Review and Evaluation of European National Clinical Practice Guidelines for the Treatment and Management of Active Charcot Neuro-Osteoarthropathy in Diabetes Using the AGREE-II Tool Identifies an Absence of Evidence-Based Recommendations.

Background: Charcot neuro-osteoarthropathy (CNO) is a rare but devastating complication of diabetes associated with high rates of morbidity; yet, many nonfoot specialists are unaware of it, resulting in missed and delayed diagnosis. Clinical practice guidelines (CPGs) have proven useful in improving quality of care and standardizing practice in diabetes and diabetic foot care. However, little is known about the consistency in recommendations for identification and management of active CNO. Aim: The aim of this study is to review European national diabetes CPGs for the diagnosis and management of active CNO and to assess their methodological rigor and transparency. Methods: A systematic search was performed to identify diabetes national CPGs across Europe. Guidelines in any language were reviewed to explore whether they provided a definition for active CNO and recommendations for diagnosis, monitoring, and management. Methodological rigor and transparency were assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE-II) tool, which comprises 23 key items organized within six domains with an overall guideline assessment score of ≥ 60% considered to be of adequate quality to recommend use. Each guideline was assessed by two reviewers, and inter-rater agreement (Kendall's W) was calculated for AGREE-II scores. Results: Seventeen CPGs met the inclusion criteria. Breadth of CNO content varied across guidelines (median (IQR) word count: 327; Q1 = 151; Q3 = 790), and 53% provided a definition for active CNO. Recommendations for diagnosis and monitoring were provided by 82% and 53%, respectively, with offloading being the most common management recommendation (88%). Four guidelines (24%) reached threshold for recommendation for use in clinical practice (≥ 60%) with the scope and purpose domain scoring highest (mean (SD): 67%, ± 23%). The remaining domains had average scores ranging between 19% and 53%. Inter-rater agreement was strong (W = 0.882; p < 0.001). Conclusions: European national CPGs for diabetes provide limited recommendations on active CNO. All guidelines showcased deficits in their methodology, suggesting that more rigorous methods should be employed for diabetes CPG development across Europe.

Microbiological, Clinical and Radiological Aspects of Diabetic Foot Ulcers Infected with Methicillin-Resistant and -Sensitive Staphylococcus aureus.

Diabetic foot ulcer (DFU) is one of the most common chronic complications of diabetes. This study aimed to assess the factors with an impact on the infection of diabetic foot ulcers by methicillin-resistant S. aureus and to evaluate the influence of methicillin resistance on the frequency of osteitis (based on classic X-ray images). A total of 863 patients suffering from DFU were analyzed during the study period. Out of 201 isolated S. aureus cases, 31 (15.4%) were methicillin-resistant (MRSA). MRSA infections were associated with a higher incidence of osteitis compared to MSSA infections (p << 0.0001), both the occurrence of smaller (<50%)) and greater (>50%) inflammatory bone changes (p << 0.0001). Furthermore, MRSA occurred significantly more frequently in men than in women (p < 0.01) and more often among patients with type 2 diabetes than among patients with type 1 diabetes (p < 0.05). MRSA were isolated statistically less often in overweight patients than in patients with normal BMI (p < 0.05). DFUs infected with MRSA were significantly more frequently associated with the presence of Pseudomonas sp. and other non-fermenting bacilli than those infected with MSSA (p < 0.05). To conclude, osteitis incidence is related to MRSA infection in patients with diabetic foot ulcers; thus, patients infected by S. aureus should be closely monitored in the course of using antibiotics and treated with narrow-spectrum antibiotics.

The role of genetic factors and monocyte-to-osteoclast differentiation in the pathogenesis of Charcot neuroarthropathy.

Charcot neuroarthropathy is a chronic, progressive condition of the skeletal system that affects some patients with diabetic neuropathy. It results in progressive destruction of bones of the foot and disorganisation of pedal joints and ligaments. Effective prevention and treatment for Charcot neuroarthropathy remain a challenge. Currently, there are no reliable repeatable markers to identify patients with diabetes who are at higher risk of developing Charcot neuroarthropathy. The pathogenesis underlying the development of Charcot neuroarthropathy also remains unclear. In this review, we provide an overview of the history, prevalence, symptoms, risk factors, diagnostics and treatment of Charcot neuroarthropathy. We also discuss the potential for OPG and RANKL gene variants to act as predictive markers for the development of Charcot neuroarthropathy. Finally, we summarise the latest research on the role of monocyte-to-osteoclast differentiation in the development of acute Charcot neuroarthropathy.

Diabetic foot syndrome: Charcot arthropathy or osteomyelitis? Part I: Clinical picture and radiography.

One of significant challenges faced by diabetologists, surgeons and orthopedists who care for patients with diabetic foot syndrome is early diagnosis and differentiation of bone structure abnormalities typical of these patients, i.e. osteitis and Charcot arthropathy. In addition to clinical examination, the patient's medical history and laboratory tests, imaging plays a significant role. The evaluation usually begins with conventional radiographs. In the case of osteomyelitis, radiography shows osteopenia, lytic lesions, cortical destruction, periosteal reactions as well as, in the chronic phase, osteosclerosis and sequestra. Neurogenic arthropathy, however, presents an image resembling rapidly progressing osteoarthritis combined with aseptic necrosis or inflammation. The image includes: bone destruction with subluxations and dislocations as well as pathological fractures that lead to the presence of bone debris, osteopenia and, in the later phase, osteosclerosis, joint space narrowing, periosteal reactions, grotesque osteophytes and bone ankylosis. In the case of an unfavorable course of the disease and improper or delayed treatment, progression of these changes may lead to significant foot deformity that might resemble a "bag of bones". Unfortunately, radiography is non-specific and frequently does not warrant an unambiguous diagnosis, particularly in the initial phase preceding bone destruction. For these reasons, alternative imaging methods, such as magnetic resonance tomography, scintigraphy, computed tomography and ultrasonography, are also indicated.

Prevalence of polymorphisms in OPG, RANKL and RANK as potential markers for Charcot arthropathy development.

Charcot arthropathy is one of the most serious complications of diabetic foot syndrome that leads to amputation of the affected limb. Since there is no cure for Charcot arthropathy, early diagnosis and implementation preventive care are the best available treatment. However, diagnosis is hindered by obscure clinical picture of the disease and lack of molecular markers for its early detection. Results of recent research suggest that OPG-RANKL-RANK axis regulating bone metabolism can be associated with Charcot arthropathy and that SNPs in OPG gene are associated with the disease. Here we report the results of comprehensive analysis of ten SNPs in OPG, RANKL and RANK genes in 260 subjects divided into diabetes, neuropathy and Charcot arthropathy groups. Besides genotype analysis we performed linkage disequilibrium and hierarchical clustering to obtain information about correlation between SNPs. Our results show that OPG 245T/G (rs3134069) and OPG 1217C/T (rs3102734) polymorphisms co-occur in patients with Charcot arthropathy (r2 = 0.99). Moreover, hierarchical clustering revealed a characteristic profile of all SNPs in Charcot arthropathy and neuropathy, which is distinct from control group. Our results suggest that analysis of multiple SNPs can be used as potential marker of Charcot arthropathy and provide insight into possible molecular mechanisms of its development.

Molecular factors involved in the development of diabetic foot syndrome.

Diabetes is one of the major challenges of modern medicine, as it is considered a global epidemic of the XXI century. The disease often leads to the development of serious, health threatening complications. Diabetic foot syndrome is a characteristic set of anatomical and molecular changes. At the macroscopic level, major symptoms are neuropathy, ischemia and chronic ulceration of the lower limb. In every third patient, the neuropathy develops into Charcot neuroarthropathy characterized by bone and joints deformation. Interestingly, all these complications are a result of impaired healing processes and are characteristic for diabetes. The specificity of these symptoms comes from impaired molecular mechanisms observed in type 1 and type 2 diabetes. Decreased wound and fracture healing reflect gene expression, cellular response, cell functioning and general metabolism. Here we present a comprehensive literature update on the molecular factors contributing to diabetic foot syndrome.

Is the advancement of diabetic angiopathy evaluated as ankle-brachial index directly associated with current glycaemic control?

INTRODUCTION AND OBJECTIVE: Diabetic patients are at high risk for peripheral arterial disease (PAD) characterized by symptoms of intermittent claudication or critical limb ischemia. Measurement of ankle-brachial index (ABI) has emerged as the diagnostic tool of choice, because it is relatively simple, non-invasive and inexpensive. It is also an independent marker of increased morbidity and mortality from cardiovascular diseases. The aim of the presented study was to assess the relationship between current glycemic control defined by glycated hemoglobin (HbA(1c)) level, and quantitative changes in the arteries of the lower limbs in patients with type 2 diabetes. MATERIALS AND METHODS: 175 patients with type 2 diabetes hospitalized in the Diabetology Ward were studied. VENO Doppler and a sphygmomanometer were used to assess blood flow. RESULTS: The average level of HbA(1c) was assessed at 8.48%. Although the average level of ABI indicator was 1.20 (normal), only 45% of evaluated patients had their individual index within the normal range. Signs of ischemia were found in 17.7% of examined subjects. There was no conclusive correlation between ABI and HbA(1c) levels. CONCLUSIONS: The current level of glycemic control evaluated as HbA(1c) has no direct impact on the advancement of diabetic angiopathy evaluated as ABI.

Current glycaemic control has no impact on the advancement of diabetic neuropathy.

UNLABELLED: The aim of the study was to assess the association between glycemic control understanding as a glycated haemoglobin level and indices of diabetic neuropathy. METHODS: We evaluated 204 patients with diabetes (type 1 - 29; type 2 - 175). Glycated haemoglobin was determined using The Diabetes Control and Complications Trial/ National Glycohemoglobin Standardization Program method. Evaluation of complaints from the lower extremities was based on the Neuropathy Syndrome Total Score questionnaire. We used a mono lament for evaluation of touch sensation (Semmes-Weinstein 5.07-10 g), a 128 Hz calibrated tune-fork for the vibration perception test, Tip-Therm to assess temperature sensation. RESULTS: The mean glycated haemoglobin level was assessed on 8.53±1.87%. The mean Neuropathy Syndrome Total Score: 11.45±6.37. Decreased sensation of touch on both sides was determined in 30% of cases, decreased sensation of temperature in 59% and decreased sensation of vibration in 30%. For Neuropathy Syndrome Total Score and glycated haemoglobin the Pearson's correlation test was 0.00910 (p≈0.99), Spearman's rank correlation test was 0.00523 (p≈0.95). Persons with sensation deficits and neuropathy symptoms had not significantly higher (Neuropathy Syndrome Total Score, temperature sensation disturbances) and not significantly lower (vibration and touch) glycated haemoglobin level compared to patients without neuropathy. CONCLUSION: There is no correlation between prevalence and advancement of sensorial neuropathy and current diabetes control in patients with long-term established diabetes.

Ultrasound-diagnosed bone and joint destruction as a typical image in advanced Charcots arthropathy - case report.

The paper presents a case of Charcot foot in a patient with long standing type 2 diabetes and complicated by peripheral neuropathy. It was initially diagnosed by an ultrasound examination and subsequently confirmed by an X-ray and an magnetic resonance imaging. Diabetic neuropathy is nowadays the most frequent cause of Charcot arthropathy, although it can be also a result of other diseases of the nervous system. In the acute phase the patient usually presents with edema, redness and increased temperature of the foot, which can suggest many other diagnoses including bacterial infection, gout, venous thrombosis or trauma. Because of its non specific clinical presentation and unsufficient awareness of the specificity of the diabetic foot syndrome among health professionals and the patients the diagnosis of this process is in many cases delayed. In the acute phase appropriate treatment needs to be initiated (mainly off loading and immobilization of the foot in a total contact cast), otherwise a rapidly progressing destruction of the bones and joints will usually begin, leading to fractures, dislocations and a severe foot deformity. Increased awareness among doctors taking care of the diabetic patients and appropriate use of the imaging methods can definitely improve efficacy of the diagnostic process and help to optimize the treatment of Charcot arthropathy. The standard approach usually includes use of radiography, magnetic resonance imaging and scintigraphy. In some cases a sonographer may be the first one to notice typical signs of bony destruction in a patient with Charcot arthropathy and suggest immediate further imaging in order to confirm the diagnosis and to minimize the risk of mutilating complications.

Mild CFTR mutations and genetic predisposition to lactase persistence in cystic fibrosis.

Taking into account the reported incidence of hypolactasia in cystic fibrosis (CF) and the possible impact of milk products on nutritional status we aimed to assess the genetic predisposition to adult-type hypolactasia (ATH) and its incidence in CF. Single nucleotide polymorphism upstream of the lactase gene (LCT) was assessed in 289 CF patients. In subject with -13910C/C genotype (C/C) predisposing to ATH, hydrogen-methane breath test (BT) with lactose loading was conducted and clinical symptoms typical for lactose malabsorption were assessed. The percentage of CF patients with C/C was similar to that observed in healthy subjects (HS) (31.5 vs 32.5% ). Eleven out of 52 (24.5%) CF C/C patients had abnormal BT results. The recalculated frequency of lactose malabsorption was similar for the entire CF and HS populations (6.9 vs 7.2%). Similarly as in the control group, few CF patients have identified and linked to lactose consumption clinical symptoms. The frequency of LCT polymorphic variants in CF patients having and not having severe mutations of CFTR gene showed significant differences. The C allele was more frequent in homozygotes of the severe mutations than in patients carrying at least one mild/unknown mutation (P<0.0028) and in patients with at least one mild mutation (P < 0.0377). In conclusion, CF patients carrying mild CFTR mutations seem to have lower genetic predisposition to ATH. Lactose malabsorption due to ATH in CF is not more frequent than in the general population. Symptomatic assessment of lactose malabsorption in CF is not reliable.

Diabetic foot - the need for comprehensive multidisciplinary approach.

Diabetes mellitus is considered to be civilization disease development of which is influenced by environmental changes. Diabetic foot (ulceration, infection, gangrene) is one of the most disabling complication of diabetes mellitus. It contributes to the increased mortality and cardiovascular death. It also frequently leads to depression, social exclusion and physical impairment. Risk factors of diabetic foot are as follows: age, race, sex, duration of diabetes, biomechanical factors, level of glycemia, smoking habits. According to international standards diabetic foot can be successfully treated only by the multidisciplinary team which can provide more comprehensive and integrated care as compared to ordinary medical team or single specialist. Multidisciplinary team consists of: diabetologist, shoemaker, orthopedist, psychologist, surgeons both vascular and general, podologists, radiologists, educators, nurses and rehabilitation team. Such coordinated attitude to a patient may be the future solution for any civilization and environment-related disease requiring treatment which cannot be successfully provided by any ordinary medical team.

Adult-type hypolactasia and lactose malabsorption in Poland.

BACKGROUND: The available data on the incidence of lactose malabsorption are contradictory. Potential bias in random selection is a major drawback of studies performed to-date. Moreover, molecular analysis of polymorphism -13910 C>T upstream of the lactase (LCT) gene (NM_005915.4:c.1917+326C>T; rs4988235) has not been reported in those studies. Therefore, in this study we aimed to assess genetic predisposition and clinical manifestation of adult-type hypolactasia (ATH). PATIENTS AND METHODS: In two-hundred randomly chosen healthy subjects (HS) aged from 18 to 20 years, the presence of -13910 C>T polymorphic variants upstream of the LCT gene was assessed. In a subgroup of subjects with genotype predisposing to ATH, hydrogen-methane breath test (BT) with lactose loading was conducted to determine the current state of lactase activity. In addition, clinical symptoms typical for lactose malabsorption were assessed using the questionnaire method. RESULTS: Sixty-three out of 200 (31.5 %) HS had -13910 C/C genotype. Thus, genetically determined lactase persistence is expected in the remaining 137 (68.5 %) subjects. Thirteen out of 53 (24.5 %) HS having -13910 C/C genotype were proved to be lactose intolerant. Recalculating the data for the entire studied population it implies the incidence of lactose malabsorption in 7.7 % of subjects. Only three out of 13 (23.1 %) subjects with abnormal BT results, reported clinical symptoms related to lactose consumption. CONCLUSIONS: Significantly lower than previously reported incidence of clinically detectable lactose malabsorption in young healthy adults in Poland has been documented. The -13910 C/C genotype upstream of the LCT gene indicates a predisposition to ATH, but definitely does not define the current ability to tolerate lactose.

Diagnostic imaging of the diabetic foot.

Diabetic foot syndrome is a significant complication of diabetes. Diagnostic imaging is a crucial factor determining surgical decision and extent of surgical intervention. At present the gold standard is MRI scanning, whilst the role of bone scanning is decreasing, although in some cases it brings valuable information. In particular, in early stages of osteitis and Charcot neuro-osteoarthropathy, radionuclide imaging may be superior to MRI. Additionally, a significant contribution of inflammation-targeted scintigraphy should be noted. Probably the role of PET scanning will grow, although its high cost and low availability may be a limiting factor. In every case, vascular status should be determined, at least with Doppler ultrasound, with following conventional angiography or MR angiography.

Why are behaviors of children suffering from various neuronopathic types of mucopolysaccharidoses different?

Mucopolysaccharidoses (MPS) are inherited metabolic disorders from the group of lysosomal storage diseases (LSD). They arise from mutations causing dysfunction of one of enzymes involved in degradation of glycosaminoglycans (GAGs) in lysosomes. Impaired degradation of these compounds results in their accumulation in cells and dysfunction of most tissues and organs of patients. If heparan sulfate (HS) is the sole or one of stored GAGs, brain functions are also affected. However, despite the fact that products of incomplete degradation of the same chemical, HS, are accumulated in brains of patients suffering from Hurler disease (MPS type I), Hunter disease (MPS type II), Sanfilippo disease (MPS type III) and Sly disease (MPS type VII), and obvious deterioration of brain functions occur in these patients, their behavior is considerably different between various types of MPS. Here we asked the question about biochemical reasons of these differences. We performed theoretical analysis of products of incomplete HS degradation that accumulate in tissues of patients diagnosed for these diseases. A correlation between chemical structures of incompletely degraded HS and behaviors of patients suffering from particular MPS types was found. We propose a hypothesis that particular chemical moieties occurring at the ends of incompletely degraded HS molecules may determine characteristic behavioral disturbances, perhaps due to chemical reactions interfering with functions of neurons in the brain. A possible experimental testing of this hypothesis is also proposed. If the hypothesis is true, it might shed some new light on biochemical mechanisms of behavioral problems occurring not only in MPS but also in some other diseases.

Role of the microcirculation in diabetic foot ulceration.

The concept of microcirculation being implicated in the pathogenesis of diabetic foot disease is being challenged by evidence that fails to confirm it. However, there is evidence of structural changes with capillary and in the basement membrane that do not permit the concept to be denied either. The lack of evidence should not be a reason to argue against surgery in the diabetic foot.