An imbalance between remyelinating and demyelinating rates underlies degenerative processes in demyelinating diseases such as multiple sclerosis. An optimal therapeutic strategy would be to stimulate ...remyelination while limiting demyelination. Although accumulation of myelin debris impairs remyelination, the mechanisms regulating the clearance of such debris by mononuclear phagocytic cells are poorly understood. We demonstrate that after cuprizone intoxication, CCR2-dependent infiltration of mouse bone marrow-derived cells is abundant in demyelinating areas, but that these cells do not impact demyelination. However, in CX3CR1-deficient mice, the clearance of myelin debris by microglia was blocked greatly, affecting the integrity of the axon and myelin sheaths and thus preventing proper remyelination. These results highlight the crucial role played by CX3CR1 in myelin removal and show that there can be no efficient remyelination after a primary demyelinating insult if myelin clearance by microglia is impaired.
ABSTRACT
The recent characterization of human homologues of Toll may be the missing link for the transduction events leading to NF‐κB activity and proinflammatory gene transcription during innate ...immune response. Indeed, CD14 is not thought to participate directly in the cell signaling, but rather one or more of the mammalian Toll‐like receptors (TLRs) acts in concert with the lipopolysaccharide (LPS) receptor to discriminate between microbial pathogens or their products and initiate transmembrane signaling. Mammalian cells may express as many as 10 distinct TLRs, although the importance of TLR4 in response to gramnegative bacteria and LPS is now supported by the fact that TLR4‐mutated mice are LPS resistant. We investigated the expression of TLR4 across the rat brain under basal conditions and in response to systemic LPS and IL‐1ß injection. We first cloned the rat TLR4 cDNA via RNA isolation and polymerase chain reaction (PCR) amplification with a proofreading polymerase. Total RNA was isolated from the rat liver tissue using Tri‐Reagent and reverse transcribed into cDNA using Superscript II reverse transcriptase and an oligonucleotide primer with a degenerate 3' end of sequence 5'‐T12(GAC)N‐3'. Positive hybridization signal was found in the leptomeninges, choroid plexus (chp), subfornical organ, organum vasculosum of the lamina terminalis, median eminence, and area postrema. Scattered small cells also displayed a convincing hybridization signal within the brain parenchyma. Few well‐defined nuclei exhibited positive TLR4 transcript: the supramamillary nucleus, cochlear nucleus, and the lateral reticular nucleus. The circumventricular organs, the leptomeninges, and chp also exhibited constitutive expression of the LPS receptor mCD14. In contrast to the strong up‐regulation of the gene encoding mCD14 during endotoxemia, neither LPS nor IL‐1β caused a convincing increase in the TLR4 mRNA levels across the CNS. A down‐regulation of the gene encoding TLR4 was found in the cerebral tissue of immune‐challenged animals. The constitutive expression of both mCD14 and TLR4 may explain the innate immune response in the brain, which originates from the structures devoid of blood‐brain barrier in presence of circulating LPS.—Laflamme, N., Rivest, S. Toll‐like receptor 4: the missing link of the cerebral innate immune response triggered by circulating gram‐negative bacterial cell wall components. FASEB J. 15, 155–163 (2001)
Statin-associated muscle symptoms (SAMS) are frequently reported. Nevertheless, few data on objective measures of muscle function are available. Recent data suggesting an important nocebo effect with ...statin use could confound such effects. The objective was to assess if subjective and objective measures of muscle function improve after drug withdrawal in SAMS reporters.
Patients (59 men, 33 women, 50.3±9.6 yrs.) in primary cardiovascular prevention composed three cohorts: statin users with (SAMS, n = 61) or without symptoms (No SAMS, n = 15), and controls (n = 16) (registered at clinicaltrials.gov, NCT01493648). Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (Fhg) were measured using isokinetic and handheld dynamometers, respectively. A 10-point visual analogue scale (VAS) was used to self-assess SAMS intensity. Measures were taken before and after two months of withdrawal.
Following withdrawal, repeated-measures analyses show improvements for the entire cohort in Eext, Efle, Ffle, Pext and Pfle (range +7.2 to +13.3%, all p≤0.02). Post-hoc analyses show these changes to occur notably in SAMS (+8.8 to +16.6%), concurrent with a decrease in subjective perception of effects in SAMS (VAS, from 5.09 to 1.85). Fhg was also improved in SAMS (+4.0 to +6.2%) when compared to No SAMS (-1.7 to -4.2%) (all p = 0.02).
Whether suffering from "true" SAMS or nocebo, those who reported SAMS had modest but relevant improvements in muscle function concurrent with a decrease in subjective symptoms intensity after drug withdrawal. Greater attention by clinicians to muscle function in frail statin users appears warranted.
This study is registered in clinicaltrials.gov (NCT01493648).
A pathological hallmark of multiple sclerosis (MS) is myelin loss in brain white matter accompanied by compromised remyelination. Demyelinated lesions are deeply associated with oligodendrocyte ...apoptosis and a robust inflammatory response. Although various studies point towards a noxious role of inflammation in MS, others emphasize a positive role for the innate immune cells in disease progression. A cytokine well-known to stimulate cell survival, proliferation and differentiation of myeloid cells, macrophage colony-stimulating factor (mCSF), was administered to mice during a 5 week-long cuprizone diet. Treated mice exhibited reduced myelin loss during the demyelination phase, together with an increased number of microglia and oligodendrocyte precursor cells in lesion sites. Tamoxifen-induced conditional deletion of the mCSF receptor in microglia from cuprizone-fed mice caused aberrant myelin debris accumulation in the corpus callosum and reduced microglial phagocytic response. mCSF therefore plays a key role in stimulating myelin clearance by the brain innate immune cells, which is a prerequisite for proper remyelination and myelin repair processes.
Nemaline myopathy is a rare disorder affecting the muscle sarcomere. Mutations in nebulin gene (
NEB
) are known to be responsible for about 50% of nemaline myopathy cases. Nebulin is a giant protein ...which is formed integrally with the sarcomeric thin filament. This complex gene is under extensive alternative splicing giving rise to multiple isoforms. In this study, we report a 6-year-old boy presenting with general muscular weaknesses. Identification of rod-shaped structures in the patient' biopsy raised doubt about the presence of a nemaline myopathy. Next-generation sequencing was used to identify a causative mutation for the patient syndrome. A homozygous deep intronic substitution was found in the intron 144 of the
NEB
. The variant was predicted by
in silico
tools to create a new donor splice site. Molecular analysis has shown that the mutation could alter splicing events of the nebulin gene leading to a significant decrease of isoforms level. This change in the expression level of nebulin could give rise to functional consequences in the sarcomere. These results are consistent with the phenotypes observed in the patient. Such a discovery of variants in this gene will allow a better understanding of the involvement of nebulin in neuromuscular diseases and help find new treatments for the nemaline myopathy.
We evaluated whether cumulative exposure to job strain increases blood pressure.
A prospective study of 8395 white-collar workers was initiated during 1991 to 1993. At follow-up, 7.5 years later, 84% ...of the participants were reassessed to estimate cumulative exposure to job strain.
Compared with men who had never been exposed, men with cumulative exposure and those who became exposed during follow-up showed significant systolic blood pressure increments of 1.8 mm Hg (95% confidence interval CI=0.1, 3.5) and 1.5 mm Hg (95% CI=0.2, 2.8), respectively, and relative risks of blood pressure increases in the highest quintile group of 1.33 (95% CI = 1.01, 1.76) and 1.40 (95% CI = 1.14, 1.73). Effect magnitudes were smaller among women. Effects tended to be more pronounced among men and women with low levels of social support at work.
Among these white-collar workers, exposure to cumulative job strain had a modest but significant effect on systolic blood pressure among men. The risk was of comparable magnitude to that observed for age and sedentary behavior. Men and women with low levels of social support at work appeared to be at higher risk for increases in blood pressure.
Abstract Background and aims FIT's value has been ascertained across Canada and worldwide, but still needs to be assessed within the province of Quebec. There also remains a gap between formal ...indications for FIT, and its actual use in clinical practice. This research aims to evaluate some aspects of FIT's effectiveness in our setting, and its application by prescribers. Methods We retrospectively identified and reviewed all the colonoscopies conducted for a positive FIT in 2014 at 2 hospitals located in Quebec City. Results Five hundred and fifty-nine (559) colonoscopies were reviewed. We obtained PPVs of 6.8% and 46.9% for the detection of CRC and AA, respectively. The PPV for the detection of SCL was higher in men compared to women (OR 1.56, 95%CI 1.11–2.20) and among justified FITs compared to unwarranted ones (OR 1.88, 95%CI 1.34–2.63). The PPV for CRC detection was 25.0% in the presence of unexplained iron deficiency anemia and 6.5% when anemia was absent (p = 0.0058). In 49.9% of cases, the prescription of a FIT was inappropriate. Conclusion The FIT holds a better PPV for detecting SCL among men and when it is indicated. Anemia is associated with a higher CRC detection rate. Half of the FITs were not initially indicated.
OBJECTIVE: To investigate the presence of cysteine-rich secretory protein 1 (CRISP1) in seminal plasma as a means of distinguishing between obstructive azoospermia (OA) and nonobstructive azoospermia ...(NOA). DESIGN: Seminal plasma from normospermic donors (n = 45) and azoospermic donors (n = 80) was examined to determine CRISP1 levels. Neutral alpha-glucosidase (NAG) enzymatic activity was measured for comparison with CRISP1 levels. SETTING: Research unit of an academic medical center. PATIENT(S): Normospermic and azoospermic donors from the clinical andrology laboratory of the centre hospitalier universitaire de Québec and from Mount Sinai Hospital. INTERVENTION(S): Seminal CRISP1 measurement by Western blot analysis. Neutral alpha-glucosidase activity was evaluated by a photometric method. MAIN OUTCOME MEASURE(S): Seminal plasma CRISP1 levels, NAG activity, cutoff value, sensitivity, and specificity. RESULT(S): All seminal plasma samples from normospermic and nonobstructive azoospermic donors were CRISP1 positive, whereas CRISP1 was absent or present at low levels in samples from patients with OA. A significant correlation between seminal CRISP1 levels and NAG activity was found in azoospermic semen samples. The cutoff point to distinguish between donors with NOA or OA was established at 0.655 (relative intensity). At this threshold, specificity was 85% and sensitivity was 92%. CONCLUSION(S): Seminal CRISP1 combined with NAG activity can potentially distinguish between OA and NOA.
Pyridoxine‐dependent epilepsy (PDE) is a relatively rare subgroup of epileptic disorders. They generally present in infancy as an early onset epileptic encephalopathy or seizures, refractory to ...standard treatments, with rapid and variable responses to vitamin B6 treatment. Whole exome sequencing of three unrelated families identified homozygous pathogenic mutation c.370_373del, p.Asp124fs in PLPBP gene in five persons. Haplotype analysis showed a single shared profile for the affected persons and their parents, leading to a hypothesis about founder effect of the mutation in Saguenay‐Lac‐St‐Jean region of French Canadians. All affected probands also shared one single mitochondrial haplotype T2b3 and two rare variations in the mitochondrial genome m.801A>G and m.5166A>G suggesting that a single individual female introduced PLPBP mutation c.370_373del, p.Asp124fs in Quebec. The mutation p.Asp124fs causes a severe disease phenotype with delayed myelination and cortical/subcortical brain atrophy. The most noteworthy radiological finding in this Quebec founder mutation is the presence of the temporal cysts that can be used as a marker of the disease. Also, both patients, who are alive, had a history of prenatal supplements taken by their mothers as antiemetic medication with high doses of pyridoxine. In the context of suspected PDE in patients with neonatal refractory seizures, treatment with pyridoxine and/or Pyridoxal‐5‐phophate has to be started immediately and continued until the results of genetic analysis received. Even with early appropriate treatment, neurological outcome of our patient is still poor.
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