Effects of r-metHuG-CSF on polymorphonuclear leucocyte kinetics and function in patients on continuous ambulatory peritoneal dialysis

End-stage renal failure (ESRF) patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are immunocompromised and exhibit abnormal circulating polymorphonuclear leucocyte (PMN) function, including reduced phagocytosis and intracellular killing. Six uraemic patients on CAPD were each given 300 μg granulocyte-colony stimulating factor (G-CSF) every day for 5 d and PMN function tests were performed daily. By day 5 of the study CD11b expression was significantly decreased in response to N -formylmethionylleucylphenylalanine (fMLP) and opsonized Staphylococcus epidermidis stimulation, and expression of L-selectin (CD62L) was significantly decreased in response to opsonized Staphylococcus epidermidis stimulation. Further, superoxide anion production and FcγRI (CD64) expression were found to be significantly increased and FcγRIII (CD16) expression was lowered. Circulating white cell and PMN counts were significantly elevated in response to treatment. Administration of G-CSF did not appear to have corrected the abnormalities in phagocytosis and intracellular killing. This study suggests that G-CSF does no harm to ESRF patients and influences uraemic PMN function in a manner that is comparable to its effects on PMN in non-uraemic subjects.     

粒细胞集落刺激因子保护急性损伤人胎肝细胞的实验研究

目的建立D-半乳糖胺(D-galactosamine,D-GalN)对人胎肝细胞急性损伤的模型,观察粒细胞集落刺激因子(Granulocyte-colony stimulating factor,G-CSF)对人胎肝细胞损伤的保护作用。方法分别用梯度浓度的D-GalN和不同的作用时间孵育人胎肝细胞,用四唑盐比色法(MTT法)检测细胞活性,以确定最佳的人胎肝细胞急性损伤造模条件。将胎肝细胞分为4组进行不同处理:第1组为空白对照组,第2组(G组)用G-CSF处理正常细胞,第3组(ND组)和第4组(GD组)都用D-GalN进行损伤造模,但GD组加入G-CSF作为治疗,第3组加入等量的0.9%氯化钠溶液作为实验对照。最后用MTT法和乳酸脱氢酶(LDH)释放量检测各组细胞活性。结果当D-GalN浓度为10 mg/ml,作用时间为12 h时,可以杀伤90%以上的人胎肝细胞,并且可以保证有足够的药物反应时间。空白对照组和G组的细胞活性差异无统计学差异,但GD组细胞活性明显高于ND组(P0.05)。结论 D-GalN对人胎肝细胞急性损伤的造模条件为D-GalN 10 mg/ml作用12 h。G-CSF对D-GalN造成的人胎肝细胞急性损伤具有保护作用。     

Successful treatment of autoimmune neutropenia with recombinant human granulocyte-colony stimulating factor (R-metHuG-CSF)

Autoimmune neutropenia (AIN) is characterized by antibody mediated peripheral destruction of neutrophils. Since there is no effective treatment, antibiotics have to be used frequently for recurrent infections. Five selected patients with serologically proven AIN were treated with r-metHuG-CSF at 5–8 μg/kg body weight (300–480 μg) daily; the dose and frequency of r-metHuG-CSF was reduced after neutrophil counts above 1.0×10⁹/l were obtained. R-metHuG-CSF is effective in AIN and causes a sustained rise in ANC which can be maintained on a low dose administered twice or thrice weekly.     

老年糖尿病足坏疽患者的临床特征及其危险因素分析

目的了解老年人糖尿病足坏疽（ＤＦ）的临床特征及其危险因素。方法对２２１例老年和１６３例老年前期ＤＦ的患病率、各种诱因的百分比、ＤＦ和非ＤＦ患者胫后感觉神经传导速度、双下肢动脉管径和血流量等检测结果进行分析。结果（１）老年和老年前期ＤＦ患者的患病率（４９．５％和２７．４％）明显高于青中年组（１１．０％）；自发性溃疡、水疱破裂、穿鞋不当摩擦伤为ＤＦ的常见诱因；湿性坏疽为ＤＦ的主要类型。（２）老年和老年前期ＤＦ患者因周围神经病变致传导速度检测不能引出波形者分别占９２％和８２％、周围血管病变致动脉狭窄和闭塞者分别占９２％和７８％，显著高于非ＤＦ组。结论老年人糖尿病易合并ＤＦ；周围神经病变和周围血管病变在ＤＦ的发生和发展中起重要作用。     

Becaplermin gel in the treatment of diabetic neuropathic foot ulcers

Diabetic foot ulcers remain a major cause of morbidity. Significant progress has been accomplished in ulcer healing by improved management of both ischemia and neuropathy in the diabetic foot. Nevertheless, there is a vital need for further improvement. Becaplermin gel represents an important therapeutic advance for diabetic neuropathic foot ulcers with adequate blood supply. Randomized controlled trials have shown that it is effective in increasing healing rates. However, this efficacy has not translated to positive clinical experience, and the drug is not widely used. Moreover, becaplermin is an expensive medication. Even though it has repeatedly been estimated as cost-effective, its high cost may be prohibitive for some clinicians, especially in developing countries. Clearly, further work is needed to clarify whether use of becaplermin is justified in everyday clinical practice. Future research also needs to assess the potential room for improvement with becaplermin, for instance by combination with other growth factors or by exploring alternative modes of drug delivery.     

Why do foot ulcers recur in diabetic patients?

AIM: To investigate factors predisposing to recurrent foot ulceration in patients with diabetes mellitus. METHODS: Two groups of patients who had attended a specialist Diabetes Foot Centre were assessed: relapsers (n = 26), whose foot ulceration had recurred at least twice, and nonrelapsers (n = 25), whose initial ulcer had not recurred for at least 2 years. RESULTS: In the relapser group 10/26 patients waited at least 24 h before reporting symptoms compared with only 2/25 in the nonrelapser group (P < 0.05). Vibration perception threshold (volts) was 38 +/- 12 (mean +/- SD) in relapsers compared with 25 +/- 13 in nonrelapsers (P < 0.005). Cold perception threshold (degrees C) was 9.1 +/- 4.6 in relapsers compared with 5.1 +/- 3.5 in nonrelapsers (P<0.005). HbA1c (%) was significantly raised at 8.5 +/- 1.7 in relapsers compared with 7.6 +/- 1.2 in nonrelapsers (P = 0.03). Alcohol intake was 0.5 (median, interquartile range 0-2) units per day in relapsers compared with 0.0 (median, interquartile range 0-0.25) units in nonrelapsers (P = 0.04). Smoking habits, housing conditions, visual acuity, threshold for warm perception and the Doppler pressure index were not significantly different in the two groups. CONCLUSIONS: Patients who develop recurrent foot ulceration delay in reporting symptoms, when compared with diabetic patients whose foot ulceration does not recur. The relapsers also have evidence of poorer glycaemic control, more neuropathy and increased alcohol intake.     

Multiple myeloma with infiltration into skeletal muscle after injections of granulocyte-colony stimulating factors

Multiple myelomas often occur in elderly people with age-related complications as they age further. A 54-year-old man was first admitted with cerebral infarction and multiple myeloma (IgG kappa, stage IIIA) in November 1989. There was partial remission following chemotherapy. The karyotype of the marrow cells was 46, XY, and no p53 gene mutations were detected by polymerase chain reaction and single-strand conformation polymorphism analysis. In February 1999, chemotherapy (melphalan, vindesine, ranimustine, prednisolone) was administered as a result of aggravation of the myeloma. Later, after daily subcutaneous injection of 50 µg of nartograstim for 6 days to treat febrile neutropenia, the soft tissues around the right eye swelled gradually, but without redness accompanied by an elevation of the serum creatine-kinase concentration. When nartograstim was discontinued, however, the swelling disappeared and the creatine-kinase level normalized. Then in July, on the sixth day of daily subcutaneous injections of 75 µg of filgrastim following the same chemotherapy regimen, similar swelling of the soft tissues occurred around the left eye, and was again reversed by withdrawal of the drug. In July 2000, infusion of dexamethasone was conducted, and following daily subcutaneous-injection of 75 µg of filgrastim for 5 days, the right subclavicular soft tissue became swollen. The patient later died of myocardial infarction and an autopsy revealed an infiltration of myeloma cells into the right subclavicular muscle and bone marrow that was packed with myeloma cells. This case suggests that exposure to granulocyte-colony stimulating factors enables myeloma cells to proliferate and infiltrate into soft tissues.     

Interventions in the management of infection in the foot in diabetes: a systematic review

The optimal approaches to managing diabetic foot infections remain a challenge for clinicians. Despite an exponential rise in publications investigating different treatment strategies, the various agents studied generally produce comparable results, and high‐quality data are scarce. In this systematic review, we searched the medical literature using the PubMed and Embase databases for published studies on the treatment of diabetic foot infections as of June 2018. This systematic review is an update of previous reviews, the first of which was undertaken in 2010 and the most recent in 2014, by the infection committee of the International Working Group of the Diabetic Foot. We defined the context of literature by formulating clinical questions of interest, then developing structured clinical questions (PICOs) to address these. We only included data from controlled studies of an intervention to prevent or cure a diabetic foot infection. Two independent reviewers selected articles for inclusion and then assessed their relevant outcomes and the methodological quality. Our literature search identified a total of 15 327 articles, of which we selected 48 for full‐text review; we added five more studies discovered by means other than the systematic literature search. Among these selected articles were 11 high‐quality studies published in the last 4 years and two Cochrane systematic reviews. Overall, the outcomes in patients treated with the different antibiotic regimens for both skin and soft tissue infection and osteomyelitis of the diabetic foot were broadly equivalent across studies, except that treatment with tigecycline was inferior to ertapenem (±vancomycin). Similar outcomes were also reported in studies comparing primarily surgical and predominantly antibiotic treatment strategies in selected patients with diabetic foot osteomyelitis. There is insufficient high‐quality evidence to assess the effect of various adjunctive therapies, such as negative pressure wound therapy, topical ointments or hyperbaric oxygen, on infection related outcomes of the diabetic foot. In general, the quality of more recent trial designs are better in past years, but there is still a great need for further well‐designed trials to produce higher quality evidence to underpin our recommendations.     

A case of anaplastic carcinoma of the pancreas producing granulocyte-colony stimulating factor

We report a case of anaplastic carcinoma of the pancreas with production of granulocyte-colony stimulating factor (G-CSF) in a 59-year-old male. He was referred to our hospital with a chief complaint of epigastralgia and suffered from leukocytosis. Differential diagnosis included pancreatic tumors and submucosal tumor of the stomach, but definite preoperative diagnosis could not be made. He underwent distal pancreactomy, total gastrectomy with Roux-en-Y reconstruction and splenectomy. He recovered uneventfully postoperatively and was discharged from hospital on the 14th postoperative day. Histological examination showed anaplastic carcinoma of the pancreas. Since the peripheral leukocyte count was sharply decreased after the operation, we suspected the tumor would be producing G-CSF. Then immunohistochemistry showed a positive stain in the tumor. Therefore, we diagnosed the tumor as anaplastic carcinoma of the pancreas producing G-CSF. Three months after the resection, local recurrence was detected by abdominal computed tomography. The patient died of hemorrhagic shock due to tumor invasion of the intestine 8 months after the operation.     

Transforming growth factor-beta 1, 2, 3 and receptor type I and II in diabetic foot ulcers.

AIMS: To study the distribution of transforming growth factor-beta (TGF-beta) 1, 2 and 3, and TGF-beta receptor types I and II in diabetic foot ulcers, diabetic skin and normal skin by immunohistochemistry, immunofluorescence and Western blotting. We also compared the TGF-betas with those of chronic venous ulcers. METHODS: Skin biopsies were obtained from the leg or the foot of non-diabetic and diabetic subjects, and from the edge of diabetic foot ulcers and chronic venous ulcers. Distribution (by immunofluorescence and immunocytochemistry) of TGF-beta 1, 2 and 3 and TGF-beta receptors (RI and RII) was done by staining 8-microm skin sections using appropriate antibodies. Protein levels of TGF-beta were measured by Western blot analysis. RESULTS: TGF-beta3 expression was increased in the epithelium at the edge of diabetic foot ulcers, being more intense than diabetic and normal skin (P = 0.03, 0.02, respectively), as was its expression in venous ulcers compared with normal skin. However, TGF-beta1 expression was not increased in diabetic foot ulcers and chronic venous ulcers, and was comparable to diabetic and normal skin. There was also no increase for the receptors in diabetic foot ulcers. CONCLUSION: The lack of TGF-beta1 up-regulation in both diabetic foot ulcers and venous ulcers may explain the impaired healing in these chronic wounds, and could represent a general pattern for chronicity.     

Carcinosarcoma of the esophagus producing granulocyte-colony stimulating factor: report of a case

A 51-year-old man was admitted to the hospital for dysphagia, pyrexia, and leukocytosis. The serum level of granulocyte-colony stimulating factor (G-CSF) was elevated. Barium esophagography and endoscopy revealed a polypoid tumor in the middle portion of the esophagus. After an esophagectomy, the leukocyte count and serum G-CSF level normalized. The pathological diagnosis was carcinosarcoma of the esophagus with two components: namely, squamous cell carcinoma and sarcoma. Moreover, cancer cells were positive for G-CSF antibody. These findings confirmed that the esophageal carcinosarcoma in this case was a G-CSF-producing tumor. Although a G-CSF-producing esophageal carcinosarcoma is very rare, this disease should be considered when a patient has symptoms such as leukocytosis and pyrexia without an associated infection.     

强化教育干预对糖尿病足预防的中远期效果

目的观察强化足部护理教育干预对糖尿病（DM）是预防的中远期效果，探讨由DM教育护士实施的DM足的预防护理教育干预的可行性和有效性。方法采用实验性研究方法，教育干预组86例（入组110例，失访24例）、对照组92例（入组110例，失访18例）。对照组实施常规DM治疗和DM基本知识教育，实验前和实验后9个月时收集相关资料。教育干预组除接受与对照组相同的措施外，给予个体化DM足预防护理知识与行为干预，首次干预后1，3，6，9个月时分别复诊继续接受强化教育指导，以调查评价研究表评价足部教育干预对DM足预防的作用。结果DM足预防护理教育干预9个月后，教育干预组患者对DM足的认识、早期筛查知识、日常足部护理、合适鞋袜选择、修剪趾甲等知识评分显著提高，日常足部护理行为均明显改善（P〈0．05-P〈0．01）。教育干预组患者足部皮肤病理性损害明显减少，足部胼胝发生率、足部皮肤损伤率、足癣发生率、皮肤干燥、皲裂发生率明显低于对照组（P〈0．05-P〈0．001）。血糖（空腹血糖、餐后2h血糖）、HbAlc、血压等代谢指标较对照组明显改善（P〈0．05）。结论由DM教育护士实施的DM足的预防护理教育干预是可行、有效的。研究结果显示了DM足的预防护理教育干预在减少DM足发生中的重要作用，以及个体化足病预防护理教育干预对DM足预防的中远期效果。     

表皮生长因子治疗糖尿病足溃疡的研究进展

糖尿病足是糖尿病常见的慢性并发症之一,15%的糖尿病患者可能发生足部溃疡。溃疡创面局部生长因子及受体活性下降和数量的绝对或相对缺乏是其难以愈合的病理生理基础。表皮生长因子(EGF)通过促进细胞迁移、增殖及细胞外基质合成等参与溃疡创面愈合。外源性EGF作为一种新的治疗手段,局部应用于糖尿病足溃疡取得显著效果。通过组织工程学技术,EGF释药方式不断改善,并可与其他生长因子联合应用,具有广泛前景。     

Evidence of greater severity of diabetic foot ulcers during COVID-19 pandemic: A real-life single-centre cohort study

Aims

In the Sars-Cov-2 pandemic era, patients with diabetes mellitus (DM) manifested more severe forms of Sars-Cov-2 with greater mortality than non-diabetic patients. Several studies documented more aggressive forms of diabetic foot ulcers (DFU) during the pandemic period even though the results were not unanimously confirmed. The aim of this study was to evaluate the clinical-demographic differences between a cohort of Sicilian diabetic patients hospitalised for DFU in the pre-pandemic 3 years and a cohort of patients hospitalised in the pandemic 2 years.

Materials and Methods

One hundred and eleven patients from the pre-pandemic period 2017–2019 (Group A) and 86 patients from the pandemic period 2020–2021 (Group B) with DFU, admitted to the division of Endocrinology and Metabolism of the University Hospital of Palermo, were retrospectively evaluated. The clinical assessment of the type, staging and grading of the lesion, and the infective complication from DFU was performed.

Results

No differences in HbA1c values were observed between the two groups. Group B showed a significantly higher prevalence of male subjects (p = 0.010), neuro-ischaemic ulcers (p < 0.001), deep ulcers with involvement of bones (p < 0.001), white blood count levels (p < 0.001), and reactive C protein (p = 0.001) compared to group A.

Conclusions

Our data show that in the COVID-19 pandemic, a greater severity of ulcers requiring a significantly greater number of revascularisations and more expensive therapy, but without an increase in the amputation rate, was observed. These data provide novel information on the impact of the pandemic on diabetic foot ulcer risk and progression.     

Economic aspects of diabetic foot care in a multidisciplinary setting: a review

BACKGROUND: To evaluate the economic aspects of diabetic foot care in a multidisciplinary setting. METHOD: A review of the English language literature, published from 1966 to November 2005. RESULTS: The results of available studies on the cost-of-illness of diabetic foot problems are difficult to compare. Nevertheless trends concerning excess of costs, protraction in time of costs, positive correlation to severity of ulcer and/or peripheral vascular disease, contribution of in-hospital stay and length of stay, and the patient's own contribution to total costs, are obvious. Only a few cost-effectiveness and cost-utility studies are available. Most use a Markov based model to predict outcome and show an acceptable result on long-term. CONCLUSIONS: Diabetic foot problems are frequent and are associated with high costs. A multidisciplinary approach to diabetic foot problems has proved to be cost saving with regard to cost of treatment itself. Nevertheless, it remained unclear if these savings could offset the overall costs involved in implementing this kind of approach. The few studies that address this issue specifically all show an acceptable cost-effectiveness, but often the profit will be evident after some years only, because long-term costs are involved. Based on these data, policymakers should foresee sufficient reimbursement for preventive and early curative measures, and not only for 'salvage manoeuvres'.     

糖尿病患者血糖波动幅度对糖尿病足的影响

目的探讨糖尿病足（DF）发生、发展的高危因素,特别是血糖波动对DF的影响。方法将192例非糖尿病足（NDF）和575例DF患者纳入研究,575例DF患者又分为DF累及到肌腱或深部的皮下组织（Wagner1～2级）组、累及骨组织（Wagner3级）组以及坏疽（Wagner4～5级）组。回顾性分析研究对象一般因素、生化指标、血糖水平的标准差（SDBG）、空腹血糖的变异系数（CV-FPG）、日内最大血糖波动幅度（LAGE）。再根据是否截肢将575例DF患者分为DF截肢组及DF非截肢组,比较各组有关血糖波动指标的差别。结果DF组较NDF组年龄、病程、血肌酐（sCr）、血尿酸（UA）、血清超敏C反应蛋白（hsCRP）、尿Alb／Cr、SDBG、CV-FPG、LAGE升高,血清总蛋白、血清白蛋白、总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL．C）降低,其中hsCRP、SDBG、CV-FPG在各组间差异均有统计学意义（P〈0．05）。DF截肢组与NDF组相比,SDBG、CV-FPG、LAGE增高（P〈O．05）,其中SDBG在DF截肢组与DF非截肢组差异亦有统计学意义（P〈O．05）。Logistic回归分析显示hsCRP、尿Alb／Cr、血清白蛋白、SDBG、CV-FPG是影响糖尿病足的独立危险因素;SDBG是DF截肢的独立危险因素。结论hsCRP、尿Alb／Cr、血清白蛋白、SDBG、CV-FPG可能与糖尿病足病的发生发展密切相关。     

A systematic review of foot ulcer in patients with Type 2 diabetes mellitus. II: treatment.

AIM: To assess the value of treatments for foot ulcers in patients with Type 2 diabetes mellitus. METHODS: A systematic review of interventions to treat diabetic foot ulcers. RESULTS: The evidence base for treating infections and dressing wounds is poor. A number of new and potentially promising treatments are being developed but currently available studies are often small, inadequately powered and use different methods and outcomes. CONCLUSIONS: Given the prevalence, morbidity and healthcare costs of diabetic foot disease, it is surprising that available trials provide inadequate evidence to improve upon current empirically based treatment approaches. Substantial effort and resources should be deployed in order to investigate both new and existing treatments in a co-ordinated, systematic and consistent manner, so that a proper evidence base can be established for this important disease area.