A brief history of gout

Gout is relatively unique among rheumatological diseases in that its effects were common and, at least in history, disproportionately represented in prominent authority figures. Effective treatments have only been available for just over a century and therefore for the most part, the disease has run relatively unchecked. Consequently, it may have had global ramifications. The history of gout, from apocryphal orthodoxy to medical clarity, is reviewed, using a few of the more colourful characters in its considerable pantheon.     

Gout: an Asia‐Pacific update

Even though, Hippocrates recognized gout as an affection of older men and a product of high living long back in 5th century BC, this painful condition promises to accompany humanity to the 21st century. The incidence is progressively rising and females are also affected in the modern era. There are also regional and ethnic variations in the incidence, the genetics of which is being studied. The recommended best therapy for the acute attacks and long term prophylaxis has improved remarkably in the recent years. However, patients are often treated inadequately and risk factors for their disease are not well explored in daily practice. Although well designed long term studies of current and newer treatment are welcomed, educating doctors especially the primary care physicians who manage majority of gout cases, in optimizing the currently available management options would improve the present care.     

Failure of rasburicase therapy in recurrent acute gout with tophi

Rasburicase, a recombinant urate oxidase enzyme, has been used successfully in several cases of chronic tophaceous gout. We report the case of an elderly woman with chronic tophaceous gout who failed rasburicase therapy due to recurrent acute episodes of gout following each rasburicase infusion, despite prophylactic therapy.     

An unusual case of knee monoarthritis

A 61‐year‐old woman, a known case of diabetic nephropathy on chronic ambulatory peritoneal dialysis, presented with acute onset severe pain in the right knee, of 7 days duration. She had red hot and tender knee and was unable to bear weight. The lower half of the right thigh was swollen and tender. Right knee synovial fluid revealed 130 cells/µL (all lymphocytes). The fluid was negative for crystals and bacterial cultures. Three week later she returned with worsening of her symptoms despite receiving non‐steroidal anti‐inflammatory drugs and intra‐articular glucocorticoid. Magnetic resonance imaging of the right thigh showed heterogeneously hyperintense right vastus medialis muscle on T2‐weighted image, suggestive of diabetic muscle infarction. Therapy with analgesics and physiotherapy led to recovery in pain and thigh swelling. Diabetic muscle necrosis is a rare complication of diabetes mellitus and may present with abrupt onset of pain and loss of function of the involved extremity, mimicking septic/reactive arthritis or pyomyositis. A high index of suspicion may avoid delay in diagnosis.     

Does prolonged systemic glucocorticoid use increase risk of tophus formation among gouty arthritis patients?

Aim: To determine the relationship of steroid use with tophus formation and other comorbid conditions among male gout patients. Methods: Review of medical records of Filipino gout patients under the care of rheumatologists was conducted. Univariate analysis (chi‐square, Student’s t‐test) and multiple logistic regression analysis were performed to establish the risk for tophus formation among glucocorticoid users. Bivariate analysis was separately done to determine the confounding effect of steroid use in the association of comorbidities and tophi formation. Results: There were 295 Filipino men with a mean age of 56 years and a mean duration of 12 years of gouty arthritis who were included in the study. Multivariate analysis showed a five times higher likelihood (OR 4.81 95% CI 1.92–12.04, P < 0.001) for tophus formation among prolonged steroid users. Confounders identified were disease duration of gout (≥ 10 years), presence of chronic kidney disease (CKD) and elevated serum creatinine level (SCr). Bivariate analysis of comorbidities showed that steroid use introduced a considerable bias in the relationship of hypertension, elevated SCr, CKD and dyslipidemia. Conclusion: Patients with equivalent prednisone intake of at least 15 mg/week for ≥ 3 months is associated with tophi formation. In the presence of hypertension, renal impairment, and elevated serum creatinine level, use of steroids confounds the individual risk that each factor carries.     

Osteoporosis in haemophilia – an underestimated comorbidity?

A relationship between haemophilia and osteoporosis has been suggested, leading to the initiative for a larger study assessing this issue. Bone mineral density (BMD) was measured by osteodensitometry using dual energy X-ray absorptiometry (DEXA) in 62 male patients with severe haemophilia A; mean age 41 +/- 13.1 years, mean body mass index (BMI) 23.5 +/- 3.6 kg m(-2). Using the clinical score suggested by the World Federation of Hemophilia, all patients were assessed to determine the severity of their arthropathy. A reduced BMD defined as osteopenia and osteoporosis by World Health Organization criteria was detected in 27/62 (43.5%) and 16/62 (25.8%) patients, respectively. Fifty-five of sixty-two (88.7%) patients suffered from haemophilic arthropathy. An increased number of affected joints and/or an increased severity were associated with lower BMD in the neck of femur. Pronounced muscle atrophy and loss of joint movement were also associated with low BMD. Furthermore, hepatitis C, low BMI and age were found to be additional risk factors for reduced BMD in the haemophiliac. Our data shows that in haemophilic patients osteoporosis represents a frequent concomitant observation. The main cause for reduced bone mass in the haemophiliac is most probably the haemophilic arthropathy being typically associated with chronic pain and loss of joint function subsequently leading to inactivity. Further studies including control groups are necessary to elucidate the impact of comorbidities such as hepatitis C or HIV on the development of osteoporosis in the haemophiliac.     

Clinical and radiographic scores in haemophilic arthropathies: how well do these correlate to subjective pain status and daily activities?

Haemophilic patients who reached adulthood before the establishment of prophylactic treatment frequently show multiple and substantial arthropathies. The aim of this study was to determine to what extent haemophiliac's subjective impairment due to arthropathies correlates with objective clinical and radiographic parameters. By means of a questionnaire and a visual analogue scale, we consulted 79 haemophiliacs concerning their joint-pain status, how these were treated and to what extent their daily activities had been affected. Using a scoring system suggested by the Advisory Committee of the World Federation of Haemophilia, clinical evaluation was performed. Radiographs of 60 patients were assessed by means of the Petterson scale. The results were statistically compared. We found a significant correlation between pain intensity and clinical pathology as well as between pain intensity and radiographic joint damage for both knees and for the right ankle. The number of painful joints correlated well with the number of clinically/radiographically affected joints. The more pronounced the objective damage to joints, the more frequently patients claimed to have constant pain, depressive episodes and a dependency on pain-relieving medication. The more pronounced the objectively assessed damage to the knee and ankle joint, the higher the likelihood that the patient suffers from severe joint pain and reduction of activity. Treatment of painful symptoms from arthropathies is often insufficient. Scores and questionnaires may help to define the haemophiliacs pain status more clearly, thereby offering a possibility of assessment and long-term observation.     

In vitro synthesis of IgM and IgM rheumatoid factor in seronegative arthritides

Summary In vitro patterns of IgM and IgM rheumatoid factor (RF) synthesis exhibited by peripheral blood B cells (MNL) obtained from healthy individuals as well as patients with seropositive and seronegative rheumatoid arthritis (RA) have been previously examined. The present study was performed in a group of patients with non-rheumatoid seronegative arthritis (SNA) in order to compare patterns of in vitro IgM and IgM RF synthesis to that previously observed with seropositive and seronegative RA. Eighteen patients with SNA (4 ankylosing spondylitis, 10 psoriatic arthritis, and 4 unclassified variant disease) were studied as well as 18 healthy adult controls.Spontaneous release of IgM RF by MNL was not observed in SNA or controls. In contrast, IgM RF was detected in pokeweed mitogen (PWM)-stimulated MNL culture supernatants from 9/18 SNA (mean±SD=17.0±9.9 ng/10⁶ cells), and 10/18 normal controls (16.7±9.9 ng). Synthesis of IgM by PWM-stimulated MNL from SNA (2 062±1 200 ng) was significantly less than observed with MNL from controls (4 093±1 896 ng) (P<0.001). There were no differences among the various SNA subsets with regards to the levels of IgM and IgM RF produced either spontaneously or after PWM stimulation. IgM RF constituted a small fraction of the total IgM in SNA and normals (0.9% and 0.5%, respectively). This is clearly distinct from seropositive RA in which we have previously established that IgM RF constitutes a substantial fraction of the total IgM (10.7%) (P<0.01). IgM and IgM RF production did not appear to be significantly influenced by immunosuppressive medication.The results suggest that regulatory mechanisms governing the expression of RF are intact in patients with SNA and that lack of in vivo RF production in these patients cannot be related to an absolute deficiency of PWM-inducible mature RF committed B cells.     

Successful pain treatment in arthropathic lower extremities by acupuncture in haemophilia patients

Acupuncture is successfully used in the treatment of degenerative osteoarthritis. The treatment of haemophilic arthropathies can require strong painkillers with severe side-effects. Therefore, a special yet simple acupuncture technique was evaluated in the treatment of these joint problems. Twelve patients with a factor VIII activity<1% and at least one painful arthropathy in both lower extremities were included in this single-blinded study. The non-treated side served as a control. Treatment was assessed by a visual analogue scale (VAS) and an orthopaedic clinical examination. Only one needle was inserted at the rear fontanelle once per week and in 15 cycles. Ten of 12 patients showed an improvement of their pain perception. The average VAS could be reduced from 6.8 to 5.0. The side not receiving treatment showed a reduction from 4.1 to 4.0. No side-effects were observed. Even though interpretation of our data are limited due to the small patient numbers, significant improvement of the VAS after treatment suggests that acupuncture has a measurable positive effect in pain management for haemophilic arthropathy of the lower extremities.     

Expression of activin A in inflammatory arthropathies

The findings that bone marrow fibroblastoid stromal cells are important for activin A production prompted our investigation of activin A expression in fibroblast-like synoviocytes in joint capsule in this and previous studies. In the proliferative reactive synovial membrane obtained from rheumatoid arthritis patients, activin A is detected prominently in the fibroblastoid synovial cells, as well as in the smooth muscle and the endothelial layer of the arteries in these vascularized proliferative tissues. The concentration of activin A in the rheumatoid arthritis synovial fluid was 33.6±5.0 ng/ml, much higher than the activin A content of osteoarthritis fluid (10.0±1.1 ng/ml). Furthermore, our previous studies also showed that inflammatory cytokines, such as interleukin (IL)-1, transforming growth factor (TGF)-β, interferon (IFN)-γ, IL-8, and IL-10 markedly enhance the expression of activin A mRNA in synoviocytes. These findings are consistent with our studies in regard to the regulatory control of activin A production in bone marrow stroma and monocytes. In addition, the relationship of activin A to IL-6-induced biological activities in various cell types was also investigated. Although activin A has not been directly associated with inflammatory processes, future studies are needed to investigate its production in response to the accumulated levels of inflammatory cytokines in the synovium of the patients, as well as the quantitative differences in activin A concentrations in many patients with other inflammatory diseases.     

基因突变与遗传性内分泌代谢性疾病

遗传性内分泌代谢性疾病是内分泌代谢疾病中相当重要的一组疾病,临床表现复杂多变,诊治困难。遗传性内分泌代谢性疾病的分子基础是其相关基因发生突变,近年随着分子生物学技术的飞速发展,相当多的致病基因被发现,人们对此类疾病的理解逐步深入,同时也为临床诊断提供了快速准确的技术平台。本文将根据致病基因功能,对近年来遗传性内分泌代谢性疾病取得的进展进行阐述。     

Direct conversion of plant biomass to ethanol by engineered Caldicellulosiruptor bescii

Ethanol is the most widely used renewable transportation biofuel in the United States, with the production of 13.3 billion gallons in 2012 [John UM (2013) Contribution of the Ethanol Industry to the Economy of the United States]. Despite considerable effort to produce fuels from lignocellulosic biomass, chemical pretreatment and the addition of saccharolytic enzymes before microbial bioconversion remain economic barriers to industrial deployment [Lynd LR, et al. (2008) Nat Biotechnol 26(2):169–172]. We began with the thermophilic, anaerobic, cellulolytic bacterium Caldicellulosiruptor bescii, which efficiently uses unpretreated biomass, and engineered it to produce ethanol. Here we report the direct conversion of switchgrass, a nonfood, renewable feedstock, to ethanol without conventional pretreatment of the biomass. This process was accomplished by deletion of lactate dehydrogenase and heterologous expression of a Clostridium thermocellum bifunctional acetaldehyde/alcohol dehydrogenase. Whereas wild-type C. bescii lacks the ability to make ethanol, 70% of the fermentation products in the engineered strain were ethanol [12.8 mM ethanol directly from 2% (wt/vol) switchgrass, a real-world substrate] with decreased production of acetate by 38% compared with wild-type. Direct conversion of biomass to ethanol represents a new paradigm for consolidated bioprocessing, offering the potential for carbon neutral, cost-effective, sustainable fuel production.Increasing demand for fuels, geopolitical instability, the limitation of global petroleum reserves, and the impact on climate change induced by greenhouse gases have increased the need for renewable and sustainable biofuels (1–5). First-generation biofuels produced from food crops, such as corn, are limited by cost and competition with food supply (6, 7). Switchgrass is a perennial grass native to North America, and its high productivity on marginal farmlands and low agricultural input requirements make it an attractive feedstock for the production of biofuels and biochemicals (8). A yield of 36.7 Mg⋅ha⁻¹ was achieved in field trials in Oklahoma (9), and switchgrass has the potential to produce 500% or more energy than is used for its cultivation (10). The use of abundant lignocellulosic plant biomass as feedstock is environmentally desirable and economically essential for enabling a viable biofuels industry (11). Current strategies for bioethanol production from lignocellulosic feedstocks require three major operational steps: physicochemical pretreatment, enzymatic saccharification, and fermentation (Fig. 1) (6, 12). Pretreatment and enzymatic hydrolysis represent substantial cost and it is estimated that the use of cellulolytic microbes for consolidated bioprocessing and eliminating pretreatment would reduce bioprocessing costs by 40% (2). Considerable effort has been made to develop single microbes capable of both saccharification and fermentation to avoid the substantial expense of using saccharolytic enzyme mixtures (13). Heterologous expression of saccharolytic enzymes has been demonstrated in a number of organisms, including Saccharomyces cerevisiae, Zymomonas mobilis, Escherichia coli, and Bacillus subtilis to ferment various model cellulosic and hemicellulosic substrates (13–15). Although these approaches have resulted in progress in cellulose utilization, the overall enzyme activity is still very low compared with that of naturally cellulolytic organisms and the rates of hydrolysis are not sufficient for an industrial process (13).Open in a separate windowFig. 1.Comparison of bioethanol production strategies and a predicted fermentative pathway in C. bescii. Depiction of “single step bioprocessing” accomplished by engineered C. bescii. CBP, consolidated bioprocessing.High-temperature fermentations facilitate biomass deconstruction and may reduce contamination and volatilize toxic products, such as alcohols. Clostridium thermocellum and Thermoanaerobacterium saccharolyticum have been used in mixed culture fermentations successfully for laboratory-scale demonstration of first-generation consolidated bioprocessing (13, 16) (Fig. 1). C. thermocellum is one promising candidate for consolidated bioprocessing because it is naturally cellulolytic, able to hydrolyze cellulose at 2.5 g⋅L⁻¹⋅h⁻¹, and produces ethanol as one fermentation product, but it has not yet been engineered to produce ethanol at high yield and lacks the ability to ferment hemicellulosic sugars (13, 17). Caldicellulosiruptor bescii, on the other hand, is the most thermophilic cellulolytic bacterium so far described, growing optimally at ∼80 °C with the ability to use a wide range of substrates, such as cellulose, hemicellulose, and lignocellulosic plant biomass without harsh and expensive chemical pretreatment (17, 18), efficiently fermenting both C₅ and C₆ sugars derived from plant biomass (17, 18). C. bescii uses the Embden–Meyerhof–Parnas pathway for conversion of glucose to pyruvate, and the predominant end-products are acetate, lactate, and hydrogen (Fig. 2) (18). A mutant strain of C. bescii (JWCB018) was recently isolated in which the lactate dehydrogenase gene (ldh) was disrupted spontaneously via insertion of a native transposon (19, 20). A complete deletion of ldh was also engineered (21), and this strain no longer produced lactate, instead diverting metabolic flux to additional acetate and H₂, demonstrating the utility of the newly developed tools to provide a platform for further strain engineering. The recent development of genetic methods for the manipulation of this organism (19, 21, 22) opens the door for metabolic engineering for the direct conversion of unpretreated plant biomass to liquid fuels, such as ethanol, via “single step bioprocessing” (Fig. 1).Open in a separate windowFig. 2.Overview of C. bescii fermentative pathways for bioconversion of hexose sugars. Pathway 1 (blue) results in 2 mol of acetic acid and 4 mol of H₂ per mole of glucose. Pathway 2 (green) produces 2 mol of lactic acid per mole of glucose. Pathway 3 (red) is a new pathway resulting from heterologous expression of the C. thermocellum adhE gene to synthesize 2 mol of ethanol per mole of glucose.     

减重代谢手术并发症单中心总结

目的 总结山东大学附属济南市中心医院胃肠外科减重代谢手术的并发症及处理方法.方法 回顾性分析自2013年11月至2018年11月在山东大学附属济南市中心医院胃肠外科接受减重代谢手术的230例患者的病例资料,其中行腹腔镜Roux-en-Y胃旁路术(LRYGB)57例和腹腔镜袖状胃切除术(LSG)173例,总结分析并发症、...