SM03, an Anti-CD22 Antibody, Converts Cis-to-Trans Ligand Binding of CD22 against α2,6-Linked Sialic Acid Glycans and Immunomodulates Systemic Autoimmune Diseases.

SM03, an anti-CD22 recombinant IgG1 mAb, is currently in a phase III clinical trial for the treatment of rheumatoid arthritis (NCT04312815). SM03 showed good safety and efficacy in phase I systemic lupus erythematosus and phase II moderate to severe rheumatoid arthritis clinical trials. We propose the success of SM03 as a therapeutic to systemic autoimmune diseases is through the utilization of a novel mechanism of action unique to SM03. CD22, an inhibitory coreceptor of the BCR, is a potential immunotherapeutic target against autoimmune diseases. SM03 could disturb the CD22 homomultimeric configuration through disrupting cis binding to α2,6-linked sialic acids, induce rapid internalization of CD22 from the cell surface of human B cells, and facilitate trans binding between CD22 to human autologous cells. This in turn increased the activity of the downstream immunomodulatory molecule Src homology region 2 domain-containing phosphatase 1 (SHP-1) and decreased BCR-induced NF-κB activation in human B cells and B cell proliferation. This mechanism of action gives rationale to support the significant amelioration of disease and good safety profile in clinical trials, as by enabling the "self" recognition mechanism of CD22 via trans binding to α2,6 sialic acid ligands on autologous cells, SM03 specifically restores immune tolerance of B cells to host tissues without affecting the normal B cell immune response to pathogens.

Association between metabolic syndrome and gingival inflammation in obese children.

BACKGROUND AND OBJECTIVE: Our previous work showed a positive association between metabolic syndrome (MetS) and gingival crevicular fluid (GCF) tumour necrosis factor-alpha (TNF-α) in a sample of obese and non-obese children. However, whether this association persists among obese children is unknown. We aim to investigate the extent to which MetS is associated with GCF TNF-α level among obese children. METHODOLOGY: We performed a cross-sectional analysis using data from visit 1 of the QUebec Adipose and Lifestyle InvesTigation in Youth cohort. A total of 219 obese children aged 8-10 years, for whom data were available for both MetS and TNF-α, were included in our analysis. The independent variable, MetS, was defined according to the International Diabetes Federation recommendations. GCF samples were collected from the gingival sulcus using a paper strip, and the concentration of TNF-α was determined by enzyme-linked immunosorbent assay. Analyses included descriptive statistics and sex-specific linear regression analyses adjusting for potential confounders. RESULTS: In this sample comprising only obese children, 24 (10.9%) had MetS. Among obese boys, those with MetS had 44.9% higher GCF TNF-α (95% confidence interval: 16.5%-73.3%) compared to those without MetS. No such association was detected in obese girls. CONCLUSION: MetS was positively associated with GCF TNF-α concentration in obese boys. These results suggest that obese boys with MetS may have a worse gingival health profile compared to their obese counterpart without MetS.

A network meta-analysis of the clinical properties of various types of supraglottic airway device in children.

We conducted both conventional pairwise and Bayesian network meta-analyses to compare the clinical properties of supraglottic airway devices in children. We searched six databases for randomised clinical trials. Our primary end-points were oropharyngeal leak pressure, risk of insertion failure at first attempt, and blood staining risk. The risk of device failure, defined as the abandonment of the supraglottic airway device and replacement with a tracheal tube or another device, was also analysed. Sixty-five randomised clinical trials with 5823 participants were identified, involving 16 types of supraglottic airway device. Network meta-analysis showed that the i-gel™, Cobra perilaryngeal airway™ and Proseal laryngeal mask airway (LMA® -Proseal) showed statistically significant differences in oropharyngeal leak pressure compared with the LMA® -Classic, with mean differences (95% credible interval, CrI) of 3.6 (1.9-5.8), 4.6 (1.7-7.6) and 3.4 (2.0-4.8) cmH2 O, respectively. The i-gel was the only device that significantly reduced the risk of blood staining of the device compared with the LMA-Classic, with an odds ratio (95%CrI) of 0.46 (0.22-0.90). The risk (95%CI) of device failure with the LMA-Classic, LMA® -Unique and LMA-Proseal was 0.36% (0.14-0.92%), 0.49% (0.13-1.8%) and 0.50% (0.23-1.1%), respectively, whereas the risk (95%CI) of the i-gel and PRO-Breathe was higher, at 3.4% (2.5-4.7%) and 6.0% (2.8-12.5%), respectively. The risk, expressed as odds ratio (95%CrI), of insertion failure at first attempt, was higher in patients weighing < 10 kg at 5.1 (1.6-20.1). We conclude that the LMA-Proseal may be the best supraglottic airway device for children as it has a high oropharyngeal leak pressure and a low risk of insertion. Although the i-gel has a high oropharyngeal leak pressure and low risk of blood staining of the device, the risk of device failure should be evaluated before its routine use can be recommended.

[The use of aluminum and its compounds for the biomedical purposes].

Taking into consideration the nanodimension of functional components of living cells, the application of nanotechnology in the biomedical purposes is currently an urgent task. One of these directions is the use of aluminum nanoparticles for molecular diagnostics, targeted delivery of drugs, the development of new pharmaceuticals. The action of aluminum chloride on the regulatory mechanisms of smooth and skeletal muscle contraction and also the effect of aluminum ions on the ATPase activity and superprecipitation of actomyosin of different types of muscles is discussed.

[Effect of C60 fullerene on viscoelastic properties of human erythrocytes membrane].

The effect of C60 fullerene aqueous colloid solution (C60FAS) on viscoelastic properties of human erythrocytes membrane has been studied. It was established that the effect of C60FAS on erythrocytes depends on the medium osmolality and concentration of C60 fullerene in it. In particular, in isotonic solution (0,15 mol/l NaCl) adding C60 fullerene in concentrations from 0,7 to 28 µmol/l did not cause the hemolytic damage of cells. In hypotonic medium when introducing C60 fullerene (7 µmol/l concentration) at the beginning of erythrocyte hemolysis its stimulating effect was maximal and when adding C60FAS in 20 s after hemolysis start no this process stimulation is observed. This points to the changes in viscoelastic properties of erythrocyte membranes even during the first seconds of its interaction with C60 fullerene.

[Perspectives of application of allogeneic multipotent mesenchymal stem cells for the adipose transplant protection from tissue resorption].

The detection of possibility differentiation towards adipogenic trend of the cells, which were obtained from adipose tissue, and their impact on the processes of adipose transplant resorption, in condition of its allogenic transplantation, have had constituted the objective of the investigation. Combined transplantation of adipose transplant and multipotent mesenchymal stem cells, obtained from allogenic adipose tissue, causes the destruction-inflammatory processes activation in the adipose transplant, as well as the adipocytes survival worsening in a meanwhile - a significant deficiency in the transplant mass.

[ATPase activity of rabbit skeletal muscles actomyosin complex under ultrasound effect].

Influence of continuous and impulsive ultrasound 0.05; 0.2; 0.4; 0.7 and 1.0 W/cm2 on ATPase activity of rabbit skeletal muscle actomyosin has been investigated in this work. It has been shown that most changes of Mg2+, Ca(2+)-ATPase activity are observed under 0.2 and 0.4 W/cm2 continuous ultrasound. K(+)-ATPase activity is inhibited by continuous ultrasound of all intensities studied. Impulsive 2 and 10 ms ultrasound did not change the Mg2+,Ca(2+)-ATPase activity. While K(+)-activity is reliably changed only under impulsive 0.7 and 1.0 W/cm2 ultrasound that can be explained by the thermal effect. It has been determined, when studying the reconstructed actomyosin with sound troponin complex, that troponin complex is the most ultrasound sensitive constituent of actomyosin.

[Transplantation of the adipose tissue enriched by allogenic mesenchymal multipotent stem cells in experimental conditions].

There was conducted experimental investigation with objective to study up the influence of transplantation of a native allogenic multipotent mesenchymal stem cells on the processes of implantation and functioning of heterotopically transplanted autologous adipose tissue. In a cellular-tissue graft, in which native allogenic mesenchymal stem cells were applied as a cellular component, there was observed a worsening of the adipocytes survival indices as well as activation of destructive and inflammatory processes.

[Influence of variuos ultrasound regimens on oxide-modified actomyosin superprecipitation reaction from skeletal muscle of rabbit].

A comparative study of rabbit skeletal muscles oxide-modified actomyosin superprecipitation reaction in dependence on continuous and impulsive (2 ms) ultrasound regimens was studied. From the analyses of kinetic curves the effect of the value of superprecipitation (A(m) - A(0)), time t1/2, required for achievement of half of its value was determined, and the normalized maximal rate of this reaction V was also calculated. It is shown that the use of continuous ultrasound to oxide-modified actomyosin was associated with a significant decrease of superprecipitation relative to controls. However, pulsed ultrasound caused a significant increase in superprecipitation value except for the values (A(m) - A(0)) in the application of the intensity of 0.2 W/cm2. The oxide-modified actomyosin superprecipitation value under the effect of continuous and impulsive ultrasound at intensity 1 W/cm2 in relative to control and all other applied intensities decrease to the most extent. It is caused perhaps by thermal influence of ultrasound. In general, the data obtained give reason to assume that the effects of continuous and pulsed ultrasound on the reaction of oxide-modified proteins complex superpretsipitatsii identical.

[Effect of continuous and impulsive ultrasound on actomyosin superprecipitation reaction from rabbit skeletal muscles].

A comparative study of the effect of continuous and impulsive (2 ms) ultrasound regimes on actomyosin superprecipitation reaction of the rabbit skeletal muscles was carried out. From the obtained kinetic curves the value of superprecipitation (D(m) - D(00)), time t1/2, which required to achieve a half its value was determined, and the normalized maximal rate of this reaction V(n) was calculated as well. It is shown that continuous ultrasound with intensities 0.7 W/cm2 and impulsive ultrasound--of 0.4 W/cm2 produced the most pronounced effect (value of superprecipitation and V(n) were maximal). The actomyosin superprecipitation value under continuous and impulsive ultrasound with intensity 1 W/cm2 relative to control and all other applied intensities was most decreased. It is caused perhaps thermal influence of the ultrasound. Thus the obtained data give every reason to assume, that impulsive ultrasound causes changes of adaptive character in actomyosin because the interrupted regime of the ultrasound signal.

A survey of snakebite management knowledge amongst select physicians in Hong Kong and the implications for snakebite training.

OBJECTIVE: The objective of the study was to assess the level of knowledge regarding snakebite management in doctors likely to treat such bites in the Special Administrative Region of Hong Kong in the People's Republic of China. Key concerns were doctor confidence, consistency of approach, use of anti-snake venom (ASV), and ancillary treatments. Hong Kong hospitals are equipped according to developed country standards, and knowledge therefore becomes the key factor in successful management. METHODS: A predesigned questionnaire consisting of 29 multiple-choice questions was submitted to physicians likely to treat snakebite victims at all Hong Kong hospitals receiving such patients. RESULTS: The key finding identified that only 29% of responding doctors were confident about treating snakebites. In the case of ASV selection between the 2 products available that deal with different species, 66% of doctors either were unsure of which to use or believed the 2 ASVs to be the same. The use of inappropriate clinical endpoints for ASV therapy suggests it is being used unnecessarily. CONCLUSIONS: There is clear room for improvement in the knowledge base and confidence level of physicians treating snakebites in Hong Kong. Key components of management, such as ASV choice, indications, dosing, and clinical endpoints for administration, were sources of confusion to the participants in this study. The results demonstrate the need for a locally developed and widely distributed snakebite management protocol.

[Gender differences in cold sensitivity: role of hormonal regulation of TRPM8 channel].

We have studied the gender differences in the perception of cutaneous cold stimuli in the innocuous temperature range (5-30 degrees C) in mice and rats. In the behavioral tests using two variable temperature plates technique female subjects displayed lower threshold for the sensation of cooling temperatures in the range of 15-25 degrees C compared to males. Patch-clamp experiments carried out on dorsal root ganglion (DRG) neurons from male and female rats maintained in the short-term cultures in the presence of testosterone or 17beta-estradiol, respectively, have revealed gender- and hormone-related differences in the electrophysiological properties of cold/menthol-sensitive TRPM8 channel: average density of menthol-activated I(TRPM8) current density in females' DRG neurons was higher compared to males', and the steady-state voltage-dependent activation curve of TRPM8 in females was shifted towards hyperpolarized potentials compared to males. These distinctive TRPM8 properties vanished upon withdrawal of testosterone and 17beta-estradiol from the culture mediums. We conclude that the observed differences in the behavioural sensitivity to innocuous cold and in functional properties of TRPM8 cold receptor are due to differential regulation of TRPM8 by sex steroid hormones, testosterone and/or 17beta-estradiol.

[A hyperpolarization-activated current in rat menthol-sensitive sensory neurons].

In the present study we have investigated the correlation between hyperpolarization-activated current (1(h)) and menthol-activated current (I(TRPM8)) in rat dorsal root ganglion (DRG) neurons. We showed that I(h) is present in 89% of menthol-sensitive neurons which makes its presence reliable, though not absolute, criterion for pre-selection of such neurons. Endogenous I(h) recorded from different neurons exhibited variable density and activation kinetics. Based on the analysis of I(h) activation kinetics we hypothesize that the population of hyperpolarization-activated channels in menthol-sensitive DRG neurons is mainly represented by HCN1, HCN2 and HCN3 channels. The expression of HCN4 isoform in these cells is very low.

[Efficacy of immunoadsorbent treatment in experimental allergic encephalomyelitis].

Hemoperfusion through the granulated hemoadsorbent SCN, fibrous carbonic adsorbent AUVM and immunoadsorbent (SCN with immobilized MBP) was applied for the treatment of experimental allergic encephalomyelitis (EAE) in guinea pigs. EAE was induced by single subcutaneous injection of 100 microg of MBP in complete Freund's adjuvant. Hemoperfusion was performed on the stage of EAE manifestation or in latent period. It was found that immunoadsorbent has the highest therapeutic efficacy and allows to eliminate up to 32% anti-MBP antibodies from the serum of guinea pigs with EAE, has up to 84% and 90% of adsorptive capacity of small and middle weight endogenous substances, respectively, and reduces the level of metabolites with molecular weight less than 30 kDa in blood plasma up to 36%.

[Functional identification of the TRPM8 cold receptor in rat prostate epithelial cells].

For the first time by means of electrophysiology we demonstrate functional expression of cold/menthol sensitive TRPM8 channel in secretory epithelial cells plasma membrane from rat prostate. Under whole-cell patch-clamp technique rapid cooling from 33 to 21 degrees C of freshly isolated rat prostate epithelial cells elicited the significant outward rectifying membrane current with close to 0 mV reversal potential characteristic of TRPM8 activation. Extracellular application of chemical analog of cooling, menthol (100 microM) at 33 degrees C evoked similar current responses. Cold- and menthol-evoked currents could be detected only in elongated epithelial cells, which in prostate slices were labeled with anti-cytokeratin 8, suggesting that they belong to the apical secretory phenotype. No such current could be detected in round apparently basal epithelial cells. We conclude that in normal rat prostate functional expression of TRPM8 is restricted to plasma membrane of luminal apical epithelial cells.

Targeted inhibition of COX-2 expression by RNA interference suppresses tumor growth and potentiates chemosensitivity to cisplatin in human gastric cancer cells.

Although selective cyclooxygenase-2 (COX-2) inhibitors suppress cell proliferation in gastric cancer, it remains debatable whether their effect is mediated through COX-2 dependent or independent pathways. We investigated the effects of the targeted inhibition of COX-2 expression by small interfering RNA (siRNA) in human gastric cancer cells and compared it to the effects of treatment with a specific COX-2 inhibitor. COX-2 mRNA and proteins were significantly reduced by up to 80% on day 2 after COX-2 siRNA transfection to the gastric cancer cell line MKN45. Concentrations of prostaglandins E2 (PGE2) in the condition medium were also reduced to 30% after siRNA transfection. Transfection of COX-2 siRNA exhibited a more potent anti-proliferative effect on MKN45 cells than treatment with high-dose (100 microM) NS398. COX-2 siRNA also significantly reduced tumor growth in nude mice. While COX-2 siRNA transfection alone had no obvious pro-apoptotic effects, unlike low-dose (10 microM) NS398 it enhanced the apoptotic reaction of MKN45 cells to cisplatin therapy. In conclusion, our results demonstrate for the first time that COX-2 siRNA inhibits cell growth and enhances the chemosensitivity of gastric cancer cells. RNA interference may be a promising alternative to specific COX-2 inhibitors in the prevention and treatment of gastric cancer.

Expression of a cyclo-oxygenase-2 transgene in murine liver causes hepatitis.

BACKGROUND: It has been proved that cyclo-oxygenase-2 (COX-2) is rapidly induced by inflammatory mediators. However, it is not known whether overexpression of COX-2 in the liver is sufficient to promote activation or secretion of inflammatory factors leading to hepatitis. AIM: To investigate the role forced expression of COX-2 in liver by using inducible COX-2 transgenic (TG) mice. METHODS: TG mice that overexpress the human COX-2 gene in the liver using the liver-specific transthyretin promoter and non-TG littermates were derived and fed the normal diet for up to 12 months. Hepatic prostaglandin E(2) (PGE(2)) content was determined using enzyme immunoassay, nuclear factor kappaB (NF-kappaB) activation by electrophoretic mobility shift assays, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labelling and proliferation by Ki-67 immunohistochemistry. RESULTS: COX-2 TG mice exhibited strongly increased COX-2 and PGE(2), elevated serum alanine aminotransferase level and histological hepatitis. Hepatic COX-2 expression in the TG mice resulted in activation of NF-kappaB and inflammatory cytokine cascade, with a marked expression of the proinflammatory cytokines tumour necrosis factor (TNF)-alpha (9.4-fold), interleukin (IL)-6 (4.4-fold), IL-1beta (3.6-fold), and of the anti-inflammatory cytokine IL-10 (4.4-fold) and chemokine macrophage inflammatory protein-2 (3.2-fold). The inflammatory response of the COX-2 TG mice was associated with infiltration macrophages and lymphocytes, increased cell proliferation and high rates of cell apoptosis. Administration of the COX-2 inhibitor celecoxib in TG mice restored liver histology to normal. CONCLUSION: Enhanced COX-2 expression in hepatocytes is sufficient to induce hepatitis by activating NF-kappaB, stimulating the secretion of proinflammatory cytokines, recruiting macrophage and altering cell kinetics. Inhibition of COX-2 represents a mechanism-based chemopreventive approach to hepatitis.

[Compulsory treatments in Macao: the first five years]. / Tratamentos compulsivos em Macau: os primeiros cinco anos.

AIMS: To characterize compulsory treatments done in Macao in the five years after its implementation in 1999. METHOD: A descriptive and retrospective study was done consulting the clinical files of persons that did compulsory treatments in Macao in the five years after its implementation. RESULTS: The court always confirmed the requests for compulsory admissions, 24 patients were admitted and 14 cases (58.3%) were men. The patients had a median age of 37.7 years (SD+/-14.4). The most frequent motive of admission was danger and incapacity to consent treatment, in 16 cases (66.5%). The admission was urgent in 18 cases (75%) and the diagnosis of psychosis was made in 23 cases (95.8%). The length of hospitalization was 69 days (SD+/-47.9; minimum=2; Maximum=170). Compulsory ambulatory treatments were made in 6 cases (25%) and lasted 771 days (SD+/-380.5; minimum=76; Maximum=963). Annually, quotas of compulsory admissions varied between 0% and 2.4% and commitment rates between 0 and 1.7. CONCLUSIONS: Quotas and commitment rates for compulsory admissions appeared inferior compared, for example, to the ones of the European Union. Compulsory treatments were important, allowing to start therapeutics, that otherwise would be impossible, and to overcome dangerous situations. There is a need in Macao to clarify the population and relevant professional sectors about these treatments so that, whenever indicated, patients can benefit from them quickly and in better circumstances.

Anti-sense trefoil factor family-3 (intestinal trefoil factor) inhibits cell growth and induces chemosensitivity to adriamycin in human gastric cancer cells.

Intestinal trefoil factor (ITF), which is normally absent in gastric mucosa, is over-expressed in gastric cancer. However, the functional significance of ITF in gastric cancer is unknown. We examined the effects of blocking ITF expression on the growth of gastric cancer cells and their responses to chemotherapeutic agents. Anti-sense ITF cDNA was cloned into mammalian expression vector pcDNA3 and was transfected into an ITF-expressing gastric cancer cell line SNU-1. We assessed the doubling time and anchorage dependent growth of the transfected cells using growth curve and soft agar assay respectively. Cell cycle analysis and apoptosis were determined by flow cytometry and cell death ELISA. The response to chemotherapeutic agents after transfecting anti-sense ITF was also examined. Anti-sense ITF transfectant (3A-5) had a significantly longer doubling time as compared to control cells which were transfected with empty vector (32.4 hr vs 26.9 hr, p < 0.05). In the soft agar assay, 3A-5 formed fewer colonies than control (3.5 colonies vs 23.5 colonies, p < 0.05). Although there was no significant difference in the cell cycle distribution between 3A-5 and control, anti-sense ITF resulted in marked increase in adriamycin-induced apoptosis. Our results demonstrated that blocking the expression of ITF inhibits growth of gastric cancer cells and enhances the response to chemotherapy.