Possible involvement of myofibroblast in the development of inflammatory aortic aneurysm

To clarify the role of myofibroblasts in the development of inflammatory aortic aneurysm (IAA), 11 cases of IAA (69.2+/-8.59 years) were investigated immunohistochemically and were morphometrically compared with 12 age-matched cases of atherosclerotic abdominal aneurysm (AAA, 69.6+/-5.94 years). The positivity of mantle sign and CRP was significantly higher in the IAA group than in the AAA group. The wall of IAA (5.41+/-1.47 mm) was significantly thicker than that of AAA (2.68+/-0.71 mm). A significant increase in the expression of alpha-smooth muscle actin was found in adventitial fibroblasts of IAA compared to those of AAA. The cell density and MIB-1 index of adventitial myofibroblasts were significantly higher in IAA than in AAA (cell density: 1.69+/-0.51 vs. 1.09+/-0.4 x 10(3) cells/mm(2); MIB-1 index: 5.25+/-2.97% vs. 1.55+/-0.71%). IAA showed a significantly lower area ratio (MAR) of adventitial microvessels than did AAA (2.92+/-1.49% vs. 7.51+/-2.64%). However, there was no significant difference in microvessel density (MVD) between IAA and AAA (84.62+/-50.5 vs. 65.1+/-32.6 vessels/mm(2)). In some cases of IAA, adventitial myofibroblasts expressed hypoxia-inducible factor 1alpha in their cytoplasm or nuclei while it was not detected in AAA. These findings suggest that the development of IAA may be partly mediated by the proliferation of adventitial myofibroblasts, which might be related to tissue hypoxia.     

An anomalous digastric muscle with three accessory bellies and one fibrous band

During our routine dissection studies we encountered an anomalous digastric muscle with three accessory bellies and one fibrous band in one embedded cadaver. All of these structures were attached to the mylohyoid raphe. This anomaly should be considered during surgical procedures involving this region.     

Myofibrosarcoma of the Upper Jawbones: A Clinicopathologic and Ultrastructural Study of Two Cases

Two problematic spindle cell sarcomas involving upper jawbones in two adult male patients have been studied by histology, immunohistochemistry, and transmission electron microscopy, and respectively graded as low-grade malignancy and high-grade malignancy. While any single methodological study did not allow confident classification of them into one or other of the classical categories of spindle cell sarcomas (fibrosarcoma versus leiomyosarcoma), the overall contribution from all three methodologiesultimately allowed them to be categorized as sarcomas with myofibroblastic differentiation. Histologically, both tumors had morphological features of an amalgama between neoplastic fibroblasts and smooth muscle cells. Immunohistochemically, both tumors expressed reactivity only for muscle specific actin and alpha smooth muscle actin, in addition to vimentin. Ultrastructurally, both tumors, while showing fibroblast-like cytoplasmic features, had a spurious and imperfectly organized cell surface defying convincing classification into any of specific categories (i.e., both appeared in terms of ultrastructure as poorly differentiated sarcoma, the former with low level of smooth muscle differentiation and possibly the presence of some fibronexus component, the latter with no smooth muscle differentiation but with possible evidence of very rare fibronectin fibril). Therefore, on balance, the most tenable diagnosis seemed to us that of a myofibrosarcoma in both cases. This work is presented considering the fact that myofibrosarcoma currently represents a topical theme of debate, and that this is the first report in medical literature concerning with myofibrosarcomas of the head and neck area in adults.     

Paragastric paraganglioma: a case report with unusual alveolar pattern and myxoid component

Paragangliomas are neural crest-derived neuroendocrine tumors. Nearly 5 to 10% occur in extraadrenal sites, from the upper cervical region to the pelvis, related to the autonomic nervous system. Very few cases of gastric or paragastric paragangliomas have been reported. We report a paraganglioma attached to the stomach of an 85-year-old man. The tumor was 15 cm in diameter and was surgically resected via a subtotal gastrectomy. Fine-needle aspiration smears showed round epithelioid cells forming acini and spindle cells attached to capillaries. Occasional cells showed excentric nuclei and pale vesicular cytoplasm. Microscopically, the tumor was characterized by an alveolar and solid pattern of growth with some unusual features, such as myxoid stroma and pseudoalveoli that contained myxoid material. Spindle cells stained with vimentin and S-100 protein, whereas epithelioid cells showed diffuse cytoplasmic staining with chromogranin A. Electron microscopy of the tumor tissue revealed the presence of neurosecretory granules. To the best of our knowledge, this pattern of growth has yet to be described in the literature and may result in a misdiagnosis if sufficient immunohistochemical markers are not employed. We briefly discuss the cytomorphological features and differential diagnosis of this tumor, which was discovered in a rare location.     

Cellular diversity of human placental stem villi: an ultrastructural and immunohistochemical study

The aim of the study was to investigate the distribution and differentiation of cell types in the stroma of human placental stem villi (SV). A total of 14 human term placental tissues were studied. Double immunolabeling was performed for desmin-vimentin, desmin--smooth actin and vimentin--smooth actin. Cytokeratin 7, proliferating cell nuclear antigen immunolabeling was also performed. Parallel tissue samples were examined by transmission electron microscopy. HSCORE was performed for the semi-quantitative analysis of distribution of cells in the stroma of SV. Vimentin-labeled cells were mostly distributed in the subtrophoblastic area. Desmin-vimentin double immunolabeling was mainly localized in the triangular area and to a lesser degree in the perivascular area and vessel walls (p=<0.001). However, desmin- smooth actin labeling was observed predominantly in the vessel wall and perivascular area. Vimentin- smooth actin immunoreactivity was significantly stronger in the triangular and perivascular areas compared to the vessel walls (p=0.003).

Ultrastructurally, cells in the stroma of SV were mesenchyme cells, reticulum cells, fibroblasts, myofibroblasts, smooth muscle cells, and Hofbauer cells, filamented and vacuolated cells. The differentiation of myofibroblasts in the triangular and perivascular areas may play a role in maturation of SV and villous contractility, modulation of the intervillous space and this may have effects on maternofetal placental circulation.     

Myofibrosarcoma of the Upper Jawbones: A Clinicopathologic and Ultrastructural Study of Two Cases

Two problematic spindle cell sarcomas involving upper jawbones in two adult male patients have been studied by histology, immunohistochemistry, and transmission electron microscopy, and respectively graded as low-grade malignancy and high-grade malignancy. While any single methodological study did not allow confident classification of them into one or other of the classical categories of spindle cell sarcomas (fibrosarcoma versus leiomyosarcoma), the overall contribution from all three methodologiesultimately allowed them to be categorized as sarcomas with myofibroblastic differentiation. Histologically, both tumors had morphological features of an amalgama between neoplastic fibroblasts and smooth muscle cells. Immunohistochemically, both tumors expressed reactivity only for muscle specific actin and alpha smooth muscle actin, in addition to vimentin. Ultrastructurally, both tumors, while showing fibroblast-like cytoplasmic features, had a spurious and imperfectly organized cell surface defying convincing classification into any of specific categories (i.e., both appeared in terms of ultrastructure as poorly differentiated sarcoma, the former with low level of smooth muscle differentiation and possibly the presence of some fibronexus component, the latter with no smooth muscle differentiation but with possible evidence of very rare fibronectin fibril). Therefore, on balance, the most tenable diagnosis seemed to us that of a myofibrosarcoma in both cases. This work is presented considering the fact that myofibrosarcoma currently represents a topical theme of debate, and that this is the first report in medical literature concerning with myofibrosarcomas of the head and neck area in adults.     

腹膜后静止型副神经节细胞瘤的临床诊治

目的 提高腹膜后功能静止型副神经节细胞瘤的诊断和治疗水平.方法 分析1997年至今资料完整、病理证实的功能静止型副神经节细胞瘤10例.术前行内分泌、影像学及核医学等检查.4例术前服用2～4周α受体拮抗剂.3例接受腹腔镜手术,7例接受经腹开放手术.结果 功能静止型副神经节细胞瘤患者血压及尿儿茶酚胺通常为正常或稍高,131 IMIBG和奥曲肽显像定位准确、敏感性高.4例肿瘤位于肾门旁,6例位于肾下方腹主动脉旁,直径3～15 cm.术后病理结果:7例为副神经节细胞瘤,3例为恶性副神经节细胞瘤.免疫组化染色:cgA( ),syn( ),NSE( ),8.100( ).1例恶性副神经节细胞瘤于术后1年发生全身转移.结论 一旦确诊功能静止型副神经节细胞瘤,应该在充分药物准备的基础上,手术切除肿瘤,术后应密切随访.     

Distribution and role of myofibroblasts in human normal seminal vesicle stroma

We studied the distribution of myofibroblasts in the stroma of normal seminal vesicles. Twelve normal seminal vesicles obtained by surgery on the diagnosis of some diseases were selected, and we evaluated the distribution of myofibroblasts in the seminal vesicles using immunohistochemical and electron and immunoelectron microscopic techniques. Immunohistochemically, myofibroblasts, which were positive for alpha-smooth muscle actin (ASMA) and negative for high molecular weight caldesmon (h-CD), were observed in the stroma just beneath the epithelium of normal seminal vesicles. Moreover, an electron microscope examination revealed the presence of spindle or stellate cells in the stroma of the lamina propria beneath the seminal vesicle epithelium, and an immunoelectron microscopic examination showed that these cells were positive for ASMA. Finally, myofibroblasts are distributed in the lamina propria of human normal seminal vesicles and may play an important role in the ejection of sperm plasm.     

Angiogenic histogenesis of stromal cells in hemangioblastoma: ultrastructural and immunohistochemical study

Controversy regarding the origin of characteristic stromal cells (SC) is responsible for the placement of hemangioblastoma as a single entity in the category of "tumors of uncertain histogenesis" in the current WHO classification of brain tumors. This subclassification of hemangioblastoma is, to a large extent, a consequence of a remarkable antigenic heterogeneity of SC demonstrated in many, often contradictory immunohistochemical studies. In contrast, most of the electron microscopic studies demonstrated a number of features indicating angiogenic nature of SC and, therefore, hemangioblastoma. This study reevaluated the histogenesis of SC, applying immunohistochemistry as well as electron microscopy and immunoelectron microscopy. Immunohistochemical studies confirmed most of the previous results indicating a very frequent expression of vimentin, S-100 protein, neuron-specific enolase, and cytokeratins. SC were less commonly immunoreactive for desmin, factor XIIIa, and Ricinus communis lectin receptors, and only occasionally for factor VIII and Ulex europeus lectin. They were negative for other markers of endothelial, neuronal, glial, neuroendocrine, and smooth muscle differentiation. Approximately 1% of SC showed Ki67 immunoreactivity, indicating their slight proliferative activity, consistent with the benign nature of the tumor. In contrast to the inconclusive results of the immunohistochemistry, electron microscopy demonstrated a clear relationship of SC to endothelial cells, smooth muscle cells, and pericytes. Occasional SC were found within the vascular lumina. SC often showed intracellular caveolae consistent with the formation of early capillary lumina. Moreover, occasional SC contained small Weibel-Palade bodies positive for factor VIII in immunoelectron microscopy. SC represent a heterogenous population of abnormally differentiating mesenchymal cells of angiogenic lineage, with some morphological features of endothelium, pericytes, and smooth muscle cells. Occurrence of SC in hemangioblastoma could be related to a limited ability of angioformative stromal cells to develop an architecture of capillary lumina integrated with the vascular network of the tumor. Hemangioblastoma should be reclassified and included together with other vascular tumors of the central nervous system.     

The penetrance of paraganglioma and pheochromocytoma in SDHB germline mutation carriers

Germline mutations in succinate dehydrogenase B (SDHB) predispose to hereditary paraganglioma (PGL) syndrome type 4. The risk of developing PGL or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate. In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure. A total of 195 SDHB mutation carriers were included, carrying 27 different SDHB mutations. The 2 most prevalent SDHB mutations were Dutch founder mutations: a deletion in exon 3 (31% of mutation carriers) and the c.423+1G>A mutation (24% of mutation carriers). One hundred and twelve carriers (57%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty‐four patients had a head and neck PGL (28%), 4 patients had a PHEO (2%), 26 patients an extra‐adrenal PGL (13%). The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment. These estimates are lower than previously reported penetrance estimates of SDHB‐linked cohorts. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.     

Multifocal presentation of gangliocytic paraganglioma in the mediastinum and esophagus

Gangliocytic paraganglioma (GP) is a rare, typically benign tumor that shows neuroectodermal (neurosustentacular or Schwannian and neuronal) and neuroendocrine differentiation. Once thought to arise exclusively in the periampullary region as a solitary lesion, recent reports have documented both origin of GP in a variety of extra-duodenal sites as well as synchronous multifocal presentation of the tumor. Herein, we describe the first reported case of simultaneous occurrence of GP in the superior mediastinum and esophagus. A mass in the mid-distal esophagus and a separate mass in the superior mediastinum at the thoracic inlet were found in a 58-year-old woman by computed tomography scan. Subsequent biopsy of the superior mediastinal mass showed nests of epithelioid tumor cells coexisting with ganglioneuromatous elements, whereas biopsy of the esophageal mass showed nests of epithelioid cells with interspersed ganglion cells. The epithelioid tumor cells showed diffuse immunohistochemical expression of keratin (CAM 5.2), chromogranin, and synaptophysin supporting true neuroendocrine differentiation; ganglion cells expressed S-100 protein and neurofilament protein; and the spindled elements expressed S-100 protein, neurofilament protein, and glial fibrillary acidic protein indicating Schwannian differentiation. The finding of another GP occurring outside the periampullary region bolsters the argument for a stem cell origin of this unusual tumor.     

Orbital solitary fibrous tumor: encompassing terminology for hemangiopericytoma, giant cell angiofibroma, and fibrous histiocytoma of the orbit: reappraisal of 41 cases

Hemangiopericytomas and solitary fibrous tumors are uncommon neoplasms found in many locations, including the orbit. Both mesenchymal neoplasms share several clinicopathologic features, thus prompting intense debate as to whether they are variants of the same entity or merit separate designations in the orbit. These 2 entities, with the addition of giant cell angiofibroma of orbit, are of benign- to uncertain-behavior, CD34-positive, collagen-rich, specialized fibroblastic tumors, which may have overlapping or histologically identical features. In addition, so-called fibrous histiocytoma of orbit, a previous designation, has overlapping morphologic features with these tumors. To date, a large series of these collagen-rich fibroblastic tumors of the orbit has not been fully explored. Forty-one fibroblastic orbital tumors, originally diagnosed as hemangiopericytomas (n = 16), fibrous histiocytomas (n = 9), mixed tumors (hemangiopericytomas/fibrous histiocytoma) (n = 14), and giant cell angiofibromas of orbit (n = 2) between 1970 and 2009, were retrieved from our consultation files, the Ophthalmic Registry, at the Armed Forces Institute of Pathology. Slides and clinical records were reviewed, analyzed, and compared. Immunochemistry was performed for CD34, CD99, Bcl-2, Ki-67, and p53. Upon histologic review, all cases were reclassified as solitary fibrous tumor (41/41). The patients included 23 (56%) males, 17 (41%) females, and 1 unknown, with a mean age at presentation of 40.7 years (range, 16-70 years). The sites of involvement were the right orbit in 18 (44%) cases and the left in 16 (39%) cases. Tumors ranged in size from 0.4 to 5.0 cm (mean, 2.2 cm). Seventeen (41%) patients presented with an orbital mass, 8 (20%) with proptosis, 2 (5%) with painful mass, and 2 (5%) with painless mass. Duration of symptoms ranged from 3 to 96 months, with a mean of 23 months (median, 9 months). Microscopically, all lesions showed considerable similarity, varying in degree of cellularity, stromal collagen, and the presence of giant cells. Overlapping features with soft tissue giant cell fibroblastoma were observed. Immunochemistry revealed positivity for CD34 in all cases (100%), p53 in 85%, CD99 in 67.5%, and Bcl-2 in 47.5%. Although Ki-67 labeling was seen in all cases, it ranged from less than 1% in 54.3% of cases to 5% to 10% in 20% of cases. Taken together, the findings of this study suggest that orbital hemangiopericytoma and some cases previously designated as fibrous histiocytoma, giant cell angiofibroma of orbit, and solitary fibrous tumor have overlapping morphologic and immunohistochemical features and should be designated as solitary fibrous tumor. Adipocytes and unusual multivacuolated adipocytic cells may be present in these tumors, as well stromal myxoid change; and even stromal intramembranous ossification can be observed. There are overlapping features of orbital solitary fibrous tumor with another CD34-positive specialized fibroblastic tumor of soft tissue, giant cell fibroblastoma. Morphologic criteria for uncertain behavior to low-grade malignant ocular solitary fibrous tumors can be made by cytologic atypia and increased mitotic activity, but overall outcome for malignant solitary fibrous tumors of the eye should be further explored.     

副神经节瘤伴腰椎转移1例并文献复习

Paraganglioma and phaeochromocytoma are neoplasms of chromaffin and non-chromaffin tissues found within the autonomic nervous system-associated paraganglia, which could occur as benign or malignant tumor ubiquitously. Paraganglioma often occurs in the retroperitoneal space, which accounts for 1.88 percent of the primary retroperitoneal tumor[1]. We report a case of paraganglioma which was incorrectly diagnosed as adrenal carcinoma preoperatively, but the frozen section analysis and clinical manifestation revealed a malignant paraganglioma.     

Duodenal gangliocytic paraganglioma: report of two cases and review of literature

We report two cases of Gangliocytic paraganglioma (GP), one of which was accompanied by lymph node metastasis. Histologically, the tumor was composed of three morphologically distinct cell populations: spindle cells, ganglion-like cells and epithelioid cells. The epithelioid cells were positive for cytokeratin (AE1/AE3), synaptophysin (Syn), chromogranin A (CgA), CD56 and progesterone receptor (PR). Ganglion-like cell types showed positive reactivity for Syn and CD56. In contrast, the spindle-shaped cells showed positive reactivity for S-100. The patient with lymph node metastasis has a good prognosis. Nonetheless, close surveillance is still necessary for patients with GP because a few cases of GP with regional lymph node metastasis and even distant metastasis have been published, including a malignant case of GP showing a lethal course.     

The myofibroblast: an assessment of controversial issues and a definition useful in diagnosis and research

Some interpretational problems associated with the myofibroblast, which affect how this cell is identified, are discussed. Questions addressed include distinguishing between "external" lamina ("basement membrane") and the fibronectin fibril of the fibronexus; the nature of stress fibers (bundles of smooth-muscle myofilaments with focal densities); the utility of some of these features to distinguish between myofibroblastic and smooth-muscle cell surfaces; and cytoskeletal immunophenotype. The following points are emphasized. Myofibroblasts have a surface characterized by prominent fibronectin fibrils and fibronexus junctions, which are distinct from lamina ("basement membrane"). This can permit a distinction to be made between smooth-muscle and myofibroblastic lesions and tumors. Myofibroblasts are typically positive for vimentin and alpha-smooth-muscle actin, but desmin is not a useful discriminant between smooth-muscle and myofibroblastic lesions. The main features for defining the myofibroblast are abundant rough endoplasmic reticulum; modestly developed peripheral myofilaments with focal densities (stress fibers); fibronexus junctions; vimentin and smooth-muscle actin immunostaining. Other features include a Golgi apparatus and collagen secretion granules, gap junctions, and actin-associated nondesmosomal junctions. Illustrations of the usefulness of these criteria in the diagnosis of soft-tissue lesions (myofibrosarcoma, so-called myofibroblastoma) are given.     

Pulmonary gangliocytic paraganglioma: a case report and review of the literature

Gangliocytic paraganglioma (GP) is a rare histologic type of neuroendocrine tumors. We report a case of pulmonary GP in a 29-year-old male presenting with an asymptomatic endobronchial nodule. Grossly, the tumor showed a 4.0x3.8x3.5 cm well-defined nodule with yellowish cut surface. Microscopically, the tumor was composed of three distinct cellular types: epithelioid cells, ganglion-like cells and spindle cells. Meanwhile, transitional cells, having morphologic features between ganglion-like and epithelioid cells, were also presented. The epithelioid cells arranged in various morphologic architectures, including Zellballen, papillary, cystic and microcystic pattern. The epithelioid cells were positive for AE1/AE3, CAM 5.2, chromogranin A and synaptophysin. Ganglion-like cells showed immunoreactivity for chromogranin A and synaptophysin. A few ganglion-like cells were also positive for AE1/AE3 and/or CAM 5.2. The spindle cells were positive for S-100 protein and neurofilament. The transitional cells showed a similar immunohistochemical profile to the epithelioid cells. The authors believe stem cell theory is a reasonable explanation for the origin of GP. GP probably originate from some kind of mucosa associated stem cell which can differentiate into diverse cellular lineages.     

肾上腺外副神经节瘤临床病理分析

目的探讨肾上腺外副神经节瘤临床病理学特征、分类、良恶性组织学判断标准及鉴别诊断。方法对21例肾上腺外(副交感神经和交感神经)副神经节瘤进行光镜及免疫组化观察,同时跟踪随访并复习相关文献。结果肾上腺外副神经节瘤21例,男性10例、女性11例,年龄9～81岁,平均年龄46.5岁。肿瘤位于腹膜后10例,头颈部7例,纵隔、膀胱、精索及肾脏各1例。有功能者3例,无功能者18例。组织学上肿瘤主要由主细胞和支持细胞两种细胞组成,主细胞排列成巢状、束状、腺泡状或实体样结构,周围被支持细胞部分或完全包绕。1例诊断为恶性,瘤细胞异型性显著,核分裂象多见,并见灶性或融合性坏死和血管侵犯,伴局部淋巴结转移,余20例诊断为良性。免疫组化肿瘤细胞表达NSE、CgA、Syn、NF,而CK、EMA和SMA阴性;支持细胞S-100蛋白阳性。1例恶性副神经节瘤仅NSE阳性,CgA弱阳性。随访18例,其中1例1年后因多脏器转移而死亡,另有1例组织学诊断为良性者3年后肿物复发并侵犯邻近器官。结论肾上腺外副神经节瘤组织形态学改变与其生物学行为不一,临床上应长期随访。同时应与形态相似的肿瘤鉴别。     

Immunocytochemical demonstration of IGF-II immunoreactivity in human phaeochromocytoma and extra-adrenal abdominal paraganglioma.

Insulin-like growth factor (IGF)-II immunoreactivity was demonstrated in 14 adrenal glands, six retroperitoneal paraganglia, 18 phaeochromocytomas, and six extra-adrenal abdominal paragangliomas through the use of a monoclonal antibody against rat IGF-II which cross-reacts with human IGF-II. A subpopulation of parenchymal cells in normal adrenal medulla and in retroperitoneal paraganglia was positively immunolabelled. Eighteen cases with phaeochromocytoma including two malignant and four multiple endocrine neoplasias all contained numerous IGF-II-immunoreactive tumour cells. All six extra-adrenal abdominal paragangliomas contained numerous immunoreactive tumour cells. Almost all the other normal human adult tissues examined failed to immunolabel. These results indicate that IGF-II-like immunoreactivity is widely expressed in normal and neoplastic human paraganglionic tissues, although its biological significance in these tissues has not been determined.     

Immunohistochemical and electron microscopic observations of stromal cells in the human oviduct mucosa

Stromal cells in the lamina propria of the human oviduct mucosa are unique cells that can differentiate into decidual cells during ectopic pregnancy in the oviduct. The nature of stromal cells is still unknown. In the present study, we investigated human oviductal stromal cells with transmission electron microscopy and immunohistochemistry and revealed that they had ultrastructural features similar to myofibroblasts and expressed alpha-smooth muscle actin, a marker used to identify myofibroblasts. Primary cilia were also one of the characteristic profiles of the stromal cells. These findings showed that the connective tissue-stromal cells in the human oviduct mucosa are myofibroblasts. They are considered to play an important role in the transport of oocytes by bringing about contraction of the mucosal folds.     

Carney''s triad: gastric leiomyosarcoma, pulmonary chondroma and extra-adrenal paraganglioma in young females

The case of a 13-year-old girl with a gastric leiomyosarcoma and a pulmonary osteochondroma is presented. The association of these two tumours and extra-adrenal paraganglioma has been described as a triad by Carney. The patient is free of recurrence of the gastric tumour with no evidence of paraganglioma 10 months after the operation. To our knowledge this is the first case of the triad reported in the UK.