ObjectiveInaccessibility of the inflammation compartmentalized to the central nervous system (CNS) may underlie the lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS). The double blind combination of Rituximab by IntraVenous and IntraThecAl injection versus placebo in patients with Low‐Inflammatory SEcondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: (1) Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and (2) If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction?MethodsPatients aged 18–65 years were randomly assigned to rituximab or placebo. Protocol‐stipulated interim analysis quantified the efficacy of B‐cell depletion.ResultsThe efficacy on cerebrospinal fluid (CSF) biomarkers failed to reach criteria for continuation of the trial. B‐cell‐related CSF biomarkers (sCD21 and B‐cell activating factor) changed only in the active‐treatment arm. While CSF B cells were killed robustly (median −79.71%, P = 0.0176), B cells in CNS tissue were depleted inadequately (~−10–20%, P < 0.0001). Consequently, the T‐cell‐specific CSF biomarker sCD27 decreased slightly (−10.97%, P = 0.0005), while axonal damage marker, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement, and paucity of cytotoxic CD56dim NK cells contribute to decreased efficacy of rituximab in the CNS.InterpretationBiomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS, exposed causes for poor efficacy and determined that RIVITALISE trial would be underpowered to measure efficacy on clinical outcomes. Identified mechanisms for poor efficacy are applicable to all CNS‐inflammation targeting monoclonal antibodies.

After a four-week polarized light therapy 20 patients with stage I-III ulcer had significant improvement in pressure ulcer healing, so it could be useful to apply polarized light in the treatment of pressure ulcers.

BALB/c mice and Wistar rats immunized with sheep red blood cells and ovalbumin were treated intraperitoneally with different doses of methionine-enkephalin, leucine-enkephalin, and naloxone. Large doses of enkephalins (10-5 mg/kg b.w.) induced a significant decrease in hemolysin-forming cell response and production of hemagglutinating antibody. Immunosuppression induced by enkephalin was dose-dependent. In rats met-enkephalin was a more potent immunosuppressor than leu-enkephalin. Rats injected with 2.5 mg/kg b.w. of enkephalins into the lateral ventricle of the brain showed more pronounced immune suppression than did animals treated intraperitoneally with 5 mg/kg b.w. of enkephalins. These neuropeptides, and met-enkephalin in particular, exhibited a protective action against anaphylactic shock in rats sensitized to ovalbumin. In those animals, passive cutaneous anaphylaxis and elaboration of precipitating anti-ovalbumin antibody were considerably reduced. On the other hand, small doses of enkephalins stimulated humoral immune responses in the rat. Thus, it appears that enkephalins both suppress and potentiate immune responsiveness, depending on the dose used. As for naloxone, a large dose of this blocker of opioid receptors enhanced humoral immune reactions in the rat.

Magnetic fields (MF) can influence biological systems in a wide range of animal species and humans. We report here on the influence of static MF, locally applied to the brain area, on immune system performances in the rat. In the first series of experiments two AKMA micromagnets (M) with the influx density of 600 Gauss were bilaterally implanted (with "N" polarity facing the cranial bones) and fixed to the skull posterior to the fronto-parietal suture (parietal brain exposure). Rats implanted with iron beads (I) and sham-operated (SO) rats served as controls. Animals were exposed to MF or I during different periods of time before and after immunization with several soluble or cellular antigens. We report here on the in vivo immunoregulating effects of centrally applied MF on plaque-forming cell (PFC) response, local hypersensitivity skin reactions and experimental allergic encephalomyelitis. The selective influence of MF applied to different brain regions on PFC response was evaluated, as well. For this purpose, two M were bilaterally implanted in the area of (a) frontal, (b) parietal and (c) occipital brain regions. Rats were under the influence of MF for 20 days before and 4 days after immunization with sheep red blood cells. Groups of nonimmunized rats were exposed for 14, 24 and 34 days to parietally implanted M or I, and the number of peripheral blood CD4+ and CD8+ cells determined by mouse anti-rat W3/25 and MRC OX 8 monoclonal antibodies. The results show an overall in vivo immunopotentiation of humoral and cell-mediated immune responses in rats exposed to MF. Furthermore, these immunomodulating effects of centrally applied MF depend on at least two basic parameters, time of exposure and brain region exposed. The highest immune performance was obtained after exposure of the occipital brain region for a total period of 24 days. The results provide further evidence of the complex interrelationship between the environment, the central nervous system and the immune system.

Ignorance and prejudices are reasons why we do not perform our job.