Presence of chronic diabetic foot ulcers is associated with more frequent and more advanced retinopathy.

AIMS: To clarify the frequency and severity of diabetic retinopathy in a group of people with Type 2 diabetes and chronic diabetic foot ulcers, and to compare visual acuity, levels of retinopathy and clinical significant macular oedema with a matched control group of people with Type 2 diabetes without a history of chronic diabetic foot ulcers. METHODS: Visual acuity and fundus imaging were evaluated in 90 white people with at least 3 months' duration of full-thickness diabetic foot ulcers below the ankle and the results compared with those in 180 white people with Type 2 diabetes without a history of chronic diabetic foot ulcers (control group). Controls were matched for age, sex and duration of diabetes. RESULTS: Despite similar age and diabetes duration, severe non-proliferative or proliferative diabetic retinopathy was present in 41% of the people in the diabetic foot ulcer group as compared to 15% in the control group (P<0.001). Only 6% in the diabetic foot ulcer group was without any diabetic retinopathy as compared to 34% among controls. Proliferative diabetic retinopathy was more common in the diabetic foot ulcer group (31% vs 8%; P<0.001), but time-to-proliferative diabetic retinopathy did not differ between groups. Clinically significant macular oedema was more frequently present, and the diabetic foot ulcer group exhibited significantly worse results in best and worst eye visual acuity testing. CONCLUSIONS: In this northern European setting almost all people with Type 2 diabetes and chronic diabetic foot ulcers had diabetic retinopathy. Almost one-third had proliferative diabetic retinopathy as compared to <10% in our matched control group. More advanced diabetic retinopathy was linked to worse visual acuity.

Relationship between ulcer healing after hyperbaric oxygen therapy and transcutaneous oximetry, toe blood pressure and ankle-brachial index in patients with diabetes and chronic foot ulcers.

AIMS/HYPOTHESIS: The randomised, double-blind, placebo-controlled Hyperbaric Oxygen Therapy (HBOT) in Diabetic Patients with Chronic Foot Ulcers (HODFU) study showed beneficial effect of HBOT. As this treatment is expensive and time-consuming, being able to select patients for therapy would be very useful. The aim of this study was to evaluate whether circulatory variables could help in predicting outcome of HBOT. METHODS: All HODFU study participants who completed therapy, predefined as receiving at least 36 out of 40 scheduled HBOT/placebo sessions, were included in this study (n = 75). Baseline transcutaneous oximetry (TcPO2), toe blood pressure (TBP) and ankle-brachial index (ABI) were measured. Ulcer healing rate was registered at the 9-month follow-up visit. An ulcer was considered healed when it was completely epithelialised and remained so at the 12-month follow-up. RESULTS: In the HBOT group TcPO2 were significantly lower for patients whose ulcer did not heal as compared with those whose ulcers healed. A significantly increased healing frequency was seen with increasing TcPO(2) levels in the HBOT group (TcPO2/healing rate: <25 mmHg/0%; 26-50 mmHg/50%; 51-75 mmHg/73%; and >75 mmHg/100%). No statistically significant relation between the level of TBP or ABI and healing frequency was seen. CONCLUSIONS/INTERPRETATION: Our results indicate that TcPO2 in contrast to ABI and TBP correlates to ulcer healing following HBOT. We suggest HBOT as a feasible adjunctive treatment modality in diabetic patients with chronic non-healing foot ulcers when basal TcPO2 at the dorsum of the foot is above 25 mmHg. TRIAL REGISTRATION: NCT00953186 FUNDING: Mrs Thelma Zoegas Foundation and Faculty of Medicine, Lund University.

Hyperbaric oxygen therapy improves health-related quality of life in patients with diabetes and chronic foot ulcer.

AIMS: Adjunctive treatment with hyperbaric oxygen therapy has recently been shown to improve ulcer healing in patients with chronic diabetic foot ulcer. The aim of the present study is to evaluate whether hyperbaric oxygen therapy improves the health related quality of life in these patients. METHODS: Prospective randomized placebo-controlled double-blinded study setting using SF-36. RESULTS: A total of 75 patients were included in the study; 38 were randomized to hyperbaric oxygen therapy and 37 to placebo (hyperbaric air). The overall mean physical and mental summary scores for the entire study population at baseline were 29.6 ± 8.8 and 47.5 ± 12.4, respectively. There was a significant difference between baseline and 1 year follow-up responses to the mental summary score and two of the eight (SF-36) (?) domains in the -hyperbaric oxygen group, whereas no significant improvement of health related quality of life was seen in the placebo group. Comparing quality of life in patients who healed their ulcer (healers) with those who did not (non-healers), post-treatment levels of the mental health summary score, social functioning and role limitations due to physical and emotional health were significantly improved in healers. No differences were seen in any SF-36 (?) domain in non-healers. CONCLUSIONS: Hyperbaric oxygen therapy improves long-term health related quality of life in patients with chronic diabetic foot ulcers, possibly attributable to better ulcer healing.

Organization of the genes encoding complement receptors type 1 and 2, decay-accelerating factor, and C4-binding protein in the RCA locus on human chromosome 1.

The organization and physical linkage of four members of a major complement locus, the RCA locus, have been determined using the technique of pulsed field gradient gel electrophoresis in conjunction with Southern blotting. The genes encoding CR1, CR2, DAF, and C4bp were aligned in that order within a region of 750 kb. In addition, the 5' to 3' orientation of the CR1 gene (5' proximal to CR2) was determined using 5'- and 3'-specific DNA probes. The proximity of these genes may be related to structural and functional homologies of the protein products. Overall, a restriction map including 1,500 kb of DNA was prepared, and this map will be important for positioning of additional coding sequences within this region on the long arm of chromosome 1.

Is chronic diabetic foot ulcer an indicator of cardiac disease?

OBJECTIVE: To evaluate presence and severity of cardiac disease in individuals with chronic diabetic foot ulcers using echocardiography. METHOD: Eighty consecutive patients with chronic foot ulcers attending the multidisciplinary diabetes foot clinic at Helsingborg Hospital underwent clinical examination, toe blood pressure measurement and a standard echocardiographic examination. RESULTS: Sixty-nine percent of the patients had a history of myocardial infarction and/or hypertension and/or heart failure; 78% had signs of left ventricular dysfunction and/or left ventricular hypertrophy and/or diastolic dysfunction; 76% of the patients without a history of cardiovascular disease had signs of cardiac dysfunction on echocardiography. CONCLUSION: Cardiac dysfunction is a common occurrence present in patients with chronic diabetic foot ulcers, even in those without known cardiac disease or hypertension. Echocardiography may be recommended as a screening procedure in the management of diabetic patients with chronic foot ulcers. The present study supports the view that diabetic chronic foot ulcers ought to be seen as a sign of cardiac disease, although further research is needed to elucidate this issue.

Transcutaneous oxygen pressure as a predictor for short-term survival in patients with type 2 diabetes and foot ulcers: a comparison with ankle-brachial index and toe blood pressure.

AIMS: Ankle-brachial index (ABI) is the most commonly used test when diagnosing peripheral vascular disease and is considered a marker for cardiovascular risk. Transcutaneous oxygen pressure (TcPO2), a test associated with microvascular function, has in several studies shown better correlation with diabetic foot ulcer (DFU) healing. Whether a low TcPO2 could be a marker for mortality in the high-risk population of DFU patients has not been evaluated before. The aim of this study was to evaluate the predictive value of TcPO2 in comparison with ABI and toe blood pressure (TBP) on 1-year mortality in type 2 diabetes patients with DFU. METHODS: Type 2 diabetes patients aged ≤ 90 years, with one DFU who attended our multidisciplinary DFU-unit during year 2013-2015 and were screened with TcPO2, ABI and TBP were retrospectively evaluated. One-year mortality was assessed from the national death register in Sweden. RESULTS: A total of 236 patients (30% women) with a median age of 76 (69-82) years were evaluated in this study. Within 1 year, 14.8% of the patients died. TcPO2 < 25 mmHg was associated with a higher 1-year mortality compared with TcPO2 ≥ 25 mmHg (27.7 vs. 11.6%, p = 0.003). TBP and ABI did not significantly influence 1-year mortality. In a Cox regression analysis adjusted for confounders, TcPO2 was independently predicting 1-year mortality with a hazard ratio for TcPO2 < 25 mmHg of 2.8 (95% CI 1.34-5.91, p = 0.006). CONCLUSIONS: This study indicates that a low TcPO2 is an independent prognostic marker for 1-year mortality among patients with type 2 diabetes and DFU.

Effects of sympatholytic therapy on insulin sensitivity indices in hypertensive postmenopausal women.

Cardiovascular risk factors are often ineffectively controlled in hypertensive postmenopausal women, and moreover, some antihypertensive drugs may increase particular risk factors such as insulin resistance. In a multicenter, multinational (Finland, Sweden, Lithuania), double-blind, prospectively randomized study hypertensive obese postmenopausal women without hormone therapy (n = 98) were randomly assigned to receive treatment with either the centrally acting agent moxonidine, 0.6 mg/day, or with the peripherally acting atenolol, 50 mg/day, for 8 weeks. In addition to blood pressure measurements, insulin sensitivity was estimated by the quantitative insulin sensitivity check index (QUICKI) and by the insulin sensitivity index (ISI-Matsuda). Subgroup analysis in insulin-resistant women (fasting P-insulin > or = 10 mU/l) and blood pressure responders (diastolic blood pressure < or = 90 mmHg and/or reduction of blood pressure > or = 10 mmHg) were also carried out. Both atenolol and moxonidine led to a significant reduction in diastolic blood pressure of 9.5 mmHg and 6.2 mmHg, respectively. Among insulin-resistant women, an increase in the insulin sensitivity assessed by ISI was improved with moxonidine treatment (p = 0.025). A decrease in insulin sensitivity assessed by QUICKI was observed with atenolol treatment in women with fasting insulin level < 10 mU/l. In patients, in whom blood pressure was reduced, an improvement in insulin sensitivity (ISI) was associated with moxonidine treatment (p = 0.019), but not with atenolol treatment. The centrally acting sympatholytic agent moxonidine did reduce blood pressure somewhat less than atenolol, but it was associated with an improved metabolic profile in terms of decreased insulin resistance both in insulin-resistant postmenopausal women and in women with a significant blood pressure response.

A prospective study: hyperbaric oxygen therapy in diabetics with chronic foot ulcers.

Research suggests that hyperbaric oxygen therapy may have beneficial effects on ulcer healing and amputation rates in diabetic patients. This paper describes the design of a study that is evaluating its effects on chronic diabetic foot ulcers.

Intrapartum fever, epidural analgesia and histologic chorioamnionitis.

OBJECTIVE: Our objective was to determine whether epidural analgesia and histologic chorioamnionitis were independent predictors of intrapartum fever. STUDY DESIGN: This secondary analysis, retrospective cohort study included term parturients with placental examination during 2005. Logistic regression used fever (⩾38 °C) as the dependent variable. Significance was defined as P⩽0.05. RESULT: There were 488 (76%) of 641 term parturients with placental examination and epidural. Independent predictors of intrapartum fever were epidural odds ratio (OR)=3.4, confidence interval (CI): 1.70, 6.81, histologic chorioamnionitis OR=3.18, 95% CI: 2.04, 4.95, birthweight OR=2.07, 95%CI: 1.38, 3.12, vaginal exams OR=1.15, 95% CI:1.06, 1.24, duration ruptured membranes OR=1.03, 95% CI: 1.01,1.05, parity⩾1 OR=0.44: 0.29, 0.66 and thick meconium OR=0.35: 95%CI: 0.24, 0.85. CONCLUSION: Epidural analgesia and histologic chorioamnionitis were independent predictors of intrapartum fever. Modification of labor management may reduce the incidence of intrapartum fever.

Renal effects of acute and long-term treatment with felodipine in essential hypertension.

Enhanced renal vasoconstriction and renal tubular sodium reabsorption mediated by noradrenaline and angiotensin II (Ang II) have been implicated in the pathogenesis of essential hypertension. Since these effects seem to be calcium-dependent, renal haemodynamic and tubular function were studied following acute and long-term treatment with the calcium antagonist felodipine in 10 patients with essential hypertension. After acute felodipine administration mean blood pressure (MBP) decreased (from 111 to 95 mmHg; P less than 0.01), renal blood flow (RBF), estimated from hippurate clearance, increased (from 1030 to 1175 ml/min; P less than 0.01) and glomerular filtration rate (GFR) was unchanged (109 versus 112 ml/min). Fractional excretion (FE) of sodium, potassium, calcium, magnesium, chloride, bicarbonate and urate increased for 12 h. Following long-term felodipine treatment, mean blood pressure was reduced (97 mmHg; P less than 0.01) and RBF and GFR were unchanged (1032 and 114 ml/min, respectively). Fractional excretion of urate and calcium was increased for 24 h (from 5.9 to 6.9%; P less than 0.05 and from 1.1 to 1.3%; P less than 0.05, respectively). Serum urate decreased (from 377 to 347 mumol/l; P less than 0.01) whereas serum calcium was unchanged. Fractional excretion of sodium, potassium and chloride was increased between 3 and 6 h after felodipine. The renal haemodynamic findings after acute felodipine administration are indicative of a direct renal vasodilator action of felodipine which augments the autoregulatory renal vasodilation to produce an overall increase in RBF. Since GFR was unchanged, the increased renal excretion of electrolytes and urate reflects an action at the tubular level. Following long-term felodipine administration autoregulatory adjustment of RBF predominated.

Serum lipid profile determines platelet reactivity to native and modified LDL-cholesterol in humans.

The effects of thrombin (0.2 U/ml) and native (n-LDL), malondialdehyde-modified (MDA-LDL) and auto-oxidized (ox-LDL) low-density lipoproteins (20 micrograms of protein/ml) on platelet activation were evaluated in seven hyperlipidemic patients and compared to seven controls (fasting serum cholesterol 8.49 +/- 0.5 and 4.61 +/- 0.4 mM, respectively). Basal and thrombin-induced increases in platelet intracellular free calcium ion concentration ([Ca2+]i; fura-2) were similar in hyperlipidemic patients and controls (45 +/- 5 vs 42 +/- 3 and 635 +/- 51 vs 599 +/- 69 mM, respectively). n-LDL, MDA-LDL and ox-LDL increased basal [Ca2+]i (16, 36 and 81 percent, p < 0.01 between LDL-types), increases were consistently smaller in patients. There was an inverse relationship between LDL-induced responses and fasting serum LDL cholesterol as well as LDL/HDL ratio. In conclusion, modified LDL activated platelets to a greater extent than n-LDL, suggesting different types of LDL-receptors. Their agonistic effect was inversely related to the fasting serum lipid profile, suggesting that blunting of platelet responses to LDL could represent a protective mechanism in hyperlipidemic patients.

Temperature-dependence of LDL binding and activation of human platelets.

The effect of low density lipoprotein (LDL) on intracellular free calcium ion concentration ([Ca2+]i), taken as an index of the degree of platelet activation, was investigated in normal volunteers. At 37 degrees C LDL, in a dose of 20 micrograms of protein/ml, increased [Ca2+]i in all subjects tested (basal 57 +/- 11 to 113 +/- 19 nM). In contrast, when measurements were performed at 20 degrees C, no effect on [Ca2+]i was seen following LDL. Thrombin (0.2 U/ml) increased [Ca2+]i to 455 +/- 98 nM. When platelets had been exposed to LDL before thrombin stimulation, this increase was less pronounced (to 301 +/- 43 nM). Our finding of a temperature dependence of LDL induced increase in platelet [Ca2+]i supports the concept of a platelet-LDL receptor mediated mechanism. Furthermore, the lower thrombin response following LDL exposure suggests a LDL-thrombin interaction, possibly at the thrombin receptor level and/or calcium recruitment from the same stores.

Amiloride compared with nitrendipine in treatment of essential hypertension.

The antihypertensive effect of amiloride was compared to that of the calcium antagonist nitrendipine in 12 patients (8 males), aged 34-62 years, with essential hypertension WHO grade I-II (mean supine blood pressure 158/103, standing 155/106 mmHg) in a double-blind placebo-controlled cross-over study design. Amiloride was given 5 mg once daily for one month followed by 20 mg twice daily for another month. Amiloride 5 mg once daily significantly reduced supine and standing DBP but not SBP (supine 151/94, standing 149/97 mmHg), whereas 10 mg once daily decreased SBP as well as DBP (supine 145/98, standing 145/101 mmHg). Nitrendipine 20 mg once daily significantly reduced supine and standing SBP and standing DBP (supine 150/97, standing 148/98 mmHg), but on 20 mg twice daily only supine SBP was significantly reduced (supine 150/99, standing 151/106 mmHg). Heart rate was transiently increased by nitrendipine 20 mg once daily and unchanged following amiloride. Plasma noradrenaline was unaltered following amiloride 10 mg once daily as well as nitrendipine 20 mg twice daily, whereas plasma renin activity and aldosterone were elevated following amiloride. Serum electrolytes, blood glucose, plasma lipids and body weight were not altered by any of the drugs. Amiloride 5-10 mg daily has a mild to moderate BP lowering effect in patients with essential hypertension. The BP reduction following nitrendipine 20 mg once daily was comparable to that of amiloride 5 mg daily. Nitrendipine 20 mg twice daily gave no additional BP decrease.

Simvastatin treatment of hypercholesterolemia in patients with insulin dependent diabetes mellitus.

The effects of 16 weeks therapy with the HMG-CoA reductase inhibitor Simvastatin 10-20 mg (n = 12) was compared to placebo (n = 13) in 25 euthyreoid males with insulin dependent diabetes mellitus and fasting total serum cholesterol above 6 mmol/l. Insulin dependence was defined as a glucagon stimulated C-peptide level less than 0.6 mmol/l. The study was placebo-controlled, double-blind with a parallel group design. Body weight, blood pressure, glycemic control as well as liver enzymes were unchanged and simvastatin was well tolerated by all patients. Ophthalmological slitlamp examination before and at the end of the study period did not show development of new lenticular opacities. Simvastatin decreased serum total cholesterol from 6.7 +/- 1.0 mmol/l (mean +/- SD) to 4.9 +/- 0.4 (p < 0.001 vs. placebo) and LDL-cholesterol from 4.6 +/- 0.7 mmol/l to 2.8 +/- 0.3 (p < 0.001 vs. placebo). HDL-cholesterol and triglycerides remained unaltered. A positive influence on the atherosclerotic process in patients with insulin dependent diabetes mellitus remains, however, to be proven.

Do placental histologic findings of chorion-decidual hemorrhage or inflammation in spontaneous preterm birth influence outcomes in the subsequent pregnancy?

INTRODUCTION: Spontaneous preterm birth (SPTB) is the common endpoint of different underlying etiologies, including chorion-decidual bleeding and inflammation. However, specific histologic findings from a prior pregnancy do not always inform clinical management in subsequent pregnancies secondary to few prior studies having evaluated the relationship between prior pregnancy pathology and subsequent outcomes in patients with SPTB. METHODS: Included subjects had: 1) a SPTB with available placental pathology and 2) a subsequent consecutive delivery at >20 weeks gestational age at our institution. For included subjects archived placenta and membrane paraffin blocks from the index SPTB were cut, stained with Prussian Blue and evaluated by a perinatal pathologist for the presence of hemosiderin. The association between histologic findings and subsequent pregnancy outcomes were evaluated through logistic and linear regression. RESULTS: A total of 131 subjects were included, of whom 39.7% had a recurrent SPTB. Funisitis at the time of preterm delivery significantly increased the risk of early (<34 weeks) recurrent preterm birth (OR 3.38, p = 0.016), though this may have been confounded by gestational age at delivery. Several histologic features were significantly associated with reductions in birth weight in the subsequent pregnancies, even if they did not increase the risk of recurrent preterm birth. DISCUSSION: The presence of chorion-decidual bleeding or inflammation in a prior pregnancy can signal an increased risk in a future pregnancy beyond the recurrent risk of SPTB itself. CONCLUSIONS: Placental histologic findings after SPTB maybe associated with differences in birth weight in a subsequent pregnancy.

Accuracy of signs of clinical chorioamnionitis in the term parturient.

OBJECTIVE: Uniform histopathologic guidelines were applied to diagnose chorioamnionitis and estimate the accuracy of clinical signs in term parturients. STUDY DESIGN: A retrospective cohort study utilized slides from term parturient placentas with Amniotic Fluid Infection Nosology Committee guidelines as the gold standard. Sensitivity, specificity and accuracy for fever, maternal tachycardia and fetal tachycardia were calculated. RESULT: Of 641 placentas, 367 (57.3%) had histologic chorioamnionitis and 274 (42.7%) were negative. Fever had a sensitivity of 42%, specificity of 86.5% and accuracy of 61%. Fever, maternal tachycardia and fetal tachycardia had a sensitivity of 18.3%, specificity of 98.2% and accuracy of 52.4%. CONCLUSION: Histologic chorioamnionitis, frequently asymptomatic, is a common finding in placentas examined from term parturients. Clinical signs are not accurate in the diagnosis. Adoption of uniform pathologic guidelines will facilitate research into the clinical significance of these lesions in the future.

Biochemical diagnosis of primary hyperparathyroidism: Analysis of the sensitivity of total and ionized calcium in combination with PTH.

OBJECTIVES: To investigate the accuracy of the biochemical diagnosis of primary hyperparathyroidism (pHPT) in a consecutive series of patients with operatively verified disease. DESIGN AND SUBJECTS: Four hundred thirty-six patients with pHPT, 340 women and 96 men, were reviewed. Biochemical variables, including total calcium (Ca), ionized calcium (Cai) and PTH were analyzed and registered in a prospective database. RESULTS: In the subgroup of patients with more mild hypercalcemia (Ca below 2.70mmol/L) the correlation between Ca and Cai was poor. 19 respectively 18 patients had preoperatively a Ca respectively Cai level within the reference range. Further 35 patients had preoperatively a normal level of PTH. The diagnostic sensitivities, in detecting pHPT, for Ca, Cai and the combination of Ca and Cai were 96%, 96% and 99%. CONCLUSION: If calcium and ionized calcium are not used in the diagnostic workup of pHPT some 4% of the patients will be overlooked. We recommend analyzing both Ca and Cai in the diagnostic workup of pHPT.