Effectiveness of psychosocial interventions for the prevention and treatment of foot ulcers in people with diabetes: a systematic review.

AIM: To identify and synthesize the evidence for the effectiveness of psychosocial interventions to promote the healing, and/or reduce the occurrence of, foot ulceration in people with diabetes. METHODS: In March 2019 we searched CENTRAL, Medline, Embase and PsycInfo for randomized controlled trials of interventions with psychosocial components for people with diabetes. The primary outcomes of this review were foot ulceration and healing. We assessed studies using the Cochrane risk-of-bias tool, the TIDieR checklist and GRADE. We conducted narrative synthesis and random-effects meta-analysis. RESULTS: We included 31 randomized controlled trials (4511 participants), of which most (24 randomized controlled trials, 4093 participants) were prevention studies. Most interventions were educational with a modest psychosocial component. Ulceration and healing were not reported in most studies; secondary outcomes varied. Evidence was of low or very low quality because of high risks of bias and imprecision, and few studies reported adherence or fidelity. In groups where participants had prior ulceration, educational interventions had no clear effect on new ulceration (low-quality evidence). Two treatment studies, assessing continuous pharmacist support and an intervention to promote understanding of well-being, reported healing but their evidence was also of very low quality. CONCLUSION: Most psychosocial intervention randomized controlled trials assessing foot ulcer outcomes in people with diabetes were prevention studies, and most interventions were primarily educational. Ulcer healing and development were not well reported. There is a need for better understanding of psychological and behavioural influences on ulcer incidence, healing and recurrence in people with diabetes. Randomized controlled trials of theoretically informed interventions, which assess clinical outcomes, are urgently required. (PROSPERO registration: CRD42016052960).

Patients with surgical wounds healing by secondary intention: A prospective, cohort study.

BACKGROUND: Surgical wounds healing by secondary intention can be difficult and costly to manage and are profoundly under researched. This prospective inception, cohort study aimed to derive a better understanding of surgical wounds healing by secondary intention and to facilitate the design of future research investigating effective treatments. OBJECTIVES: To investigate the clinical characteristics of patients with surgical wounds healing by secondary intention and the surgeries that preceded their wounds; to clearly delineate the clinical outcomes of these patients, specifically focusing on time to wound healing and its determinants; to explore the types of treatments for surgical wounds healing by secondary intention; and to assess the impact surgical wounds healing by secondary intention have on patients' quality of life. DESIGN: Prospective, inception cohort study. SETTING: Acute and community settings in eight sites across two large centres in the United Kingdom (Hull and Leeds, UK). METHODS: Patients with a surgical wounds healing by secondary intention (an open wound, <3 weeks' duration, resulting from surgery), were recruited and followed up for at least 12 months. Key outcome events included: time to healing; treatment type; infection; hospital re-admission and further procedures; health-related quality of life and pain. RESULTS: In total, 393 patients were recruited. Common co-morbidities were cardiovascular disease (38%), diabetes (26%) and peripheral vascular disease (14.5%). Baseline median SWHSI area was 6 cm2 (range 0.01-1200). Abdominal (n = 132), foot (n = 59), leg (n = 58) and peri-anal (n = 34) wounds were common. The majority of wounds (236, 60.1%) were intentionally left open following surgery; the remainder were mostly dehisced wounds. Healing was observed in 320 (81.4%) wounds with a median time to healing of 86 days (95% CI: 75-130). Factors associated with delayed healing included wound infection at any point and baseline wound area above the median. Health-related quality of life scores were low at baseline but improved with time and healing. CONCLUSIONS: This is the first inception cohort study in patients with surgical wounds healing by secondary intention. Patient characteristics have been clearly defined, with prolonged healing times and adverse events being common impacting on patient's health-related quality of life. Areas for, and factors crucial to the design of, future research have been identified.

A survey of patients with surgical wounds healing by secondary intention; an assessment of prevalence, aetiology, duration and management.

BACKGROUND: Surgical wounds healing by secondary intention (SWHSI) are often difficult and costly to treat. There is a dearth of clinical and research information regarding SWHSI. The aim of this survey was to estimate the prevalence of SWHSI and to characterise the aetiology, duration and management of these wounds. METHODS: Anonymised data were collected from patients with SWHSI receiving treatment in primary, secondary and community settings. Over a two weeks period, data were collected on the patients, their SWHSI, clinical and treatment details. RESULTS: Data were collected from 187 patients with a median age of 58.0 (95% CI = 55 to 61) years. The prevalence of SWHSI was 0.41 (95% CI = 0.35 to 0.47) per 1000 population. More patients with SWHSI were being treated in community (109/187, 58.3%) than in secondary (56/187, 29.9%) care settings. Most patients (164/187, 87.7%) had one SWHSI and the median duration of wounds was 28.0 (95% CI = 21 to 35) days. The most common surgical specialities associated with SWHSI were colorectal (80/187, 42.8%), plastics (24/187, 12.8%) and vascular (22/187, 11.8%) surgery. Nearly half of SWHSI were planned to heal by secondary intention (90/187, 48.1%) and 77/187 (41.2%) were wounds that had dehisced. Dressings were the most common single treatment for SWHSI, received by 169/181 (93.4%) patients. Eleven (6.1%) patients were receiving negative pressure wound therapy. CONCLUSIONS: This survey provides a previously unknown insight into the occurrence, duration, treatment and types of surgery that lead to SWHSI. This information will be of value to patients, health care providers and researchers.

Therapeutic ultrasound for pressure ulcers.

BACKGROUND: Pressure ulcers have been recorded as occurring in 5 to 32% of patients admitted to a UK District General Hospital (the precise rate depends on case-mix) and 4 to 7% in the community. They represent a major burden of sickness and reduced quality of life for patients and their carers, and are costly to health service providers. Pressure ulcers are treated by using wound dressings, relieving pressure on the wound, by treating concurrent conditions which may delay healing, and by the use of physical therapies such as electrical stimulation, laser therapy and ultrasound. OBJECTIVES: To assess the effect of therapeutic ultrasound on the healing of pressure ulcers. SEARCH STRATEGY: We searched the Cochrane Wounds Group Specialised Register and the Cochrane Central Register of Controlled Trials in May 2006. In addition we hand searched journals, conference proceedings, bibliographies and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing therapeutic ultrasound with sham ultrasound or standard treatment. DATA COLLECTION AND ANALYSIS: Two authors independently checked the result of the search to identify relevant RCTs. Details of eligible studies were extracted and summarised using a data extraction sheet. Attempts were made to obtain missing information by contacting authors. Data extraction was checked by a second author. Meta-analysis was used to combine the results of trials where the interventions and outcome measures were sufficiently similar. MAIN RESULTS: Three trials involving 146 people were included. Two RCTs compared ultrasound therapy with sham ultrasound and the third compared a combination of ultrasound and ultraviolet light with laser and with standard treatment. Neither of the two RCTs comparing ultrasound with sham found a significant difference in healing rates. The trials were pooled, in the absence of significant heterogeneity. There was no evidence of benefit associated with the use of ultrasound in the treatment of pressure ulcers. In the three-arm comparison there was no statistically significant difference in ulcers healed. AUTHORS' CONCLUSIONS: There is no evidence of benefit of ultrasound therapy in the treatment of pressure ulcers. However, the possibility of beneficial or harmful effect cannot be ruled out due to the small number of trials, some with methodological limitations and small numbers of participants. Further research is needed.

Pressure relieving support surfaces: a randomised evaluation.

OBJECTIVES: To determine differences between alternating pressure overlays and alternating pressure replacement mattresses with respect to the development of new pressure ulcers, healing of existing pressure ulcers, patient acceptability and cost-effectiveness of the different pressure-relieving surfaces. Also to investigate the specific additional impact of pressure ulcers on patients' well-being. DESIGN: A multicentre, randomised, controlled, open, fixed sample, parallel-group trial with equal randomisation was undertaken. The trial used remote, concealed allocation and intention-to-treat (ITT) analysis. The main trial design was supplemented with a qualitative study involving a purposive sample of 20-30 patients who developed pressure ulcers, to assess the impact of the pressure ulcers on their well-being. In addition, a focus group interview was carried out with clinical research nurses, who participated in the PRESSURE (Pressure RElieving Support SUrfaces: a Randomised Evaluation) Trial, to explore the experiences of their role and observations of pressure area care. SETTING: The study took place in 11 hospital-based research centres within six NHS trusts in England. PARTICIPANTS: Acute and elective patients aged 55 years or older and admitted to vascular, orthopaedic, medical or care of the elderly wards in the previous 24 hours were investigated. INTERVENTIONS: Patients were randomised to either an alternating pressure overlay or an alternating pressure mattress replacement, with mattress specifications clearly defined to enable the inclusion of centres using products from different manufacturers, and to exclude hybrid mattress systems (which either combine foam or constant low pressure with alternating pressure in one mattress, or can be used as either an overlay or a replacement mattress). MAIN OUTCOME MEASURES: Development of a new pressure ulcer (grade < or =2, i.e. partial-thickness wound involving epidermis/dermis only) on any skin site. Also healing of existing pressures ulcers, patient acceptability and cost-effectiveness. RESULTS: In total, 6155 patients were assessed for eligibility to the trial and 1972 were randomised: 990 to the alternating pressure overlay (989 after one postrandomisation exclusion) and 982 to the alternating pressure mattress replacement. ITT analysis found no statistically significant difference in the proportions of patients developing a new pressure ulcer of grade 2 or above [10.7% overlay patients, 10.3% mattress replacement patients, a difference of 0.4%, 95% confidence interval (CI) -2.3 to 3.1%, p = 0.75]. When logistic regression analysis was used to adjust for minimisation factors and prespecified baseline covariates, there was no difference between the mattresses with respect to the odds of ulceration (odds ratio 0.94, 95% CI 0.68 to 1.29). There was no evidence of a difference between the mattress groups with respect to time to healing (p = 0.86). The Kaplan-Meier estimate of the median time to healing was 20 days for each intervention. More patients allocated overlays requested mattress changes due to dissatisfaction (23.3%) than mattress replacement patients (18.9%, p = 0.02) and more than one-third of patients reporting difficulties associated with movement in bed and getting into or out of bed. There is a higher probability (64%) that alternating mattress replacements are cost-saving; they were associated with lower overall costs (74.50 pounds sterling per patient on average, mainly due to reduced length of stay) and greater benefits (a delay in time to ulceration of 10.64 days on average). Patients' accounts highlighted that the development of a pressure ulcer could be pivotal in the trajectory from illness to recovery, by preventing full recovery or causing varied impacts on their quality of life. CONCLUSIONS: There is no difference between alternating pressure mattress replacements and overlays in terms of the proportion of patients developing new pressure ulcers; however, alternating pressure mattress replacements are more likely to be cost-saving. The results suggest that when renewing alternating pressure surfaces or ordering equipment within a rental contract, mattress replacements should be specified; however, overlays are acceptable if no replacement mattress is available. Similarly, patient preferences can be supported, without any great increase in risk, if individual patients request an overlay rather than a replacement mattress. Further research could include a randomised controlled trial comparing alternating pressure mattress replacements and high-specification foam mattresses in patients at moderate to high risk; an accurate costing study to understand better how much pressure ulcers cost health and social services in the UK; and trials in higher risk groups of patients. Also future trials should measure time to ulceration as the primary end-point, since this is more informative economically and possibly also from a patient and clinical perspective.

Electromagnetic therapy for treating pressure ulcers.

BACKGROUND: Pressure ulcers are defined as areas "of localized damage to the skin and underlying tissue caused by pressure, shear, friction and/or the combination of these". In the UK, pressure ulcers occur in 5 to 32% of District General Hospitals people and in 4 to 7% of people in community settings. Electromagnetic therapy, in which electrodes produce an electromagnetic field across the wound, may improve healing of chronic wounds such as pressure ulcers. OBJECTIVES: To assess the effects of electromagnetic therapy on the healing of pressure ulcers. SEARCH STRATEGY: For this first update, we searched the Cochrane Wounds Group Specialised Register (last searched October 2005); CENTRAL (The Cochrane Library 2005, Issue 4); MEDLINE (1966 to October 2005); EMBASE (1980 to October 2005); and CINAHL (1982 to October 2005). SELECTION CRITERIA: Randomised controlled trials comparing electromagnetic therapy with sham electromagnetic therapy, or other (standard) treatment. DATA COLLECTION AND ANALYSIS: For this first update, two authors independently scrutinized the results of the search to identify relevant RCTs and obtained full reports of potentially eligible studies. For the original review, details of eligible studies were extracted and summarised using a data extraction sheet. Attempts were made to obtain missing data by contacting authors. Data extraction was checked by a second author. Meta-analysis was applied to combine the results of trials when the interventions and outcome measures were sufficiently similar. MAIN RESULTS: This update identified no new trials. Two RCTs were identified for inclusion in the original review (total of 60 participants). One was a three-armed study comparing electromagnetic therapy with electromagnetic therapy in combination with standard therapy, and with standard therapy alone, on 17 female and 13 male with grade II and III pressure ulcers. The other study compared electromagnetic therapy with sham therapy in 30 male participants with a spinal cord injury and a grade II or grade III pressure ulcer.Neither study found a statistically significant difference between the healing rates of pressure ulcers in people treated with electromagnetic therapy compared with those in the control group. AUTHORS' CONCLUSIONS: The results provide no evidence of benefit in using electromagnetic therapy to treat pressure ulcers. However, the possibility of a beneficial or harmful effect cannot be ruled out, due to the fact that there were only two included trials both with methodological limitations and small numbers of participants. Further research is recommended.

VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.

OBJECTIVES: To compare the clinical and cost-effectiveness of two different compression bandages for the healing of venous leg ulcers. DESIGN: A pragmatic, randomised controlled trial with an economic evaluation. SETTING: Community, district nurse-led services; community leg ulcer clinics; hospital leg ulcer clinics with community outreach. A range of urban and rural settings in England and Scotland. PARTICIPANTS: Patients with a venous leg ulcer of at least 1-week's duration, at least 1 cm in length or width and an ankle:brachial pressure index of at least 0.8. INTERVENTIONS: The four-layer bandage (4LB) (which is multilayer elastic compression) compared with the short-stretch bandage (SSB) (multilayer, inelastic compression). MAIN OUTCOME MEASURES: The primary end-point was complete healing of all the ulcers on the trial leg. Secondary outcomes were the proportion of patients healed at 12 and 24 weeks, rate of recurrence, costs of leg ulcer treatment and quality of life. RESULTS: Between April 1999 and December 2000 the trial recruited 387 people aged from 23 to 97 years at trial entry. The majority of patients in this trial (82%; 316/387) had a reference ulcer of area

Systematic review of antimicrobial agents used for chronic wounds.

BACKGROUND: This paper is one of a series of eight systematic reviews that aim to identify effective interventions for chronic wounds. Here, antimicrobial agents are evaluated. METHODS: Electronic databases and other relevant sources were accessed to identify published and unpublished material. Studies were eligible for inclusion if they used concurrent controls, recruited participants with chronic wounds, evaluated an intervention designed to prevent or treat chronic wounds, and incorporated an objective assessment of wound healing. All included studies were assessed against a comprehensive checklist for methodological quality. A narrative overview was conducted. RESULTS: Thirty trials were included, 25 of randomized design. Small sample size and other methodological problems meant that findings were often difficult to interpret. Results do not support the routine use of systemic antibiotics for leg ulcers or diabetic foot ulcers without acute infection, but they may be useful as an adjunct to surgery for pilonidal sinuses. Several topical preparations may be helpful, including dimethyl sulphoxide, silver sulphadiazine, benzoyl peroxide, oxyquinoline and gentamicin. CONCLUSION: Most of this research requires replication in larger, well designed studies to establish both clinical and cost effectiveness.

Compression for preventing recurrence of venous ulcers.

BACKGROUND: Up to 1% of adults will suffer from leg ulceration at some time. The majority of leg ulcers are venous in origin and are caused by high pressure in the veins due to blockage or weakness of the valves in the veins of the leg. Prevention and treatment of venous ulcers is aimed at reducing the pressure either by removing / repairing the veins, or by applying compression bandages / stockings to reduce the pressure in the veins. The vast majority of venous ulcers are healed using compression bandages. Once healed they often recur and so it is customary to continue applying compression in the form of bandages, tights, stockings or socks in order to prevent recurrence. Compression bandages or hosiery (tights, stockings, socks) are often applied for ulcer prevention. OBJECTIVES: To assess the effects of compression hosiery (socks, stockings, tights) or bandages in preventing the recurrence of venous ulcers. To determine whether there is an optimum pressure/type of compression to prevent recurrence of venous ulcers. SEARCH STRATEGY: Searches of 19 databases including the Cochrane Wounds Group trials register and the Cochrane Controlled Trials Register, handsearching of journals, conference proceedings, and bibliographies up to June 2000. SELECTION CRITERIA: Randomised controlled trials evaluating compression bandages or hosiery for prevention of venous leg ulcers. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of study quality were undertaken by two reviewers independently. MAIN RESULTS: No trials compared recurrence rates with and without compression. One trial (300 patients) compared high (UK Class 3) compression hosiery with moderate (UK Class 2) compression hosiery. A intention to treat analysis found no significant reduction in recurrence at five years follow up associated with high compression hosiery compared with moderate compression hosiery (relative risk of recurrence 0.82, 95% confidence interval 0.61 to 1.12). This analysis would tend to underestimate the effectiveness of the high compression hosiery because a significant proportion of people changed from high compression to medium compression hosiery. Compliance rates were significantly higher with medium compression than with high compression hosiery. One trial (166 patients) found no difference in recurrence between two types of medium (UK Class 2) compression hosiery (relative risk of recurrence with Medi was 0.74, 95% confidence interval 0.45 to 1.2). Both trials reported that not wearing compression hosiery was strongly associated with ulcer recurrence and this is circumstantial evidence that compression reduces ulcer recurrence. No trials were found which evaluated compression bandages for preventing ulcer recurrence. REVIEWER'S CONCLUSIONS: No trials compared compression with vs no compression for prevention of ulcer recurrence. Not wearing compression was associated with recurrence in both studies identified in this review. This is circumstantial evidence of the benefit of compression in reducing recurrence. Recurrence rates may be lower in high compression hosiery than in medium compression hosiery and therefore patients should be offered the strongest compression with which they can comply. Further trials are needed to determine the effectiveness of hosiery prescribed in other settings, i.e. in the UK community, in countries other than the UK.

A systematic review of laser therapy for venous leg ulcers.

A systematic review of randomised controlled trials (RCTs) was conducted to establish the effectiveness of low-level laser therapy as a treatment for venous leg ulcers. Wound-care journals, conference proceedings and electronic databases (including Medline and Cinahl) were searched up to October 1997 for RCTs comparing low-level laser therapy with sham laser, no laser, or non-coherent light of other wavelengths. In addition, companies who manufacture or distribute therapeutic lasers were contacted for any unpublished or ongoing studies. Results from searches were scrutinised by one reviewer to identify possible RCTs and full reports of these were obtained. Details of eligible studies were extracted and summarised using a data extraction sheet. Data extraction was checked by a second reviewer. Meta-analysis was used to combine the results of trials where the interventions and outcome measures were sufficiently similar. A total of four eligible RCTs were identified. Two compared treatment with laser therapy to sham or placebo laser treatment. One study compared laser therapy with ultraviolet therapy. The fourth was a three-armed study which compared the effects of laser therapy alone, laser therapy plus infrared light, and non-coherent unpolarised red light. The comparisons of laser therapy with placebo, and laser therapy with ultraviolet therapy, showed no significant difference between treatments with regard to ulcer healing rates. The comparison of laser with red light showed a significant increase in complete healing at nine months for the combination of laser and infrared light compared to non-coherent unpolarised red light. We have not found any evidence of the benefit of low-level laser therapy per se on venous leg ulcer healing. It appears that a combination of HeNe laser and infrared light may promote the healing of venous ulcers, however more research is needed.

An exploration of midwives' attitudes to research and perceived barriers to research utilisation.

OBJECTIVE: To explore midwives' views about research and their perceived barriers to research utilisation. SETTING: Thirty-two midwives from four midwifery units in the north west of England. The units ranged in size from a small district unit (52 midwives, and 1200 deliveries per annum), to a large regional centre (290 midwives, 6500 deliveries per annum). METHODS: Midwives' opinions concerning research were explored using focus group interviews; within the interviews midwives were asked to discuss how they viewed the relevance of research to midwifery care, the constraints which they felt prevented them from delivering research-based care and existing and potential methods of disseminating research. FINDINGS: There was a consensus among the midwives that they aspired to deliver research-based care. However, there are clearly a number of barriers preventing this. Research was poorly accessible to most midwives, both in terms of its physical location and complexity. Furthermore, midwives felt they lacked the knowledge and skills to appraise research, and lacked the confidence to judge when research should be implemented. CONCLUSIONS: The current trend to demedicalise childbirth demands that midwives become proficient users of research. However, the means of disseminating research findings to midwives in the north west of England does not meet their needs.

Nursing treatment of patients with chronic leg ulcers in the community.

A descriptive survey of current reported practice by 146 community nurses for their nursing treatment of leg ulcers was undertaken. Sixty-four per cent of nurses reported they would apply compression bandages to only venous ulcers; in only 23% of cases could the products described achieve an adequate level of compression. A variety of modern wound dressings were used by the nurses; 89% of nurses reported using a combination of different products layered over the ulcer. There is no evidence that this has any beneficial effect and could therefore be a potential waste of money, as well as contributing to allergic skin reactions. It would be useful if primary-health-care teams and Family Health Service Authority information pharmacists formulated protocols based upon effective treatments for patients with chronic leg ulcers.

Patients' perceptions of chronic leg ulcers.

Leg ulceration affects approximately 0.15% of the UK population at any point in time1, and the disease is typically one of ulceration, healing and re-ulceration. The cost of leg ulceration in both financial and human terms is large; however, human costs (pain, immobility, social isolation, embarrassment) have been largely ignored by researchers. This study aimed to explore patients' perceptions of their leg ulcer disease, and the impact of leg ulceration on quality of life. A random sample of leg ulcer patients was interviewed in the patients' own homes, and a variety of data were collected using semi-structured interviews and validated health-assessment tools. A sample of healthy elderly subjects participated by completing the health and quality of life assessment. Data analysis is currently at a preliminary stage.

Glycation of brain actin in experimental diabetes.

Actin is a neuronal protein involved in axonal transport and nerve regeneration, both of which are known to be impaired in experimental diabetes. To determine if actin is subject to glycation, we rendered rats diabetic by injection of streptozotocin. Two or 6 weeks later brains were removed and a preparation of cytoskeletal proteins was analyzed by two-dimensional polyacrylamide gel electrophoresis. Brains from diabetic animals contained an extra polypeptide that migrated close to actin and reacted with monoclonal antibody C4 against actin. It was also found in a preparation of soluble synaptic proteins from diabetic rat brain, indicating that it was at least partly neuronal in origin. This polypeptide could be produced by incubation of cytoskeletal proteins from brains of nondiabetic rats with glucose-6-phosphate in vitro. The appearance of this glycated actin in diabetic animals was prevented by administration of insulin for a period of 6 weeks. We could not detect any effect of glycation in vitro on the ability of muscle G-actin to form F-actin filaments and its significance for the function of actin remains to be determined. The finding that glycation of platelet-derived actin from diabetic patients was significantly increased implies that the abnormality may also occur in clinical diabetes.

Posttranslational modifications of nerve cytoskeletal proteins in experimental diabetes.

Axonal transport is known to be impaired in peripheral nerve of experimentally diabetic rats. As axonal transport is dependent on the integrity of the neuronal cytoskeleton, we have studied the way in which rat brain and nerve cytoskeletal proteins are altered in experimental diabetes. Rats were made diabetic by injection of streptozotocin (STZ). Up to six weeks later, sciatic nerves, spinal cords, and brains were removed and used to prepare neurofilaments, microtubules, and a crude preparation of cytoskeletal proteins. The extent of nonenzymatic glycation of brain microtubule proteins and peripheral nerve tubulin was assessed by incubation with 3H-sodium borohydride followed by separation on two-dimensional polyacrylamide gels and affinity chromatography of the separated proteins. There was no difference in the nonenzymatic glycation of brain microtubule proteins from two-week diabetic and nondiabetic rats. Nor was the assembly of microtubule proteins into microtubules affected by the diabetic state. On the other hand, there was a significant increase in nonenzymatic glycation of sciatic nerve tubulin after 2 weeks of diabetes. We also identified an altered electrophoretic mobility of brain actin from a cytoskeletal protein preparation from brain of 2 week and 6 week diabetic rats. An additional novel polypeptide was demonstrated with a slightly more acidic isoelectric point than actin that could be immunostained with anti-actin antibodies. The same polypeptide could be produced by incubation of purified actin with glucose in vitro, thus identifying it as a product of nonenzymatic glycation. These results are discussed in relation to data from a clinical study of diabetic patients in which we identified increased glycation of platelet actin. STZ-diabetes also led to an increase in the phosphorylation of spinal cord neurofilament proteins in vivo during 6 weeks of diabetes. This hyperphosphorylation along with a reduced activity of a neurofilament-associated protein kinase led to a reduced incorporation of 32P into purified neurofilament proteins when they were incubated with 32P-ATP in vitro. Our combined data show a number of posttranslation modifications of neuronal cytoskeletal proteins that may contribute to the altered axonal transport and subsequent nerve dysfunction in experimental diabetes.

Antibodies to tubulin and microtubule-associated proteins. A study in diabetes mellitus, systemic lupus erythematosus, and rheumatoid arthritis.

We report the results of a study of serum antibodies to proteins of the nerve cytoskeleton in patients with Type I and Type II diabetes mellitus, both with and without clinical signs of diabetic neuropathy. In contrast to previous reports, elevated levels of antibody to tubulin or glycated tubulin were not associated with either diabetes or diabetes with related neuropathy. Similarly, clinical evidence of neuropathy in patients with diabetes did not relate to increased levels of antibody to native or glycated microtubule-associated proteins (MAPs). The levels of antibody to MAPs and glycated MAPs were higher in control subjects over the age of 45 years compared with younger control subjects. Increased levels of antibody to tubulin and glycated tubulin were found in the sera of patients with systemic lupus erythematosus, but not rheumatoid arthritis.

Glycation of rat sciatic nerve tubulin in experimental diabetes mellitus.

Diabetic neuropathy is associated with some early defects of axonal transport in experimental animals. Axonal transport is dependent on intact microtubules, and unsubstituted lysine residues of tubulin are essential for microtubule polymerization. As lysine residues are the major target for the non-enzymatic attachment of glucose, the effect of diabetes on the extent of glycation of tubulin was investigated. There was a more than four-fold increase in the extent of glycation of tubulin in the sciatic nerve of rats with streptozotocin-induced diabetes of 2 weeks duration compared with control rats. In contrast, no such increase in glycation was observed in brain microtubule protein from diabetic rats at that stage of diabetes. Incubation of brain microtubule protein with glucose prior to in vitro polymerization showed that the early stages of glycation were not associated with inhibition of microtubule assembly. The observed glycation of peripheral nerve tubulin in early experimental diabetes may nevertheless contribute to axonal transport abnormalities through an as yet undetermined impairment of microtubule function.

Impaired induction of ornithine decarboxylase activity following nerve crush in the streptozotocin-diabetic rat.

Ornithine decarboxylase activity was measured in the dorsal root ganglia from crushed and uncrushed contralateral sciatic nerve of control and streptozotocin-diabetic rats. A further group of diabetic rats was treated with insulin throughout the experiment. Ornithine decarboxylase activity in ganglia from uncrushed nerves was the same in diabetic and non-diabetic rats. A significant (greater than 4-fold) increase in mean levels of ornithine decarboxylase activity 72 h after crush injury was found in ganglia from crushed nerves in non-diabetic but not in diabetic rats. The enzyme activity in ganglia from diabetic rats treated with insulin resembled that in non-diabetic rats. Twenty-four hours after crush injury, ornithine decarboxylase activity in ganglia from crushed nerves was higher in non-diabetic than in diabetic animals. This may be responsible for the delayed and defective nerve regeneration known to occur in peripheral nerve of the streptozotocin-diabetic rat.