Validity and reliability of the behavioral signs of respiratory instability (BSRI) © scale during activity for infants with bronchopulmonary dysplasia.

OBJECTIVE: There is no reliable evidence on how best to evaluate the overall status of infants with severe forms of bronchopulmonary dysplasia (BPD). The Behavioral Signs of Respiratory Instability (BSRI) scale was developed as an objective measure of developmental capacity during occupational and physical therapy sessions. The purpose of this study was to determine the psychometric properties of the BSRI Scale. STUDY DESIGN: The BSRI and Respiratory Severity Score (RSS) were compared for 25 infants with BPD and 15 infants without BPD. A cross-sectional design was used to test inter-rater reliability among 10 NICU occupational and physical therapists. A prospective cohort design was used to evaluate validity. RESULTS: The BSRI demonstrated good to excellent inter-rater reliability (ρ = 0.47-0.91) and was strongly correlated with RSS (ρ = -0.77, p < 0.001; concurrent validity). CONCLUSION: The BSRI Scale has preliminary psychometric support. Standardized measures like the BSRI may provide accurate, objective data that can improve care planning within interdisciplinary teams that supports brain growth and potentially improves neurodevelopment.

Shortening the washout to 4 weeks when switching from natalizumab to fingolimod and risk of disease reactivation in multiple sclerosis.

BACKGROUND: There is limited evidence about the optimal length of washout when switching from natalizumab to fingolimod. OBJECTIVE: To study if a washout period of 4 weeks is associated with less disease activity compared to 8 weeks. METHODS: 25 patients with Relapsing Remitting Multiple Sclerosis were included in an open label, prospective study with a follow-up of 108 weeks. The primary endpoint (PE) was defined as "time to first relapse or MRI disease activity up to week 56". In addition, a recurrent event analysis (REA) was performed up to week 108. RESULTS: The PE was not met (HR 0.67, 95% CI [0.22,1.97], p = 0.462). Number of relapses before stopping natalizumab was positively associated with the hazard of relapse (HR 3.91, p = 0.0117, 95% CI [1.36, 11.28]). The REA showed a reduction of the hazard to develop a relapse by 77% (HR 0.23, 95% CI [0.08, 0.69], p = 0.00854) in favor of the cohort with 4 weeks washout. CONCLUSIONS: Our study suggests that switching from natalizumab to fingolimod with a shorter washout of 4 weeks might reduce the risk of disease reactivation after switching.

Tissue Distribution Dynamics of Human NK Cells Inferred from Peripheral Blood Depletion Kinetics after Sphingosine-1-Phosphate Receptor Blockade.

Human natural killer (NK) cell subsets differentially distribute throughout the organism. While CD56(dim) and CD56(bright) NK cell subsets similarly reside in the bone marrow (BM), the CD56(dim) population predominantly accumulates in non-lymphoid tissues and the CD56(bright) counterpart in lymphoid tissue (LT). The dynamics with which these NK cell subsets redistribute to tissues remains unexplored. Here, we studied individuals newly exposed to fingolimod, a drug that efficiently blocks sphingosine-1-phosphate (S1P)-directed lymphocyte - including NK cell - egress from tissue to blood. During an observation period of 6h peripheral blood depletion of CD56(bright) NK cells was observed 3 h after first dose of fingolimod, with 40-50% depletion after 6 h, while a decrease of the numbers of CD56(dim) NK cells did not reach the level of statistical significance. In vitro, CD56(bright) and CD56(dim) NK cells responded comparably to the BM-homing chemokine CXCL12, while CD56(bright) NK cells migrated more efficiently in gradients of the LT-homing chemokines CCL19 and CCL21. In conjuncture with these in vitro studies, the indirectly observed subset-specific depletion kinetics from blood are compatible with preferential and more rapid redistribution of CD56(bright) NK cells from blood to peripheral tissue such as LT and possibly also the inflamed central nervous system. These data shed light on an unexplored level at which access of NK cells to LT, and thus, for example antigen-presenting cells, is regulated.

Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development.

BACKGROUND: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis (MS) patients. NAbs evolve in up to 44% of treated patients, usually between 6-18 months on therapy. OBJECTIVES: To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution. METHODS: We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment in this prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2. RESULTS: We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b treatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers ≥ 1:2400 predicted NAb evolution with a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the BAb/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAb-negative samples, respectively, were also diminished compared to BAb/NAb-negative samples. CONCLUSIONS: BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its abrogation by anti-IFN-b antibodies.

Clinical immunology of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in multiple sclerosis.

The oral sphingosine 1-phosphate (S1P) receptor (S1PR) modulator fingolimod has been shown to be effective in the treatment of patients with relapsing multiple sclerosis (MS). The drug binds with high affinity to 4 of the 5 G-protein-coupled S1P receptors (S1P(1-5)). After binding, the receptors are internalized, degraded, and thus functionally antagonized by fingolimod. Under physiologic conditions, S1P(1) mediates the egress of lymphocytes from secondary lymphoid organs to the peripheral circulation. Functional antagonism of S1P(1) by fingolimod results in a reduction in peripheral lymphocyte counts by inhibiting egress of lymphocytes, including potentially encephalitogenic T cells and their naïve progenitors that would otherwise be present within the circulation. Despite the fingolimod-mediated reduction of lymphocyte counts, fingolimod-treated patients with MS have been shown to have few infections and related complications and were able to mount antigen-specific immune responses in vaccination studies.

Neurofilament heavy chain in CSF correlates with relapses and disability in multiple sclerosis.

OBJECTIVE: Neurodegeneration is now accepted as a pathologic hallmark of multiple sclerosis (MS). We sought to discover whether CSF levels of neurofilament heavy chain protein (NfH(SMI35)) correlate with disability, disease activity, or specific stages of MS. METHODS: An electrochemiluminescence immunoassay was used to retrospectively measure NfH(SMI35) in CSF of patients with clinically isolated syndrome (CIS) (n = 63), relapsing-remitting multiple sclerosis (RRMS) (n = 39), secondary progressive multiple sclerosis (SPMS) (n = 25), primary progressive multiple sclerosis (PPMS) (n = 23), or controls (n = 73). Cell count and CSF levels of immunoglobulin and albumin were also measured. RESULTS: CSF levels of NfH(SMI35) increased with age in controls (r(s) = 0.50, p < 0.0001) and CIS (r(s) = 0.50, p < 0.0001); this effect was less pronounced in RRMS (r(s) = 0.35, p = 0.027) and absent in SPMS/PPMS. After age correction, NfH(SMI35) levels were found to be higher in all disease stages compared to control. Relapses were associated with higher CSF NfH(SMI35) values compared with stable disease. NfH(SMI35) levels correlated with EDSS scores in patients with CIS and RRMS (r(s) = 0.33, p = 0.001), and during relapse (r(s) = 0.35, p = 0.01); the correlation was most prominent in RRMS during relapse (r(s) = 0.54, p = 0.01). This was not the case for any of the other CSF markers examined. CONCLUSIONS: Neuronal loss is a feature of aging, and the age-dependent increase of CSF NfH(SMI35) suggests that this loss accelerates over time. For MS, increased NfH(SMI35) levels reflect the superimposed presence of further neurodegenerative processes. Evaluation of NfH(SMI35) levels is likely to provide a useful surrogate for measuring the rate of neurodegeneration in MS. Furthermore, the dissociation of NfH(SMI35) levels with biomarkers of inflammation suggests that the mechanisms responsible for their production are at least partly independent.

Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis.

OBJECTIVE: FTY720 is a sphingosine 1-phosphate (S1P) receptor modulator that showed efficacy in phase II and III clinical trials in patients with multiple sclerosis (MS). FTY720 inhibits lymphocyte egress from secondary lymphoid organs into the peripheral circulation, thereby reducing the number of circulating naïve and central memory T cells, but not effector memory T cells in blood. Little is known to which of these memory T-cell subsets interleukin 17 (IL-17)-producing T cells (Th17 cells) belong, which are considered to be key mediators of inflammation in MS, and how they are affected by treatment with FTY720. In this study, we determined the phenotype and frequency of Th17 cells in blood of untreated, FTY720-treated, and interferon-beta (IFNbeta)-treated patients with MS and healthy donors. METHODS: In a prospective observational study, circulating T cells were phenotypically characterized and Th17 cells enumerated in T-cell subsets ex vivo. Production of IL-17 upon activation and expression of the Th17-specific transcription factor RORC2 was assessed in vitro. RESULTS: Th17 cells were found primarily within central memory T cells in all study populations. FTY720 treatment reduced blood central memory T cells, including RORC2+ and IL-17-producing T cells, by >90%. FTY720 did not per se affect IL-17 production when added to activated T cells in vitro. CONCLUSION: Phenotypic Th17 cells are defined by a central memory T-cell phenotype. FTY720 reduces these Th17 cells in blood. This is presumably because central memory T cells are retained by FTY720 in secondary lymphoid organs.

Retinal vessels in patients with multiple sclerosis: baseline diameter and response to flicker light stimulation.

BACKGROUND: Transparency of ocular media enables the precise quantitative analysis of vessels of retina, a neuronal tissue which can be affected by multiple sclerosis (MS). PATIENTS AND METHODS: Eyes with no history of optic neuritis (non-ON eyes) of 21 patients with MS were examined with Retinal Vessel Analyzer. Segments of vessels of 500 microm length were measured proximal and distal from the optic disc and compared to those of 21 age- and gender-matched controls. Baseline diameters and peak response to flicker light stimulation of retinal vessels were analyzed. RESULTS: MS eyes had thinner arterioles (p = 0.02) and thicker venules (p = 0.008) than controls: arterioles 111 +/- 14 microm (proximal), 99 +/- 11 microm (distal) in MS eyes and 121 +/- 15 and 107 +/- 9 in controls, respectively. Values for venules were 157 +/- 18 and 136 +/- 20 (MS); 147 +/- 15 and 119 +/- 20 (controls). Peak response was higher in MS eyes than in controls for arterioles (p = 0.007), but comparable for venules (p = 0.35). CONCLUSION: Narrower arterioles and wider venules might be a consequence of subclinical swelling of optic nerve axons in eyes with negative history of ON in MS patients.

Rigidity of retinal vessels in patients with multiple sclerosis.

PURPOSE: The aim of this study was to analyze pulse wave propagation in the ocular circulation by assessing the phase delay between retinal arterioles and venules and calculating the pulse delay between the retinal and choroidal circulations in MS patients and in control subjects. SUBJECTS AND METHODS: Twenty patients with multiple sclerosis (38.3 +/- 6.2 years) and twenty healthy subjects (37.4 +/- 15.2 years) were examined with the Retinal Vessel Analyzer. In addition, an average peripapillary RNFL (retinal nerve fiber layer) thickness was measured by means of ocular coherence tomography in MS patients. The phase delay between the arteriole and venule pulsations was assessed at three sites: in the close retinal vicinity of the disc, 1 - 2 disc diameters and 3 - 4 disc diameters away from the disc. Assuming that venules are counterphased to the choroidal circulation, a choroid-to-retina pulse delay was calculated. RESULTS: The choroid-to-retina pulse delay was 0.26 +/- 0.11, 0.27 +/- 0.13 and 0.34 +/- 0.15 sec in eyes with history of optic neuritis (ON-eyes); in eyes of MS patients without such a history (non-ON eyes) the corresponding values were 0.27 +/- 0.14, 0.29 +/- 0.11 and 0.30 +/- 0.15 sec, and in control eyes 0.32 +/- 0.19, 0.38 +/- 0.16 and 0.45 +/- 0.20 sec, respectively, at three sites centrifugal from the disc. The choroid-to-retina pulse delay was significantly longer in healthy control eyes than both in ON eyes (p = 0.012) and non-ON eyes of MS patients (p = 0.004). The interocular difference of the choroid-to-retina pulse delay and OCT RNFL thickness showed a significant correlation in MS patients (Pearson r = 0.54, p = 0.015; Spearman R = 0.66, p = 0.0016). CONCLUSION: Patients with multiple sclerosis seem to demonstrate an increased rigidity of the retinal vessels. The interocular difference in retinal vessel rigidity was significantly correlated with the interocular difference in RNFL thickness in MS patients.

Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is classically assumed to be a neurodegenerative disorder. Inflammation has been observed in CNS tissue in ALS patients. We investigated the expression and prognostic relevance of proinflammatory chemokines in ALS. METHODS: We analyzed nine chemokines, eotaxin, eotaxin-3, IL-8, IP-10, MCP-1, MCP-4, macrophage derived chemokine (MDC), macrophage inflammatory protein-1beta (MIP-1beta), and serum thymus and activation- regulated chemokine (TARC) in serum and cerebrospinal fluid (CSF) of 20 ALS- and 20 non-inflammatory neurological disease (NIND)-patients. RESULTS: MCP-1 and IL-8 levels in CSF in ALS were significantly higher than in NIND (1304 pg/ml vs. 1055 pg/ml, P = 0.013 and 22.7 pg/ml vs. 18.6 pg/ml, P = 0.035). The expression of MCP-1 and IL-8 were higher in CSF than in serum (P < 0.001). There was a trend towards higher MCP-1 CSF levels in ALS patients with shorter time between first symptoms and diagnosis (r = -0.407; P = 0.075). CONCLUSIONS: We confirmed previous findings of increased MCP-1 levels in CSF of ALS patients. Furthermore, increased levels of IL-8 in CSF suggest a stimulation of a proinflammatory cytokine cascade after microglia activation. We found a tendency for higher MCP-1 values in patients with a shorter diagnostic delay, who are known to have also a shorter survival. This may suggest an association of higher MCP-1 levels with rapidly progressing disease.

FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.

BACKGROUND: The oral immunomodulator FTY720 has shown efficacy in patients with relapsing multiple sclerosis (MS). FTY720 functionally antagonizes sphingosine 1-phosphate receptor-1 (S1P1) on T cells and consequently inhibits S1P/S1P1-dependent lymphocyte egress from secondary lymphoid organs. Little is known about the phenotype and function of T cells remaining in peripheral blood during long-term FTY720 treatment. METHODS: T cells from FTY720-treated, interferon-beta (IFNbeta)-treated and untreated patients with MS, and healthy donors (HD) were analyzed with respect to T cell subpopulation composition, proliferation, and cytokine production. RESULTS: In FTY720-treated patients (n = 16), peripheral blood CD4+ and CD8+ T cell counts were reduced by approximately 80% and 60% when compared to the other groups (IFN beta: n = 7; untreated: n = 5; HD: n = 10). This related to selective reduction of naive (CCR7+CD45RA+) and central memory (CCR7+CD45RA-) T cells (TCM), and resulted in a relative increase of peripheral effector memory (CCR7-CD45RA- [TEM] and CCR7-CD45RA+ [TEMRA]) T cells. The remaining blood T cell populations displayed a reduced potential to secrete IL-2 and to proliferate in vitro, but rapidly produced interferon-gamma upon reactivation, confirming a functional TEM/TEMRA phenotype. Neither FTY720 nor FTY720-P directly suppressed proliferation or cytokine production by T cells. CONCLUSION: Therapeutic dosing of FTY720 reduces naïve T cells and TCM, but not TEM, in blood, without affecting T cell function. This is presumably because naive T cells and TCM express the homing receptor CCR7, allowing recirculation to secondary lymphoid tissues on a regular basis and, thus, trapping of the cells by FTY720 in lymph nodes.

Pattern of macular thickness changes measured by ocular coherence tomography in patients with multiple sclerosis.

BACKGROUND: An analysis of the pattern of retinal thickness changes in macula in patients with multiple sclerosis (MS) was performed. PATIENTS AND METHODS: In fifteen patients with MS retinal thickness measurements in the central (fovea plus inner macular ring) and peripheral (outer ring) macula obtained by ocular coherence tomography (OCT-3 device) were compared to those of 15 age-matched healthy controls. RESULTS: Eyes of MS patients had on the average a thinner macula (241.8 +/- 20.6 micrometers) than control eyes (252.0 +/- 16.4, p value 0.038). Significant segmental differences occurred in the central macula (p = 0.013). Eight eyes with a positive history of optic neuritis (ON) had on average a thinner macula (226.8 +/- 14.0) than eyes of MS patients without a history of ON (non-ON eyes: 247.3 +/- 20.1, p value 0.01). The only measure significantly different between non-ON and control eyes was the ratio between the central and peripheral macular thickness (p = 0.017). Average macular thickness in non-ON eyes, unlike control eyes (r = - 0.63, p = 0.0002), did not correlate with age (r = 0.01, p = 0.97), however, it did show a borderline correlation with disease duration (r = - 0.41, p = 0.056). CONCLUSIONS: Preferential thinning in the central relative to the peripheral macular region is present in eyes of patients with MS. The macular thickness pattern is likely due to the histological distribution of nerve fibre layer and retinal ganglion cell in the macular area and seems to be particularly informative of neurodegeneration in the eyes of MS patients without a history of optic neuritis.