Bone homeostasis depends on the resorption of bones by osteoclasts and formation of bones by the osteoblasts. Imbalance of this tightly coupled process can cause diseases such as osteoporosis. Thus, the mechanisms that regulate communication between osteoclasts and osteoblasts are critical to bone cell biology. It has been shown that osteoblasts and osteoclasts can communicate with each other through direct cell-cell contact, cytokines, and extracellular matrix interaction. Osteoblasts can affect osteoclast formation, differentiation, or apoptosis through several pathways, such as OPG/RANKL/RANK, RANKL/LGR4/RANK, Ephrin2/ephB4, and Fas/FasL pathways. Conversely, osteoclasts also influence formation of bones by osteoblasts via the d2 isoform of the vacuolar (H+) ATPase (v-ATPase) V0 domain (Atp6v0d2), <em>complement</em> <em>component</em> 3a, semaphorin <em>4D</em> or microRNAs. In addition, cytokines released from the resorbed bone matrix, such as TGF-β and IGF-1, also affect the activity of osteoblasts. Drugs could be developed by enhancing or restricting some of these interactions. Several reviews have been performed on the osteoblast-osteoclast communication. However, few reviews have shown the research advances in the recent years. In this review, we summarized the current knowledge on osteoblast-osteoclast communication.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for <em>complement</em> <em>component</em> <em>4d</em> tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

The role of donor-specific anti-human leukocyte antigen antibodies (DSAs) that develop late after living donor liver transplantation is unknown. Seventy-nine pediatric recipients who had good graft function and underwent protocol liver biopsy more than 5 years after transplantation (median = 11 years, range = 5-20 years) were reviewed. DSAs were determined with the Luminex single-antigen bead assay at the time of the last biopsy, and <em>complement</em> <em>component</em> <em>4d</em> (C<em>4d</em>) immunostaining was assessed at the times of the last biopsy and the previous biopsy. The donor specificity of antibodies could be identified in 67 patients: DSAs were detected in 32 patients (48%), and they were usually against human leukocyte antigen class II (30 cases) but were rarely against class I (2 cases). These patients had a higher frequency of bridging fibrosis or cirrhosis (28/32 or 88%) than DSA-negative patients (6/35 or 17%, P < 0.001). Fibrosis was likely to be centrilobular-based. DSA-positive patients, in comparison with DSA-negative patients, had higher frequencies of diffuse/focal endothelial C<em>4d</em> staining (P < 0.001) and mild/indeterminate acute rejection [15/32 (47%) versus 5/35 (14%), P = 0.004]. Four DSA-negative patients were off immunosuppression, whereas no patients in the DSA-positive group were (P = 0.048). In conclusion, the high prevalence of graft fibrosis and anti-class II DSAs in late protocol biopsy samples suggests that humoral alloreactivity may contribute to the process of unexplained graft fibrosis late after liver transplantation.

Digital subtraction angiography (DSA) remains the gold standard to diagnose intracranial arteriovenous malformations (AVMs) but is invasive. Existing magnetic resonance angiography (MRA) is suboptimal for assessing the hemodynamics of AVMs. The objective of this study was to evaluate the clinical utility of a novel noncontrast four-dimensional (<em>4D</em>) dynamic MRA (dMRA) in the evaluation of intracranial AVMs through comparison with DSA and time-of-flight (TOF) MRA. Nineteen patients (12 women, mean age 26.2±10.7 years) with intracranial AVMs were examined with <em>4D</em> dMRA, TOF and DSA. Spetzler-Martin grading scale was evaluated using each of the above three methods independently by two raters. Diagnostic confidence scores for three <em>components</em> of AVMs (feeding artery, nidus and draining vein) were also rated. Kendall's coefficient of concordance was calculated to evaluate the reliability between two raters within each modality (dMRA, TOF, TOF plus dMRA). The Wilcoxon signed-rank test was applied to compare the diagnostic confidence scores between each pair of the three modalities. dMRA was able to detect 16 out of 19 AVMs, and the ratings of AVM size and location matched those of DSA. The diagnostic confidence scores by dMRA were adequate for nidus (3.5/5), moderate for feeding arteries (2.5/5) and poor for draining veins (1.5/5). The hemodynamic information provided by dMRA improved diagnostic confidence scores by TOF MRA. As a completely noninvasive method, <em>4D</em> dMRA offers hemodynamic information with a temporal resolution of 50-100 ms for the evaluation of AVMs and can <em>complement</em> existing methods such as DSA and TOF MRA.

We analyzed 60 patients with idiopathic early allograft loss (defined as death or retransplantation at <90 days) to determine the relative contribution of preformed donor-specific human leukocyte antigen alloantibodies (DSAs) to this endpoint, and we defined strict criteria for the diagnosis of antibody-mediated rejection (AMR) in liver allografts. The inclusion criteria encompassed the availability of a pretransplant serum sample and both postreperfusion and follow-up tissue specimens for a blinded, retrospective re-review of histology and <em>complement</em> <em>component</em> <em>4d</em> (C<em>4d</em>) staining. AMR was diagnosed on the basis of the presence of all 4 of the following strict criteria: (1) DSAs in serum, (2) histopathological evidence of diffuse microvascular injury/microvasculitis consistent with antibody-mediated injury, (3) diffuse C<em>4d</em> staining in the portal microvasculature with or without staining in the sinusoids or central veins in at least 1 sample, and (4) the exclusion of other causes of a similar type of injury. Patients thought to be experiencing definite AMR on the basis of routine histopathology alone showed the highest levels of DSA sensitization. Forty percent of patients with pretransplant DSAs with a pattern of bead saturation after serial dilutions developed AMR. Another multiparous female developed what appeared to be a strong recall response, which resulted in combined AMR and acute cellular rejection (ACR) causing graft failure. A contribution of DSAs to allograft failure could not be excluded for 3 additional patients who received marginal grafts. In conclusion, liver allograft recipients with preformed DSAs with a high mean fluorescence intensity despite dilution seem to be at risk for clinically significant allograft injury and possibly for loss from AMR, often in combination with ACR.

Acute antibody-mediated rejection (AMR) occurs in a small minority of sensitized liver transplant recipients. Although histopathological characteristics have been described, specific features that could be used (1) to make a generalizable scoring system and (2) to trigger a more in-depth analysis are needed to screen for this rare but important finding. Toward this goal, we created training and validation cohorts of putative acute AMR and control cases from 3 high-volume liver transplant programs; these cases were evaluated blindly by 4 independent transplant pathologists. Evaluations of hematoxylin and eosin (H&E) sections were performed alone without knowledge of either serum donor-specific human leukocyte antigen alloantibody (DSA) results or <em>complement</em> <em>component</em> <em>4d</em> (C<em>4d</em>) stains. Routine histopathological features that strongly correlated with severe acute AMR included portal eosinophilia, portal vein endothelial cell hypertrophy, eosinophilic central venulitis, central venulitis severity, and cholestasis. Acute AMR inversely correlated with lymphocytic venulitis and lymphocytic portal inflammation. These and other characteristics were incorporated into models created from the training cohort alone. The final acute antibody-mediated rejection score (aAMR score)--the sum of portal vein endothelial cell hypertrophy, portal eosinophilia, and eosinophilic venulitis divided by the sum of lymphocytic portal inflammation and lymphocytic venulitis--exhibited a strong correlation with severe acute AMR in the training cohort [odds ratio (OR) = 2.86, P < 0.001] and the validation cohort (OR = 2.49, P < 0.001). SPSS tree classification was used to select 2 cutoffs: one that optimized specificity at a score>> 1.75 (sensitivity = 34%, specificity = 86%) and another that optimized sensitivity at a score>> 1.0 (sensitivity = 81%, specificity = 71%). In conclusion, the routine histopathological features of the aAMR score can be used to screen patients for acute AMR via routine H&E staining of indication liver transplant biopsy samples; however, a definitive diagnosis requires substantiation by DSA testing, diffuse C<em>4d</em> staining, and the exclusion of other insults.

There is a paucity of data concerning the correlation of <em>complement</em> <em>component</em> <em>4d</em> (C<em>4d</em>) staining in liver allografts and antibody-mediated rejection. Data about the location and character of C<em>4d</em> deposits in native and allograft liver tissues are inconsistent. We performed C<em>4d</em> immunofluorescence (IF) on 141 fresh-frozen liver allograft biopsy samples and native livers, documented the pattern of C<em>4d</em> IF staining, and correlated the findings with the presence of donor-specific alloantibodies (DSAs). A linear/granular sinusoidal pattern of C<em>4d</em> IF was noted in 18 of 28 biopsy samples obtained after transplantation from patients with positive crossmatch and detectable donor-specific alloantibody (pos-XM/DSA) findings. None of the 59 tested biopsy samples from patients with negative crossmatch and detectable donor-specific alloantibody (neg-XM/DSA) findings were C<em>4d</em>-positive (P < 0.001). No significant association was found between pos-XM/DSA and C<em>4d</em> IF staining in other nonsinusoidal liver compartments. To compare the results of sinusoidal C<em>4d</em> staining with IF and 2 immunohistochemistry (IHC) techniques, C<em>4d</em> IHC was performed on 19 liver allograft biopsy samples in which a sinusoidal pattern of C<em>4d</em> IF had been noted. Sinusoidal C<em>4d</em> IHC findings were negative for 17 of the 19 biopsy samples; 2 showed weak and focal staining, and both patients had pos-XM/DSA findings. Portal vein endothelium staining was present in only 1 IF-stained biopsy sample (pos-XM/DSA) but in 11 IHC-stained biopsy samples (2 of the 11 samples had neg-XM/DSA findings). We conclude that sinusoidal C<em>4d</em> deposits detected by IF in frozen tissue samples from liver allograft recipients correlate with the presence of DSAs and an antibody-mediated alloresponse. These observations are similar to findings reported for other solid organ transplants and can provide relevant information for patient management. Further validation of IHC techniques for C<em>4d</em> detection in liver allograft tissue is required.

De novo immune hepatitis (DNIH) is a form of late graft dysfunction after liver transplantation. The fine mechanisms leading to the development of DNIH are not known, and whether this hepatitis is a form of rejection or a result of an auto/alloimmune injury has not been established. In our patients, DNIH was always preceded by the production of donor-specific antibodies against the glutathione S-transferase T1 (GSTT1) enzyme because of a genetic mismatch in which the donors carried the wild-type gene and the recipients displayed the null genotype. <em>Complement</em> <em>component</em> <em>4d</em> (C<em>4d</em>) immunopositivity in 12 paraffin-embedded liver biopsy samples from 8 patients diagnosed with DNIH associated with anti-GSTT1 antibodies was retrospectively evaluated. Six patients with a diagnosis of chronic rejection (CR) and 7 patients with hepatitis C virus recurrence were included as control groups. Among the patients with DNIH, 7 showed C<em>4d</em>-positive immunostaining localized in the portal tracts, whereas in the tested biopsy samples of the 2 control groups, this staining pattern was absent. Four biopsy samples of the CR group showed C<em>4d</em>-positive sinusoidal staining. This study confirms the activation of the <em>complement</em> pathway in the presence of donor-specific antibodies, which was shown by the deposition of C<em>4d</em> elements in liver biopsy samples of patients with DNIH. The use of C<em>4d</em> as a marker of antibody-mediated rejection in liver allografts in the presence of antidonor antibodies is discussed, and it may contribute to improved differential diagnoses based on biopsy findings.

<em>Complement</em> regulation leads to the generation of <em>complement</em> split products (CSPs) such as <em>complement</em> <em>component</em> (C)<em>4d</em>, a marker for disease activity in autoimmune syndromes or antibody-mediated allograft rejection. However, the physiologic role of C<em>4d</em> has been unknown. By screening murine thymoma BW5147 cells expressing a cDNA library generated from human monocyte-derived dendritic cells with recombinant human C<em>4d</em>, we identified Ig-like transcript (ILT)4 and ILT5v2 as cellular receptors for C<em>4d</em>. Both receptors, expressed on monocytes, macrophages, and dendritic cells, also interacted with the CSPs C3d, C4b, C3b, and iC3b. However, C<em>4d</em> did not bind to classic <em>complement</em> receptors (CRs). Interaction between cell surface-resident ILT4 and soluble monomeric C<em>4d</em> resulted in endocytosis of C<em>4d</em>. Surprisingly, binding of soluble ILT4 to C<em>4d</em> covalently immobilized to a cellular surface following classic <em>complement</em> activation could not be detected. Remarkably, C<em>4d</em> immobilized to a solid phaseviaits intrinsic thioester conferred a dose-dependent inhibition of TNF-α and IL-6 secretion in monocytes activatedviaFc-cross-linking of up to 50% as compared to baseline. Similarly, C<em>4d</em> conferred an attenuation of intracellular Ca(2+)flux in monocytes activatedviaFc-cross-linking. In conclusion, ILT4 represents a scavenger-type endocytotic CR for soluble monomeric C<em>4d</em>, whereas attenuation of monocyte activation by physiologically oriented C<em>4d</em> on a surface appears to be dependent on a yet to be identified C<em>4d</em> receptor.-Hofer, J., Forster, F., Isenman, D. E., Wahrmann, M., Leitner, J., Hölzl, M. A., Kovarik, J. K., Stockinger, H., Böhmig, G. A., Steinberger, P., Zlabinger, G. J. Ig-like transcript 4 as a cellular receptor for soluble <em>complement</em> fragment C<em>4d</em>.

Antibody-mediated rejection (AMR) is difficult to diagnose after ABO-compatible or ABO-identical (ABO-C) liver transplantation. To determine whether <em>complement</em> <em>component</em> <em>4d</em> (C<em>4d</em>) immunostaining would be useful for diagnosing AMR, we compared the results of C<em>4d</em> immunohistochemistry for allograft biopsy samples with assays for anti-donor antibodies performed at the time of biopsy. One hundred fourteen patients with ABO-C grafts and 29 patients with ABO-incompatible (ABO-I) grafts were included. Linear C<em>4d</em> endothelial staining (identifiable with a 4× objective lens) or staining seen in 50% or more of the portal tracts was considered positive. Five of the 114 patients (4%) with ABO-C grafts and 15 of the 29 patients (52%) with ABO-I grafts showed C<em>4d</em> positivity. In the ABO-C cases, C<em>4d</em> positivity in late biopsy samples (≥30 days after transplantation) was associated with stage 2 or higher fibrosis (METAVIR score; P = 0.01) and with the presence of donor-specific anti-human leukocyte antigen DR antibodies (HLA-DR DSAs) with a mean fluorescence intensity>> 5000 according to the Luminex single-antigen bead assay (P = 0.04). Conversely, the presence of HLA-DR DSAs was associated with the presence of stage 2 or higher fibrosis, acute cellular rejection, and C<em>4d</em> positivity. During the 2-year follow-up, neither C<em>4d</em> positivity nor HLA-DR DSAs were related to graft loss. Among ABO-I patients, C<em>4d</em> positivity was not associated with allograft dysfunction or fibrosis. Only 3 of the 15 C<em>4d</em>-positive patients (20%) showed periportal hemorrhagic edema, which could be a histological sign of AMR in ABO-I grafts, and they were the only cases associated with elevations in anti-donor A/B antibody titers. In conclusion, C<em>4d</em> endothelial positivity among ABO-C patients is an uncommon event that could be associated with chronic graft damage with or without clinical AMR. C<em>4d</em> positivity is common among ABO-I patients and may not be associated with allograft dysfunction if alloantibody titers are not elevated.

The significance of preexisting donor-specific HLA antibodies (HLA-DSAs) for liver allograft function is unclear. Our previous studies have shown that humoral alloreactivity frequently accompanies acute cellular rejection (ACR). In the present study, we set out to determine whether pretransplant HLA-DSAs correlate with clinically significant ACR in the first 90 days after transplantation and, if so, to determine their predictive values. Class I HLA-DSAs and class II HLA-DSAs were determined by single-antigen bead flow cytometry for 113 consecutive adult transplants. A statistical analysis was performed for data from 109 consecutive patients with graft survival greater than or equal to 90 days. All patients who developed biochemical graft dysfunction underwent liver biopsy for hematoxylin-eosin and <em>complement</em> <em>component</em> <em>4d</em> staining. Cox proportional hazards models and associated hazard ratios revealed a significant association of pretransplant HLA-DSAs with clinically significant ACR: this association started with a mean fluorescence intensity (MFI) as low as 300 for both class I (hazard ratio = 2.7, P < 0.01) and class II (hazard ratio = 6.0, P < 0.01). Pretransplant HLA-DSAs were associated with an increased risk of ACR: P < 0.01 for class I (42% versus 18%), P < 0.001 for class II (37% versus 7%), and P < 0.001 for either class I or II (36% versus 3%). Class I or II HLA-DSAs with an MFI ≥ 1000 had the best positive predictive value for clinically significant ACR at 46%, whereas class I or II HLA-DSAs with an MFI ≥ 300 had the best negative predictive value at 97.1%. Although our study was based on consecutive patients, it was limited by the relatively low number of single-center subjects. In conclusion, the present study indicates that pretransplant HLA-DSAs, even at low levels of allosensitization, correlate with the risk of clinically significant ACR. Our findings suggest that anti-human leukocyte antigen antibodies could serve as donor-specific markers of immunoreactivity to the liver graft.

Only limited information is available on the role of <em>complement</em> activation in malignant pleural mesothelioma (MPM). Thus, we investigated the circulating and tissue levels of the <em>complement</em> <em>component</em> <em>4d</em> (C<em>4d</em>) in MPM. Plasma samples from 55 MPM patients, 21 healthy volunteers (HV) and 14 patients with non-malignant pleural diseases (NMPD) were measured by ELISA for C<em>4d</em> levels. Tissue specimens from 32 patients were analyzed by C<em>4d</em> immunohistochemistry. Tumor volumetry was measured in 20 patients. We found no C<em>4d</em> labeling on tumor cells, but on ectopic lymphoid structures within the tumor stroma. Plasma C<em>4d</em> levels did not significantly differ between MPM, HV or NMPD. Late-stage MPM patients had higher plasma C<em>4d</em> levels compared to early-stage (p = 0.079). High circulating C<em>4d</em> was associated with a higher tumor volume (p = 0.047). Plasma C<em>4d</em> levels following induction chemotherapy were significantly higher in patients with stable/progressive disease compared to those with partial/major response (p = 0.005). Strikingly, patients with low C<em>4d</em> levels at diagnosis had a significantly better overall survival, confirmed in a multivariate cox regression model (hazard ratio 0.263, p = 0.01). Our findings suggest that circulating plasma C<em>4d</em> is a promising new prognostic biomarker in patients with MPM and, moreover, helps to select patients for surgery following induction chemotherapy.

The effect of preformed donor-specific antibodies (DSAs) on liver transplantation (LT) remains unclear, especially in the field of living donor LT (LDLT). Herein, we evaluated the prevalence of preformed DSAs and their effect on graft outcome in LDLT in the first year following surgery. Using the Luminex® Single Antigen assay, we analyzed the preoperative sera of 61 adult LDLT recipients between 2014 and 2015. Clinical outcomes and pathologic findings including <em>complement</em> <em>component</em> <em>4d</em> (C<em>4d</em>) expression in the first year after LT were retrospectively reviewed. Regardless of the class of DSA, DSAs with mean fluorescence intensity (MFI) ≥1000 were defined as positive and preformed DSA with MFI ≥5000 was defined as strongly positive. Fifteen patients (24.6%) had preformed DSAs, and 8 patients (13.1%) showed strongly positive preformed DSAs. Among 15 DSA positive patients, 2 (13.3%) showed persistent DSAs after LDLT. No de novo DSAs were noted in patients without preformed DSAs. Preformed DSAs were not related to graft dysfunction, laboratory values, or C<em>4d</em> expression or other pathologic findings in the first year of LDLT. In conclusion, preformed DSAs persisted during follow-up in 13.3% of cases and did not have adverse effect on histologic or clinical outcomes in the first year of LDLT.

The signature lesion of SSA/Ro autoantibody-associated congenital heart block (CHB) is fibrosis and a macrophage infiltrate, supporting an experimental focus on cues influencing the fibroblast <em>component</em>. The transcriptomes of human fetal cardiac fibroblasts were analyzed using two <em>complement</em>ary approaches. Cardiac injury conditions were simulated in vitro by incubating human fetal cardiac fibroblasts with supernatants from macrophages transfected with the SSA/Ro-associated noncoding Y ssRNA. The top 10 upregulated transcripts in the stimulated fibroblasts reflected a type I interferon (IFN) response [e.g., IFN-induced protein 44-like (IFI44L), of MX dynamin-like GTPase (MX)1, MX2, and radical S-adenosyl methionine domain containing 2 (Rsad2)]. Within the fibrotic pathway, transcript levels of endothelin-1 (EDN1), phosphodiesterase (PDE)<em>4D</em>, chemokine (C-X-C motif) ligand (CXCL)2, and CXCL3 were upregulated, while others, including adenomedullin, RAP guanine nucleotide exchange factor 3 (RAPGEF3), tissue inhibitor of metalloproteinase (TIMP)1, TIMP3, and dual specificity phosphatase 1, were downregulated. Agnostic Database for Annotation, Visualization and Integrated Discovery analysis revealed a significant increase in inflammatory genes, including <em>complement</em> C3A receptor 1 (C3AR1), F2R-like thrombin/trypsin receptor 3, and neutrophil cytosolic factor 2. In addition, stimulated fibroblasts expressed high levels of phospho-MADS box transcription enhancer factor 2 [a substrate of MAPK5 (ERK5)], which was inhibited by BIX-02189, a specific inhibitor of ERK5. Translation to human disease leveraged an unprecedented opportunity to interrogate the transcriptome of fibroblasts freshly isolated and cell sorted without stimulation from a fetal heart with CHB and a matched healthy heart. Consistent with the in vitro data, five IFN response genes were among the top 10 most highly expressed transcripts in CHB fibroblasts. In addition, the expression of matrix-related genes reflected fibrosis. These data support the novel finding that cardiac injury in CHB may occur secondary to abnormal remodeling due in part to upregulation of type 1 IFN response genes.NEW & NOTEWORTHY Congenital heart block is a rare disease of the fetal heart associated with maternal anti-Ro autoantibodies which can result in death and for survivors, lifelong pacing. This study provides in vivo and in vitro transcriptome-support that injury may be mediated by an effect of Type I Interferon on fetal fibroblasts.

OBJECTIVE

To evaluate the complement system in cord blood and its relationship with the degree of maturation and intrauterine growth.

METHODS

Serum levels of C(3), C(4) and CH(50) were measured in premature, small for gestational age and appropriate for gestational age newborns. The activation of complement system was searched by clivage product determination C(3d) and C(4d). Serum IgG levels were also determined in all children.

RESULTS

The levels of C(3), C(4), CH(50) and IgG were significantly lower in preterm (p < 0,001); C(4) and IgG values were also significantly lower in small for date than those in normal newborn. C(3d) and C(4d) were not detected, indicating that the complement system had not been activated.

CONCLUSIONS

The lower complement component levels and IgG in newborn are related to gestational age as well as to intrauterine growth.

We present a 47-year-old woman with a 10-year disease course consisting of episodic confusion, aphasia, psychosis, depression, migrainous headaches and seizures. There was mild elevation of protein levels in the cerebrospinal fluid, progressive cerebral atrophy, and numerous small T1 hypointensities appearing as central "holes" in the corpus callosum on magnetic resonance imaging. She eventually expired due to status epilepticus and subsequent significant respiratory complications. In the central nervous system, there was generalized brain atrophy, and patchy labeling of blood vessels by antibodies to <em>complement</em> <em>component</em> <em>4d</em> (C<em>4d</em>) and membrane attack complex. Innumerable small patches with loss of cell bodies (neurons and glial cells in gray matter and glial cells in white matter) and demyelination were scattered throughout the brain and spinal cord. There was no cavitation and the passing axons were mostly preserved. Large solid calcified foci were present predominantly in the pons along with disseminated focal calcification involving neuron cell bodies, neurites, and capillaries. Patchy labeling of glial cells and linear structures suggestive of myelin sheaths with C<em>4d</em> antibodies was observed while immunostains for SV40, tau, amyloid-β, alpha synuclein, p62, and trans-activation response DNA-binding protein 43 kDa were negative. Whole-exome sequencing did not reveal any clinically significant variants. Although the radiological findings are suggestive of Susac's syndrome (a rare condition characterized by encephalopathy, hearing loss, and branch retinal artery occlusion), in the absence of audiovisual manifestations, a definitive diagnosis cannot be rendered and therefore, this case may be representing a new entity. Further reports of similar cases are needed for clarification.

Objectives: Autoimmune hepatitis (AIH) is a form of severe hepatitis that can recur after orthotopic liver transplant (OLT). Presentation of AIH in patients with OLT who do not have a history of AIH is called de novo AIH (DNAIH). We evaluated the clinicopathologic characteristics of AIH and DNAIH.

Methods: Clinicopathologic and outcome measures of 11 patients with recurrent AIH (RAIH) and 22 with DNAIH identified between 2000 and 2017 were compared.

<strong class="sub-title"> Results: </strong> Both cohorts showed female predominance. The mean clinical follow-up was 13 and 7.8 years in the in the RAIH and DNAIH groups, respectively (P = .1). Moderate portal inflammation was more common in patients with RAIH (64% vs 27%, P = .043). A trend was observed for more cases of DNAIH showing severe inflammation (36% vs 9%, P = .09) and submassive necrosis compared with RAIH (23% vs 0%, P = .086). A trend for more advanced fibrosis was also noted in the RAIH group (27% vs 5%, P = .059). Three patients with RAIH lost their grafts because of RAIH. Five-year disease-specific graft survival (GS) (P = .012) and overall GS (P = .015) were worse in patients with RAIH. <em>Complement</em> <em>component</em> <em>4d</em> immunohistochemistry was positive in 2 patients with RAIH and 3 with DNAIH but showed no correlation with GS or other parameters.

Conclusions: RAIH seems to have a more aggressive clinical course than DNAIH and warrants closer clinical follow-up and aggressive treatment.

<strong class="sub-title"> Keywords: </strong> Acute cellular rejection (ACR); Autoimmune hepatitis (AIH); <em>Complement</em> <em>component</em> <em>4d</em> (C<em>4d</em>); De novo autoimmune hepatitis (DNAIH); Liver transplantation; Orthotopic liver transplant (OLT); Recurrent autoimmune hepatitis (RAIH).

Lodging is one of the main factors in reducing the yield and grain quality of winter and spring wheat varieties. The resistance of wheat cultivars to lodging largely depends on environmental factors, biological and morphological features of the stem and root systems. Selection of the varieties for resistance to lodging is relevant in many countries of the world and has a number of achievements. Plant height is one of the most important morphological characters associated with lodging resistance. Breeding of the varieties carrying the dwarfing genes (Rht) is the main direction to reduce the risk of lodging. The Rht-B1b, Rht-D1b, Rht8 and Rht11 genes are widely used throughout the world due to their significant influence on agronomically valuable traits, including lodging. It turned out to be important to study the anatomical and morphological features and chemical composition of stem tissues, which <em>complement</em> the assessment of resistance to lodging and allow the varietal material to be more fully characterized. The thickness of stem internodes and their anatomical structure play an important role in the stem strength. The diameter of the stem, its thickness and weight, a large number of vascular bundles and a wide ring of mechanical tissues correlate with resistance to lodging. The content of lignin, silicon and cellulose are important structural <em>components</em> and provide the stem strength of wheat plants. Molecular genetic analysis and mapping of genes and quantitative trait loci are of great importance in identifying the genetic basis of the relationship between the anatomical and morphophysiological characters of the stem and root system and lodging. Genetic factors reflecting correlations between the lodging and the thickness of the stem wall, the number of vascular bundles and other characters were mapped to chromosomes 1A, 1B, 2A, 2D, 3A, 4B, <em>4D</em>, 5A, 5D, 6D and 7D. It has been found that loci with high phenotypic effects on lodging tolerance are colocalized with loci responsible for plant height, stem diameter and stem strength. To increase resistance to lodging, it is necessary to develop a set of agrotechnical methods that reduce the influence of soil and climatic factors and create wheat varieties tolerant to lodging.

Полегание является одной из основных проблем снижения урожайности и качества зерна озимой и яровой пшеницы. Устойчивость этой культуры к полеганию в значительной степени зависит от факторов внешней среды, биологических и морфологических особенностей стебля и корневой системы. Селекция сортов на устойчивость к полеганию актуальна во многих странах мира, и в данном направлении получен ряд достижений. Высота растений – важный морфологический признак, связанный с устойчивостью к полеганию. Основным направлением для снижения риска возникновения полегания стало выведение сортов, несущих гены короткостебельности (Rht). Гены Rht-B1b, Rht-D1b, Rht8, Rht11 получили широкое распространение во всем мире среди сортов мягкой пшеницы благодаря значительному влиянию на хозяйственно ценные признаки, включая полегание. Немаловажным оказалось изучение анатомо-морфологических особенностей и химического состава тканей стебля, которые дополняют оценку устойчивости к полеганию и позволяют более полно характеризовать изучаемый сортовой материал. Особенно большую роль в прочности стебля многие исследователи отводят толщине стенок междоузлий и их анатомическому строению. Диаметр соломины, ее толстостенность и вес, большое количество сосудистых пучков и широкое кольцо механических тканей коррелируют с устойчивостью к полеганию. Важными структурными компонентами, обеспечивающими прочность стебля у пшеницы, являются содержание лигнина, кремния и целлюлозы. Большое значение в выявлении генетической основы взаимоотношений между анатомическими и морфофизиологическими признаками стебля и корневой системы и полеганием имеют молекулярно-генетический анализ и картирование генов и локусов количественных признаков. Генетические факторы, отражающие корреляции между полеганием и толщиной стенки стебля, числом проводящих пучков и другими параметрами, были картированы в хромосомах 1А, 1B, 2A, 2D, 3A, 4B, <em>4D</em>, 5A, 5D, 6D и 7D. Установлено, что локусы с высоким фенотипическим эффектом в отношении толерантности к полеганию колокализуются с локусами, ответственными за высоту растения, диаметр и прочность стебля. Для повышения устойчивости к полеганию необходимы разработка комплекса агротехнических методов, снижающих влияние почвенноклиматических факторов, и создание толерантных к полеганию сортов.

Keywords: Rht genes; anatomical and morphological characters; lignin; lodging; stem; wheat.