Changes in health among Syrian refugees along their migration trajectories from Lebanon to Norway: a prospective cohort study.

OBJECTIVES: Conflict-driven displacement is an indisputable social determinant of health. Yet, data on changes in health along the migration trajectories of refugees are scarce. This study aims to assess the longitudinal changes in somatic and mental health and use of medication among Syrian refugees relocating from a conflict-near transit setting in the Middle East to a resettlement setting in Europe. Further, we examine different health status trajectories and factors that predict health in the early postmigration period. STUDY DESIGN: This is a prospective cohort study. METHODS: Survey data were collected during 2017-2018 among adult Syrian refugees in Lebanon selected for quota resettlement and at follow-up approximately one year after resettlement in Norway. Our primary outcomes were non-communicable disease (NCD), chronic impairment, chronic pain, anxiety/depression, post-traumatic stress symptoms, and daily use of drugs. We estimated longitudinal changes in prevalence proportions using generalized estimating equations and evaluated effect modification of health outcomes. RESULTS: Altogether, 353 Syrians participated. NCDs declined (12%-9%), while the prevalence of chronic impairment, chronic pain, and use of drugs remained nearly unchanged (29%-28%, 30%-28%, and 20%-18%) between baseline and follow-up. Conversely, mental health outcomes improved (anxiety/depression 33%-11%, post-traumatic stress disorder 5%-2%). Effect modifiers for improvement over time included younger age, short length of stay, and non-legal status in the transit country before resettlement in Europe. CONCLUSIONS: We find that mental health outcomes improve from a conflict-near transit setting in Lebanon to an early resettlement setting in Norway, while somatic health outcomes remain stable. Temporal changes in health among moving populations warrant attention, and long-term changes need further scrutiny.

Differentiated thyroid carcinoma in early adulthood patients.

BACKGROUND: This paper reviews the clinico-pathologic features and outcomes of differentiated thyroid -carcinoma in early adulthood patients. STUDY DESIGN: Retrospective study. MATERIAL: From january 2000 to december 2012, 71 patients aged between 20 and 44 years who underwent thyroidectomy for differentiated thyroid carcinoma were included. The following parameters were recorded : age, gender, pre-operative symptoms and diagnosis, thyroid hormonal status, substernal extension, operative details, preoperative and postoperative calcium and phosphorous values, perioperative complications, length of hospital stay, final histology, survival and disease progression. RESULTS: There were 59 females (83%) and 12 males with a median age of 29 years (20-44 years). None had a previous neck irradiation. Total thyroidectomy was performed on 65 patients (92%). There were 66 papillary (93%) and 5 follicular carcinomas. Extrathyroidal invasion and lymph node involvement were present in 44% and 37% of cases respectively. Transient hypocalcemia and dysphonia occurred in 15% and 4 % of cases respectively. Permanent hypocalcemia and vocal cord paralysis occurred in 1% and 0% of cases respectively. Adjuvant radioactive I(131) therapy was given to 50 patients. There were 7 cases (10%) of lymph node recurrences but no disease-related deaths. The only statistical differences between this group and all ages group were the extracapsular invasion (44% vs 20% p = 0,0014) and lymph node metastasis (37% vs 18% p = 0,0091). CONCLUSIONS: Differentiated thyroid carcinoma has a good prognosis in early adulthood patients. Although death from this condition is rare, recurrence is frequent and long term follow up is mandatory.

Inhibition by new glucocorticoid antedrugs [16α, 17α-d] isoxazoline and [16α, 17α-d]-3'-hydroxy-iminoformyl isoxazoline derivatives of chemotaxis and CCL26, CCL11, IL-8, and RANTES secretion.

The underlying inflammation present in chronic airway diseases is orchestrated by increased secretion of CC and CXC chemokines that selectively recruit the leukocyte populations into the pulmonary system. Human chemokines, eotaxins (CCL11 and CCL26), RANTES, and interleukin (IL)-8, are dramatically upregulated through G-protein receptors in cell inflammation, including human asthma. In previous studies, a series of new glucocorticoid antedrugs (GCAs) were synthesized as derivatives of isoxazoline and oxime, and their pharmacological properties based on the antedrug concepts were evaluated. Utilizing both human airway epithelium (HAE) and eosinophil (EOS) cell culture models, we carried out studies to test the hypothesis that new GCA cell treatment would ameliorate Th-1/Th-2-driven secretion of these asthmatic biomarkers, eotaxins (CCL11 and CCL26), RANTES, and IL-8 chemokines, that would in turn decrease recruitment, proliferation, and activation of EOS cells. Results demonstrate that isoxazoline and oxime derivatives exhibit concentration-dependent inhibition, and specifically the compound No. 7 decreases significantly the secretion of eotaxins, RANTES, and IL-8 in cytokine-stimulated HAE cells. It was shown that EOS proliferation and activation were reduced considerably, and cell apoptosis occurred when exposed to nonfluorinated isoxazoline derivatives. These results provide evidence that concentration and structural manipulation of GCAs could increase the anti-inflammatory potency in treatment of chronic diseases, including asthma.

CCL26-targeted siRNA treatment of alveolar type II cells decreases expression of CCR3-binding chemokines and reduces eosinophil migration: implications in asthma therapy.

The underlying inflammation present in chronic airway diseases is orchestrated by increased expression of CC chemokines that selectively recruit leukocyte populations into the pulmonary system. Human CCL26 signals through CC chemokine receptor 3 (CCR3), is dramatically upregulated in challenged asthmatics, and stimulates recruitment of eosinophils (EOSs) and other leukocytes. CCL26 participates in regulation of its receptor CCR3 and modulates expression of a variety of chemokines in alveolar type II cells. Utilizing the A549 alveolar type II epithelial cell culture model, we carried out studies to test the hypothesis that CCL26-siRNA treatment of these cells would ameliorate Th2-driven release of the eotaxins and other CCR3 ligands that would, in turn, decrease recruitment and activation of EOSs. Results demonstrate that CCL26-siRNA treatments decreased interleukin-4-induced CCL26 and CCL24 expression by >70%. CCL26-directed small-interfering RNA (siRNA) treatments significantly decreased release of CCL5 (RANTES), CCL15 (MIP-1δ), CCL8 (MCP-2), and CCL13 (MCP-4). In bioactivity assays it was shown that EOS migration and activation were reduced up to 80% and 90%, respectively, when exposed to supernatants of CCL26-siRNA-treated cells. These results provide evidence that CCL26 may be an appropriate target for development of new therapeutic agents designed to alleviate the underlying inflammation associated with chronic diseases of the airways.

Post-transcriptional silencing of CCR3 downregulates IL-4 stimulated release of eotaxin-3 (CCL26) and other CCR3 ligands in alveolar type II cells.

Trafficking and inflammation in airway diseases are, in part, modulated by members of the CC chemokine family, eotaxin-1 (CCL11), eotaxin-2 (CCL24), and eotaxin-3 (CCL26), which transduce signals through their CCR3 receptor. In this context, we hypothesized that transfecting alveolar type II epithelial cells with CCR3-targeted siRNA or antisense (AS-ODN) sequences will downregulate cellular synthesis and release of the primary CCR3 ligands CCL26 and CCL24 and will modulate other CCR3 ligands. The human A549 alveolar type II epithelium-like cell culture model was used for transfection and subsequent effects on CCR3 agonists. siRNAs were particularly effective. PCR showed a 60-80% decrease in mRNA and immunoblots showed up to 75-84% reduction of CCR3 in siRNA treated cells. CCR3-siRNA treatments reduced IL-4 stimulated CCL26 release and constitutive CCL24 release by 65% and 80%, respectively. Release of four additional CCR3 agonists RANTES, MCP-2, MCP-3 and MCP-4 was also significantly reduced by CCR3-siRNA treatments of the alveolar type II cells. Activation of eosinophils, assessed as superoxide anion generation, was reduced when eosinophils were treated with supernatants of A549 cells pretreated with CCR3-targeted siRNAs or AS-ODNs. Collectively, the data suggest that post-transcriptional regulation of CCR3 receptors may be a potential therapeutic approach for interrupting proinflammatory signaling.

Nucleolar assembly of the rRNA processing machinery in living cells.

To understand how nuclear machineries are targeted to accurate locations during nuclear assembly, we investigated the pathway of the ribosomal RNA (rRNA) processing machinery towards ribosomal genes (nucleolar organizer regions [NORs]) at exit of mitosis. To follow in living cells two permanently transfected green fluorescence protein-tagged nucleolar proteins, fibrillarin and Nop52, from metaphase to G1, 4-D time-lapse microscopy was used. In early telophase, fibrillarin is concentrated simultaneously in prenucleolar bodies (PNBs) and NORs, whereas PNB-containing Nop52 forms later. These distinct PNBs assemble at the chromosome surface. Analysis of PNB movement does not reveal the migration of PNBs towards the nucleolus, but rather a directional flow between PNBs and between PNBs and the nucleolus, ensuring progressive delivery of proteins into nucleoli. This delivery appeared organized in morphologically distinct structures visible by electron microscopy, suggesting transfer of large complexes. We propose that the temporal order of PNB assembly and disassembly controls nucleolar delivery of these proteins, and that accumulation of processing complexes in the nucleolus is driven by pre-rRNA concentration. Initial nucleolar formation around competent NORs appears to be followed by regroupment of the NORs into a single nucleolus 1 h later to complete the nucleolar assembly. This demonstrates the formation of one functional domain by cooperative interactions between different chromosome territories.

Effects of anti-fibrillarin antibodies on building of functional nucleoli at the end of mitosis.

During mitosis some nuclear complexes are relocalized at the chromosome periphery and are then reintegrated into the re-forming nuclei in late telophase. To address questions concerning translocation from the chromosome periphery to nuclei, the dynamics of one nucleolar perichromosomal protein which is involved in the ribosomal RNA processing machinery, fibrillarin, was followed. In the same cells, the onset of the RNA polymerase I (RNA pol I) activity and translocation of fibrillarin were simultaneously investigated. In PtK1 cells, RNA pol I transcription was first detected at anaphase B. At the same mitotic stage, fibrillarin formed foci of increasing size around the chromosomes, these foci then gathered into prenucleolar bodies (PNBs) and later PNBs were targeted into the newly formed nucleoli. Electron microscopy studies enabled the visualization of the PNBs forming the dense fibrillar component (DFC) of new nucleoli. Anti-fibrillarin antibodies microinjected at different periods of mitosis blocked fibrillarin translocation at different steps, i.e. the formation of large foci, foci gathering in PNBs or PNB targeting into nucleoli, and thereby modified the ultrastructural organization of the nucleoli as well as of the PNBs. In addition, antibody-bound fibrillarin seemed localized with blocks of condensed chromatin in early G1 nuclei. It has been found that blocking fibrillarin translocation reduced or inhibited RNA pol I transcription. It is postulated that when translocation of proteins belonging to the processing machinery is inhibited or diminished, a negative feed-back effect is induced on nucleolar reassembly and transcriptional activity.

When rDNA transcription is arrested during mitosis, UBF is still associated with non-condensed rDNA.

The mechanisms that control inactivation of ribosomal gene (rDNA) transcription during mitosis is still an open question. To investigate this fundamental question, the precise timing of mitotic arrest was established. In PtK1 cells, rDNA transcription was still active in prophase, stopped in prometaphase until early anaphase, and activated in late anaphase. Because rDNA transcription can still occur in prophase and late anaphase chromosomes, the kinetics of rDNA condensation during mitosis was questioned. The conformation of the rDNA was analyzed by electron microscopy from the G2/M transition to late anaphase in the secondary constriction, the chromosome regions where the rDNAs are clustered. Whether at transcribing or non-transcribing stages, non-condensed rDNA was observed in addition to axial condensed rDNA. Thus, the persistence of this non-condensed rDNA during inactive transcription argues in favor of the fact that mitotic inactivation is not the consequence of rDNA condensation. Analysis of the three-dimensional distribution of the rDNA transcription factor, UBF, revealed that it was similar at each stage of mitosis in the secondary constriction. In addition, the colocalization of UBF with non-condensed rDNA was demonstrated. This is the first visual evidence of the association of UBF with non-condensed rDNA. As we previously reported that the rDNA transcription machinery remained assembled during mitosis, the colocalization of rDNA fibers with UBF argues in favor of the association of the transcription machinery with certain rDNA copies even in the absence of transcription. If this hypothesis is correct, it can be assumed that condensation of rDNA as well as dissociation of the transcription machinery from rDNA cannot explain the arrest of rDNA transcription during mitosis. It is proposed that modifications of the transcription machinery occurring in prometaphase could explain the arrest of transcription, while reverse modifications in late anaphase could explain activation.

Relative distribution of rDNA and proteins of the RNA polymerase I transcription machinery at chromosomal NORs.

Using confocal and immunofluorescence microscopy the relative distribution of the ribosomal chromatin and some proteins of the RNA polymerase I transcription machinery such as upstream binding factor (UBF), RNA polymerase I and DNA topoisomerase I was analyzed on chromosomal nucleolus organizer regions (NORs) of PtK1 cells. Staining with various DNA fluorochromes revealed that the ribosomal chromatin may be found at the axial region of the NOR and also at lateral expansions around the axis that can also be detected by in situ hybridization. It was observed that the transcription machinery shows a crescent-shaped distribution around the axial ribosomal chromatin at the NOR of metaphase and anaphase chromatids. An ultrastructural analysis of serially sectioned NORs supports this crescent-shape organization. Taking into account previous and present results and the loop/scaffold model of chromosome structure, we propose a model of NOR organization. The model proposes that ribosomal genes that were inactive in the preceding interphase would be present as condensed short Q-loops occupying the axial region of the NOR. Ribosomal genes previously active during interphase would be undercondensed as large R-loops associated with the transcription machinery, which is distributed in a crescent-shaped fashion around the previously active ribosomal DNA.

Gray platelet syndrome. Dissociation between abnormal sorting in megakaryocyte alpha-granules and normal sorting in Weibel-Palade bodies of endothelial cells.

The gray platelet syndrome (GPS) is a rare congenital bleeding disorder in which megakaryocytes and platelets are deficient in alpha-granule secretory proteins. Since the Weibel-Palade bodies (WPB) of endothelial cells as well as the alpha-granules contain the von Willebrand Factor (vWF) and P-selectin, we examined by transmission electron microscopy the dermis capillary network of two patients with GPS. Endothelial cells showed the presence of normal WPB with typical internal tubules. Using single and double immunogold labeling for vWF and P-selectin, we detected vWF within WPB, where it was codistributed with the tubules, whereas P-selectin delineated the outline of WPB. Therefore, the fundamental targeting defect in GPS is specific to the megakaryocytic cell line.

Heterogeneous distribution of Weibel-Palade bodies and von Willebrand factor along the porcine vascular tree.

Vessels obtained from different levels of pig vascular tree were examined by transmission electron microscope, with the aim of determining whether or not their endothelial cells contain Weibel-Palade bodies (WPB). As these organelles are known to store the von Willebrand factor (vWF), a two-step immunogold labeling of this protein also was performed. Our results showed for the first time a heterogeneous distribution of WPB along the vascular tree of the normal pig: These structures were absent from the thoracic aorta, rare in the abdominal aorta, present in myocardial capillaries, and numerous in the inferior vena cava and pulmonary artery. Atypical WPB devoid of tubules were seen in all endothelial cells. The ultrastructural labeling of vWF demonstrated its presence only in the WPB, being absent in the subendothelium, and showed the same variation in its distribution along the vascular tree as for its storage organelle. Pigs homozygous for the von Willebrand disease were found to have only the atypical WPB, and do not express the vWF.

Weibel-Palade bodies in pig megakaryocytes.

Originally described in vascular endothelial cells, Weibel-Palade bodies were considered as specific of this cellular type, as they have never been reported elsewhere. Weibel-Palade bodies serve as storage granules for von Willebrand factor which is stored in microtubular form. Besides endothelial cells von Willebrand factor is also synthetized by bone marrow megakaryocytes. Von Willebrand factor has been located in alpha-granules of megakaryocytes and blood platelets. We describe true Weibel-Palade bodies in pig megakaryocytes, and also alpha-granules which look like an evolutionary form of Weibel-Palade bodies. Von Willebrand Factor is most likely stored in microtubular form in these two types of structure. This is supported by the absence of microtubules in these granules in cells obtained from pigs homozygous for the von Willebrand disease (lacking totally this protein).

Ultrastructure of human umbilical vessels: a possible role in amniotic fluid formation?

Human umbilical vessels obtained from neonates delivered at term after uneventful pregnancies were examined by light and transmission electron microscopy, with the aim of determining whether or not their structure is compatible with possible fluid exchange between the circulating blood and Wharton's jelly. A comparison of arteries and veins showed that although these vessels have common characteristics, they differ in some elements of their fine structure. The endothelium of both vessels appeared to be highly active metabolically. In the artery, the endothelial cells often protruded into the lumen. This aspect was related to the fine filaments concentrated in the basal part of the cells. This zone, free of organelles, was absent in the venous endothelium, but here pinocytotic vesicles and Weibel-Palade bodies were more abundant. The media included the same elements but was much thicker in the arteries than in the veins. There were two cellular types: typical myocytes and myofibroblasts rich in organelles. Their cytoplasmic processes extended into the interstitial space which was occupied by a material with a loose structure, that is, material containing a well-developed ground substance at the expense of the elastic and collagen fibres. The ultrastructural features of the umbilical vessels suggest an increased endothelial permeability, and it is suggested that transfer across the umbilical vessels may play a role in the formation of amniotic fluid.

[Structure and function of the fetal umbilical vessels]. / Structure et fonction des vaisseaux ombilicaux foetaux.

A morphological study carried out using electron microscopy has shown that there is an endothelium in the umbilical blood vessels consisting of intercellular spaces which interdigitate with one another and that are not specialization in junction complex. The endothelial cells are rich in their typical organ structure and have pinocytotic vesicles. There media contains a muscular coat which is thicker in the artery than in the veins. The smooth muscle cells also show pinocytotic vesicles. This morphological state leads the authors to two groups of thought: There is active diffusion by a process of "plasma perfusion" from the lumen of the vessels through the vascular wall which forms a physiological system for taking up fluids which in turn is capable of providing for the energy and plastic requirements of the umbilical vessels: The umbilical arteries, because of their thick muscular tunic and because of the ability of the lumen to dilate as there is an absence of an internal elastic membrane, can function not only as tubes for conducting blood but also as organs that regulate the blood flow. On the other hand the umbilical vein, which cannot stretch and cannot retract because its wall is so thin, behaves as an organ to return the blood flow, particularly because it does have an inner limiting layer preventing over-stretching.