Morphological and functional evaluation of chronic pancreatitis with magnetic resonance imaging

Magnetic resonance imaging(MRI)techniques for assessment of morphology and function of the pancreas have been improved dramatically the recent years and MRI is very often used in diagnosing and follow-up of chronic pancreatitis(CP)patients.Standard MRI including fat-suppressed T1-weighted and T2-weighted imaging techniques reveal decreased signal and glandular atrophy of the pancreas in CP.In contrast-enhanced MRI of the pancreas in CP the pancreatic signal is usually reduced and delayed due to decreased perfusion as a result of chronic inflammation and fibrosis.Thus,morphological changes of the ductal system can be assessed by magnetic resonance cholangiopancreatography(MRCP).Furthermore,secretin-stimulated MRCP is a valuable technique to evaluate side branch pathology and the exocrine function of the pancreas and diffusion weighted imaging can be used to quantify both parenchymal fibrotic changes and the exocrine function of the pancreas.These standard and advanced MRI techniques are supplementary techniques to reveal morphological and functional changes of the pancreas in CP.Recently,spectroscopy has been used for assessment of metabolite concentrations in-vivo in different tissues and may have the potential to offer better tissue characterization of the pancreas.Hence,the purpose of the present review is to provide an update on standard and advanced MRI techniques of the pancreas in CP.     

Hepatic senescence,the good and the bad

Gradual alterations of cell’s physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells.Once becoming senescent,the cell stops dividing permanently but remains metabolically active.Cellular senescence does not have a single marker but is characterized mainly by a combination of multiple markers,such as,morphological changes,expression of cell cycle inhibitors,senescence associatedβ-galactosidase activity,and changes in nuclear membrane.When cells in an organ become senescent,the entire organism can be affected.This may occur through the senescence-associated secretory phenotype(SASP).SASP may exert beneficial or harmful effects on the microenvironment of tissues.Research on senescence has become a very exciting field in cell biology since the link between age-related diseases,including cancer,and senescence has been established.The loss of regenerative and homeostatic capacity of the liver over the age is somehow connected to cellular senescence.The major contributors of senescence properties in the liver are hepatocytes and cholangiocytes.Senescent cells in the liver have been implicated in the etiology of chronic liver diseases including cirrhosis and hepatocellular carcinoma and in the interference of liver regeneration.This review summarizes recently reported findings in the understanding of the molecular mechanisms of senescence and its relationship with liver diseases.     

Analysis of risk factors for susceptibility of frequent gout attacks:A case-control study of 579 patients with primary gout

正Objective To analyze the risk factors of frequent gout flare,and to evaluate its susceptibility to identify patients with≥2 acute attacks per year.Methods A total of 579 of cases gout patients with no history of taking urate lowering treatment (ULT) in recent 12 months were enrolled.The patients were divided into frequent group (gout episodes≥twice per year) and non-frequent group (gout attacks twice per year).The clinical information was collected and relevant biochemical indices     

Chromosome 11 aneusomy in esophageal cancers and precancerous lesions- an early event in neoplastic transformation： An interphase fluorescence in situ hybridization study from south India

AIM： To detect aneusomic changes with respect to chromosome 11 copy number in esophageal precancers and cancers wherein the generation of cancer-specific phenotypes is believed to be associated with specific chromosomal aneuploidies.
METHODS： We performed fluorescence in situ hybridization （FISH） on esophageal tissue paraffin sections to analyze changes in chromosome 11 copy number using apotome-generated images by optical sectioning microscopy. Sections were prepared from esophageal tumor tissue, tissues showing preneoplastic changes and histologically normal tissues （control） obtained from patients referred to the clinic for endoscopic evaluation.
RESULTS： Our results demonstrated that aneusomy was seen in all the cancers and preneoplastic tissues, while none of the controls showed aneusomic cells. There was no increase in aneusomy from precancers to cancers.
CONCLUSION： Our results suggest that evaluation of chromosome 11 aneusomy in esophageal tissue using FISH with an appropriate signal capture-analysis system, can be used as an ancillary molecular marker predictive of early neoplastic changes. Future studies can be directed towards the genes on chromosome 11,which may play a role in the neoplastic transformation of esophageal precancerous lesions to cancers.     

Multimodal imaging evaluation in staging of rectal cancer

Rectal cancer is a common cancer and a major cause of mortality in Western countries.Accurate staging is essential for determining the optimal treatment strategies and planning appropriate surgical procedures to control rectal cancer.Endorectal ultrasonography(EUS)is suitable for assessing the extent of tumor invasion,particularly in early-stage or superficial rectal cancer cases.In advanced cases with distant metastases,computed tomography(CT)is the primary approach used to evaluate the disease.Magnetic resonance imaging(MRI)is often used to assess preoperative staging and the circumferential resection margin involvement,which assists in evaluating a patient’s risk of recurrence and their optimal therapeutic strategy.Positron emission tomography(PET)-CT may be useful in detecting occult synchronous tumors or metastases at the time of initial presentation.Restaging after neoadjuvant chemoradiotherapy(CRT)remains a challenge with all modalities because it is difficult to reliably differentiate between the tumor mass and other radiation-induced changes in the images.EUS does not appear to have a useful role in post-therapeutic response assessments.Although CT is most commonly used to evaluate treatment responses,its utility for identifying and following-up metastatic lesions is limited.Preoperative high-resolution MRI in combination with diffusion-weighted imaging,and/or PET-CT could provide valuable prognostic information for rectal cancer patients with locally advanced disease receiving preoperative CRT.Based on these results,we conclude that a combination of multimodal imaging methods should be used to precisely assess the restaging of rectal cancer following CRT.     

Relationship between retinopathy and cirrhosis

AIM: To evaluate ophthalmic disorders with special attention to retinopathy in cirrhotic patients. Vitamin A deficiency-related ophthalmopathy, xerophthalmia, and color blindness may be documented in cirrhosis due to various etiologies. Retinopathy is an obscure feature of cirrhosis. METHODS: Thirty-two cirrhotic patients, who were followed up by Clinics of Gastroenterology, Izmir Ataturk Teaching and Research Hospital, were enrolled to the study. Associated systemic diseases such as diabetes mellitus and hypertension were excluded. Thirty-two healthy volunteers took part as the control subjects. All participants had ophthalmologic examination in the same hospital. RESULTS: Five (15.6%) of the cirrhotic subjects had soft exudate in the retina. None of the control subjects had retinopathy (P<0.05). Intraocular pressure (IOP) measured for both eyes were also significantly lower in the cirrhotics (P<0.05 vs P= 0.01). There were no statistically significant differences between the two groups in terms of other ophthalmic pathologies. The ophthalmic findings did not show up any differences according to the etiology of cirrhosis. CONCLUSION: Soft exudates may develop in cirrhotic patients probably due to loss of synthetic function of liver and hemodynamic effects of portal hypertension. Retinopathy must be sought in cirrhosis because of its severe morbidity.     

Rationale for the potential use of mesenchymal stromal cells in liver transplantation

Mesenchymal stromal cells(MSCs) are multipotent and self-renewing cells that reside essentially in the bone marrow as a non-hematopoietic cell population, but may also be isolated from the connective tissues of most organs. MSCs represent a heterogeneous population of adult, fibroblast-like cells characterized by their ability to differentiate into tissues of mesodermal lineages including adipocytes, chondrocytes and osteocytes. For several years now, MSCs have been evaluated for their in vivo and in vitro immunomodulatory and ‘tissue reconstruction’ properties, which could make them interesting in various clinical settings, and particularly in organ transplantation. This paper aims to review current knowledge on the properties of MSCs and their use in pre-clinical and clinical studies in solid organ transplantation, and particularly in the field of liver transplantation. The first available clinical data seem to show that MSCs are safe to use, at least in the medium-term, but more time is needed to evaluate the potential adverse effects of long-term use. Many issues must be resolved on the correct use of MSCs. Intensive in vitro and pre-clinical research are the keys to a better understanding of the way that MSCs act, and to eventually lead to clinical success.     

Mucosal blood flow measurements using laser Doppler perfusion monitoring

Perfusion of individual tissues is a basic physiological process that is necessary to sustain oxygenation and nutrition at a cellular level. Ischemia, or the insufficiency of perfusion, is a common mechanism for tissue death or degeneration, and at a lower threshold, a mechanism for the generation of sensory signalling including pain. It is of considerable interest to study perfusion of peripheral abdominal tissues in a variety of circumstances. Microvascular disease of the abdominal organs has been implicated in the pathogenesis of a variety of disorders, including peptic ulcer disease, inflammatory bowel disease and chest pain. The basic principle of laser Doppler perfusion monitoring （LDPM） is to analyze changes in the spectrum of light reflected from tissues as a response to a beam of monochromatic laser light emitted. It reflects the total local microcirculatory blood perfusion, including perfusion in capillaries, arterioles, venules and shunts. During the last 20-25 years, numerous studies have been performed in different parts of the gastrointestinal （GI） tract using LDPM. In recent years we have developed a multi-modal catheter device which includes a laser Doppler probe, with the intent primarily to investigate patients suffering from functional chest pain of presumed oesophageal origin. Preliminary studies show the feasibility of incorporating LDPM into such catheters for performing physiological studies in the GI tract. LDPM has emerged as a research and clinical tool in preference to other methods; but, it is important to be aware of its limitations and account for them when reporting results.     

Differential expression of genes during aflatoxin B(1)-induced hepatocarcinogenesis in tree shrews

AIM:Through exploring the regulation of gene expression during hepatocarcinogenesis induced by aflatoxin B1 (AFB1),to find out the responsible genes for hepatocellular carcinoma (HCC) and to further understand the underlying molecular mechanism.METHODS:Tree shrews ( Tupaia belangeri chinensis)were treated with or without AFB1 for about 90 weeks. Liver biopsies were performed regularly during the animal experiment. Eight shares of total RNA were respectively isolated from 2 HCC tissues, 2 HCC-surrounding noncancerous liver tissues, 2 biopsied tissues at the early stage(30^th week) of the experiment from the same animals as above, 1 mixed sample of three liver tissues biopsied at the beginning (0^th week) of the experiment, and another i mixed sample of two liver tissues from the untreated control animals biopsied at the 90^th week of the experiment. The samples were then tested with the method of Atlas^TM cDNA microarray assay. The levels of gene expression in these tissues taken at different time points during hepatocarcinogenesis were compared.RESULTS:The profiles of differently expressed genes were quite different in different ways of comparison.At the same period of hepatocarcinogenesis, the genes in the same function group usually had the same tendency for up-or down-regulation. Among the checked 588 genes that were known to be related to human cancer, 89 genes (15.1%) were recognized as “important genes” because they showed frequent changes in different ways of comparison. The differentially expressed genes during hepatocarcinogenesis could be classified into four categories: genes up-regulated in HCC tissue, genes with similar expressing levels in both HCC and HCC-surrounding liver tissues which were higher than that in the tissues prior to the development of HCC,genes down-regulated in HCC tissue, and genes up-regulated prior to the development of HCC but down-regulated after the development of HCC.CONCLUSION: A considerable number of genes could change their expressing levels both in HCC and in HCC-surrounding non-cancerous liver tissues. A few modular genes were up-regulated only in HCC but not in surrounding liver tissues, while some apoptosis-related genes were down-regulated in HCC and up-regulated in surrounding liver tissues. To compare gene-expressing levels among the liver tissues taken at different time points during hepatocarcinogenesis may be helpful to locate the responsible gene (s) and understand the mechanism for AFB1 induced liver cancer.     

痛风的影像学研究进展

影像学检查可以帮助临床医师评价痛风.X线成像只能显示慢性痛风进展期的典型变化.CT可能是评价痛风骨改变和痛风石的最好方法,双源CT可以评估全身周围关节的尿酸盐总沉积量.MRI适合评估软组织、滑膜厚度和炎性反应,对痛风的早期病变敏感性很高,也能够较好的显示痛风石.超声检查可以评价软骨、软组织、尿酸盐沉积和滑膜炎性反应.核医学有助于在细胞和分子层面理解痛风性关节炎的发病机制.     

Multimodality imaging of chronic tophaceous gout

The diagnosis of gout is usually based on clinical presentation and laboratory findings. Imaging plays a role in the assessment and grading of articular damage related to chronic, long-standing disease, which is characterized by granulomatous synovitis, tophi, and erosions. Multimodality imaging of chronic tophaceous gout may be useful in clinical practice for a variety of purposes, including assessment of disease-related anatomical changes and monitoring of articular and soft-tissue lesions over time, especially in response to urate-lowering therapy. Radiography remains the primary imaging technique. Ultrasonography may detect monosodium urate crystals on cartilage, is helpful to assess small joint effusion, to guide to joint aspiration, and to evaluate the volume of tophi. Computed tomography is considered to be more sensitive than plain radiography in the detection and evaluation of cortical bone erosions associated with tophi. MRI represents the only imaging modality which provides visualization of bone marrow oedema associated with erosions and may be useful to characterize and distinguish tophi from other soft tissue nodules.     

Management of gout and hyperuricemia: Multidisciplinary consensus in Taiwan

Gout is an inflammatory disease manifested by the deposition of monosodium urate (MSU) crystals in joints, cartilage, synovial bursa, tendons or soft tissues. Gout is not a new disease, which was first documented nearly 5,000 years ago. The prevalence of gout has increased globally in recent years, imposing great disease burden worldwide. Moreover, gout or hyperuricemia is clearly associated with a variety of comorbidities, including cardiovascular diseases, chronic kidney disease, urolithiasis, metabolic syndrome, diabetes mellitus, thyroid dysfunction, and psoriasis. To prevent acute arthritis attacks and complications, earlier use of pharmacotherapeutic treatment should be considered, and patients with hyperuricemia and previous episodes of acute gouty arthritis should receive long‐term urate‐lowering treatment. Urate‐lowering drugs should be used during the inter‐critical and chronic stages to prevent recurrent gout attacks, which may elicit gradual resolution of tophi. The goal of urate‐lowering therapy should aim to maintain serum uric acid (sUA) level <6.0 mg/dL. For patients with tophi, the initial goal can be set at lowering sUA to <5.0 mg/dL to promote tophi dissolution. The goal of this consensus paper was to improve gout and hyperuricemia management at a more comprehensive level. The content of this consensus paper was developed based on local epidemiology and current clinical practice, as well as consensuses from two multidisciplinary meetings and recommendations from Taiwan Guideline for the Management of Gout and Hyperuricemia.     

Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout

OBJECTIVE: The optimal serum urate levels necessary for elimination of tissue deposits of monosodium urate in patients with chronic gout is controversial. This observational, prospective study evaluates the relationship between serum urate levels during therapy and the velocity of reduction of tophi in patients with chronic tophaceous gout. METHOD: Sixty-three patients with crystal-confirmed tophaceous gout were treated with allopurinol, benzbromarone, or combined therapy to achieve serum uric acid levels less than the threshold for saturation of urate in tissues. The tophi targeted for evaluation during followup were the largest in diameter found during physical examination. RESULTS: Patients taking benzbromarone alone or combined allopurinol and benzbromarone therapy achieved faster velocity of reduction of tophi than patients taking allopurinol alone. The velocity of tophi reduction was linearly related to the mean serum urate level during therapy. The lower the serum urate levels, the faster the velocity of tophi reduction. CONCLUSION: Serum urate levels should be lowered enough to promote dissolution of urate deposits in patients with tophaceous gout. Allopurinol and benzbromarone are equally effective when optimal serum urate levels are achieved during therapy. Combined therapy may be useful in patients who do not show enough reduction in serum urate levels with single-drug therapy.     

Effect of urate‐lowering therapy on the velocity of size reduction of tophi in chronic gout

Objective

The optimal serum urate levels necessary for elimination of tissue deposits of monosodium urate in patients with chronic gout is controversial. This observational, prospective study evaluates the relationship between serum urate levels during therapy and the velocity of reduction of tophi in patients with chronic tophaceous gout.

Method

Sixty‐three patients with crystal‐confirmed tophaceous gout were treated with allopurinol, benzbromarone, or combined therapy to achieve serum uric acid levels less than the threshold for saturation of urate in tissues. The tophi targeted for evaluation during followup were the largest in diameter found during physical examination.

Results

Patients taking benzbromarone alone or combined allopurinol and benzbromarone therapy achieved faster velocity of reduction of tophi than patients taking allopurinol alone. The velocity of tophi reduction was linearly related to the mean serum urate level during therapy. The lower the serum urate levels, the faster the velocity of tophi reduction.

Conclusion

Serum urate levels should be lowered enough to promote dissolution of urate deposits in patients with tophaceous gout. Allopurinol and benzbromarone are equally effective when optimal serum urate levels are achieved during therapy. Combined therapy may be useful in patients who do not show enough reduction in serum urate levels with single‐drug therapy.

     

Gout and Organ Transplantation

Acute and chronic gout are common complications following organ transplantation. Risk factors include those shared with the general population (eg, diuretic use) and transplant-specific risk factors (eg, cyclosporine). Clinical features of gout are similar to those seen in the general population, although tophi may be more common. A definitive diagnosis requires demonstration of monosodium urate crystals within synovial fluid or tophi. Treatment is often empiric, although a poor response should prompt joint aspiration to exclude septic arthritis. Corticosteroids are commonly used to treat acute gout due to the adverse profile and drug interactions with NSAIDs and colchicine. Sustained reduction of serum urate (≤6 mg/dL) is critical in long-term management. Allopurinol is the most commonly used agent, although vigilant monitoring is required if combined with azathioprine. Other options include febuxostat and benzbromarone. The role of newer agents such as interleukin-1 inhibitors and uricases remains to be determined. General measures should include minimizing diuretic use.     

A rare and asymptomatic case of mitral valve tophus associated with severe gouty tophaceous arthritis

Gouty arthritis is characterized by the deposition of monosodium urate crystals in the joints and soft tissues. Clinical manifestations include acute and chronic arthritis and tophaceous deposits. Chronic tophaceous gout has become less common since the introduction of the pharmacological treatment. Moreover, cardiac valve gouty tophi have been very rarely reported.     

Identification and characterization of peripheral vascular color-coded DECT lesions in gout and non-gout patients: The VASCURATE study

ObjectiveTo characterize peripheral vascular plaques color-coded as monosodium urate (MSU) deposition by dual-energy computed tomography (DECT) and assess their association with the overall soft-tissue MSU crystal burden.MethodsPatients with suspected crystal arthropathies were prospectively included in the CRYSTALILLE inception cohort to undergo baseline knees and ankles/feet DECT scans; treatment-naive gout patients initiating treat-to-target urate-lowering therapy (ULT) underwent repeated DECT scans with concomitant serum urate level measurements at 6 and 12 months. We determined the prevalence of DECT-based vascular MSU-coded plaques in knee arteries, and assessed their association with the overall DECT volumes of soft-tissue MSU crystal deposition and coexistence of arterial calcifications. DECT attenuation parameters of vascular MSU-coded plaques were compared with dense calcified plaques, control vessels, control soft tissues, and tophi.ResultsWe investigated 126 gout patients and 26 controls; 17 ULT-naive gout patients were included in the follow-up study. The prevalence of DECT-based vascular MSU-coded plaques was comparable in gout patients (24.6%) and controls (23.1%; p=0.87). Vascular MSU-coded plaques were strongly associated with coexisting arterial calcifications (p<0.001), but not with soft-tissue MSU deposition. Characterization of vascular MSU-coded plaques revealed specific differences in DECT parameters compared with control vessels, control soft tissues, and tophi. During follow-up, vascular MSU-coded plaques remained stable despite effective ULT (p=0.64), which decreased both serum urate levels and soft-tissue MSU volumes (p<0.001).ConclusionOur findings suggest that DECT-based MSU-coded plaques in peripheral arteries are strongly associated with calcifications and may not reflect genuine MSU crystal deposition. Such findings should therefore not be a primary target when managing gout patients     

Enhanced osteoclastogenesis in patients with tophaceous gout: urate crystals promote osteoclast development through interactions with stromal cells

OBJECTIVE: To analyze cellular mechanisms of bone erosion in gout. METHODS: Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) from patients with gout were analyzed for the presence of osteoclast precursors. Fixed tophus and bone samples were analyzed by immunohistochemistry. Mechanisms of osteoclastogenesis were studied by culturing murine preosteoclast RAW 264.7 cells, bone marrow stromal ST2 cells, and human synovial fibroblasts with monosodium urate monohydrate (MSU) crystals. RESULTS: PBMCs from patients with severe erosive gout had the preferential ability to form osteoclast-like cells in culture with RANKL and monocyte colony-stimulating factor (M-CSF). The number of PBMC-derived tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells strongly correlated with the number of tophi (r = 0.6296, P = 0.630). Patients with severe erosive and tophaceous gout also had higher circulating concentrations of RANKL and M-CSF. Furthermore, greater numbers of TRAP-positive multinucleated cells were cultured from SFMCs derived from gouty knee effusions than from paired PBMCs (P = 0.004). Immunohistochemical analysis demonstrated numerous multinucleated cells expressing osteoclast markers within tophi and at the interface between soft tissue and bone. MSU crystals did not directly promote osteoclast formation from RAW 264.7 cells in vitro. However, MSU crystals inhibited osteoprotegerin gene and protein expression in ST2 cells and human synovial fibroblasts, without significantly altering RANKL gene expression. Conditioned medium from ST2 cells cultured with MSU crystals promoted osteoclast formation from RAW 264.7 cells in the presence of RANKL. CONCLUSION: Chronic tophaceous and erosive gout is characterized by enhanced osteoclast development. These data provide a rationale for the study of osteoclast-targeted therapies for the prevention of bone damage in chronic gout.     

Intraarticular tophi in a joint without a previous gouty attack

Subcutaneous tophi are usually a late clinical manifestation of gout. However, intraarticular tophi may develop very early, since crystal shedding has been presumed to precipitate an acute gouty attack. There is little direct evidence of intraarticular tophi before the initial gouty attack. We describe a patient who had gout for 3 years without subcutaneous tophi. Whitish intraarticular deposits, presumably representing urate tophi, were noted during right knee arthroscopy for a posterior cruciate ligament tear. This observation illustrates that tophi deposition may occur early, even in previously unaffected joints.