High resolution spectral domain optical coherence tomography (SD-OCT) in multiple sclerosis: the first follow up study over two years

Background

“Non-invasive, faster and less expensive than MRI” and “the eye is a window to the brain” are recent slogans promoting optical coherence tomography (OCT) as a new surrogate marker in multiple sclerosis (MS). Indeed, OCT allows for the first time a non-invasive visualization of axons of the central nervous system (CNS). Reduction of retina nerve fibre layer (RNFL) thickness was suggested to correlate with disease activity and duration. However, several issues are unclear: Do a few million axons, which build up both optic nerves, really resemble billions of CNS neurons? Does global CNS damage really result in global RNFL reduction? And if so, does global RNFL reduction really exist in all MS patients, and follow a slowly but steadily ongoing pattern? How can these (hypothesized) subtle global RNFL changes be reliably measured and separated from the rather gross RNFL changes caused by optic neuritis? Before generally being accepted, this interpretation needs further critical and objective validation.

Methodology

We prospectively studied 37 MS patients with relapsing remitting (n = 27) and secondary progressive (n = 10) course on two occasions with a median interval of 22.4±0.5 months [range 19–27]. We used the high resolution spectral domain (SD-)OCT with the Spectralis 3.5 mm circle scan protocol with locked reference images and eye tracking mode. Patients with an attack of optic neuritis within 12 months prior to the onset of the study were excluded.

Principal Findings

Although the disease was highly active over the observation period in more than half of the included relapsing remitting MS patients (19 patients/32 relapses) and the initial RNFL pattern showed a broad range, from normal to markedly reduced thickness, no significant changes between baseline and follow-up examinations could be detected.

Conclusions

These results show that caution is required when using OCT for monitoring disease activity and global axonal injury in MS.     

The genetic basis of multiple sclerosis: a model for MS susceptibility

Background  

MS-pathogenesis is known to involve both multiple environmental events, and several independent genetic risk-factors.     

Assessing the effectiveness of rapamycin on angiomyolipoma in tuberous sclerosis: a two years trial

Background

Tuberous sclerosis (TS) is a rare autosomal dominant systemic disease with an estimated prevalence of 1/6000. Renal angiomyolipoma (AML) is a benign tumour with high morbidity frequently present in TS. The aim of the study was to test the effect of rapamycin in reducing the volume of AML in TS.

Methods

Twenty four-month prospective open-label, single arm, unicentre Phases II andIII study. The primary endpoint was to evaluate the effect of treatment on the reduction of at least 50% AML volume from baseline at 24 months. The secondary endpoints were: average tumour reduction, surgical complications, skin lesions and drug safety.The study population comprised 17 patients, aged >10 years who were diagnosed with TS and had ≥1 renal AML >2 cm of diameter and had a serum creatinine < 2mg/dl and urine protein/creatinine ratio < 22.6 mg/mmol. The trial was conducted at Fundació Puigvert. Rapamycin was given to achieve stable plasma levels between 4 and 8 ng/ml. AML volume was estimated using orthogonal measurements by MRI at baseline, 6, 12 and 24 months.

Results

Ten out of 17 patients were success responders for the main outcome ?58.8%, 95%CI: 32.9% to 81.6%-. After 6 months of therapy, the mean volume decrease was 55.18% (5.01 standard error (SE); p<0.001) and 66.38% (4.41 SE; p<0.001) at year 1. There was no significant decrease between year 1 and 2. According to RECIST criteria, all patients achieved a partial response at year 1 and all but two had already achieved this partial response after 6 months.The main analysis was performed according to the intention-to-treat principle analysis. Tumour volume was analyzed over time by means of mixed models for repeated measurement analysis. We used the baseline tumour volume as a covariate for the absolute change and percentage change from baseline data. The analysis was performed using SAS version 9.2 software, and the level of significance was established at 0.05 (two-sided).

Conclusions

This study show that mTOR inhibitors are a relatively safe, efficacious and less aggressive alternative than currently available options in the management of AML in TS.

Trial registration

EudraCT number: 2007-005978-30, ClinicalTrials.gov number: NCT0121712

     

Yeast population dynamics in spontaneous fermentations: Comparison between two different wine-producing areas over a period of three years

Yeast ecology, biogeography and biodiversity are important and interesting topics of research. The population dynamics of yeasts in several cellars of two Spanish wine-producing regions was analysed for three consecutive years (1996 to 1998). No yeast starter cultures had been used in these wineries which therefore provided an ideal winemaking environment to investigate the dynamics of grape-related indigenous yeast populations. Non-Saccharomyces yeast species were identified by RFLPs of their rDNA, while Saccharomyces species and strains were identified by RFLPs of their mtDNA. This study confirmed the findings of other reports that non-Saccharomyces species were limited to the early stages of fermentation whilst Saccharomyces dominated towards the end of the alcoholic fermentation. However, significant differences were found with previous studies, such as the survival of non-Saccharomyces species in stages with high alcohol content and a large variability of Saccharomyces strains (a total of 112, all of them identified as Saccharomyces cerevisiae) with no clear predominance of any strain throughout all the fermentation, probably related to the absence of killer phenotype and lack of previous inoculation with commercial strains.     

Impact of natalizumab on cognitive performances and fatigue in relapsing multiple sclerosis: a prospective, open-label, two years observational study

Background and Objectives

Natalizumab reduces the relapse rate and magnetic resonance imaging activity in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). So far the influence of natalizumab on cognitive functions and fatigue in MS remains uncertain. The aim of this prospective, open-label, observational study was to evaluate the possible effects of natalizumab on cognition and fatigue measures in RRMS patients treated for up to two years.

Methods

Cognitive performances were examined by the Rao''s Brief Repeatable Battery (BRB), the Stroop test (ST) and the Cognitive Impairment Index (CII), every 12 months. Patients who failed in at least 3 tests of the BRB and the ST were classified as cognitively impaired (CI). Fatigue Severity Scale (FSS) was administered every 12 months to assess patient''s self-reported fatigue. One hundred and 53 patients completed 1 and 2 year-natalizumab treatment, respectively.

Results

After 1 year of treatment the percentage of CI patients decreased from 29% (29/100) at baseline to 19% (19/100) (p = 0.031) and the mean baseline values of CII (13.52±6.85) and FSS (4.01±1.63) scores were significantly reduced (10.48±7.12, p<0.0001 and 3.61±1.56, p = 0.008). These significant effects were confirmed in the subgroup of patients treated up to two years.

Conclusions

These results demonstrate that a short-term NTZ treatment may significantly improve cognitive performances and fatigue in RRMS patients.     

Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis

Objective To quantify the association between stressful life events and exacerbations of multiple sclerosis.Data sources PubMed, PsychInfo, and Psychological Abstracts searched for empirical papers from 1965 to February 2003 with terms “stress”, “trauma”, and “multiple sclerosis”.Review methods Three investigators independently reviewed papers for inclusion/exclusion criteria and extracted the relevant data, including methods, sample statistics, and outcomes.Results Of 20 studies identified, 14 were included. The meta-analysis showed a significant increase in risk of exacerbation in multiple sclerosis after stressful life events, with a weighted average effect size of d = 0.53 (95% confidence interval 0.40 to 0.65), P < 0.0001. The studies were homogenous, Q = 16.62, P = 0.22, I² = 21.8%. Neither sampling nor study methods had any effect on study outcomes.Conclusions There is a consistent association between stressful life events and subsequent exacerbation in multiple sclerosis. However these data do not allow the linking of specific stressors to exacerbations nor should they be used to infer that patients are responsible for their exacerbations. Investigation of the psychological, neuroendocrine, and immune mediators of stressful life events on exacerbation may lead to new behavioural and pharmacological strategies targeting potential links between stress and exacerbation.     

Spatiotemporal fire occurrence in Borneo over a period of 10 years

South-east Asia's tropical rainforests are experiencing the highest rate of deforestation worldwide and fire is one of the most important drivers of forest loss and subsequent carbon dioxide emissions. In this study, we analyzed all fire events in Borneo recorded by satellites over a period of 10 years. About 16.2 Mha, which corresponds to 21% of the land surface, have been affected by fire at least once and 6% more than one time. During El Niño conditions, which cause prolonged droughts in the region, the fire-affected area was on average three times larger than during normal weather conditions. Similarly, fires in forests affected 0.3 Mha in normal years and 1 Mha during El Niño years. Carbon rich peat swamp forest ecosystems were most severely affected. There is a pronounced difference in fire occurrence between different countries and provinces in Borneo although ecosystem and land use are very similar across the island. Compared with Sarawak, Sabah (Malaysia) and Brunei the relative annual fire-affected area in Kalimantan, the Indonesian part of Borneo, was on average five times larger. During El Niño conditions the fire-affected area increased only in Kalimantan and not in Brunei and the Malaysia. A similar pattern was observed in National Parks. This suggests, that El Niño related droughts are not the only cause of increased fire occurrence and do not necessarily lead to a higher number of fire events. These results improve our understanding of existing fire regimes and drivers of fire in SE Asian tropical ecosystems and may help to better protect the remaining rainforests.     

Succession of bacterial community composition over two consecutive years in two aquatic systems: a natural lake and a lake-reservoir

The succession in bacterial community composition was studied over two years in the epilimnion and hypolimnion of two freshwater systems: a natural lake (Pavin Lake) and a lake-reservoir (Sep Reservoir). The bacterial community composition was determined by cloning-sequencing of 16S rRNA and by terminal restriction fragment length polymorphism. Despite large hydrogeological differences, in the Sep Reservoir and Pavin Lake the dominant bacteria were from the same taxonomic divisions, particularly Actinobacteria and Betaproteobacteria. In both ecosystems, these major bacterial divisions showed temporal fluctuations that were much less marked than those occurring at a finer phylogenetic scale. Nutrient availability and mortality factors, the nature of which differed from one lake to another, covaried with the temporal variations in the bacterial community composition at all sampling depths, whereas factors related to seasonal forces (temperature and outflow for Sep Reservoir) seemed to account only for the variation of the hypolimnion bacterial community composition. No seasonal reproducibility in temporal evolution of bacterial community from one year to the next was observed.     

Cognitive performance in relapsing remitting multiple sclerosis: A longitudinal study in daily practice using a brief computerized cognitive battery

Background  

There is need for a cognitive test battery that can be easily used in clinical practice to detect or monitor cognitive performance in patients with multiple sclerosis (MS). In order to conduct, in this patient group, a preliminary investigation of the validity and utility of a brief computerized battery, the Cognitive Drug Research (CDR) battery, we longitudinally assessed cognition in patients with relapsing remitting (RR) MS.     

Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis

Chronic progression of two T cell-mediated central nervous system (CNS) demyelinating models of multiple sclerosis, relapsing EAE (R-EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is dependent on the activation of T cells to endogenous myelin epitopes (epitope spreading). Using transfer of carboxyfluorescein succinyl ester (CFSE)-labeled T-cell receptor (TCR)-transgenic T cells and mixed bone marrow chimeras, we show that activation of naive proteolipid protein (PLP)139-151-specific T cells in SJL mice undergoing PLP178-191-induced R-EAE or TMEV-IDD occurs directly in the CNS and not in the cervical lymph nodes or other peripheral lymphoid organs. Examination of the antigen-presentation capacity of antigen-presenting cell (APC) populations purified from the CNS of mice with PLP178-191-induced R-EAE shows that only F4/80-CD11c+CD45hi dendritic cells (DCs) efficiently present endogenous antigen to activate naive PLP139-151-specific T cells in vitro. In contrast, DCs as well as F4/80+CD45hi macrophages and F4/80+CD45lo microglia activate a PLP139-151-specific helper T cell line. The data suggest that naive T cells enter the inflamed CNS and are activated by local APCs, possibly DCs, to initiate epitope spreading.     

Clinical and quality of life responses to high-dose chemotherapy plus autologous stem cell transplantation in patients with multiple sclerosis: two case reports

During the last several years high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) has been established as a therapeutic option for multiple sclerosis (MS) patients. We report on the long-term effects of HDCT + ASCT in two female patients affected by secondary progressive and relapsing-remitting types of MS, respectively. As a result, disease stabilization was achieved in the first case and disease improvement in the second one. Both patients were off immunosuppressive or immunomodulating therapy throughout the post-transplant period. Notably, HDCT + ASCT resulted in an excellent quality of life (QoL) response in both cases. Our findings demonstrate that HDCT + ASCT could be considered as an effective treatment for MS patients. Moreover, QoL measurement seems to be an effective approach to assessment of treatment outcomes at long-term follow-up of patients with MS.     

Sudden unexpected deaths and vaccinations during the first two years of life in Italy: a case series study

Background

The signal of an association between vaccination in the second year of life with a hexavalent vaccine and sudden unexpected deaths (SUD) in the two days following vaccination was reported in Germany in 2003. A study to establish whether the immunisation with hexavalent vaccines increased the short term risk of SUD in infants was conducted in Italy.

Methodology/Principal Findings

The reference population comprises around 3 million infants vaccinated in Italy in the study period 1999–2004 (1.5 million received hexavalent vaccines). Events of SUD in infants aged 1–23 months were identified through the death certificates. Vaccination history was retrieved from immunisation registries. Association between immunisation and death was assessed adopting a case series design focusing on the risk periods 0–1, 0–7, and 0–14 days after immunisation. Among the 604 infants who died of SUD, 244 (40%) had received at least one vaccination. Four deaths occurred within two days from vaccination with the hexavalent vaccines (RR = 1.5; 95% CI 0.6 to 4.2). The RRs for the risk periods 0–7 and 0–14 were 2.0 (95% CI 1.2 to 3.5) and 1.5 (95% CI 0.9 to 2.4). The increased risk was limited to the first dose (RR = 2.2; 95% CI 1.1 to 4.4), whereas no increase was observed for the second and third doses combined.

Conclusions

The RRs of SUD for any vaccines and any risk periods, even when greater than 1, were almost an order of magnitude lower than the estimates in Germany. The limited increase in RRs found in Italy appears confined to the first dose and may be partly explained by a residual uncontrolled confounding effect of age.     

Cerebrospinal fluid and serum prealbumin (transthyretin) in patients with multiple sclerosis (MS): Comparison of particular subgroups of MS patients

The levels of prealbumin (PAB, transthyretin) were determined and evaluated in the cerebrospinal fluid (CSF) and serum in various subgroups of the multiple sclerosis (MS) patients. In severely disabled patients, serum PAB was elevated more frequently. CSF and serum PAB concentrations were higher in treated than in nontreated patients; the values above the upper reference limits were also more frequently found in treated patients. PAB index showed a tendency to decrease during the course of the disease. The routine determination of PAB in CSF and serum is, therefore, recommended to be recognized in MS patients as a substantial clinical value and, thus, be comprised, including also immunoglobulins and other parameteres, into the spectrum of characteristics in Protein Pannel.     

Epidemiology of onychomycosis and paronychia in the area of ANCONA (ITALY) over a period of 5 years

We retrospectively evaluated the epidemiology of onychomycosis and/or paronychia in 172 patients attending the Clinic of Dermatology and Venereology over a 5 year period. Although yeast isolates, belonging to the Candida species, represented the most frequent etiologic agents of these infections, an increasing prevalence of fungal infections due to emerging fungal pathogens (EFP) was noted throughout this time period. In particular, EFP as causative agents of these infections increased from 0 to 28.4% from 1998 to 2002.     

Only a matter of time: the impact of daily and seasonal rhythms on phytochemicals

Phytochemistry Reviews - Plants regulate molecular bioactivity in response to daily and seasonal environmental fluctuations in temperature, light, humidity, and precipitation. These rhythms...     

Breastfeeding and its impact on daily life in women with type 1 diabetes during the first six months after childbirth: a prospective cohort study

Background

For mothers with diabetes, breastfeeding is a great challenge due to their struggle with potentially unstable blood glucose levels. This paper explores breastfeeding attitudes and impact of breastfeeding on the daily life of mothers with type 1 diabetes compared with non-diabetic mothers.

Methods

We performed a prospective cohort study of 108 mothers with type 1 diabetes and a reference group of 104 mothers in the west of Sweden. Data were collected through medical records and structured telephone interviews at 2 and 6 months after childbirth.

Results

Women in both the diabetes group and the reference group had high levels of confidence (84% and 93% respectively) in their breastfeeding capacity before childbirth, and 90% assessed breastfeeding as a positive and an important experience during the six months of follow-up. About 80% assessed breastfeeding as influencing daily life ‘very much’ or ‘quite a lot’ at 2 months as did 60% at 6 months, with no difference between the groups. In mothers with diabetes, the impact of breastfeeding on the priority of other duties decreased over time, as did feelings of time pressure and negative effects on patterns of sleep. Compared to the reference group, mothers with diabetes at 6 months remained more affected by disruptions in daily life and they felt more worried about their health both at 2 and 6 months after childbirth. For the reference group mothers’ sensitivity to unexpected disruptions in daily routines decreased between 2 and 6 months after childbirth, and they expressed a greater need to organize their time than mothers with diabetes.

Conclusion

Mothers with diabetes type 1 express more worry for own health and are more sensitive to distruptions. To balance their everyday life and to reduce the risk of stress and illhealth they are therefor, compared to other mothers, likely to need additional professional and peer support.