator for breast cancer screening in Portugal