Automated brain volumetrics in multiple sclerosis: a step closer to clinical application.

BACKGROUND: Whole brain volume (WBV) estimates in patients with multiple sclerosis (MS) correlate more robustly with clinical disability than traditional, lesion-based metrics. Numerous algorithms to measure WBV have been developed over the past two decades. We compare Structural Image Evaluation using Normalisation of Atrophy-Cross-sectional (SIENAX) to NeuroQuant and MSmetrix, for assessment of cross-sectional WBV in patients with MS. METHODS: MRIs from 61 patients with relapsing-remitting MS and 2 patients with clinically isolated syndrome were analysed. WBV measurements were calculated using SIENAX, NeuroQuant and MSmetrix. Statistical agreement between the methods was evaluated using linear regression and Bland-Altman plots. Precision and accuracy of WBV measurement was calculated for (1) NeuroQuant versus SIENAX and (2) MSmetrix versus SIENAX. RESULTS: Precision (Pearson's r) of WBV estimation for NeuroQuant and MSmetrix versus SIENAX was 0.983 and 0.992, respectively. Accuracy (Cb) was 0.871 and 0.994, respectively. NeuroQuant and MSmetrix showed a 5.5% and 1.0% volume difference compared with SIENAX, respectively, that was consistent across low and high values. CONCLUSIONS: In the analysed population, NeuroQuant and MSmetrix both quantified cross-sectional WBV with comparable statistical agreement to SIENAX, a well-validated cross-sectional tool that has been used extensively in MS clinical studies.

Relapses in patients treated with fingolimod after previous exposure to natalizumab.

In post hoc analyses of an open-label, phase 3b study (FIRST), relapse rates during 4 months of fingolimod therapy were compared in patients with and without previous natalizumab exposure. Reductions in the proportion of patients experiencing relapses and annualized relapse rates (ARRs) from years 1 and 1-2 pre-study were evident between months 1 and 2 of fingolimod treatment, and were most pronounced in natalizumab-naïve patients and those who discontinued natalizumab >6 months pre-study. Patients who discontinued natalizumab 3-6 months pre-study had a peak ARR during month 1 of fingolimod treatment, followed by a decrease during months 2-4. These data indicate that fingolimod has the potential to reduce disease reactivation but that timing of treatment initiation may be critical for achieving an optimal effect.

A decade with nucleic acid-based microbiological methods in safety control of foods.

In the last decade, nucleic acid-based methods gradually started to replace or complement the culture-based methods and immunochemical assays in routine laboratories involved in food control. In particular, real-time polymerase chain reaction (PCR) was technically developed to the stage of good speed, sensitivity and reproducibility, at minimized risk of carry-over contamination. Basic advantages provided by nucleic acid-based methods are higher speed and added information, such as subspecies identification, information on the presence of genes important for virulence or antibiotic resistance. Nucleic acid-based methods are attractive also to detect important foodborne pathogens for which no classical counterparts are available, namely foodborne pathogenic viruses. This review briefly summarizes currently available or developing molecular technologies that may be candidates for involvement in microbiological molecular methods in the next decade. Potential of nonamplification as well as amplification methods is discussed, including fluorescent in situ hybridization, alternative PCR chemistries, alternative amplification technologies, digital PCR and nanotechnologies.

Endoscopic ultrasound for differential diagnosis of duodenal lesions.

PURPOSE: Duodenal tumors are rare and require a different management from that of esophagogastric neoplasia. The present study retrospectively analyses the endoscopic ultrasound (EUS) features of duodenal tumors of both epithelial and subepithelial origin. MATERIALS AND METHODS: During a 12 year period, all duodenal tumors with histologic confirmation by surgery or biopsy were collected including endoscopic and endosonographic images. EUS images were analyzed for specific features (echogenicity, wall layer structure and relation, outer margins) to possibly distinguish epithelial (polyps and carcinoma versus lymphoma) and subepithelial (tumor type) tumors. RESULTS: 53/80 cases had histologic confirmation (mean age 53.1 ±â€Š11.4 years, m:f = 33:20), 31 were epithelial (13 adenomas, 12 carcinomas, 6 lymphomas) and 22 subepithelial (11 GISTs, 7 Brunneromas, 1 lipoma, 3 NETs). EUS did not recognize carcinomas in 2/13 adenomas. EUS features suggesting carcinoma were loss of wall layers and irregular margins. 5/6 lymphomas showed inhomogeneous thickening with layers partially recognizable. Tumor type of subepithelial lesions correlated with echogenicity: GIST tumors were mostly (62.5 %) hypocheoic with the 3 malignant cases being characterized by heterogeneous echopattern with irregular outer margins. Of the hyperechoic lesions, lipomas had a homogeneous whitish appearance, while NET and Brunneromas were less hyperechoic. In the latter, the endoscopic aspect was also helpful for differential diagnosis. Accuracy of combined endoscopic/EUS imaging for all duodenal lesions was 84.9 % (45/53). No procedural complications occurred among all patients that received EUS examinations. CONCLUSION: EUS contributes to the differential diagnosis of epithelial lesions known to be malignant; in subepithelial tumors, tissue confirmation is still required.

The ACROSS study: Long-term efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: In chronic diseases such as multiple sclerosis requiring lifelong treatment, studies on long-term outcomes are important. OBJECTIVE: To assess disability and magnetic resonance imaging-related outcomes in relapsing multiple sclerosis patients from a Phase 2 study of fingolimod 10 or more years after randomization and to compare outcomes in patients who had a higher fingolimod exposure versus those with a lower fingolimod exposure. METHODS: ACROSS was a cross-sectional follow-up study of patients originally enrolled in a Phase 2 fingolimod proof-of-concept study (NCT00333138). Disability and magnetic resonance imaging-related outcomes were assessed in patients grouped according to fingolimod treatment duration, based on an arbitrary cut-off: ≥8 years (high exposure) and <8 years (low exposure). RESULTS: Overall, 175/281 (62%) patients participated in ACROSS; 104 (59%) of these were classified "high exposure." At 10 years, patients in the high-exposure group had smaller increases in Expanded Disability Status Scale (+0.55 vs. +1.21), and lower frequencies of disability progression (34.7% vs. 56.1%), wheelchair use (4.8% vs. 16.9%), or transition to secondary progressive multiple sclerosis (9.6% vs. 22.5%) than those in the low-exposure group. The high-exposure patients also had less progression in most magnetic resonance imaging-related outcomes. CONCLUSION: After 10 years of fingolimod treatment, disability progression was lower in the high-exposure group than in the low-exposure group.

Factors associated with determinants of sexual functioning in midlife women.

OBJECTIVES: The present study was conducted to assess the associations between a woman's passionate love for her partner and sexual satisfaction and demographic factors, health and life-style characteristics, menopausal status, and menopausal symptoms. METHODS: A cross-sectional study was conducted among women (40-60 years) residing in Maryland (n = 846). chi(2)-tests were performed to evaluate the associations between each of the outcome variables (sexual satisfaction and passionate love for the partner) and predictor/independent variables. Logistic regression analysis was performed to determine whether significant associations from chi(2) analyses remained significant after adjustment for confounders. RESULTS: Older age (adjusted odds ratio (OR) 1.04; 95% confidence interval (CI) 1.01, 1.07), higher education (OR 1.47; 95% CI 1.09, 1.99), and alcohol intake (OR 1.42; 95% CI 1.03, 1.95) were associated with low passion for the partner. Older age was also a significant predictor of low sexual satisfaction (OR 1.04; 95% CI 1.01, 1.07). Women experiencing vaginal dryness had higher odds of low passion for partner (OR 1.67; 95% CI 1.21, 1.31) and low sexual satisfaction (OR 1.58; 95% CI 1.14, 2.20) than women not experiencing vaginal dryness. CONCLUSIONS: Older age, higher education, alcohol intake, and vaginal dryness are significantly associated with lower levels of passionate love for the partner, while older age and vaginal dryness are significantly associated with lower levels of sexual satisfaction in midlife women.

[A new approach to the transvaginal needle suspension technique after Raz. Technique and long-term results]. / Eine neue Annäherungsweise im transvaginalen Nadelsuspensionsverfahren nach Raz. Technik und langfristige Ergebnisse.

AIM: Our aim is to describe the surgical technique and to present a long-term evaluation of the results. MATERIALS AND METHODS: A total of 53 patients with stress incontinence underwent a Raz transvaginal needle suspension operation with the introduction of a polypropylene mesh strip (15x1.5-2 cm) pulled under the suspension threads. The suspension threads occur on the endopelvic fascia in order to support the bladder neck and to permit the function of the polypropylene mesh strip, which, however, does not take part in supporting the bladder neck. The same urologist carried out 53 consecutive operations with clinical evaluation at 6 months, 1 and 5 years after surgery. RESULTS: After 6 months, 51 of the patients (96.2%) reported remaining dry after increasing intra-abdominal pressure. Two (3.7%) still had stress incontinence symptoms. After 1 and 5 years, 47 (88.6%) were dry and urinated normally, with spontaneous disappearance of nightly enuresis in two and surgery for subvesicular obstruction in one. CONCLUSIONS: The introduction of a polypropylene mesh strip in the suspension threads in cases using the trasvaginal suspension technique has good, long-term results for the treatment of patients with stress incontinence.

The role of the primate amygdala in conditioned reinforcement.

Conditioned reinforcement refers to the capacity of a conditioned stimulus to support instrumental behavior by acquiring affective properties of the primary reinforcer with which it is associated. Conditioned reinforcers maintain behavior over protracted periods of time in the absence of, and potentially in conflict with, primary reinforcers and as such may play a fundamental role in complex social behavior. A relatively large body of evidence supports the view that the amygdala (and in particular the basolateral area) contributes to conditioned reinforcement by maintaining a representation of the affective value of conditioned stimuli. However, a recent study in primates (Malkova et al., 1997), using a second-order visual discrimination task, suggests that the amygdala is not critical for the conditioned reinforcement process. In the present study, excitotoxic lesions of the amygdala in a new world primate, the common marmoset, resulted in a progressive impairment in responding under a second-order schedule of food reinforcement. In addition, the responding of amygdala-lesioned animals was insensitive to the omission of the conditioned reinforcer, unlike that of control animals, for which responding was markedly reduced. In contrast, lesioned animals were unimpaired when responding on a progression of fixed-ratio schedules of primary reinforcement. These data confirm that the amygdala is critical for the conditioned reinforcement process in primates, and taken together with other recent work in monkeys, these results suggest that the contribution of the amygdala is to provide the affective value of specific reinforcers as accessed by associated conditioned stimuli.

Efficacy of fingolimod in patients with highly active relapsing-remitting multiple sclerosis.

OBJECTIVE: There is a need to identify effective switch therapies for patients with relapsing-remitting multiple sclerosis (RRMS) who experience high disease activity despite receiving disease-modifying therapy (DMT). The objective of this study was to assess the efficacy of fingolimod versus placebo in patients with RRMS who had experienced high disease activity despite previously receiving DMT, using post hoc analyses of two phase 3 trials: FREEDOMS (NCT00289978) and FREEDOMS II (NCT00355134). RESEARCH DESIGN AND METHODS: Clinical and magnetic resonance imaging outcomes over 24 months were analyzed in patients from FREEDOMS and FREEDOMS II who had received treatment in the previous year and had: (1) ≥1 relapse in the previous year and either ≥1 gadolinium (Gd) enhancing T1 lesion or ≥9 T2 lesions at baseline and/or (2) as many or more relapses in the year before baseline as in the previous year (as per fingolimod's EU label). MAIN OUTCOME MEASURES: The inclusion criteria were fulfilled by 249 and 257 patients in the fingolimod and placebo groups, respectively. Annualized relapse rates were reduced by 48% for fingolimod versus placebo (p < 0.001). Fingolimod reduced the risk of 3 month and 6 month confirmed disability progression by 34% (p = 0.031) and 45% (p = 0.016), respectively, versus placebo. Brain volume loss was reduced by 46% for fingolimod versus placebo (p < 0.001). The reduction in Gd-enhancing T1 lesion counts for fingolimod versus placebo was 65% (p < 0.001). Furthermore, fingolimod reduced the number of new or newly enlarged T2 lesions by 69% relative to placebo (p < 0.001). LIMITATION: The analyses are post hoc, but the population is specified by the European Medicines Agency in the label for fingolimod. CONCLUSIONS: Fingolimod demonstrated efficacy across all four key RRMS disease measures analyzed in patients with high disease activity despite previous DMT.

The effects of endocrine disrupting chemicals on the ovary.

Endocrine disrupting chemicals (EDCs) are natural or synthetic chemicals that mimic, enhance, or inhibit endogenous hormones. In this article, we review possible targets of EDCs within the ovary and explore whether EDCs may be acting as estrogen mimics, interfering with apoptosis, altering cell signaling pathways, or affecting estrogen metabolism. Though the study of EDCs has remained controversial, it is important to study them because our society continues to release large amounts of industrial chemicals into our environment and uncovering the mechanisms of action may lead to treatments of any potential adverse effects. In addition, studying how EDCs affect the ovary may lead to serendipitous discoveries about ovarian function and dysfunction. Finally, understanding the science behind endocrine disruption may influence the political and regulatory handling of EDCs.

Postnatal development of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) positive neurons in rat prefrontal cortex.

First nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d)-positive perikarya in rat prefrontal cortex (PFC) are present at birth. On postnatal day (P) 1, there is an increase of NADPH-d-positive neurons in all developing layers of PFC. From P1 to P7, a further increase in the overall number of positive neurons is observed. First laminar and area shifts are noted on P21, while morphological maturation of NADPH-d-positive neurons is finished around P30. In conclusion, the postnatal development of NADPH-d neurons in PFC is in concordance with other developmental events in rat cerebral cortex.

Effect of extracellular NADH on human tumor cell proliferation.

We investigated the antiproliferative effects of extracellular nicotinamide adenine dinucleotide against human malignant CaCo-2 (colon carcinoma), Hep-2 (laryngeal carcinoma), MCF-7 (breast carcinoma), CaSki (cervix carcinoma) cell lines, as well as against murine fibrosarcoma and normal human embryonal fibroblast (HEF). NADH was very potent in the growth inhibition of murine fibrosarcoma and human Hep-2 cells, regardless of the dose applied. During the observed period (4 or 5 days) only one dose of NADH was sufficient in reducing the growth rate for up to 92%. It had no effect on the growth of other cell lines tested. The identification of DNA-fragmentation and p53 and Ki-67 genes expression suggest that the mechanism of NADH action is different from disregulation of genes considered as check-points in cell cycle.

Treatment of Alzheimer's disease with stabilized oral nicotinamide adenine dinucleotide: a randomized, double-blind study.

This study was designed to evaluate the effect of stabilized oral reduced nicotinamide adenine dinucleotide (NADH) on cognitive functioning in patients with Alzheimer's disease (AD). NADH is a coenzyme that plays a key role in cellular energy production and stimulates dopamine production. In previous trials NADH has been shown to improve cognitive functioning in patients with Parkinson's disease, depression and AD. The present trial was a randomized, placebo-controlled, matched-pairs, double-blind, 6-month clinical study. Patients with probable AD (n = 26) were randomized to receive either stabilized oral NADH (10 mg/day) or placebo. Twelve pairs of subjects were matched for age and baseline total score on the Mattis Dementia Rating Scale (MDRS) and the Mini Mental State Examination. After 6 months of treatment, subjects treated with NADH showed no evidence of progressive cognitive deterioration and had significantly higher total scores on the MDRS compared with subjects treated with placebo (p < 0.05). Analysis of MDRS subscales revealed significantly better performance by NADH subjects on measures of verbal fluency (p = 0.019), visual-constructional ability (p = 0.038) and a trend (p = 0.08) to better performance on a measure of abstract verbal reasoning. There were no differences between groups in measures of attention, memory, or in clinician ratings of dementia severity (Clinical Dementia Rating). Consistent with earlier studies, the present findings support NADH as a treatment for AD.

Correlates of sexual functioning among mid-life women.

OBJECTIVE: Studies have reported a decline in sexual functioning among women undergoing the menopausal transition. Few studies, however, have examined the associations between hormones and sexual dysfunction during this time period. Therefore, the purpose of this study was to examine the associations between participant characteristics and endogenous hormones with sexual functioning in mid-life women. METHODS: Data were analyzed from a community-based sample of 441 women aged 45-54 years who stated that they were sexually active at the time of the study. Each participant completed a survey that included questions pertaining to sexual functioning and provided a blood sample that was used to measure estrogen and androgen concentrations. RESULTS: Among women who reported being sexually active, poorer self-reported health and the experiencing of depressive symptoms were significantly associated with not being satisfied with sexual relations after adjustment for other covariates. None of the hormones examined were significantly associated with overall sexual satisfaction. However, statistically significant associations between both total testosterone levels and the free testosterone index with satisfaction with the frequency of sexual relations were observed. CONCLUSIONS: Our findings indicate that the experiencing of depressive symptoms and the reporting of poor overall health are important correlates of sexual dysfunction. Further, our results suggest that higher total and free testosterone levels are significantly associated with a desire for increased frequency of sexual relations among mid-life women.

Ovarian follicle development and transgenic mouse models.

Ovarian follicle development is a complex process that begins with the establishment of what is thought to be a finite pool of primordial follicles and culminates in either the atretic degradation of the follicle or the release of a mature oocyte for fertilization. This review highlights the many advances made in understanding these events using transgenic mouse models. Specifically, this review describes the ovarian phenotypes of mice with genetic mutations that affect ovarian differentiation, primordial follicle formation, follicular growth, atresia, ovulation and corpus luteum (CL) formation. In addition, this review describes the phenotypes of mice with mutations in a variety of genes, which affect the hormones that regulate folliculogenesis. Because studies using transgenic animals have revealed a variety of reproductive abnormalities that resemble many reproductive disorders in women, it is likely that studies using transgenic mouse models will impact our understanding of ovarian function and fertility in women.

[Peritoneal hepatobiliary cystadenoma--case report].

Hepatobiliary cystadenoma with mesenchymal stroma are infrequent form of cystic neoplasm that may be found in females only. It is difficult to reach correct diagnosis prior to surgery. We are presenting a case of 32 years-old female referred to our institution for revealing a cause of discomfort and pain in right subcostal region whereas peritoneal hepatobiliary cystadenoma has been determined. Abdominal ultrasonography and computerized tomography revealed cystic lesion adjacent to gall bladder, which was initially thought to be of echynococcal origin. At surgery, a mesenterial cystic neoplasm has been revealed, having a close contact with gall bladder, without signs of its infiltration. Pathophysiology discovered hepatobiliary cystadenoma with mesenchymal stroma. Pre-surgical differential diagnosis in hepatobiliary cystadenoma may be very difficult, especially if, like in the presented case, neoplasm has extra hepatic localization. Radical surgical excision is treatment of choice, concerning malignant potential of these neoplasms.

[Endoscopic ultrasonography in choledocholithiasis].

Diagnosis of choledocholithiasis is still difficult to establish and presents a great challenge in gastroenterology and surgery of biliary tract, since it requires expensive and sophisticated examining techniques. 10 to 15% of patients with symptomatic cholelithiasis were presented with choledocholithiasis as well. By EUS is possible to establish a diagnosis of choledocholithiasis with accuracy of 90 to 100% and precisely estimate dimensions of revealed stones. The main purpose of this survey is to present a great importance and many advantages of EUS as a contemporary diagnostic method. All patients were examined by Olympus equipment for endoscopic ultrasound with radial probe working with the frequency of 7,5 and 12 MHz at the Department for Endoscopic Ultrasound of the Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia. They were previously diagnosed with choledocholithiasis by ERCP method. We examined 16 patients, which were selected by estimated risk for cholelithiasis. We have tried to evaluate the importance of diameter of choledochus, defined by common ultrasonography, as well as values of alkaline phosphatase and serum ?GT. We defined 3 groups of patients: group no.1, with 2 patients presented with a low risk for choledocholithiasis; group no.2, with 6 patients with a moderate risk for choledocholithiasis, and group no.3, with 8 patients presented with significant risk for cholelithiasis. According to obtained results, EUS presents the most effective method for detecting of choledocholithiasis, which is sometimes even more efficient than ERCP. After choledocholithiasis is previously revealed by EUS, it is much easier to decide if some invasive method such as EPT or precut papillotomy has to be used. EUS is always recommended as a diagnostic method when it is necessary to avoid some expected complications, such as pancreatitis.

[The role of endoscopic ultrasonography in diagnostic and estimation of common bile duct carcinoma invasion].

The main purpose of this survey is to present the importance of EUS in establishing a diagnosis of tumor of the choledochus. It is also important to emphasize that EUS is the most suitable diagnostic method for determination of tumor invasion to choledochus, i.e. to determine TN patient status and to predict if tumor could be successfully resected. The author would like to present his own experience in using of EUS as a contemporary method for establishing a diagnosis and effective treatment of patients with tumor of choledochus. All patients were examined by Olympus equipment for endoscopic ultrasound with radial probe working with the frequency of 7,5 and 12 MHz at the Department for Endoscopic Ultrasound of the Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia. All examined patients were subjected to surgical exploration after that. Therefore it was possible to compare preoperative estimation of tumor invasion with a final result obtained by surgical exploration. Five patients were diagnosed with tumor of choledochus localized at the distal part of choledochus. TN status of examined patients was specified by standard criteria. Estimated TN status for two patients was defined as T2N1a and T2N0, which indicate the possibility of excessive surgical treatment, what was confirmed by surgical exploration as well. A small number of patients was not possible to use for statistical evaluation. Our conclusion is that EUS presents the most effective method to estimate a degree of tumor invasion to choledochus, since it provides an accurate definition of TN patient status and predicts if tumor could be successfully resected.

[The role of endosonography (EUS) in preoperative staging of patients with stomach cancer].

BACKGROUND: To evaluate the diagnostic accuracy of endosonography (EUS) in preoperative staging of stomach cancer. METHODS: Sixty-two patients with gastric carcinoma were investigated by endosonography. 49 underwent surgery. EUS reports were compared with operative and histology findings. Tumours were staged according to the 2000. TNM classification. RESULTS: EUS had a diagnostic accuracy of 89.8% for the T category, 83.7% for the N category. CONCLUSION: EUS is an excellent clinical procedure for the staging of local-regional spread of gastric cancer and useful complement to the other gastrointestinal examinations for evaluation of these tumours.

[Endoscopic ultrasound (EUS) in initial assessment and follow-up of patients with MALT lymphoma treated drug therapy].

BACKGROUND: Endoscopic ultrasonography (EUS) is an important tool for diagnosis and pretreatment staging of primary gastric lymphoma. The aim of the study was to evaluate the diagnostic importance of endosonography (EUS) in gastric lymphoma; to assess the depth of tumoral infiltration in low-grade gastric lymphoma of mucosa-associated lymphoid tissue (MALT) and to assess EUS response to medical treatment (Cyclophosphamid/Mabtera and/or anti-Helicobacter pylori therapy). METHODS: 26 patients with MALT gastric lymphoma were investigated by EUS. Six of them were evaluated after the eradication of Helicobacter pylori infection and 20 after and during the cyclophosphamide/Mabtera and anti H. pylori treatment. EUS staging was compared with histopathology. Tumours were staged according to the 2000 TNM and modified Ann Arbor classification. RESULTS: Six patients were treated with anti - Helicobacter pylori eradication therapy. Full regression of lymphoma was observed in 2 of 6 (33.3%) patients, which was endoscopicaly and histologicaly proved. EUS correlated with histology in all (6/6). In 20 patients treated with cyclophosphamide/Mabtera therapy, EUS revealed regression of lymphoma in 14 cases. Positive correlation with histology was found in 11 patients (11/14; 78%). The initial EUS showed an increased wall thickness more than 5mm in 24 of 26 patients (92%). The thickening was predominantly of mucosa and submucosa and in 11 patients extended the muscularis propria. After the therapy, the gastric wall thickening returned to normal in 14 patients, however, 3 of them still had positive histology findings. In 2 cases, during the follow-up, the EUS showed remained thickening of gastric wall, whereas biopsies were negative. Six months later histology revealed progressive low-grade MALT lymphoma in this cases. CONCLUSION: EUS appears to be a sensitive procedure for initial staging and assessment of treatment response and long-term follow up in patients with gastric lymphoma. The importance of EUS lies in abbility to detect relapse early, too.