21 research outputs found
Serum Leptin Levels in Treatment-Naive Patients with Clinically Isolated Syndrome or Relapsing-Remitting Multiple Sclerosis
Several studies have investigated leptin levels in patients with multiple sclerosis (MS) with somewhat conflicting results. They have all focused on patients with established relapsing-remitting (RR) MS but have not specifically looked at patients with clinically isolated syndrome (CIS) suggestive of MS, in the early stages of disease. In this study, serum leptin levels were measured in 89 treatment-naïve patients with CIS (53 patients) or RRMS (36 patients) and 73 controls searching for differences between the groups and for associations with several disease parameters. The expected significant sexual dimorphism in leptin levels (higher levels in females) was observed in both MS patients and controls. Increased leptin levels were found in female patients with RRMS compared to female controls (P=.003) and female CIS patients (P=.001). Female CIS patients had comparable levels to controls. Leptin levels correlated positively to disease duration, but not to EDSS, in female patients with RRMS. The results of the present study do not indicate involvement of leptin in the early stages of MS. Normal leptin levels in patients with CIS suggest that leptin does not have a pathogenic role. The ratio leptin/BMI increases during disease course in female MS patients in a time-dependent and disability-independent manner
Genetic Variants of the <i>BAFF </i>Gene and Risk of Fatigue Among Patients With Primary Sjögren’s Syndrome
BACKGROUND/PURPOSE: Primary Sjögren’s Syndrome (SS) is characterized by B lymphocyte hyperactivity with B cell activating factor (BAFF) acting as an important regulator. Single Nucleotide Polymorphisms (SNPs) of the BAFF gene have been implicated in the pathogenesis of several autoimmune diseases characterized by heightened fatigue levels, including primary SS. We aimed to explore potential associations between BAFF SNPs and fatigue status of primary SS patients. METHODS: Fatigue status was assessed in 199 consecutive primary SS patients (Greek cohort) using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale. Clinical, histological, laboratory, psychometric and personality data were also collected. DNA extracted from peripheral blood of all patients underwent evaluation for the presence of five BAFF SNPs (rs9514827, rs1041569, rs9514828, rs1224141, rs12583006) by PCR. To confirm our findings, an independent replicative cohort of 62 primary SS patients (Dutch cohort) was implemented. Finally, 52 multiple sclerosis (MS) patients were served as disease controls (MS cohort). Analysis of BAFF SNPs in association with fatigue levels was performed by the online platforms SNPStats and SHEsis and the SPSS 26 and Graph Pad Prism 8.00 software. RESULTS: TT genotype of the rs9514828 BAFF polymorphism was significantly less frequent in the fatigued primary SS patients of the Greek cohort compared to the non-fatigued (14.1% vs 33.3%). The corresponding ORs [95%CI] in the dominant and overdominant models were 0.33 [0.15-0.72], p=0.003 and 0.42 [0.23-0.78], p=0.005 respectively. The association remained significant after adjustment for the variables contributing to fatigue in the univariate analysis (OR [95% CI]: 0.3 [0.1-0.9], p=0.026). Accordingly, in the Dutch cohort, there was a trend of lower mental fatigue among patients carrying the TT rs9514828 BAFF genotype compared to their CC counterparts (4.1 ± 2.4 vs 6.0 ± 2.2 respectively, p=0.06). The rs9514828 BAFF SNP was not significantly associated with fatigue in the MS cohort. CONCLUSIONS: We report a novel association between genetic makeup and primary SS-associated fatigue with the rs9514828 TT genotype decreasing the likelihood of fatigue development among these patients. These findings need validation in multi-center studies
Specific myeloid signatures in peripheral blood differentiate active and rare clinical phenotypes of multiple sclerosis
Current understanding of Multiple Sclerosis (MS) pathophysiology implicates perturbations in adaptive cellular immune responses, predominantly T cells, in Relapsing-Remitting forms (RRMS). Nevertheless, from a clinical perspective MS is a heterogeneous disease reflecting the heterogeneity of involved biological systems. This complexity requires advanced analysis tools at the single-cell level to discover biomarkers for better patient-group stratification. We designed a novel 44-parameter mass cytometry panel to interrogate predominantly the role of effector and regulatory subpopulations of peripheral blood myeloid subsets along with B and T-cells (excluding granulocytes) in MS, assessing three different patient cohorts: RRMS, PPMS (Primary Progressive) and Tumefactive MS patients (TMS) (n=10, 8, 14 respectively). We further subgrouped our cohort into inactive or active disease stages to capture the early underlying events in disease pathophysiology. Peripheral blood analysis showed that TMS cases belonged to the spectrum of RRMS, whereas PPMS cases displayed different features. In particular, TMS patients during a relapse stage were characterized by a specific subset of CD11c+CD14+ CD33+, CD192+, CD172+-myeloid cells with an alternative phenotype of monocyte-derived macrophages (high arginase-1, CD38, HLA-DR-low and endogenous TNF-a production). Moreover, TMS patients in relapse displayed a selective CD4 T-cell lymphopenia of cells with a Th2-like polarised phenotype. PPMS patients did not display substantial differences from healthy controls, apart from a trend toward higher expansion of NK cell subsets. Importantly, we found that myeloid cell populations are reshaped under effective disease-modifying therapy predominantly with glatiramer acetate and to a lesser extent with anti-CD20, suggesting that the identified cell signature represents a specific therapeutic target in TMS. The expanded myeloid signature in TMS patients was also confirmed by flow cytometry. Serum neurofilament light-chain levels confirmed the correlation of this myeloid cell signature with indices of axonal injury. More in-depth analysis of myeloid subsets revealed an increase of a subset of highly cytolytic and terminally differentiated NK cells in PPMS patients with leptomeningeal enhancement (active-PPMS), compared to those without (inactive-PPMS). We have identified previously uncharacterized subsets of circulating myeloid cells and shown them to correlate with distinct disease forms of MS as well as with specific disease states (relapse/remission)
Central Nervous System Demyelination in a Charcot-Marie-Tooth Type 1A Patient
Introduction. Central nervous system involvement, either clinical or subclinical, has been reported mainly in X-linked Charcot-Marie-Tooth (CMT-X) patients. Case Presentation. We present the case of a 31-year-old man with a genetically confirmed history of CMT1A who developed CNS involvement mimicking multiple sclerosis (MS). Clinical, imaging, and laboratory findings suggested an autoimmune CNS demyelination. Discussion. Although the simultaneous existence of CMT1A and MS could be coincidental we postulate that overexpression of PMP22, the target protein in CMT1A, might influence the immunological self-tolerance to CNS proteins via molecular mimicry, leading to a CNS autoimmune demyelinating disorder
Serum total cholesterol correlates positively to central serotonergic turnover in male but not in female subjects
Reduced central serotonergic activity and low total serum cholesterol
have been related to increased aggression, violent behavior, and
suicidality. Searching for a correlation between them, we estimated
serum total cholesterol and CSF levels of the main serotonin metabolite
5-HIAA in medication free male and female subjects for whom diagnostic
lumbar puncture was performed. To eliminate age influence, we included
in the study subjects in the age range 26 to 45 years. In a group of 62
subjects (30 males), found negative after diagnostic neurological
examination, the correlation was not significant for the whole group,
but after sex stratification, a significant positive correlation was
revealed for males but not for females. These results were replicated in
a second group of 76 subjects (31 males) with clinical and laboratory
findings suggestive of multiple sclerosis (clinically isolated
syndrome). The results link low cholesterol to low serotonergic activity
only in males, predisposing them for violent and risky behaviors. This
phenomenon could be seen as an evolutionary trait, possibly a result of
the distinct role of males in a hunter-gatherer environment of
evolutionary adaptedness, and may contribute to the understanding of the
higher incidence of violent behavior observed in males. (C) 2010
Elsevier Inc. All rights reserved
Neurochemical and neuroendocrine correlates of overactive bladder at first demyelinating episode
AimsBladder dysfunction is frequent during the course of multiple
sclerosis (MS), observed in up to 75% of patients. Urinary
symptomatology can be a feature of the first episode of MS in a minority
of cases, and most often shows characteristics of an overactive bladder
(OAB), with voiding symptoms seen less frequently, often in combination
with OAB. The neural control of micturition is complex, involving
systems located in the brain, spinal cord, and periphery, and
implicating central noradrenergic, serotonergic, and dopaminergic
activities. Urinary disorders are also linked to anxiety and depression,
conditions connected to hypothalamus-pituitary-adrenal axis activity. In
this study we aimed to investigate neurochemical and neuroendocrine
correlates of bladder dysfunction in early MS.
MethodsWe included 101 patients at first demyelinating episode
suggestive of MS that were drug-free at assessment. We evaluated the
presence of urinary symptomatology and estimated CSF levels of the main
metabolites of noradrenaline, serotonin, and dopamine, as well CSF-ACTH
and serum cortisol.
ResultsIn total, 15 patients (15%) reported urinary dysfunction
suggestive of OAB. Four of these had coexistent voiding symptomatology.
The serotonin metabolite 5-HIAA was significantly reduced (P=0.017) in
patients with OAB syndrome, while there were no differences in the
metabolites of noradrenaline (MHPG) and of dopamine (HVA). Additionally,
significantly lower serum cortisol (P=0.009) and borderline lower
CSF-ACTH (P=0.08) were found in patients with OAB.
ConclusionsMS patients with OAB syndrome at the first demyelinating
episode show reductions in central serotonergic activity and stress
hormones. Whether the same changes persist at later disease stages
remains to be investigated. Neurourol. Urodynam. 35:955-958, 2016. (c)
2015 Wiley Periodicals, Inc
Evidence for Involvement of Central Noradrenergic Activity in Crying Proneness
Crying as a response to emotionally-charged situations varies greatly
among individuals, genders, and cultures. Information on the neural
systems involved in crying behavior comes mainly from studies of
pathological laughing and crying in patients after brain injury. The
authors assessed crying proneness (CPR) as expressed by the score on the
“crying easily” item of the SCL-90 questionnaire in 65 men and 105
women subjects in whom lumbar puncture was performed for diagnostic
reasons. None of the subjects showed pathological laughing or crying.
The authors estimated the levels of the main metabolites of
noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA) in CSF, and
searched for associations to CPR score. Subjects with high CPR showed
significantly lower MHPG levels than subjects with low CPR, and no
differences in 5-HIAA or HVA levels. Higher frequencies of women were
found in the subgroups with high CPR. The “crying easily” score was
positively associated with the Interpersonal Sensitivity subscale of the
SCL-90 questionnaire in female but not in male subjects, indicating the
cultural dimension of crying behavior, while it was not associated with
the Depression subscale score. It is suggested that central
noradrenergic mechanisms control the threshold for tear production in
normal crying behavior. (The Journal of Neuropsychiatry and Clinical
Neurosciences 2011; 23:403-408
Methylprednisolone stimulated gene expression (GILZ, MCL-1) and basal cortisol levels in multiple sclerosis patients in relapse are associated with clinical response
Glucocorticoids (GCs) are the main treatment of relapse in multiple
sclerosis (MS). Decreased sensitivity to GCs in MS patients has been
associated with lack of the suppressive effect of GCs on inflammatory
molecules as well as increased resistance to apoptosis. We investigated
GC-sensitivity by measuring the effect of intravenous methylprednisolone
(IVMP) treatment on transactivation of anti-inflammatory and apoptotic
genes (GILZ, MCL-1 and NOXA respectively), in accordance to clinical
outcome. Thirty nine MS patients were studied: 15 with clinically
isolated syndrome (CIS), 12 with relapsing remitting (RRMS) and 12 with
secondary progressive (SPMS) under relapse. Patients underwent treatment
with IVMP for 5 days. Blood was drawn before IVMP treatment on day 1 and
1 h after IVMP treatment on days 1 and 5. GIlZ, MCL-1 and NOXA were
determined by qPCR. The Expanded Disability Status was evaluated and
patients were divided according to their clinical response to IVMP. GILZ
and MCL-1 gene expression were significantly higher following first IVMP
treatment in responders, compared to non-responders. Furthermore, serum
basal cortisol and 1,25-OH Vitamin D levels were significantly higher in
clinical-responders as compared to non-clinical responders. Our findings
suggest that the differential GILZ and MCL-1 gene expression between
clinical-responders and non-clinical responders may implicate the
importance of GILZ and MCL-1 as possible markers for predicting
glucocorticoid sensitivity and response to GC-therapy in MS patients
following first IVMP injection
New Strategies in Neurogenic Heterotopic Ossification
The term neurogenic heterotopic ossification (NHO) is used to describe
the pathological bone formation in soft tissues, due to spinal cord or
brain injury. Commonly is presented with pain and stiffness of the
affected joint. NHO affects the quality of life of these patients,
delays their rehabilitation and therefore increases morbidity. The aim
of this article is to emphasize pathophysiology mechanism and review new
molecular treatments of heterotopic ossification (HO). It was
demonstrated that potent treatment strategies are based on understanding
the molecular mechanisms and aiming to inhibit the pathological process
of the HO in various stages. New treatments are targeting several
factors such as bone morphogenetic proteins (BMPs), retinoic acid
receptors (RARs), hypoxic inhibitors (Hif1-inhibitors, rapamycin), free
radical scavengers and immunological agents (imatinib). The endogenous
pathways that lead to HO at molecular and cellular levels have been the
aim of many studies in recent years. New treatment options for HO should
be recommended due to the ineffectiveness of traditional older options,
such as anti-inflammatory drugs and radiation, especially in the case of
NHO