Automated analysis of FDG PET as a tool for single-subject probabilistic prediction and detection of Alzheimer's disease dementia.

PURPOSE: To introduce, evaluate and validate a voxel-based analysis method of ¹8F-FDG PET imaging for determining the probability of Alzheimer's disease (AD) in a particular individual. METHODS: The subject groups for model derivation comprised 80 healthy subjects (HS), 36 patients with mild cognitive impairment (MCI) who converted to AD dementia within 18 months, 85 non-converter MCI patients who did not convert within 24 months, and 67 AD dementia patients with baseline FDG PET scan were recruited from the AD Neuroimaging Initiative (ADNI) database. Additionally, baseline FDG PET scans from 20 HS, 27 MCI and 21 AD dementia patients from our institutional cohort were included for model validation. The analysis technique was designed on the basis of the AD-related hypometabolic convergence index adapted for our laboratory-specific context (AD-PET index), and combined in a multivariable model with age and gender for AD dementia detection (AD score). A logistic regression analysis of different cortical PET indexes and clinical variables was applied to search for relevant predictive factors to include in the multivariable model for the prediction of MCI conversion to AD dementia (AD-Conv score). The resultant scores were stratified into sixtiles for probabilistic diagnosis. RESULTS: The area under the receiver operating characteristic curve (AUC) for the AD score detecting AD dementia in the ADNI database was 0.879, and the observed probability of AD dementia in the six defined groups ranged from 8% to 100% in a monotonic trend. For predicting MCI conversion to AD dementia, only the posterior cingulate index, Mini-Mental State Examination (MMSE) score and apolipoprotein E4 genotype (ApoE4) exhibited significant independent effects in the univariable and multivariable models. When only the latter two clinical variables were included in the model, the AUC was 0.742 (95% CI 0.646 - 0.838), but this increased to 0.804 (95% CI 0.714 - 0.894, bootstrap p=0.027) with the addition of the posterior cingulate index (AD-Conv score). Baseline clinical diagnosis of MCI showed 29.7% of converters after 18 months. The observed probability of conversion in relation to baseline AD-Conv score was 75% in the high probability group (sixtile 6), 34% in the medium probability group (merged sixtiles 4 and 5), 20% in the low probability group (sixtile 3) and 7.5% in the very low probability group (merged sixtiles 1 and 2). In the validation population, the AD score reached an AUC of 0.948 (95% CI 0.625 - 0.969) and the AD-Conv score reached 0.968 (95% CI 0.908 - 1.000), with AD patients and MCI converters included in the highest probability categories. CONCLUSION: Posterior cingulate hypometabolism, when combined in a multivariable model with age and gender as well as MMSE score and ApoE4 data, improved the determination of the likelihood of patients with MCI converting to AD dementia compared with clinical variables alone. The probabilistic model described here provides a new tool that may aid in the clinical diagnosis of AD and MCI conversion.

Surgical Outcomes in a Lung Cancer-Screening Program Using Low Dose Computed Tomography.

OBJECTIVE: Lung cancer (LC) is the leading cause of death from cancer worldwide. More than 27,000 LCs are diagnosed annually in Spain, and most are unresectable. Early detection and treatment reduce LC mortality. This study describes surgical outcomes in a longstanding LC screening cohort in Spain. METHODS: We conducted a retrospective study of surgical outcomes in a LC screening (LCS) program using low dose computed tomography (LDCT) since the year 2000. A descriptive analysis of clinical and radiological parameters, presence or absence of a preoperative diagnosis, pathological staging, morbidity, mortality, and survival was performed. RESULTS: Ninety-seven (2.5%) LC were diagnosed in 3825 screened. Twenty individuals with LC had no surgery due to advanced stage or small cell histology. Eighty-seven surgical procedures were carried out for suspected or biopsy proven LC, detected by LDCT. Most operated patients were male (57[85%]) aged 64±9.1 years. Nine patients underwent a second operation for a metachronous primary lung cancer. Mean tumor size was 15.2±7.6mm. Eight nodules were benign (9.2%). Lobectomy was performed in 56 cases (83.6%). Adenocarcinoma (n=39; 58.2%) was the most frequent histological type followed by squamous cell carcinoma (n=17; 25.4%). Fifty-nine (88%) tumors were in Stage I. Thirteen patients (15.4%) had 16 complications. The estimated survival rates at 5 and 10 years for stage I were 93% (95% CI: 79%-98%) and 83% (95% CI: 65%-92%), respectively. CONCLUSION: Lung cancer screening was associated with excellent surgical outcomes with 5 and 10-year survival rates exceeding 90 and 80%, respectively.

Surgical Outcomes in a Lung Cancer-Screening Program Using Low Dose Computed Tomography / Resultados quirúrgicos de un programa de cribado de cáncer de pulmón utilizando tomografía computarizada de baja dosis

OBJECTIVE: Lung cancer (LC) is the leading cause of death from cancer worldwide. More than 27,000 LCs are diagnosed annually in Spain, and most are unresectable. Early detection and treatment reduce LC mortality. This study describes surgical outcomes in a longstanding LC screening cohort in Spain. METHODS: We conducted a retrospective study of surgical outcomes in a LC screening (LCS) program using low dose computed tomography (LDCT) since the year 2000. A descriptive analysis of clinical and radiological parameters, presence or absence of a preoperative diagnosis, pathological staging, morbidity, mortality, and survival was performed. RESULTS: Ninety-seven (2.5%) LC were diagnosed in 3825 screened. Twenty individuals with LC had no surgery due to advanced stage or small cell histology. Eighty-seven surgical procedures were carried out for suspected or biopsy proven LC, detected by LDCT. Most operated patients were male (57[85%]) aged 64 ± 9.1 years. Nine patients underwent a second operation for a metachronous primary lung cancer. Mean tumor size was 15.2 ± 7.6 mm. Eight nodules were benign (9.2%). Lobectomy was performed in 56 cases (83.6%). Adenocarcinoma (n = 39; 58.2%) was the most frequent histological type followed by squamous cell carcinoma (n = 17; 25.4%). Fifty-nine (88%) tumors were in Stage I. Thirteen patients (15.4%) had 16 complications. The estimated survival rates at 5 and 10 years for stage I were 93% (95% CI: 79%-98%) and 83% (95% CI: 65%-92%), respectively. CONCLUSION: Lung cancer screening was associated with excellent surgical outcomes with 5 and 10-year survival rates exceeding 90 and 80%, respectively

OBJETIVO: El cáncer de pulmón (CP) es la principal causa de muerte por cáncer en todo el mundo. En España se diagnostican anualmente más de 27.000 CP y la mayoría son irresecables. La detección y el tratamiento tempranos reducen la mortalidad por CP. Este estudio describe los resultados quirúrgicos en una cohorte de cribado de CP de larga duración en España. MÉTODOS: Llevamos a cabo un estudio retrospectivo de los resultados quirúrgicos de un programa de cribado de CP (CCP) usando tomografía computarizada de baja dosis (LDCT, por sus siglas en inglés) en marcha desde el año 2000. Se realizó un análisis descriptivo de los parámetros clínicos y radiológicos, presencia o ausencia de un diagnóstico preoperatorio, estadificación patológica, morbilidad, mortalidad y supervivencia. RESULTADOS: Se diagnosticaron 97 (2,5%) CP entre 3.825 sujetos cribados. Veinte personas con CP no se sometieron a cirugía debido a un estado avanzado de la enfermedad o a una histología de células pequeñas. Se llevaron a cabo 87 procedimientos quirúrgicos por sospecha de CP o CP demostrado mediante biopsia, detectados en la LDCT. La mayoría de los pacientes operados fueron varones (57 [85%]) de 64 años ± 9,1 años. Nueve pacientes se sometieron a una segunda operación por un cáncer de pulmón primario metacrónico. El tamaño medio del tumor fue de 15,2 ± 7,6 mm. Ocho nódulos fueron benignos (9,2%). Se realizó lobectomía en 56 casos (83,6%). El adenocarcinoma (n = 39; 58,2%) fue el tipo histológico más frecuente seguido por el carcinoma de células escamosas (n = 17; 25,4%); 59 (88%) tumores se encontraban en estadio I. Trece pacientes (15,4%) tuvieron 16 complicaciones. Las tasas de supervivencia estimadas a los 5 y 10 años para el estadio I fueron del 93% (IC 95%: 79 al 98%) y del 83% (IC 95%: 65 al 92%), respectivamente. CONCLUSIÓN: El CCP se asoció con excelentes resultados quirúrgicos y con tasas de supervivencia a los 5 y 10 años superiores al 90 y al 80%, respectivamente

Specific and general HLA-DR binding motifs: comparison of algorithms.

Using panels of peptides well characterized for their ability to bind to HLA DR1, DRB1*1101, or DRB1*0401 molecules, algorithms were deduced to predict binding to these molecules. These algorithms consist of blocks of 8 amino acids containing an amino acid anchor (Tyr, Phe, Trp, Leu, Ile, or Val) at position i and different amino acid combinations at positions i+2 to i+7 depending on the class II molecule. The sensitivity (% of correctly predicted binder peptides) and specificity (% of correctly predicted non-binder peptides) of these algorithms, were tested against different independent panels of peptides and compared to other algorithms reported in the literature. Similarly, using a panel of 232 peptides able to bind to one or more HLA molecules as well as 43 non-binder peptides, we deduced a general motif for the prediction of binding to HLA-DR molecules. The sensitivity and specificity of this general motif was dependent on the threshold score used for the predictions. For a score of 0.1, the sensitivity and specificity were 84.7% and 69.8%, respectively. This motif was validated against several panels of binder and non-binder peptides reported in the literature, as well as against 35, 15-mer peptides from hepatitis C virus core protein, that were synthesized and tested in a binding assay against a panel of 19 HLA-DR molecules. The sensitivities and specificities against these panels of peptides were similar to those attained against the panels used to deduce the algorithm. These results show that comparison of binder and non-binder peptides, as well as correcting for the relative abundance of amino acids in proteins, is a useful approach to deduce performing algorithms to predict binding to HLA molecules.

Age-related differences in the thermogenic and ponderal effects following the administration of fragment peptides from the rat ob protein.

The ob gene encodes a protein, which regulates satiety, metabolic rate and fat storage. The administration of a pool of five 20-amino-acid fragment peptides derived from the carboxy-terminal region of the ob protein produced a statistically significant reduction in body weight gain in adult rats, while rectal temperature showed a statistically significant increase. Administration of the same pool of peptides to young rats did not produce changes in body weight gain, although a statistically significant transient increase in rectal temperature was observed. These results envisage the possibility that small sequences of amino acids derived from the ob protein may mimic the effects of the whole protein on temperature and ponderal regulation. Furthermore, data suggest possible age-related differences in the response to leptin administration.

Systemic onset juvenile chronic arthritis, polyarticular pattern and hip involvement as markers for a bad prognosis.

OBJECTIVE: To explore all the common clinical and biological variables that are characteristic of Systemic onset Juvenile Chronic Arthritis (SoJCA) in order to determine which of them are suitable as predictors of a bad articular outcome (persistence of inflammatory symptoms and/or established limitation of the range of motion (ROM). MATERIAL AND METHODS: Clinical charts for 124 SoJCA patients were retrospectively reviewed. From them, 91 were finally included in the study because they had all of the clinical and biological data at disease onset properly recorded. All have been followed for at least 3 years since the beginning of the disease. Data collected at onset, and after 3 and 6 months of the disease included: 1) systemic symptoms; 2) joint involvement, using both the usual articular count and the value of an articular index (Helsinki Index = HI) which intentionally excludes those joints that are not uniformly recorded in clinical charts; and 3) biological data. HI was used to separate the patients into two groups. When applied 3 years after the disease onset, HI > or = 10 represented a bad articular outcome while HI < 10 meant a good prognosis. SPSS for Windows 6.1 was used for both the univariate and multivariate analyses. RESULTS: From the multivariate logistic regression analysis, two different "clusters" of clinical data were found to be the best predictors of a bad articular outcome. A bad prognosis was linked at onset with the presence of generalized lymphadenopathies, age < 8 years and an HI > 6; at six months a bad outcome was linked with the presence of a polyarticular pattern plus hip involvement. CONCLUSION: Clinical parameters at the beginning of the disease were shown to be extremely useful in predicting the articular outcome of SoJCA. Therefore, they could constitute a good instrument to help clinicians tailor the best therapy for their patients.

Comparation of the new rebound tonometer IOPen and the Goldmann tonometer, and their relationship to corneal properties.

PURPOSE: To compare the intraocular pressures (IOPs) obtained with the IOPen rebound tonometer, Goldmann applanation tonometer (GAT) and the ocular response analyzer (ORA) and investigate the effects of corneal biomechanical properties on IOPen measurements. METHODS: A total of 198 normal eyes were included in this cross-sectional and randomized study. Three measurements were taken using IOPen. Agreement between tonometers was calculated using the Bland and Altman limits of agreement (LoA) analysis. RESULTS: The median IOPen IOP was 3 mm Hg below the GAT (P < 0.001), 3 mm Hg below the ORA IOP similar to Goldmann (IOPg), and 3 mm Hg below the ORA IOP corrected using corneal parameters (IOPcc)(P < 0.01). The LoA width between the IOPen and GAT IOPs varied between 13.92 (mean IOPen IOP) and 15.99 mm Hg (third IOPen measurement). The central corneal thickness (CCT) was unrelated to IOPen measurements (P > 0.05). Corneal hysteresis (CH) and corneal rigidity factor (CRF) were correlated with IOPen and GAT. CONCLUSIONS: IOPen underestimated the IOP compared with GAT and ORA. The effect of measurement quality or measurement order on IOPen was low. CCT did not affect the IOPen, but the CH and CRF did. The LoA width between the IOPen and GAT IOPs was higher than between the ORA IOPg or ORA IOPcc and GAT IOPs.

Factor analysis and correlation between Dizziness Handicap Inventory and Dizziness Characteristics and Impact on Quality of Life scales.

In order to assess the different dimensions of disability and handicap analyzed in the Dizziness Handicap Inventory (DHI) and Dizziness Characteristics and Impact on Quality of Life (UCLA-DQ) questionnaires a factor analysis study was done. The instruments used were the corresponding transculturally adapted versions of the originals into Spanish. The study included 337 patients with dizziness, independent of location and etiology, who were able to respond to all the items in the questionnaires given before vestibular testing. Factor analysis was used to determine the structure of both scales; a principal components analysis with orthogonal rotation (Varimax) was conducted on data collected from the patients. A three-factor solution was obtained in the DHI and a two-factor solution for the UCLA-DQ. The factors obtained from the DHI were related to vestibular handicap, vestibular disability and visuo-vestibular disability; the factors from the UCLA-DQ were related to frequency and severity of dizziness. There was no coincidence between the items in each of the factor obtained in the DHI questionnaire and the items in the subscales provided in the original version. The main relation between factors was found between vestibular handicap and frequency. The DHI and UCLA-DQ questionnaires are multidimensional questionnaires for the assessment of the impact of dizziness and provide a model for vestibular disability and handicap.

Effect of intraperitoneal sterile urine injection on abdominal myoelectrical activity in the spinal rat model.

The abdominal muscle reflex contractions in response to intraperitoneal injection of homologous sterile urine and acid, alkaline, hypo- and hyperosmolar solutions are studied in an acute spinal rat model by conventional and integrated electromyographic techniques. Intraperitoneal injection of homologous sterile urine causes a powerful and almost immediate abdominal muscle contracture of relative short duration. This response seems not to be related to urine pH or osmolarity, since only when solutions with extreme variations in these parameters are injected intraperitoneally are significant abdominal muscle contractions observed.

Detection of anti-hepatitis C virus antibodies by ELISA using synthetic peptides.

A novel ELISA assay for the detection of anti-hepatitis C virus antibodies in the sera of infected individuals is described. This assay is based on a mixture of three 15-amino acid synthetic peptides encompassing regions of core and NS4 proteins of hepatitis C virus. Comparison with other available ELISA assays based on recombinant polypeptides shows that, short synthetic peptides have the advantage over some larger recombinant peptides by giving higher specificity without loss of sensitivity.

Prediction of the response of chronic hepatitis C to interferon alfa: a statistical analysis of pretreatment variables.

Pretreatment variables that could predict the response of chronic hepatitis C to interferon alfa treatment have not been fully assessed. Eighteen baseline variables were evaluated in a series of 100 consecutive patients treated with a 12 month course of interferon alfa. For the purposes of this study, response was defined as the return to normal of aminotransferase activities before the third month of treatment. Seventy per cent of the patients responded to treatment. Six variables were associated with an increased likelihood of response assessed by univariate analysis. With stepwise multiple regression analysis assessment, however, only three variables remained independently predictive of response: low gamma glutamyltransferase (gamma GT) activities (p < 0.001), absence of obesity (p = 0.005), and absence of cirrhosis (p = 0.01). The response rate in patients with gamma GT activities < 0.66 mu kat/l (n = 55) was 78% and 60% in patients with values > 0.66 mu kat/l (n = 45) (p = 0.048). Response was attained in 75% of non-obese patients (n = 80), compared with only 50% of obese patients (n = 20) (p = 0.03). Finally, 80% of patients without cirrhosis (n = 76) responded, while among those with cirrhosis (n = 24) the response rate was only 37% (p < 0.001). All 23 patients without cirrhosis, <40 years old, and with gamma GT activities <0.66 mu kat/l responded to treatment, while only 28.5% of 14 patients with cirrhosis, >40 years old, and with gamma GT activities >0.66 mu kat/l responded to interferon alfa (p<0.001). Those findings may be useful when evaluating interferon alfa trials and it is suggested that this treatment should be applied early in the course of chronic hepatitis C.

Histological outcome of chronic hepatitis C treated with a 12-month course of lymphoblastoid alfa interferon.

To assess the effect of long-term alfa interferon therapy (12 months) on liver histology of chronic hepatitis C, we studied 61 treated patients, and compared their outcome with 28 untreated cases followed as controls. A liver biopsy was taken from all patients, before (month 0) and after the completion of the treatment or the control period (month 12). A third liver specimen taken at month 24 was available in 29 treated cases. Liver biopsies were blindly graded following Knodell's method. In 33 out of the 61 treated patients (54.1%), aminotransferase levels became normal shortly after starting therapy and remained within normal values until the end of treatment (sustained response). Nine (27%) sustained responders relapsed after interferon discontinuation, while the remaining 24 (73%) continued with normal aminotransferase values during follow-up (16.8 +/- 9.9 months). All histological parameters, except fibrosis, improved significantly after 12 months of therapy (periportal necrosis, month 0: 2.7 +/- 1.0, month 12: 1.6 +/- 1.1, p < 0.0001; lobular damage, month 0: 2.5 +/- 1.1, month 12: 1.4 +/- 0.9, p < 0.0001; portal inflammation, month 0: 3.6 +/- 0.5, month 12: 3.0 +/- 0.9, p < 0.0001). Histological improvement was especially marked in patients who did not relapse, although those who relapsed and partial responders also improved. Overall histological diagnoses improved in most patients. A sustained response to interferon was predicted by high periportal and lobular scores, and by a low fibrosis score on the pretreatment liver biopsy. At 24 months, histological improvement persisted in patients without posttreatment relapse, while liver inflammation had returned to pretreatment levels in the remaining cases.

Prediction of sustained remission of chronic hepatitis C after a 12-month course of alfa interferon.

alpha-Interferon therapy normalizes aminotransferase levels in approximately 50% of the patients with chronic hepatitis C, but post-therapy relapses are common and predictive factors of sustained response remain largely unknown. We retrospectively assessed several parameters as predictors of sustained remission after a 12-month course of lymphoblastoid alpha-interferon: the Knodell histological activity index, serum levels of procollagen type III peptide, serum HCV-RNA, anti-alpha-interferon antibodies, and anti-HCV antibodies (C-100-3), all at month 12. Thirty-seven patients were studied. Fourteen patients were non-responders (38%), 15 patients experienced a sustained response (40.5%) and eight patients responded similarly but relapsed after alpha-interferon withdrawal (21.5%). A decrease in the histological activity index above 5, normalization of procollagen type III peptide levels (< 12 ng/ml) and the absence of viremia after treatment were all significantly associated with a sustained response (p = 0.008, p = 0.007 and p = 0.037, respectively). Anti-interferon antibodies were detected in only one non-responder patient. Anti-C-100-3 antibodies became undetectable at month 12 in 5 of the 15 sustained responders. The best prediction of sustained response was obtained from the three variables independent of multivariate analysis according to the following equation: F = 0.872 + 0.067 x K (decrease of histological index) -0.052 x P (procollagen type III peptide levels at month 12) -0.28 x R (HCV-RNA at month 12; R = 2 when present and R = 1 when absent). A score higher than 0 predicted sustained remission with a 100% sensitivity and specificity in this series of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Simple strategy to induce antibodies of distinct specificity: application to the mapping of gp120 and inhibition of HIV-1 infectivity.

In this study 96 15-mer peptides encompassing the entire sequence of HIV-1 gp120 were synthesized and used to immunize BALB/c mice (i) alone or (ii) in conjunction with the T helper cell determinant FISEAIIHVLHSR (FIS) from sperm whale myoglobin, which is well recognized by major histocompatibility complex (MHC) class II molecules of BALB/c. Of these peptides 39 were immunogenic per se and 57 were not. Out of the 57 non-immunogenic peptides 53 could be rendered immunogenic with the second immunization protocol. With the exception of 4 cases, the anti-peptide antibody titers induced in (ii) were equal (14 cases) or higher (78 cases) than those induced in (i). From the 96 anti-peptide antibodies tested, 12 were able to recognize recombinant gp120 with good antibody titers, a result in agreement with previously identified B cell epitopes from gp120 by anti-peptide antibodies induced with longer peptides conjugated to a carrier protein. Moreover, 4 of the 12 anti-peptide antisera that recognized gp120 were able to neutralize HIV-1 infectivity in vitro, showing that the strategy of co-immunization with FIS may afford functional antibodies.

Cellular immunity to hepatitis C virus core protein and the response to interferon in patients with chronic hepatitis C.

To investigate the involvement of T-cell response against hepatitis C virus (HCV) antigens in viral clearance after interferon therapy, we measured interleukin-2 (IL-2) production by peripheral mononuclear cells in response to HCV core in patients with chronic hepatitis C. In a cohort of 43 patients, we investigated the frequency of circulating core-specific T-helper (Th) cell precursors by the limiting-dilution assay, and in a second cohort of 60 patients, we analyzed the response to specific core epitopes using 52 synthetic 15-mer overlapping peptides. We observed that the frequency of core-specific Th cell precursors was significantly higher in patients with sustained biochemical and virological response (SR) after interferon (IFN) therapy (median, 1/55,736) than in untreated patients (1/274,023) or that in patients who remained viremic after completion of the treatment-nonresponders (NR) plus transient responders (TR) (1/1,909,972). Patients who failed to respond to IFN (NR) and those who relapsed after IFN discontinuation (TR) had a similarly low number of precursors. The number of core peptides recognized by SR, TR, NR, UT, and healthy controls was 8.2 +/- 1.5, 6.5 +/- 1.2, 2.0 +/- 0.5, 2.7 +/- 0.9, and 0.3 +/- 0.2, respectively. In SR, the intensity of the proliferative response to core peptides as estimated by the summation of stimulation indexes (sigmaSI) was significantly higher than in NR and than in UT, but not different from that of TR. Our results indicate that both expansion of HCV-specific Th cell precursors and Th cell recognition of multiple core epitopes seem to be important in the elimination of HCV after IFN therapy.

Poliposis gástrica esporádica / Sporadic gastric polyposis

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