Plasma cell depletion with bortezomib in the treatment of refractory N-methyl-d-aspartate (NMDA) receptor antibody encephalitis. Rational developments in neuroimmunological treatment.

BACKGROUND AND PURPOSE: The aim was to assess the therapeutic potential of bortezomib in the treatment of refractory N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis and its potential in other immune-mediated, B-cell-driven neurological diseases. METHODS: Two cases of severe NMDAR antibody encephalitis, resistant to first and second line therapy with steroids, intravenous immunoglobulins, plasma exchange, cyclophosphamide and rituximab, were treated with four and five cycles of 1.3 mg/m2 bortezomib at 350 and 330 days following initial presentation. RESULTS: Both patients showed significant clinical improvement with reductions of NMDAR antibody titres following bortezomib treatment. This is the first case in the literature where the NMDAR antibody level was undetectable following treatment with bortezomib. CONCLUSION: Bortezomib's unique ability to target long-lived autoreactive plasma cells appears to be a useful adjunct to standard second line immunosuppressive therapy in treatment-refractory NMDAR antibody encephalitis. The drug's pharmacodynamics, cell targeting and mechanism of action are reviewed, and it is postulated that bortezomib may be useful in a host of B-cell-driven neuroimmunological diseases.

Impaired awareness of motor intention in functional neurological disorder: implications for voluntary and functional movement.

BACKGROUND: Functional neurological disorders (FNDs), also known as conversion disorder, are unexplained neurological symptoms unrelated to a neurological cause. The disorder is common, yet poorly understood. The symptoms are experienced as involuntary but have similarities to voluntary processes. Here we studied intention awareness in FND. METHOD: A total of 26 FND patients and 25 healthy volunteers participated in this functional magnetic resonance study using Libet's clock. RESULTS: FND is characterized by delayed awareness of the intention to move relative to the movement itself. The reporting of intention was more precise, suggesting that these findings are reliable and unrelated to non-specific attentional deficits. That these findings were more prominent with aberrant positive functional movement symptoms rather than negative symptoms may be relevant to impairments in timing for an inhibitory veto process. Attention towards intention relative to movement was associated with lower right inferior parietal cortex activity in FND, a region early in the processing of intention. During rest, aberrant functional connectivity was observed with the right inferior parietal cortex and other motor intention regions. CONCLUSIONS: The results converge with observations of low inferior parietal activity comparing involuntary with voluntary movement in FND, emphasizing core deficiencies in intention. Heightened precision of this impaired intention is consistent with Bayesian theories of impaired top-down priors that might influence the sense of involuntariness. A primary impairment in voluntary motor intention at an early processing stage might explain clinical observations of slowed effortful voluntary movement, heightened self-directed attention and underlie functional movements. These findings further suggest novel therapeutic targets.

Comparative Expression Analysis of Gametogenesis-Associated Genes in Foetal and Adult Bubaline (Bubalus bubalis) Ovaries and Testes.

This study was conducted to identify and analyse the expression of gametogenesis-associated genes and proteins in foetal and adult buffalo gonads of both the sexes. Relative quantification of the genes was determined by qPCR and Western blotting. Immunohistochemistry was also performed for various gametogenesis-associated proteins in foetal and adult gonads of both the sexes. We observed significantly (p < 0.05) increased expression of primordial germ cell-specific, meiotic as well as genes associated with oocyte maturation and development in foetal ovaries as compared to the adult ones. However, significantly (p < 0.05) increased expression of proteins associated with oocyte maturation like GDF9 and ZP4 was found in adult ovaries, indicating temporal regulation of mRNA translation during oogenesis. Meiotic genes showed significantly (p < 0.05) increased expression in adult testes as compared to foetal testes and ovaries, indicating onset of meiosis at a later stage in spermatogenesis. In general, the expression of primordial germ cell-associated as well as meiotic genes was higher in adult testes, indicating the increased biological activity in the organ. Immunohistochemistry revealed localized expression of gametogenesis-associated proteins in ovarian follicles and seminiferous tubules of testes, while the surrounding somatic tissues were devoid of these proteins. The study gives an understanding of the sequential and temporal events of gene expression as well as mRNA translation during male and female gametogenesis. It could also be concluded that follicles and seminiferous tubules are the functional units of the female and male gonads, respectively, and their function could be enhanced by appropriate chemical and genetic intervention of the somatic tissue immediately surrounding them. This assumes importance in the context that buffalo attains sexual maturity at an older age of 2-3 years and have smaller ovaries with lesser number of primordial follicles in comparison with cattle, which is suggested to be the main reason of their poor breeding performance.

Genome-wide analysis of population structure, effective population size and inbreeding in Iranian and exotic horses.

Population structure and genetic diversity are the key parameters to study the breeding history of animals. This research aimed to provide a characterization of the population structure and to compare the effective population size (Ne), LD decay, genetic diversity, and genomic inbreeding in Iranian native Caspian (n = 38), Turkmen (n = 24) and Kurdish (n = 29) breeds and some other exotic horses consisting of Arabian (n = 24), Fell pony (n = 21) and Akhal-Teke (n = 20). A variety of statistical population analysis techniques, such as principal component analysis (PCA), discriminant analysis of principal component (DAPC) and model-based method (STRUCTURE) were employed. The results of the population analysis clearly demonstrated a distinct separation of native and exotic horse breeds and clarified the relationships between studied breeds. The effective population size (Ne) for the last six generations was estimated 54, 49, 37, 35, 27 and 26 for the Caspian, Kurdish, Arabian, Turkmen, Akhal-Teke and Fell pony breeds, respectively. The Caspian breed showed the lowest LD with an average r2 value of 0.079, while the highest was observed in Fell pony (0.148). The highest and lowest average observed heterozygosity were found in the Kurdish breeds (0.346) and Fell pony (0.290) breeds, respectively. The lowest genomic inbreeding coefficient based on run of homozygosity (FROH) and excess of homozygosity (FHOM) was in the Caspian and Kurdish breeds, respectively, while based on genomic relationship matrix) FGRM) and correlation between uniting gametes) FUNI) the lowest genomic inbreeding coefficient was found in the Kurdish breed. The estimation of genomic inbreeding rates in the six breeds revealed that FROH yielded lower estimates compared to the other three methods. Additionally, the Iranian breeds displayed lower levels of inbreeding compared to the exotic breeds. Overall, the findings of this study provide valuable insights for the development of effective breeding management strategies aimed at preserving these horse breeds.

Bacterial coinfection among coronavirus disease 2019 patient groups: an updated systematic review and meta-analysis.

The pandemic of severe acute respiratory syndrome coronavirus 2 raised the attention towards bacterial coinfection and its role in coronavirus disease 2019 (COVID-19) disease. This study aims to systematically review and identify the pooled prevalence of bacterial coinfection in the related articles. A comprehensive search was conducted in international databases, including MEDLINE, Scopus, Web of Science, and Embase, to identify the articles on the prevalence of bacterial coinfections in COIVD-19 patients from 1 December 2019 until 30 December 2020. All observational epidemiological studies that evaluated the prevalence of bacterial coinfections in patients with COVID-19 were included without any restriction. Forty-two studies including a total sample size of 54,695 were included in the analysis. The pooled estimate for the prevalence of bacterial coinfections was 20.97% (95% CI: 15.95-26.46), and the pooled prevalence of bacterial coinfections was 5.20% (95% CI: 2.39-8.91) for respiratory subtype and 4.79% (95% CI: 0.11-14.61) for the gastrointestinal subtype. The pooled prevalence for Eastern Mediterranean Regional Office and South-East Asia Regional Office was 100% (95% CI: 82.35-100.00) and 2.61% (95% CI: 1.74-3.62). This rate of coinfection poses a great danger towards patients, especially those in critical condition. Although there are multiple complications and adverse effects related to extensive use of antibiotics to treat patients with COVID-19, it seems there is no other option except applying them, and it needs to be done carefully.

Histological evaluation of inferior alveolar nerve injury after osteotomy of mandibular buccal cortex using piezoelectric versus conventional rotary devices: a split-mouth randomised study in rabbits.

Up until now, only a limited number of evidence-based studies with different results has evaluated traumatic nerve injury after maxillofacial surgery using piezoelectric devices versus rotary instruments. The present experiment was performed to evaluate damage to the inferior alveolar nerve (IAN), histologically, after osteotomy of the buccal cortex of the mandible using piezoelectric devices versus surgical handpieces. Forty rabbits underwent bilateral osteotomy of the mandibular buccal cortex. For the osteotomy of one side, piezoelectric devices were used, and for the other, conventional rotary handpieces. After cleavage of the osteotomised cortical bone segments, the exposed part of the IAN was excised and examined histologically for nerve injury. IAN damage was scored histologically from Grade 0 (no nerve damage) to Grade 4 (complete nerve transection). It was found that 25% and 17.5% of nerves had Grade 0; 17.5% and 10% had Grade 1; 25% and 20% had Grade 2; 17.5% and 27.5% had Grade 3; and 15% and 25% had Grade 4 injury in piezosurgery and rotary groups, respectively. Statistical analyses revealed no significant difference between groups in damage to the IAN. The present study showed that piezosurgery devices, similar to conventional rotary instruments, have the potential to cause severe nerve damage during surgery and should therefore be used with care.

First service pregnancy rates following post-AI use of HCG in Ovsynch and Heatsynch programmes in lactating dairy cows.

Lactating dairy cows (n = 667) at random stages of the oestrous cycle were assigned to either ovsynch (O, n = 228), heatsynch (H, n = 252) or control (C, n = 187) groups. Cows in O and H groups received 100 microg of GnRH agonist, i.m. (day 0) starting at 44 +/- 3 days in milk (DIM), and 500 microg of cloprostenol, i.m. (day 7). In O group, cows received 100 microg of GnRH (day 9) and were artificially inseminated without oestrus detection 16-20 h later. In H group, cows received 1 mg oestradiol benzoate (EB) i.m., 24 h after the cloprostenol injection and were artificially inseminated without oestrus detection 48-52 h after the EB injection. Cows in C group were inseminated at natural oestrus. On the day of artificial insemination (AI), cows in all groups were assigned to subgroups as follows: human Chorionic Gonadotrophin (O-hCG) (n = 112), O-saline (n = 116), H-hCG (n = 123), H-saline (n = 129), C-hCG (n = 94) and C-saline (n = 93) subgroups. Cows in hCG and saline subgroups received 3000 IU hCG i.m. and or 10 ml saline at day 5 post-AI (day 15), respectively. Pregnancy status was assessed by palpation per rectum at days 40 to 45 after AI. The logistic regression model using just main effects of season (summer and winter), parity (primiparous and pluriparous), method(1) (O, H and C) and method(2) (hCG and saline) showed that all factors, except method(1), were significant. Significant effects of season (p < 0.01), hCG and parity (p < 0.01), and a trend of parity and season (p < 0.1) were detected. A clear negative effect of warm period on first service pregnancy rate was noted (p < 0.01). The pregnancy rate was the lowest in the H protocol during warm period (p < 0.05). Treatment with hCG 5 days after AI significantly improved pregnancy rates in those cows that were treated with the H protocol compared with saline treatments (41.5% vs 24.8%; p < 0.01). O and H were more effective in primiparous than in pluriparous cows (46.1% vs 29.9%; p < 0.1 and 43.6% vs 24.6%; p < 0.01). First service pregnancy rates were higher in primiparous hCG-treated than in pluriparous hCG-treated cows (57.9% vs 32.3%; p < 0.01). The pregnancy rate was higher for the hCG-treated cows compared with saline-treated cows during warm period (37.9% vs 23.6%; p < 0.001).

Construction and development of FimH lectin domain for rising immune response after injection by uropathogenic E. coli.

Uropathogenic E. coli is one of the major agents of urinary tract infection. Today, no effective treatment or vaccine against this infection is exist. Accordingly, in the present study, a genetic constrruct for inducing of cellular immune system was designed. At first, fimH gene from E. coli 35218 was amplified using PCR. PCR product inserted into pET23a expression vector and the recombinant vector was analysed by sequencing. The vector was transformed to E. coli strain Origami and the protein was expressed under the 1 mM IPTG. FimH was purified with Ni-NTA column and the purified protein was used for immunization of BALB/c. Two weeks after the last injection, lymphocyte proliferation assay was carried out. In addition, IL-4 and IFN-γ cytokines, total antibody serum, IgG1 and IgG2a isotypes were quantified. Finally, protection ability of the vaccine in bladder and kidney infection of mice was evaluated.The results indicated that cellular immune response has a main protective role against UTI and FimH, as a vaccine candidate, significantly increase lymphocyte proliferation, IFN-γ response and total antibody amount. Immunization of mice with FimH conferred effective protection of kidney and bladder against urinary tract infection by uropathogenic E. coli (P< 0.002). It can be concluded that, the current FimH will be valuable for more trying to prepare a new vaccine against UTI.

Fabrication of curcumin-loaded electrospun nanofiberous polyurethanes with anti-bacterial activity.

Two series of polyurethane (PU), based on polycaprolactone (PCL) as soft segments with two different molecular weights (2000 and 530 Da), and hexamethylene diisocyanate (HDI) and 1,4-butandiol (BDO) as hard segments were synthesized to fabricate curcumin-loaded electrospun nanofibrous PCL-based PU substrate. Chemical structures of the synthesized PUs were characterized by FTIR and NMR spectroscopy techniques. The thermal properties were analyzed by differential scanning calorimetry (DSC) and surface hydrophilicity was studied by static contact angle and bulk hydrophilicity was evaluated by water uptake test. Thereafter, bead-free PU nanofiberous substrate containing curcumin was fabricated by electrospinning and morphology of the mats was observed by scanning electron microscopy (SEM). Mechanical properties of the electrospun mats in comparison with polymeric films were assessed by a universal test machine. The in vitro release of curcumin was studied by UV-Vis spectroscopy. The optical density of the bacterial solutions was used to evaluate the antibacterial activity of the curcumin-loaded nanofibrous mats against Escherichia coli (E-coli ATCC: 25922). The results showed that curcumin-loaded PU synthesized by PCL with molecular weight of 2000 Da displayed better mechanical properties as well as better antibacterial properties in wound dressing application.

Correction to: Cure kinetic study of methacrylate-POSS copolymers for ocular Lens.

The original version of this article unfortunately contained a mistake: the spelling of the Ebrahim Gafar-Zadehs' name was incorrect. The corrected name is given above.

Study of the cephalometric features of parents of children with cleft lip and/or palate anomaly.

The purpose of this retrospective case-control study was to compare the cephalometric features of parents of children with cleft anomalies to those of parents of normal children in the hope of finding potential markers of predisposition for this condition. There were 22 sets of parents of cleft children (study group) and 22 sets of parents of normal children (control group). A total of 88 lateral cephalograms were traced twice by two observers separately and analyzed using Student's t-test. Seven linear, two angular and five triangular cephalometric variables were measured. Mandibular body length (Go-Gn) in mothers was larger in the study than the control group, posterior cranial base (S-Ba) in fathers was shorter in the study than the control group, anterior maxillary triangle (S.N.A) in parents in the study group was larger than in the control group and posterior maxillary triangle (S.N.Pns) in study group mothers was larger than in control group mothers. In conclusion, the craniofacial morphology of the parents of children with cleft anomalies differs from that of parents of normal children and may have some predictive value.

Cure kinetic study of methacrylate-POSS copolymers for ocular lens.

The physical, mechanical and biological properties of multicomponent acrylate-based hard lenses are directly influenced by degree of conversion achieved during copolymerization. In this research, polyhedral oligomeric silsesquioxane (POSS) acrylate is introduced into the polymer backbone in combination with hydroxyethyl methacrylate, dimethyl itaconate, methyl methacrylate, 3-(trimethoxysilyl) propyl methacrylate and triethylene glycol dimethacrylate in free-radical bulk polymerization. Kinetics of curing process was investigated by two techniques: differential scanning calorimetry and FTIR spectroscopy. Reaction kinetics in free-radical bulk polymerization of the system was studied by isothermal DSC performed at 65, 75, 85, and 95 °C using different quantities of initiator. Three compounds were prepared in different concentrations (0.2, 0.4 and 0.6 mol%) of 2,2'-azobisisobutyronitrile as initiator. Conversion rate was calculated as a function of time using data obtained from DSC measurements. The kinetic parameters of the reaction such as reaction constants, reaction orders and activation energies were obtained from the isothermal DSC data according to the autocatalytic model developed by Kamal and Sourour. The results showed that the experimental values were in good agreement with theoretically estimated values and our results may suggest that the polymerization reaction of this system is well described by Kamal's model. Cytotoxicity results, performed on extracts 28 days after PBS incubation, showed no toxicity of the materials extracted from the lenses indicating that they can be considered as safe materials in ocular lens applications. The viability and proliferation of L929 fibroblast cells in extracting media were followed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and they may have a great potential as ideal supporting lens in people who suffer from keratoconus disease.

Effectiveness of cold therapy in reducing pain, trismus, and oedema after impacted mandibular third molar surgery: a randomized, self-controlled, observer-blind, split-mouth clinical trial.

Cold therapy is a conventional and widely used modality for reducing pain, trismus, and oedema after dentoalveolar surgeries. However, information reported in the literature on its effectiveness is insufficient and controversial. This study was performed to evaluate the effect of local cold application in reducing pain, trismus, and swelling after impacted mandibular third molar surgery. Thirty patients (seven males and 23 females) with bilateral symmetrical mandibular impacted third molars were enrolled in this randomized, self-controlled, observer-blind clinical trial. The patients were aged between 18 and 30 years. After surgical removal of the tooth on one side (intervention), ice pack therapy was given for 24h after surgery; for the other side (control), no cold therapy was given. The time interval between the two surgeries was at least 4 weeks. The amount of pain, trismus, and facial swelling was measured on days 2 and 7 postoperative, and patient satisfaction with the cold therapy vs. no cold therapy was assessed. The amount of pain, trismus, and facial swelling, and the extent of patient satisfaction were not significantly different between the intervention and control sides. Cold therapy had no beneficial effects on postoperative sequelae after impacted mandibular third molar surgery.

Engineered electrospun poly(caprolactone)/polycaprolactone-g-hydroxyapatite nano-fibrous scaffold promotes human fibroblasts adhesion and proliferation.

Polycaprolactone (PCL)/hydroxyapatite nano-composites are among the best candidates for tissue engineering. However, interactions between nHAp and PCL are difficult to control leading to inhomogeneous dispersion of the bio-ceramic particles. Grafting of polymer chains at high density/chain length while promotes the phase compatibility may result in reduced HAp exposed surface area and therefore, bioactivity is compromised. This issue is addressed here by grafting PCL chains onto HAp nano-particles through ring opening polymerization of ε-caprolactone (PCL-g-HAp). FTIR and TGA analysis showed that PCL (6.9wt%), was successfully grafted on the HAp. PCL/PCL-g-HAp nano-fibrous scaffold showed up to 10 and 33% enhancement in tensile strength and modulus, respectively, compared to those of PCL/HAp. The effects of HAp on the in vitro HAp formation were investigated for both the PCL/HAp and PCL/PCL-g-HAp scaffolds. Precipitation of HAp on the nano-composite scaffolds observed after 15days incubation in simulated body fluid (SBF), as confirmed by scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDX). Human fibroblasts were seeded on PCL, PCL/HAp and PCL/PCL-g-HAp scaffolds. According to MTT assay, the highest cell proliferation was recorded for PCL/PCL-g-HAp nano-composite, at all time intervals (1-21days, P<0.001). Fluorescent microscopy (of DAPI stained samples) and electron microscopy images showed that all nano-fibrous scaffolds (PCL, PCL/HAp, and PCL/PCL-g-HAp), were non-toxic against cells, while more cell adhesion, and the most uniform cell distribution observed on the PCL/PCL-g-HAp. Overall, grafting of relatively short chains of PCL on the surface of HAp nano-particles stimulates fibroblasts adhesion and proliferation on the PCL/PCL-g-HAp nano-composite.

Silane crosslinking of electrospun poly (lactic acid)/nanocrystalline cellulose bionanocomposite.

Biodegradable nanofibrous mats fabricated by electrospinning are commonly used in tissue engineering, however, lack of essential mechanical properties of such nanofibers is a challenging issue. In this work, vinyltrimethoxysilane (VTMS) was grafted onto poly (lactic acid) (PLA) and the silane grafted PLA was subsequently applied in electrospinning process. Electrospun nanofibrous mats based on PLA/nanocrystalline cellulose (NCC) and PLA-g-silane/NCC nanocomposites were fabricated and immersed in hot water (70°C) for crosslinking of silane grafted PLA. It was found that introducing NCC to the samples cause to reduction in fiber diameter and the other hand the silane crosslinking of PLA increase the mean fiber diameter. DSC thermograms also revealed that silane grafting caused a reduction in mobility of polymer segments, and consequently reduction of crystallinity. On the contrary, the NCC in the PLA-g-silane samples effectively influenced the crystal nucleation, while in the PLA nanofibers the nucleation was lower. The impact of NCC on tensile strength enhancement of samples was notable. The results suggested that the chemical crosslinking remarkably improves the mechanical properties of PLA nanofibers. Furthermore, biocompatibility of such modified nanofibers was also evaluated through cytotoxicity results, therefore the modified PLA nanocomposite can be considered as a practical candidate for hard tissue engineering applications.

Investigation on artificial blood or substitute blood replace the natural blood.

Blood is a liquid tissue in which dissolved with abundant chemical factors and millions of different cells The reduction of unwanted side effects, especially diseases that emerge through blood such as HIV and hepatitis, has a significant role for modern medicine of transfusion and transplantation. The issues and costs of human blood collection and storage, direct this procedure towards the use of alternatives blood. Two important research fields of this area were oxygen carriers based on hemoglobin and perfluoro chemicals. While they do not have the same quality as the blood cell products, the oxygen carrier solutions have potential clinical and non-clinical applications. The result showed that these products can reach to the body tissues easier than normal red blood cells, and can control the oxygen directly. The final aim of transfusion is to establish a transfusion system with no side effects, and the fact that oxygen carrier artificial blood has this property. The article attempts to step towards solving some problems of blood transfusion through describing the properties of artificial blood alternatives.

Photo-crosslinkable cyanoacrylate bioadhesive: shrinkage kinetics, dynamic mechanical properties, and biocompatibility of adhesives containing TMPTMA and POSS nanostructures as crosslinking agents.

The study investigates the photo-polymerization shrinkage behavior, dynamic mechanical properties, and biocompatibility of cyanoacrylate bioadhesives containing POSS nanostructures and TMPTMA as crosslinking agents. Adhesives containing 2-octyl cyanoacrylate (2-OCA) and different percentages of POSS nanostructures and TMPTMA as crosslinking agents were prepared. The 1-phenyl-1, 2-propanedione (PPD) was incorporated as photo-initiator into the adhesive in 1.5, 3, and 4 wt %. The shrinkage strain of the specimens was measured using bonded-disk technique. Shrinkage strain, shrinkage strain rate, maximum and time at maximum shrinkage strain rate were measured and compared. Mechanical properties of the adhesives were also studied using dynamic mechanical thermal analysis (DMTA). Biocompatibility of the adhesives was examined by MTT method. The results showed that shrinkage strain increased with increasing the initiator concentration up to 3 wt % in POSS-containing and 1.5 wt % in TMPTMA-containing specimens and plateaued out at higher concentrations. By increasing the crosslinking agent, shrinkage strain, and shrinkage strain rate increased and the time at maximum shrinkage strain rate decreased. The study indicates that the incorporation of crosslinking agents into the cyanoacrylate adhesives resulted in improved mechanical properties. Preliminary MTT studies also revealed better biocompatibility profile for the adhesives containing crosslinking agents comparing to the neat specimens.