Distinct B cell profiles characterise healthy weight and obesity pre- and post-bariatric surgery.

BACKGROUND/OBJECTIVES: Obesity-associated metabolic dysfunction and inflammation can be ameliorated by bariatric surgery. While obesity is also linked to impaired B cell activation, differentiation, and persistence in response to infection and vaccination little is known about post-operative immune B cell compartment and to what extent dysregulation in B cell pathways can be reversed. To bridge this gap in knowledge, we carried out in-depth evaluation of B cell composition in individuals with obesity prior to and following bariatric surgery compared to lean controls. SUBJECTS/METHODS: We recruited individuals with obesity (BMI at least 35 kg/m2) before bariatric surgery (n = 21) and followed them up 6 months post-operatively (n = 17). As controls we recruited age- and sex-matched lean (BMI < 25) individuals (n = 18). We carried out comprehensive immunophenotyping of peripheral blood B cells as well as interrogated their association with inflammatory and metabolic parameters. RESULTS: In obesity the balance of antigen-inexperienced and memory B cells in the peripheral blood is altered, with an expansion of naïve and a reduction in total memory B cells. 6 months following bariatric surgery this balance is restored. However, post-operative patients are uniquely characterised by an increase in B cell subsets associated with chronic inflammation - CD11c+CXCR5-IgD-CD27- double negative 2 (DN2) B cells and CD27+CD38++ plasmablasts. Correlations between B cells subsets, inflammatory and metabolic parameters were distinct in lean people and individuals with obesity pre- and post-bariatric surgery. CONCLUSIONS: Bariatric surgery patients display a unique B cell profile 6 months post-operatively; this bears minimal resemblance to that of pre-operative patients and only partially overlaps with that of lean controls. Post-operative differences in the B cell compartment compared to lean controls are detected despite global amelioration of inflammation and restoration of metabolic health. Collectively, this indicates that bariatric surgery creates a specific immunometabolic state with potential implications for health outcomes.

Dickkopf-related protein 1 expression in bone marrow of multiple myeloma patients: correlation with bone disease and plasma cell malignancy type.

BACKGROUND: Previous studies have pointed out the role of dickkopf-related protein 1 (DKK 1) - Wnt inhibitor, which is essential for osteoblast functioning, in the development of osteolytic lesions in multiple myeloma (MM). AIM: To assess the DKK 1 expression displayed by myeloma cells in bone marrow trephine biopsies of patients with and without osteolytic lesions, and in different malignancy grades of the disease. METHODS: The expression level of DKK 1 was assessed immunohistochemically in bone marrow of 49 MM patients presented with and without osteolytic lesions (the 1st and the 2nd group, respectively). RESULTS: Levels of weak, moderate, and strong DKK 1 expression were distributed - as 43.33, 27.78 and 25.56%, and 63.91, 18.80, and 1.50%, respectively when evaluating the samples obtained from the 1st and the 2nd group. Statistically significant differences were found when the levels of DKK 1 expression in the 1st and the 2nd group were compared (χ2 = 51; df = 3; p < 0.001). CONCLUSIONS: DKK 1 contributes to the development of osteolytic lesions in MM. The present study provides morphological evidence that inhibition in Wnt signaling may lead to bone damage observed in the advanced stage of the disease.

Current Echocardiographic Techniques for Evaluation of the Right Ventricle.

The review is dedicated to the new echocardiographic techniques in the assessment of right ventricular (RV) function, such as twodimensional speckle tracking and determining the RV volume by a three-dimensional model. Subclinical changes in RV function are of great importance for the diagnosis and assessment of prognosis of multiple cardiovascular as well as non-cardiac pathologies. Two-dimensional speckle tracking allows to assess longitudinal strain of the RV myocardium and to detect pathological changes before their clinical manifestations. Three-dimensional echocardiography enables calculation of the RV ejection fraction, what was not possible before with the use of ultrasound. Currently, both methods are promising for a comprehensive assessment of RV function.

[Current Echocardiographic Techniques for Evaluation of the Right Ventricle].

The review is dedicated to the new echocardiographic techniques in the assessment of right ventricular (RV) function, such as two-dimensional speckle tracking and determining the RV volume by a three-dimensional model. Subclinical changes in RV function are of great importance for the diagnosis and assessment of prognosis of multiple cardiovascular as well as non-cardiac pathologies. Two-dimensional speckle tracking allows to assess longitudinal strain of the RV myocardium and to detect pathological changes before their clinical manifestations. Three-dimensional echocardiography enables calculation of the RV ejection fraction, what was not possible before with the use of ultrasound. Currently, both methods are promising for a comprehensive assessment of RV function.

Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient.

UNLABELLED: Progressive multifocal leukoencephalopathy (PML) is a neurological disease caused by infection of the central nervous system (CNS) with the JC polyomavirus (JCV). JCV is endemic and infects a large proportion (70-90%) of healthy individuals worldwide, but infection is latent. JCV reactivation may occur, if the immune function is compromised. AIM: To present a PML case in a CLL patient after a long course of disease and treatment with fludarabine. JCV virus infection in this patient was proven both in brain biopsy material and blood. METHODS: Patient with a nine-year history of CLL was hospitalized with the weakness in the right leg and left hand, tremors, speech difficulties. An MRI diagnosed infiltrative glial tumor of the left hemisphere, proliferating predominantly in the frontal lobe, more in the gyrus frontalis superior region. CNS tumor biopsy performed. RESULTS: Morphology and immunoprofile of the lesion consistent with progressive multifocal leukoencephalopathy. The material from biopsy was diagnosed as positive for JCV DNA. JCV and HHV-7 genomic sequences were found in patient's PBL DNA sample. In a plasma DNA sample, only genomic sequences were detected. CONCLUSION: The present case draws attention to the fact that the use of fludarabine and its combinations in CLL therapy increases the risk of JCV infection reactivation and development of serious complications like PML.

Unfolded protein response is involved in the pathology of human congenital hypothyroid goiter and rat non-goitrous congenital hypothyroidism.

The unfolded protein response (UPR) is an intracellular signaling pathway that regulates the protein folding and processing capacity of the endoplasmic reticulum (ER). The UPR is induced by the pharmacological agents that perturb ER functions but is also activated upon excessive accumulation of the mutant secretory proteins that are unable to attain correct three-dimensional structure and are thus retained in the ER. Such defects in intracellular protein transport underlie the development of a number of phenotypically diverse inherited pathologies, termed endoplasmic reticulum storage diseases (ERSD). We have studied UPR development in two similar ERSDs, human congenital goiter caused by the C1264R and C1996S mutations in the thyroglobulin (Tg) gene and non-goitrous congenital hypothyroidism in rdw dwarf rats determined by the G2320R Tg mutation. In both cases, these mutations rendered Tg incapable of leaving the ER. A major ER chaperone immunoglobulin-binding protein (BiP), and a novel putative escort chaperone endoplasmic reticulum protein 29 KDa (ERp29) were found to be associated with Tg, which might be interpreted as the contribution of the quality control machinery to the previously shown retention of Tg in the ER. We have extended our earlier observations of ER chaperone induction with the identification of the additional ER (ERp29, ERp72, calreticulin, protein disulfide isomerase (PDI)), cytoplasmic (heat shock protein (HSP)70, HSP90) and mitochondrial (mtHSP70) upregulated chaperones and folding enzymes. Activation of the transcriptional arm of UPR, as judged by the appearance of the spliced (active) form of X-box binding protein (XBP1) and processed activating transcription factor 6 (ATF6) transcription factors was suggested to contribute to the overexpression of the ER chaperones. The processing of ATF6 was observed in both human and rat tissues with Tg mutations. Whereas, in human tissues, weak splicing of XBP1 mRNA was detected only in the C1264R mutant, all rat thyroids including wild-type contained significant amounts of the spliced form of XBP1 as opposed to human liver and rat brain tissues, implying the existence of a previously unknown tissue-specific regulation of XBP1 processing.