Autoantigen Tetramer Silences Autoreactive B Cell Populations.

Many autoimmune therapies focus on immune suppression to reduce symptom severity and halt disease progression; however, currently approved treatments lack specificity for the autoantigen and rely on more global immune suppression. Multivalent antigen arrays can disarm pathogenic autoimmune B cell populations that specifically recognize the antigen of interest via their B cell receptor (BCR). Disarmament may be achieved by BCR engagement, cross-linking, and sustained receptor occupancy as a result of multivalent, high avidity BCR binding. To engage and explore this mechanism, a tetramer display of the encephalogenic proteolipid peptide (PLP139-151), referred to as 4-arm PLP139-151, was synthesized by copper-catalyzed azide-alkyne cycloaddition chemistry. Subcutaneous administration of 4-arm PLP139-151 completely ameliorated symptoms of paralysis in a mouse model of multiple sclerosis known as experimental autoimmune encephalomyelitis. Competitive binding of 4-arm PLP139-151 to PLP139-151-specific IgG in the mouse serum demonstrated the enhanced avidity associated with the multivalent array compared to the free peptide. Furthermore, key PLP139-151-reactive B cells were depleted following 4-arm PLP139-151 treatment, resulting in significant reduction of proinflammatory cytokines. Together, these data demonstrate the potential of 4-arm PLP139-151 to silence autoreactive B cell populations and limit the downstream activation of effector cells.

Sero-survey of polio antibodies and quality of acute flaccid paralysis surveillance in Chongqing, China: A cross-sectional study.

Serums were collected from people to assess whether polio immunity level was high enough to satisfy the polio vaccine immunization switch in Chongqing.People in 7 age groups (<1 year, 1-2 years, 3-4 years, 5-6 years, 7-14 years, 15-19 years, ≧20 years) were randomly selected in 3 areas by different geographical features in 2015. Peripheral venous blood samples were obtained and assays to detect poliovirus (PV) -neutralizing antibodies were performed. Acute flaccid paralysis (AFP) data was collected from 2012 to 2016 in Chongqing to evaluate the performance of AFP surveillance system by indicator analysis.A total of 636 people were tested for PV neutralization antibodies (NA). Overall NA seroprevalence for PV1, PV2 and PV3 were 93.40%, 96.38% and 91.82%, and geometric mean titers (GMTs) were 61.14, 66.78 and 21.47, respectively. GMTs and NA seroprevalence for PV1, PV2 and PV3 in older people were lower than young people. There were significant differences in seroprevalences of PV1 and PV3 among geographic areas (P < .05) in Chongqing.High seroprevalence for PV1, PV2, and PV3 and qualified capability for monitoring AFP cases showed that the polio eradication program has made positive achievements in Chongqing and established a stable base for a polio vaccine immunization switch. Nevertheless, GMTs were negatively associated with age in the geographic districts with poor economical features, which will increase the risk of emergence of vaccine-derived PV after polio vaccine switch. More than 1 dose of inactivated polio vaccine should be introduced into the polio vaccine schedule, and the supplementary immunization of polio should still be annually carried out after polio vaccine switch, especially among elder children and the adults.

Coronary artery bypass grafting is associated with immunoparalysis of monocytes and dendritic cells.

Coronary artery bypass grafting (CABG) triggers a systemic inflammatory response that may contribute to adverse outcomes. Dendritic cells (DC) and monocytes are immunoregulatory cells potentially affected by CABG, contributing to an altered immune state. This study investigated changes in DC and monocyte responses in CABG patients at 5 time-points: admission, peri-operative, ICU, day 3 and day 5. Whole blood from 49 CABG patients was used in an ex vivo whole blood culture model to prospectively assess DC and monocyte responses. Lipopolysaccharide (LPS) was added in parallel to model responses to an infectious complication. Co-stimulatory and adhesion molecule expression and intracellular mediator production was measured by flow cytometry. CABG modulated monocyte and DC responses. In addition, DC and monocytes were immunoparalysed, evidenced by failure of co-stimulatory and adhesion molecules (eg HLA-DR), and intracellular mediators (eg IL-6) to respond to LPS stimulation. DC and monocyte modulation was associated with prolonged ICU length of stay and post-operative atrial fibrillation. DC and monocyte cytokine production did not recover by day 5 post-surgery. This study provides evidence that CABG modulates DC and monocyte responses. Using an ex vivo model to assess immune competency of CABG patients may help identify biomarkers to predict adverse outcomes.

Time course and prognostic value of serum GFAP, pNFH, and S100ß concentrations in dogs with complete spinal cord injury because of intervertebral disc extrusion.

BACKGROUND: A noninvasive biomarker is needed to predict recovery from severe spinal cord injury (SCI) because of thoracolumbar intervertebral disc extrusion (TL-IVDE). Proteins released from neural and glial cells can be detected in the blood and show promise as prognostic tools, but their concentration is influenced by time after injury. HYPOTHESIS/OBJECTIVES: Serum concentrations of glial fibrillary acidic protein (GFAP), phosphorylated neurofilament heavy chain (pNFH), and S100ß will follow different time courses; measurement of combinations of these proteins will predict outcome. ANIMALS: Thirty-one dogs with TL-IVDE causing paralysis with no pain perception. METHODS: Prospective study. Serum samples were taken at presentation and intervals over 56 days and banked at -80°C. Glial fibrillary acidic protein, pNFH, and S100ß concentrations were measured using ELISA tests and plotted against time from onset of nonambulatory status. Outcome was established at 6 months. The association between biomarker concentration and outcome was examined using logistic regression, receiver operator characteristics curve analysis, and model development. RESULTS: Thirty-one dogs participated, 3/31 (10%) developed progressive myelomalacia and 19/31 (62%) recovered ambulation. Glial fibrillary acidic protein and S100ß concentrations rose for the first 1 to 3 days, and were undetectable by 14 and 28 days, respectively. Phosphorylated neurofilament heavy chain concentrations peaked at 14 days and were detectable at 56 days. Glial fibrillary acidic protein concentrations in the first 72 hours after onset of nonambulatory status predicted recovery with an accuracy of 76.7%-89% depending on sample timing. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum GFAP concentrations can be used to predict outcome in clinically complete SCI. A rapid inexpensive bedside test is needed.

An atypical presentation of high potassium renal secretion rate in a patient with thyrotoxic periodic paralysis: a case report.

BACKGROUND: Hypokalemia is one of the most common clinical electrolyte imbalance problems, and thyrotoxic periodic paralysis (TPP) is a leading cause of presentation to the emergency department. Low renal potassium secretion rates, a normal acid-base balance in the blood, and hyperthyroidism are the hallmarks of suspected TPP. CASE PRESENTATION: Here we report the case of a 36-year-old man who presented to the emergency department with a sudden onset of acute muscle weakness at 5 h prior to admission. Biochemistry tests revealed hypokalemia with hyperthyroidism and renal potassium wasting. TPP was initially not favored due to the presence of renal potassium wasting. However, his serum potassium level rebounded rapidly within several hours after potassium supplementation, indicating that the intracellular shifting of potassium ions was the main etiology for his hypokalemia. The early stage of TPP development may have contributed to this paradox. CONCLUSION: Therefore, it is premature to rule out TPP based on the presentation of high renal potassium secretion rates alone. This finding may result in an incorrect impression being made in the early stage of TTP and may consequently lead to an inappropriate potassium supplementation policy.

Bioactive extracellular compounds produced by the dinoflagellate Alexandrium minutum are highly detrimental for oysters.

Blooms of the dinoflagellate Alexandrium spp., known as producers of paralytic shellfish toxins (PSTs), are regularly detected on the French coastline. PSTs accumulate into harvested shellfish species, such as the Pacific oyster Crassostrea gigas, and can cause strong disorders to consumers at high doses. The impacts of Alexandrium minutum on C. gigas have often been attributed to its production of PSTs without testing separately the effects of the bioactive extracellular compounds (BECs) with allelopathic, hemolytic, cytotoxic or ichthyotoxic properties, which can also be produced by these algae. The BECs, still uncharacterized, are excreted within the environment thereby impacting not only phytoplankton, zooplankton but also marine invertebrates and fishes, without implicating any PST. The aim of this work was to compare the effects of three strains of A. minutum producing either only PSTs, only BECs, or both PSTs and BECs, on the oyster C. gigas. Behavioral and physiological responses of oysters exposed during 4 days were monitored and showed contrasted behavioral and physiological responses in oysters supposedly depending on produced bioactive substances. The non-PST extracellular-compound-producing strain primarily strongly modified valve-activity behavior of C. gigas and induced hemocyte mobilization within the gills, whereas the PST-producing strain caused inflammatory responses within the digestive gland and disrupted the daily biological rhythm of valve activity behavior. BECs may therefore have a significant harmful effect on the gills, which is one of the first organ in contact with the extracellular substances released in the water by A. minutum. Conversely, the PSTs impact the digestive gland, where they are released and mainly accumulated, after degradation of algal cells during digestion process of bivalves. This study provides a better understanding of the toxicity of A. minutum on oyster and highlights the significant role of BECs in this toxicity calling for further chemical characterization of these substances.

Diurnal blood pressure and urine production in acute spinal cord injury compared with controls.

STUDY DESIGN: This is a prospective observational study. OBJECTIVES: The objective of this study was to determine time-dependent changes in diurnal blood pressure (BP) and urine production in acute spinal cord injury (SCI). SETTING: This study was conducted in a specialist, state-based spinal cord service in Victoria, Australia. METHODS: Consenting patients admitted consecutively with acute SCI were compared with patients confined to bed rest while awaiting surgery and with mobilising able-bodied controls. Participants underwent ambulatory BP monitoring (ABPM), measurement of diurnal urine production and rated orthostatic symptoms over 1 year. Participants with night:day systolic BP (SBP) <90% were classified as dippers, 90-100% as non-dippers and >100% as reverse dippers. RESULTS: Participants comprised tetraplegics (n=47, 40.0±17.3 years), paraplegics (n=35, 34.4±13.9 years), immobilised (n=18, 30.9±11.3 years) and mobilising (n=44, 33.1±13.5 years) controls. At baseline, 24-h BP was significantly lower in tetraplegics (111.8±1.9/62.1±1.1 mm Hg) but not in paraplegics (116.7± 1.4/66.0±1.1 mm Hg), compared with controls (117.1 ±1.3/69.1±1.1 mm Hg), adjusting for gender. This difference was not observed at 1 year. The average night:day SBP in mobilising controls was 86.1±0.7%, differing from paraplegics (94.0±1.5%, P<0.001) and tetraplegics (101.5±1.5%, P<0.001). Urine production in tetraplegics and paraplegics did not fall at night compared with the day. Abnormal diurnal BP and orthostatic symptoms in tetraplegics persisted throughout the study. Nocturnal hypertension was observed in 27% (n=9) of tetraplegics, of whom only 2 had day hypertension. All mobilising controls with nocturnal hypertension (n=6, 14%) had day hypertension. CONCLUSION: People with SCI have a high prevalence of isolated nocturnal hypertension, reverse dipping, orthostatic intolerance and nocturnal polyuria. Cardiovascular risk management and assessment of orthostatic symptoms should include ABPM.

Exploratory study to suggest the possibility of MMP-8 and MMP-9 serum levels as early markers for remission after traumatic spinal cord injury.

STUDY DESIGN: A prospective observational study reporting the correlation between matrix metalloprotein serum levels and remission after traumatic spinal cord injury (SCI). OBJECTIVES: To investigate serum cytokine levels as predictive markers. SETTING: Germany, Rhineland-Palatinate (Rheinland-Pfalz). METHODS: Between 2010 and 2015, data sets from 115 patients (33 female, 82 male) after traumatic SCI were recorded at the BG Trauma Centre Ludwigshafen. We examined the serum levels of Matix metallopraoteinases (MMPs) MMP-2, MMP-8, MMP-9, MMP-10 and MMP-12 over a 12-week period, that is, at admission and 4, 9, 12 h, 1 and 3 days and 1, 2, 4, 8 and 12 weeks after trauma. Following the same match-pair procedure as in our previous studies, we selected 10 patients with SCI and neurological remission (Group 1) and 10 patients with an initial American Spinal Injury Association (ASIA) A grade and no neurological remission (Group 0). Ten patients with an isolated vertebral fracture without neurological deficits served as a control group (Group C). Our analysis was performed using a Luminex Performance Human High Sensitivity Cytokine Panel. Multivariate logistic regression models were used to examine the predictive value of MMPs with respect to neurological remission vs no neurological remission. RESULTS: MMP-8 and MMP-9 provided significantly different values. The favoured predictive model allows to differentiate between neurological remission and no neurological remission in 97% of cases. CONCLUSIONS: The results indicate that further studies with an enlarged collective are warranted in order to investigate current monitoring, prognostic and tracking techniques as well as scoring systems.

Lower Extremity Paralysis.

Severe hypokalemia in the absence of other electrolyte abnormalities, the result of diarrhea, caused striking electrocardiographic changes, generalized weakness, flaccid paralysis of the lower extremities, and biochemical evidence of mild skeletal and cardiac rhabdomyolysis in a 33-year-old man. Repletion of potassium reversed all abnormalities in 24 hours.

Sudden flaccid paralysis.

Periodic thyrotoxic paralysis is a genetic condition, rare in the West and in Caucasians. Thyrotoxicosis, especially in western hospitals, is an easily overlooked cause of sudden-onset paralysis. We present a case of a 40-year-old man who awoke one morning unable to stand. He had bilateral lower limb flaccid weakness of 0/5 with reduced reflexes and equivocal plantars; upper limbs were 3/5 with reduced tone and reflexes. ECG sinus rhythm was at a rate of 88/min. PR interval was decreased and QT interval increased. Bloods showed potassium of 1.8 mEq/L (normal range 3.5-5), free T4 of 29.2 pmol/L (normal range 6.5-17) and thyroid-stimulating hormone (TSH) of <0.01 mIU/L (normal range 0.35-4.94). Random urinary potassium was 8.8 mEq/L (normal range 12.5-62.5). The patient was admitted initially to intensive therapy unit and given intravenous potassium. His symptoms resolved within 24 h. He was diagnosed with thyrotoxic periodic paralysis. He was discharged on carbimazole and propanolol, and follow-up was arranged in the endocrinology clinic.

[Diagnostic value of determination of the blood concentrations of serotonin and high-sensitivity C-reactive protein in patients with tick-borne encephalitis].

The paper shows the informative value of changes in the serum levels of serotonin and high-sensitivity C-reactive protein in 44 patients in the acute period of tickborne encephalitis. Group 1 included 35 patients with non-paralytic neuroinfection; Group 2 comprised 9 patients with paralytic neuroinfection. The serum level of high-sensitivity C-reactive protein increased and that of serotonin decreased in relation to the form and severity of the disease at its height. The elevated level of the former and the low concentration of the latter may serve as an early predictor of the development of a severe paralytic form. Investigating their serum concentrations should be included into an examination plan for patients with acute tick-borne encephalitis.

Severe hypokalemic paralysis as a manifestation of a mitochondrial disorder.

Mitochondrial disorder (MtD) is usually a multisystem disease due to impaired mitochondrial energy production. Severe hypokalemia resulting in muscle weakness and rhabdomyolysis has not been reported as a phenotypic feature of MtD. Here we describe a 60-year-old male patient who developed myalgias followed by generalized muscle weakness a few days before admission. Symptoms were attributed to severe hypokalemia that occurred after the patient had discontinued spironolactone, a competitive antagonist of the aldosterone receptor, four months earlier on his own judgment. Spironolactone was given for 10 years to treat suspected primary hyperaldosteronism (Conn's syndrome). He presented with myopathic face, bilateral ptosis, hypertelorism, brachydactylia, weakness of the axial and limb muscles, and bilateral leg edema. Hypertelorism and brachydactylia are known as physical traits of MtD. Laboratory investigations revealed hypokalemia of 1.7 mmol/l and elevated serum levels of creatine kinase (2,772 U/l). Electrocardiogram showed sinus rhythm, left bundle-branch-block, repolarization abnormalities, and prolonged QTc (571 ms), which is associated with a propensity to ventricular arrhythmias. Diagnostic work-up revealed bilateral adenomas of the suprarenal glands. Conn's syndrome was regarded as a manifestation of MtD, since MtDs are frequently associated with endocrine abnormalities. The patient also presented with occasional double vision, ptosis, renal insufficiency, bilateral renal cysts, hypertriglyceridemia, arterial hypertension, and hypertrophic cardiomyopathy. Taken together, we have made the diagnosis of MtD. In conclusion, MtD may be associated with adrenal adenomas, which may cause severe symptomatic hypokalemia, manifesting as generalized weakness and myalgias due to rhabdomyolysis. Endocrine involvement may be a phenotypic feature of MtD.

Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation.

The amyloid-forming proteins tau, αB crystallin, and amyloid P protein are all found in lesions of multiple sclerosis (MS). Our previous work established that amyloidogenic peptides from the small heat shock protein αB crystallin (HspB5) and from amyloid ß fibrils, characteristic of Alzheimer's disease, were therapeutic in experimental autoimmune encephalomyelitis (EAE), reflecting aspects of the pathology of MS. To understand the molecular basis for the therapeutic effect, we showed a set of amyloidogenic peptides composed of six amino acids, including those from tau, amyloid ß A4, major prion protein (PrP), HspB5, amylin, serum amyloid P, and insulin B chain, to be anti-inflammatory and capable of reducing serological levels of interleukin-6 and attenuating paralysis in EAE. The chaperone function of the fibrils correlates with the therapeutic outcome. Fibrils composed of tau 623-628 precipitated 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, supporting the hypothesis that the fibrils are active biological agents. Amyloid fibrils thus may provide benefit in MS and other neuroinflammatory disorders.

[Comparative study on effects between electroacupuncture and acupuncture for spastic paralysis after stroke].

OBJECTIVE: To observe the differences of therapeutic effect of spastic paralysis after stroke between electroacupuncture and acupuncture and explore the mechanism. METHODS: Sixty-four cases were randomly divided into an electroacupuncture group (n = 33) and an acupuncture group (n = 31). Both groups were treated with Bobath facilitation techniques and medicine treatments. Quchi (LI 11), Hegu (LI 4), Yanglingquan (GB 34), Sanyinjiao (SP 6), et al. on the affected side were selected in each group. The needle was retained for 30 min, and the manipulation was applied for 1 min in the acupuncture group, and electroacupuncture was added in the electroacupuncture group. Stroke Impairment Assessment Set (SIAS) was adopted to assess the whole function status after sroke, and the contents of glutamate (Glu) and gamma-aminobutyric acid (GABA) in serum and clinical efficacy were observed in the two groups. RESULTS: The SIAS score increased after treatment as compared with that before treatment in either group (both P < 0.01), and the electroacupuncture group was superior to the acupuncture group (P < 0.01); the content of Glu in blood serum and ratio of Glu/GABA reduced, while the content of GABA in serum increased after treatment as compared with those before treatment in either group (all P < 0.01), but the improvement of above indices were much more apparently in the electroacupuncture group as compared with those in the acupuncture group (P < 0.01, P < 0.05); the total effective rate of 90.9% (30/33) in the electroacupuncture group was superior to that of 83.9% (26/31) in the acupuncture group (P < 0.05). CONCLUSION: Electroacupuncture can improve therapeutic effect of spastic paralysis after stroke, it's mechanism may be ralated to ajusting the contents of Glu and GABA in serum.

Focal hypokalemic paralysis: report of 2 cases and review of the literature.

Hypokalemia is one of the most frequent electrolytic disturbances encountered in clinical practice. It usually presents with symmetrical generalized muscle weakness and, on occasions, with arrhythmias. There are scarce reports of cases presenting with asymmetric or focal weakness in the literature and no systematic reviews on the subject. Therefore, our aim is to describe 2 cases of hypokalemic paralysis that presented as monoparesis and to review the literature on focal hypokalemic paralysis. Hypokalemic paralysis is usually reversible. However, it can be fatal if the diagnosis and treatment are delayed. It is important to take into account this presentation because failure to recognize it could lead to misdiagnosis, delaying the adequate treatment.

Levels of arsenic, cadmium, lead, manganese and zinc in biological samples of paralysed steel mill workers with related to controls.

The determination of essential trace and toxic elements in the biological samples of human beings is an important clinical screening procedure. This study aimed to assess the possible effects of environmental exposure on paralysed male workers (n = 75) belonging to the production and quality control departments of a steel mill. In this investigation, the concentrations of arsenic, cadmium, lead, manganese and zinc were determined in biological samples (blood, urine and scalp hair samples) of exposed paralysis and non-paralysed steel mill workers. For comparative purposes, unexposed healthy subjects of same age group were selected as referents. The elements in the biological samples were measured by atomic absorption spectrophotometry prior to microwave-assisted acid digestion. The validity of the methodology was checked by the biological certified reference materials. The results indicate that the level understudy elements in all three biological samples were significantly higher in paralysed workers of both groups (quality control and production) as compared to referents (p < 0.01). The possible connection of these elements with the aetiology of disease is discussed. The results also show the need for immediate improvements of workplace ventilation and industrial hygiene practices.

[Cold pathology and experimental therapy of deep hypothermia].

A complete cold paralysis of respiration and thermoregulation occurs in rats at the temperature in the brain 16.6 +/- 0.3 and in the rectum 15.2 +/- 0.3 degrees C. Under the conditions of room temperature 18-19 degrees C, the respiration never restores, and the animals die. This is believed [6] to be the result of calcium ion Ca2+ accumulation in the cells of respiration and thermoregulation centers. After the arrest of respiration the animals were injected with the solution of disodium salt of ethylenediaminetetraacetic acid (Na2EDTA), which binds calcium ions in the blood and facilitates their removal from the cell (explanations in the text). In 7-9 min after the injection the calcium content in the blood decreased and the respiration began to restore at the temperature of the cold paralysis. Thermoregulation was also restored. All the test animals survived. All the control animals, which were not injected with Na2EDTA, died.