Foot ulceration and its association with mortality in diabetes mellitus: a meta-analysis.

BACKGROUND: Diabetic foot ulcers portend an almost twofold increase in all-cause mortality compared with diabetes on its own. AIM: To investigate the association between diabetic foot ulcers and risk of death. METHODS: We performed a meta-analysis of all observational studies investigating the association between diabetic foot ulcers and all-cause mortality. Risk ratios and risk differences were pooled in a random-effects model. The I2 statistic was used to quantify heterogeneity between studies. RESULTS: Altogether, we identified 11 studies that reported 84 131 deaths from any cause in 446 916 participants with diabetes during a total of 643 499 person-years of follow-up. The crude event rate for all-cause mortality in individuals with diabetes who did not develop foot ulceration was 22% lower at 181.5 deaths (per 1000 person-years) than in those who developed foot ulcers (230.8 per 1000 person-years). Diabetic foot ulceration was associated with an increased risk of all-cause mortality (pooled relative risk 2.45, 95% CI 1.85-2.85). We did not observe any tangible differences in risk of all-cause mortality from diagnosis in studies reporting a mean duration of follow-up of ≤3 years (relative risk 2.43, 95% CI 2.27-2.61) or >3 years (relative risk 2.26, 95% CI 2.13-2.40) years. Funnel plot inspection revealed no significant publication bias among studies included in this meta-analysis. CONCLUSIONS: Our study shows an excess rate of all-cause mortality in people with diabetic foot ulceration when compared to those without foot ulceration. It is imperative that early interventions to prevent foot ulceration and modify cardiovascular disease risk factors are put in place to reduce excess mortality.

Developing a foot ulcer risk model: what is needed to do this in a real-world primary care setting?

AIM: To determine how routinely collected data can inform a risk model to predict de novo foot ulcer presentation in the primary care setting. METHODS: Data were available on 15 727 individuals without foot ulcers and 1125 individuals with new foot ulcers over a 12-year follow-up in UK primary care. We examined known risk factors and added putative risk factors in our logistic model. RESULTS: People with foot ulcers were 4.2 years older (95% CI 3.1-5.2) than those without, and had higher HbA1c % (mean 7.9 ± 1.9 vs 7.5 ± 1.7) / HbA1c mmol/mol (63 ± 21 vs 59 ± 19) (p<0.0001) concentration [+0.45 (95% CI 0.33-0.56), creatinine level [+6.9 µmol/L (95% CI 4.1-9.8)] and Townsend score [+0.055 (95% CI 0.033-0.077)]. Absence of monofilament sensation was more common in people with foot ulcers (28% vs 21%; P<0.0001), as was absence of foot pulses (6.4% vs 4.8%; P=0.017). There was no difference between people with or without foot ulcers in smoking status, gender, history of stroke or foot deformity, although foot deformity was extremely rare (0.4% in people with foot ulcers, 0.6% in people without foot ulcers). Combining risk factors in a single logistic regression model gave modest predictive power, with an area under the receiver-operating characteristic curve of 0.65 (95% CI 0.62-0.67). The prevalence of ulceration in the bottom decile of risk was 1.8% and in the top decile it was 13.4% (compared with an overall prevalence of 6.5%); thus, the presence of all six risk factors gave a relative risk of 7.4 for development of a foot ulcer over 12 years. CONCLUSION: We have made some progress towards defining a variable set that can be used to create a foot ulcer prediction model. More accurate determination of foot deformity/pedal circulation in primary care may improve the predictive value of such a future risk model, as will identification of additional risk variables.

Measuring vitamin D levels: surrogates are insufficient.

AIMS: With the increasing evidence of adverse consequences because of low vitamin D levels on health demand for vitamin D, screening is increasing. The objective of the study was to assess whether parathyroid hormone (PTH) levels/bone profile is sufficient to identify patients with vitamin D insufficiency or deficiency, or whether vitamin D should be measured directly. METHODOLOGY: A total of 1560 serum specimens, with requests for 25-hydroxyvitamin D (25-OH vitamin D), calcium, phosphate, alkaline phosphatase (ALP), creatinine and PTH on the same sample were analysed at Salford Royal Hospital from November 2010 to November 2012. RESULTS: The prevalence of total vitamin D insufficiency or deficiency (defined as total 25-OH vitamin D < 50 nmol/l) was 62.9% (981/1560) overall, with males having higher proportions (67.2 vs. 59.3 per cent; χ(2) = 8.78, p = 0.003). There was no overall trend in mean serum adjusted calcium across categories of 25-OH vitamin D status but mean serum phosphate was significantly lower (F = 6.53, p < 0.0001) in patients with a 25-OH vitamin D level < 50 nmol/l. However in patients with vitamin D deficiency, a significant proportion had PTH, calcium, phosphate and alkaline phosphatase levels within the laboratory normal range. Even at a 25-OH vitamin D < 10 nmol/l, 71.6% had a normal PTH, 89.8% had normal serum calcium levels, 84.9% had normal phosphate levels and 81.6% had normal serum ALP. CONCLUSIONS: Therefore, despite the costs associated with the measurement of vitamin D, our findings show that no surrogate is adequate for screening for vitamin D deficiency.

The 40Ar(d,p)41Ar cross section between 3-7 MeV.

To determine the safety of using argon as a deuteron beam stopping material, the  40Ar(d,p)41Ar cross section was measured at average deuteron energies of 3.6 MeV, 5.5 MeV, and 7.0 MeV using an activation method. A 16-MeV deuteron beam produced by Lawrence Berkeley National Laboratory's 88-Inch Cyclotron was degraded to each energy by nickel foils and the front wall of an aluminum gas chamber. The reduced-energy deuterons were used to activate a sample of natAr gas. After each irradiation, the gas chamber's  41Ar activation was measured with a high-purity germanium detector. The cross sections measured were larger than a previous measurement by ∼40%.

Chirped-pulse amplification with narrowband pulses.

We demonstrate a compact hyperdispersion stretcher and compressor pair that permit chirped-pulse amplification in Nd:YAG. We generate 750 mJ, 0.2 nm FWHM, 10 Hz pulses recompressed to an 8 ps near-transform-limited duration. The dispersion-matched pulse compressor and stretcher impart a chirp of 7300 ps/nm, in a 3 m x 1 m footprint.

Isotope-specific detection of low-density materials with laser-based monoenergetic gamma-rays.

What we believe to be the first demonstration of isotope-specific detection of a low-Z and low density object shielded by a high-Z and high-density material using monoenergetic gamma rays is reported. The isotope-specific detection of LiH shielded by Pb and Al is accomplished using the nuclear resonance fluorescence line of L7i at 478 keV. Resonant photons are produced via laser-based Compton scattering. The detection techniques are general, and the confidence level obtained is shown to be superior to that yielded by conventional x-ray and gamma-ray techniques in these situations.

Success Rates in a Diabetes Specialist Nurse-Led Education Programme: Re-setting the Glucostat.

Analysis of National Diabetes Audit data from 2011-2012 of newly diagnosed people with type 1 diabetes mellitus (DM) found low initial success rates in much of the UK at 20% on initial training, while an unusually high success rate of 75% achieving target HbA1C<58 mmol/mol (< 7.5%) was found in Cheshire (England average=40.8%). We present a review of the approach taken by the Cheshire Diabetes team in the 12 months following diagnosis. Between 2012 and 2013, 15 consecutive newly diagnosed people with type 1 DM were followed up for 18 months. All received support and advice by community Diabetes Specialist Nurses (DSNs) and Dieticians covering Central and Eastern Cheshire, UK. Mean±SD age at diagnosis was 23±3 years. The period of contact with the DSN service varied from 7-12 weeks. Baseline HbA1C of 99 mmol/mol [11.2%] (95% CI: 86-111 mmol/mol [10.0-12.3%]) declined by ~50% to 49 mmol/mol [6.6%] (41-57 mmol/mol [5.9-7.4%]; F=16.9, p<0.001) at 6 months and did not change between 6-12 months. Of those newly diagnosed with type 1 DM, 84.6% achieved a target HbA1C<58 mmol/mol (<7.5%) and 61.5% met a target<48 mmol/mol (<6.5%). There was no significant weight change during the study. The key elements of this bio-psycho-social approach by the DSN team included providing psychological support, patient engagement, demonstrating positive regard, gaining trust, identifying health-seeking behaviour, providing key decision-making skills and developing a self-management plan. This resulted in improvements in overall glycaemic control well above the national average without untoward weight gain. The UK National Diabetes Audit (2011-2012) in newly diagnosed type 1 diabetics in Cheshire, UK, showed a success rate at 6 months post-diagnosis of 75% achieving a target HbA1C<58 mmol/mol (<7.5%) compared with the national average of 40.8%. Initially thought to be erroneous, these excellent results were confirmed. The approach taken to achieve them is herein described.

Insulin-like growth factor binding protein-2 (IGFBP-2) is a marker for the metabolic syndrome.

AIMS/HYPOTHESIS: IGFs and their binding proteins are increasingly recognised as important in understanding the pathogenesis of cardiovascular disease. Low IGFBP-1, particularly coupled with low IGF-I, is associated with increased cardiovascular risk. In relation to structural and regulatory parallels between IGFBP-1 and - 2 we have now examined the hypothesis that IGFBP-2 may be a marker for cardiovascular risk. METHODS: Fasting IGFBP-2, IGFBP-1, IGFBP-3, IGF-I, IGF-II, insulin, C-peptide, glucose, lipids, NEFAs, and HbA1c were measured in a cohort of 163 patients with type 2 diabetes. Individuals were categorised according to the presence or absence of the metabolic syndrome. RESULTS: Patients with the metabolic syndrome had a lower IGFBP-2 concentration. Low circulating IGFBP-2 was associated with elevated fasting glucose (rho = - 0.23, p = 0.003). IGFBP-2 correlated negatively with triglycerides (rho = - 0.19, p = 0.01) and LDL-cholesterol (rho = - 0.20, p = 0.01), and positively with insulin sensitivity (HOMA-S) (rho = 0.26, p = 0.02). Multivariate logistic regression demonstrated that low IGFBP-2 was independently associated with an increased risk of the metabolic syndrome (OR 0.31 [95 % CI 0.11 - 0.90]; p = 0.03). IGFBP-3 did not differ according to the presence or absence of metabolic syndrome. CONCLUSION/INTERPRETATION: Low IGFBP-2 is associated with multiple cardiovascular risk factors similarly to IGFBP-1. Such associations were not apparent for IGFBP-3. Lack of marked prandial regulation of IGFBP-2, in contradistinction to IGFBP-1, may make IGFBP-2 a more robust biomarker for identification of insulin-resistant individuals at high cardiovascular risk in epidemiological studies.

Low sex hormone binding globulin is a potential marker for the metabolic syndrome in different ethnic groups.

Hepatic sex-hormone binding globulin (SHBG) production is down-regulated by insulin and low levels reflect insulin resistance. Because insulin resistance is closely related to the development of cardiovascular disease in different ethnic groups we examined ethnic variation in SHBG across populations with different baseline cardiovascular risk and metabolic syndrome prevalence. Participants were population-based, of European (n = 142), Pakistani (n = 130), and African-Caribbean (AfC) origin (n = 193). SHBG, fasting lipids, and glucose concentrations plus insulin sensitivity (HOMA-S) were determined. Age adjusted SHBG was significantly lower in both Pakistani men and women. Circulating SHBG levels were lower in those with impaired vs. normal glucose homeostasis. SHBG correlated positively with HOMA-S (rho = 0.28, p < 0.001), and negatively with WHR (rho = - 0.38, p < 0.001), BMI (r = - 0.30, p < 0.001), and diastolic blood pressure (rho = - 0.14, p < 0.01) across all ethnic groups. In multivariate logistic regression analysis a low SHBG increased the likelihood of the metabolic syndrome (odds ratio [OR] = 0.42 [0.21 - 0.82], p = 0.01) as did higher fasting NEFA (OR 1.47 [1.04 - 2.08], p = 0.03), low IGFBP-1 concentrations (OR 0.6 [0.44 - 0.81], p = 0.001), age (OR 1.05 [1.02 - 1.09], p = 0.003), and Pakistani ethnicity (p = 0.001) in a model which also contained gender, lnCRP, IGF-I, and IGF-II. As ethnic differences in SHBG level closely parallel differences in insulin resistance. Its measurement may be useful in identifying individuals at particular risk of the metabolic syndrome, for early intervention.

Socioeconomic deprivation independently predicts painful diabetic neuropathy in type 2 diabetes.

OBJECTIVE: Painful peripheral neuropathy in people with type 2 diabetes is a disabling complication. We explored associations of this condition with socioeconomic deprivation. RESEARCH DESIGN AND METHODS: The Townsend index of socioeconomic deprivation was examined in the pseudonymised GP records of 15388 (44.1% female) individuals with type 2 diabetes in the Cheshire county of England, and related to prevalence of drug treated painful diabetic neuropathy. We also analysed prescription trends with respect to pharmacotherapy for neuropathy pain relief. RESULTS: Treatment for neuropathic pain was initiated in 3 266 (21.2%) of patients. Those on treatment were older [68.2 (95% CI 67.8-68.7) vs. 66.6 (66.4-66.8) years] than those not on treatment. There was no difference in HbA1c (7%, 55 mmol/mol).There were significant differences between the groups for the Townsend deprivation index, with a greater proportion (30.6% vs. 22.8% of patients with treated neuropathic pain) having a score of ≥1 (Χ(2)=83.9, p<0.0001).Multivariate logistic regression analyses indicated that each unit increment in the Townsend index was associated with an 6% increased odds of requiring neuropathic pain treatment [odds ratio (95%CI) 1.06 (1.05-1.08), p<0.0001] independent of 5 year age band, BMI, gender, systolic BP, eGFR, HbA1C and total cholesterol. CONCLUSIONS: In this study using pseudonymised clinical records, a higher level of socioeconomic deprivation seemingly may predispose to severe neuropathic pain in diabetes requiring pharmacological intervention. Targeted allocation of healthcare resources to this group may offer clinical benefits.

Hypertension in four African-origin populations: current 'Rule of Halves', quality of blood pressure control and attributable risk of cardiovascular disease.

OBJECTIVE: To assess the public health burden from high blood pressure and the current status of its detection and management in four African-origin populations at emerging or high cardiovascular risk. DESIGN: Cross-site comparison using standardized measurement and techniques. SETTING: Rural and urban Cameroon; Jamaica; Manchester, Britain. SUBJECTS: Representative population samples in each setting. African-Caribbeans (80% of Jamaican origin) and a local European sample in Manchester. MAIN OUTCOME MEASURES: Cross-site age-adjusted prevalence; population attributable risk. RESULTS: Among 1,587 men and 2,087 women, age-adjusted rates of blood pressure > or =160 or 95 mmHg or its treatment rose from 5% in rural to 17% in urban Cameroon, despite young mean ages, to 21% in Jamaica and 29% in Caribbeans in Britain. Treatment rates reached 34% in urban Cameroon, and 69% in Jamaican- and British-Caribbean-origin women. Sub-optimal blood pressure control (> 140 and 90 mmHg) on treatment reached 88% in European women. Population attributable risks (or fractions) indicated that up to 22% of premature all-cause, and 45% of stroke mortality could be reduced by appropriate detection and treatment. Additional benefit on just strokes occurring on treatment could be up to 47% (e.g. in both urban Cameroon men and European women) from tighter blood pressure control on therapy. Cheap, effective therapy is available. CONCLUSION: With mortality risk now higher from non-communicable than communicable diseases in sub-Saharan Africa and elsewhere, systematic measurement, detection and genuine control of hypertension once treated can go hand-in-hand with other adult health programmes in primary care. Cost implications are not great. The data from this collaborative study suggest that such efforts should be well rewarded.

A high transmission hemispherical energy analyzer for ion spectrometry.

A hemispherical energy analyzer was constructed by using a novel approach to control the fringing electrostatic field. It provides several properties useful in ion spectrometers: namely, rather simple fabrication and compact size, high transmission efficiency at moderate resolution, and the capability to adjust resolution by changing the intersphere potentials. A computer program was developed to evaluate ion trajectories through the hemispherical analyzer. Data obtained from the trajectories were used to predict the characteristics of the analyzer. Experiments performed to determine the kinetic energy dependence of the absolute transmission and the resolution functions are in accord with theoretical calculations.

Management of threatened abortion with real-time sonography.

Real-time sonography was used to evaluate 158 patients with threatened abortion. Fetal motion was first detected during the seventh gestational week and with increasing frequency thereafter in 73 patients with viable pregnancies continuing to term. Only 2 of 65 patients who aborted demonstrated fetal motion. The presence or absence of fetal motion was most reliable after 7 weeks' gestation for establishing a prognosis for a given pregnancy. Seventy-two of 74 pregnancies with fetal motion continued to term, whereas 63 of 64 pregnancies without fetal motion aborted. A method for using real-time sonography in the management of threatened abortion is presented.

Real-time sonography in obstetrics.

Three hundred fifty real-time scans were performed on pregnant women for various indications. Placental localization was satisfactorily obtained in 173 of 174 studies. Estimates of fetal gestation from directly measured biparietal diameter were +/-2 weeks of actual gestation in 153 of 172 (88.9%) measurements. The presence or absence of fetal motion and cardiac activity established a diagnosis of fetal viability or fetal death in 32 patients after the first trimester. Accurate diagnosis was made in 52 of 57 patients with threatened abortions, and two of these errors occurred in scans performed before completion of the eighth postmenstrual week. Because of the ability to demonstrate fetal motion, real-time sonography should have many applications in obstetrics.

A case of automobile trauma during pregnancy.

Accidental injury is an important complication of pregnancy. In North Carolina the rate of maternal deaths secondary to accidents has remained constant since 1966; however, because of a reduction in other causes, the percentage of maternal deaths due to accidents has doubled (11.4%). As a result, it is appropriate to reassess the evaluation of injuries sustained in automobile accidents. A case of automobile trauma to a pregnant woman at term is presented, and a plan of management involving fetal monitoring is recommended.

Natural history and prognostic factors of diabetic nephropathy in type 2 diabetes.

BACKGROUND: The causes and mechanisms of increased mortality of patients with diabetic nephropathy are unclear, and its natural history is poorly understood. AIM: To evaluate risk factors for mortality in type 2 diabetic patients with nephropathy. DESIGN: Retrospective study of clinical and biochemical parameters in diabetic nephropathic patients and controls sampled from a secondary care register. METHODS: We studied 170 type 2 diabetic patients (from 1987 to 1995) with nephropathy (proteinuria >0.5 g/24 h) and 170 non-nephropathic patients. Follow-up was until death or December 1997. Details of demographics, clinical and treatment history were obtained from medical records. RESULTS: Mean follow-up was 5.3 years. Of the patients with nephropathy at baseline, 63 (37%) died compared with 14 (8%) non-nephropathic patients (chi(2)=53.8, p<0.0001). Age- and sex-adjusted all-cause mortality rates were 8.1 (6.4, 9.8) and 1.4 (0.5, 2.2) deaths per 100 person-years, respectively (rate ratio 5.8). Forty-four patients (57%) died from cardiovascular causes (rate ratio 5.4). Mortality was directly proportional to degree of proteinuria: 0.5-2 g/24 h, 4.6 (2.9-7.1); >2 g/24 h, 9.9 (7.3-13.5) per 100 patient-years. A 36% (5-78%) excess risk of mortality was observed for each log unit increase in proteinuria. Multivariate Cox regression analyses confirmed a five-fold excess risk for all-cause and cardiovascular mortality in patients with nephropathy compared with those without. This was independent of other risk factors including baseline age [5% (1-8%)/year], creatinine [2.5 (1.12-5.6)/10 micromol/l] and glycaemic control (HbA(1c)) [15% (1-31%) per 1% rise]. CONCLUSIONS: Proteinuria is a potentially preventable and reversible risk factor associated with high mortality in type 2 diabetic patients. Prevention of the development of overt nephropathy and improvement in diabetes control may reduce mortality in these patients.

Pathogenesis of hemorrhage induced by proteinase H from eastern diamondback rattlesnake (Crotalus adamanteus) venom.

The pathogenesis of hemorrhage of a purified hemorrhagic toxin, proteinase H from Crotalus adamanteus venom, was studied. Female, white CD-1 mice were injected intramuscularly with sublethal doses of the hemorrhagic toxin and tissue samples were obtained at 10 min, 1, 3 and 24 hr following injection. Severe local hemorrhage was observed grossly within 10 min. Hemorrhage was observed in the connective tissue of skeletal muscle and within adjacent adipose tissue. Many larger vessels were congested with erythrocytes and platelets. By 3 hr inflammatory cell infiltration was observed and necrosis of some muscle cells was evident. Transmission electron microscopy showed that the capillary endothelium was ruptured, leading to hemorrhage per rhexis. Capillary basal laminae were disorganized and often wholly or partially absent.

Systemic hemorrhage induced by proteinase H from Crotalus adamanteus (eastern diamondback rattlesnake) venom.

The systemic effects of a purified hemorrhagic toxin, proteinase H, from Crotalus adamanteus venom, were studied. Female, white CD-1 mice were injected intravenously with proteinase H and tissue samples were obtained at 1, 3 and 24 hr after injection. Hemorrhage was observed grossly within 1 hr in several internal organs including the stomach and small intestine, the heart and the lungs. Surface discolorations thought to be petechial hemorrhages were observed in the kidneys. The livers of treated animals were visibly swollen and darkened and lobules were accentuated. Tissue samples were taken from the stomach, duodenum, heart, lungs, liver and kidneys and prepared for observation by light and electron microscopy. Frank hemorrhage was observed by light microscopy in the walls of the stomach and duodenum, in the myocardium and in the lungs. Pulmonary hemorrhage was severe, with involvement of nearly all of the pulmonary tissue within 3 hr. A1 doses of 5 micrograms/g, hepatic degeneration was observed by 3 hr. Renal glomeruli were noticeably swollen and the lumena of the proximal convoluted tubules indistinct. Closer examination by electron microscopy revealed that the endothelial cells comprising the fenestrated glomerular capillaries remained intact but signs of degeneration (i.e. cytoplasmic swelling and mitochondrial swelling) were observed. Proteinase H induces systemic hemorrhage in the heart, lungs, stomach and small intestine, renal glomerulonephropathy and hepatic degeneration.

Comparison of the immunogenicity and antigenic composition of ten Central American snake venoms.

The immunological reactivity of five crotaline antivenoms for the venoms of ten Costa Rican snakes was determined. Venoms from Bothrops asper, B. godmani, B. lateralis, B. nasutus, B. ophryomegas, B. schlegelii, B. nummifer, B. picadoi, Crotalus durissus durissus and Lachesis muta stenophrys were separated by SDS-PAGE, transferred to cellulose nitrate membrane and reacted against five different antivenoms. Antisera used in the immunoblotting were prepared in rabbits to the crotaline venoms from Crotalus viridis viridis (prairie rattlesnake), Crotalus durissus terrificus (South American rattlesnake), Crotalus atrox (western diamondback rattlesnake), and Bothrops atrox (fer de lance). SDS-PAGE analysis of the ten venoms indicated that all venoms had components in the high-medium mol. wt (> 15,000) and low mol. wt (< 15,000) range, but they all had at least twice as many components in the high-medium mol. wt range. The venoms of B. nummifer and B. nasutus have the greatest number of bands (24) whereas B. asper has the lowest (17). There appeared to be no difference in immunogenicity between high-medium mol. wt components and low mol. wt components; however, with the venoms of B. nasutus, B. ophryomegas, and B. schlegelii, there were few reactions between antivenoms and low mol. wt components. Half of the ten venoms tested had the highest reactivity with antivenom against B. atrox venom. Two venoms reacted most with antivenom against C. adamanteus venom; one with antivenom to C. atrox venom; one with antivenom to C. v. viridis venom and one with antivenom to C. d. terrificus venom.(ABSTRACT TRUNCATED AT 250 WORDS)