Short-term impact of HbA1c on morbidity and all-cause mortality in people with type 2 diabetes: a Danish population-based observational study.

AIMS/HYPOTHESIS: In a population-based setting, we investigated whether diabetes-related morbidity and all-cause mortality within 2 years of HbA(1c) measurement were associated with that HbA(1c) level in individuals with type 2 diabetes. The main objective was to compare outcomes in those with HbA(1c) ≥ and <7% (53 mmol/mol). METHODS: Individuals with type 2 diabetes from Aarhus County, Denmark, were identified from public data files in a 3 year period (2001-2003). Stratifying the 17,760 individuals by HbA(1c), we estimated HRs for diabetes-related morbidities and all-cause mortality using Cox regression. Results were also stratified by treatment modality. RESULTS: In total, 1,805 individuals experienced at least one diabetes-related morbidity and 1,859 individuals died. In general, the HRs in adjusted analyses of diabetes-related morbidity and mortality were increased for HbA(1c) ≥ 7% (53 mmol/mol): morbidity, HR 1.48 (95% CI 1.34, 1.63); and mortality, HR 1.26 (95% CI 1.15, 1.39). On grouping individuals according to HbA(1c) <5% (31 mmol/mol), 5.0-5.9% (31-41 mmol/mol), 6.0-6.9% (42-52 mmol/mol), 7.0-7.9% (53-63 mmol/mol), 8.0-8.9% (64-74 mmol/mol) and ≥ 9% (75 mmol/mol), the HRs for mortality formed a U shape, with HbA(1c) 6.0-6.9% (42-52 mmol/mol) at the lowest point. For diabetes-related morbidity, a dose-response pattern appeared (lowest for HbA(1c) < 5% [31 mmol/mol]). Patterns of HR differed with treatment modality. CONCLUSIONS/INTERPRETATION: An HbA(1c) level ≥ 7% (53 mmol/mol) was associated with increased morbidity and mortality. Both high and very low levels of HbA(1c) were associated with increased mortality. A dose-response pattern appeared for morbidity. The impact of HbA(1c) level on morbidity and mortality depended on treatment modality.

Improved quality of Type 2 diabetes care following electronic feedback of treatment status to general practitioners: a cluster randomized controlled trial.

AIMS: To evaluate the effect of an electronic feedback system to general practitioners on quality of Type 2 diabetes care. METHODS: A cluster randomized, controlled trial with 15 months follow-up. Eighty-six general practices (158 general practitioners) in a Danish county caring for 2458 people 40-70 years old with Type 2 diabetes were randomized to receive or not to receive electronic feedback on quality of care. People with Type 2 diabetes were identified using a validated algorithm. Primary end-points were processes of care according to guidelines on prescriptions redeemed for Type 2 diabetes treatments, measuring of glycated haemoglobin and cholesterol and visits to ophthalmologists. Secondary end-points were changes in level of glycated haemoglobin and serum cholesterol. Data were analysed using generalized linear models accounting for clustering at practice level. RESULTS: During follow-up, people with Type 2 diabetes in the intervention group more often redeemed recommended prescriptions than people in the control group, respectively, as follows: oral antidiabetic treatment (32.8 vs. 12.0%, P =0.002), insulin treatment (33.8 vs. 12.4%, P < 0.001), lipid-lowering medication (38.3 vs. 18.6%, 0.004) and blood pressure medication (27.6 vs. 16.3%, P = 0.026). There were no differences in mean glycated haemoglobin and serum cholesterol between the two groups. CONCLUSIONS: Electronic feedback to general practitioners on the quality of Type 2 diabetes care resulted in significantly improved quality regarding processes of care according to guidelines. It was not possible to demonstrate any effect on secondary end-point measures within the follow-up period. Electronic feedback on quality of diabetes care can be effective in improving adherence to treatment according to evidence-based guidelines.

Decreased work productivity due to primary palmar hyperhidrosis. What is the cost?

A decrease of 7,2 % in productivity was found in patients suffering from palmar hyperhidrosis. A correction of this could more than pay for the treatment with botulinum-toxins, even 3 or 4 times a year.

The Danish National Diabetes Register: trends in incidence, prevalence and mortality.

AIMS/HYPOTHESIS: The aim of the study was to describe trends in the incidence rate, prevalence and mortality rate for diabetes in Denmark. METHODS: Healthcare registers at the National Board of Health were used to compile a register of diabetic patients in the Danish population (5.4 million people). Age- and sex-specific prevalence, incidence rates, mortality rates and standardised mortality ratios relative to the non-diabetic part of the population were calculated. RESULTS: The register contains records for about 360,000 persons with diabetes; 230,000 were alive at 1 January 2007, corresponding to an overall prevalence of 4.2%. The prevalence increased by 6% per year. In 2004 the incidence rates were 1.8 per 100,000 at age 40 years and 10.0 per 100,000 at age 70 years. The incidence rate increased 5% per year before 2004 and then stabilised. The mortality rate in the diabetic population decreased 4% per year, compared with 2% per year in the non-diabetic part of the population. The mortality rate decreased 40% during the first 3 years after inclusion in the register. The standardised mortality ratio decreased with age, from 4.0 at age 50 years to 2.5 at age 70 years and just under 2 at age 85 years, identically for men and women. The standardised mortality ratio decreased 1% per calendar year. The lifetime risk of diabetes was 30%. CONCLUSIONS/INTERPRETATION: The prevalence of diabetes in Denmark rose in 1995-2006, but the mortality rate in diabetic patients decreased faster than that of the non-diabetic population. The mortality rate decreased markedly just after inclusion in the register. Incidence rates have shown a tendency to decrease during the last few years, but this finding should be viewed with caution.

Antibodies to a 64,000 Mr human islet cell antigen precede the clinical onset of insulin-dependent diabetes.

Antibodies in sera from newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients are directed to a human islet cell protein of relative molecular mass (Mr) 64,000. Since IDDM seems to develop after a prodromal period of beta-cell autoimmunity, this study has examined whether 64,000 Mr antibodies could be detected in 14 individuals who subsequently developed IDDM and five first degree relatives who have indications of altered beta-cell function. Sera were screened by immunoprecipitation on total detergent lysates of human islets and positive sera retested on membrane protein preparations. Antibodies to the 64,000 Mr membrane protein were consistently detected in 11/14 IDDM patients, and in all 5 first degree relatives. 10 IDDM patients were already positive in the first samples, obtained 4-91 mo before the clinical onset of IDDM, whereas 1 patient progressed to a high 64,000 Mr immunoreactivity, at a time where a commencement of a decline in beta-cell function was detected. 64,000 Mr antibodies were detected before islet cell cytoplasmic antibodies (ICCA) in two patients. In the control groups of 21 healthy individuals, 36 patients with diseases of the thyroid and 5 SLE patients, the 64,000 Mr antibodies were detected in only one individual, who was a healthy sibling to an IDDM patient. These results suggest that antibodies against the Mr 64,000 human islet protein are an early marker of beta-cell autoimmunity and may be useful to predict a later development of IDDM.

The effect of penile vibratory stimulation on male fertility potential, spasticity and neurogenic detrusor overactivity in spinal cord lesioned individuals.

PURPOSE: Present the possibility for treatment of male infertility, spasticity, and neurogenic detrusor overactivity in spinal cord lesioned (SCL) individuals with penile vibratory stimulation (PVS). METHOD: Obtaining reflex-ejaculation by PVS, by using a vibrator developed for this purpose. The stimulation was performed with a vibrating disc of hard plastic placed against the frenulum of the penis (amplitude > or = 2.5 mm). The vibration continued until antegrade ejaculation or for a maximum of 3 minutes followed by a pause of 1 minute before the cycle was repeated, maximally 4 times. RESULTS: >80% SCL men are able to obtain ejaculation with PVS. Pregnancy rates obtained with home PVS and intra-vaginal insemination was 22-62% (4 studies), and with PVS or electroejaculation and intrauterine insemination/in-vitro fertilization/intracytoplasmatic sperm injection 39-64% (9 studies). PVS was demonstrated to decrease spasticity significantly when measured by the modified Ashworth scale. In addition, a decrease of the number of spontaneous EMG events which probably indicate spasms was observed. Increase in bladder capacity at leakpoint following 4 weeks of frequent ejaculation with PVS treatment was likewise demonstrated. CONCLUSION: PVS has proved its importance for SCL male fertility, in the years to come its place in treatment of spasticity and neurogenic detrusor overactivity has to be established.

Local regulation of digital blood flow in generalized scleroderma.

A decreasing activity of the vascular bed upon changes in vascular transmural pressure and changes in arterial perfusion pressure head was observed from hand to fingers and from subcutis to cutis in patients suffering from generalized scleroderma. These findings are expressions of deteriorating vascular smooth muscle function. The reactive hyperemia response was decreased in subcutaneous as well as cutaneous tissue in patients fingers and in 4 of 7 patients the response was absent from the finger tip. The reactive hyperemia response of the patients resembled responses obtained in normal fingers during decrease in local perfusion blood pressure, during local cooling or after infiltration of norepinephrine around the digital arteries. This implied an increased digital artery resistance in generalizing scleroderma. A positive feed back loop between cooling, increase in digital artery resistance, increase in blood viscosity and a passive vascular bed is proposed as an important factor in Raynaud's phenomenon.

Blood flow in fingers in generalized scleroderma with Raynaud's phenomenon: influence of arterial blood pressure reduction and proximal vasodilatation.

Maximum reactive hyperemia following vascular occlusion can be taken as an estimate of tissue blood flow capacity. Ten patients with generalized scleroderma and Raynaud's phenomenon and 7 normals were studied. Blood flow was estimated in subcutaneous tissue of fingers by the local 133Xenon washout technique. Blood pressure cuffs were applied around the upper arm and a finger just proximal to the 133Xenon depot. Blood flow was estimated before and after inflation of each cuff. Decrease in arterial perfusion pressure head in fingers was obtained in 3 ways, viz. (a) by proximal vasodilatation, (b) by elevation of the limb, and (c) the combination of (a) and (b). At heart level, maximum 133Xenon washout rate was always lower when the whole arm participated in the hyperemia illustrating the effect of proximal vasodilatation. Maximum blood flow was significantly decreased in the patients as compared to normals. When the fingers were elevated by 40 cm, reactive hyperemia disappeared in the patients. In normals, hyperemia was not abolished until the fingers were elevated by 60 cm. This simple maneuvre might be a suitable provocation test showing the effect of a decrease in arterial perfusion pressure, when organic vascular stenosis exists. Seemingly unimportant lowerings of systemic blood pressure probably are followed by similar changes in finger blood pressure in the patients where they may represent a drastic reduction in blood pressure. This effect may have consequences for the use of systemic vasodilator drugs in late scleroderma.

Reactive hyperemia in cutaneous tissue in generalized scleroderma.

Reactive hyperemia following ischemia in cutaneous tissue of human fingers was studied in 6 normal persons and 9 patients suffering from generalized scleroderma. Ischemia lasting 6 or 12 min was induced by inflating a cuff placed around the proximal phalanx to 300 mm Hg. Blood flow was measured by the local atraumatic 133Xenon wash-out technique. The following parameters were calculated: (1) Maximum blood flow was calculated from the steepest part of the wash-out curve following release of the cuff. (2) Excess cumulative blood flow, i.e., the integrated blood flow from release of cuff until preischemic blood flow values were obtained, minus preischemic blood flow times duration of ischemia. (3) Repayment, i.e., excess cumulative blood flow in percent of preischemic blood flow times duration of ischemia. Maximum blood flow, excess cumulative blood flow and repayment was decreased in the patients compared to normals. This might be due to structural changes of the blood vessel walls and/or functional changes of the vascular smooth muscle cells in scleroderma.

Distensibiltiy of the papaverine-induced passive vascular bed in dermis of generalized scleroderma.

Passive distensibility of of the vascular bed in cutaneous tissue of the hand was examined in 7 normal persons and 15 patients suffering from generalized scleroderma of the acrosclerosis type. Paralysis of vascular smooth muscle cells was obtained by locally injected papaverine. Increase in vascular transmural pressure was induced by lowering the limb. Blood flow was estimated by the local Xenon wash-out technique. There was no significant difference between the patients and the normals in relative blood flow during lowering, when injection volumes of 0.005 and 0.02 ml were used, indicating that distensibility of the vascular bed in cutaneous tissue in generalized scleroderma is not diminished. However, in generalized scleroderma an injection volume of 0.1 ml caused a significant decrease in relative blood flow during lowering. This phenomenon observed in the patients probably reflects changes in total tissue pressure opposing distension of the vascular bed. This suggests an altered pressure-volume relationship of the interstitial fluid spaces in cutaneous tissue of generalized scleroderma.

Studies on 133Xe wash-out from human skin: quantitative measurements of blood flow in normal and corticosteroid-treated skin.

Blood flow was measured by the 133Xe technique in normal and corticosteroid-treated skin. Epicutaneous and intracutaneous methods of tracer application were compared in normal skin. The two labeling methods were equally suitable for measuring cutaneous blood flow provided calculations in both cases were based on a biexponential resolution of the wash-out curve in its cutaneous and subcutaneous components and provided the traumatic hyperemia phase was considered, when intracutaneous application of the tracer was used. Results were invalidated if calculations were based on initial slope of the wash-out curves.Topical application of beta-methasone valerate in a reduction in cutaneous blood flow as measured by the intracutaneous technique with curve resolution, whereas no effect could be demonstrated when calculations were based on the initial slopes of the curves. The 133Xe technique is a simple and reliable method for measuring cutaneous blood flow, which might prove useful in estimations of penetration ability and potency of topical corticosteroids.

Evaluation of cutaneous blood flow responses by 133Xenon washout and a laser-Doppler flowmeter.

A new method for noninvasive measurement of cutaneous blood flow is laser-Doppler flowmetry. The technique is based on the fact that laser light is back-scattered from the moving red blood cells, with Doppler-shifted frequencies; these impulses lead to photodetectors and are converted to flow signals. In this work we used a new system with a low noise level. Comparison was made between this technique and the atraumatic epicutaneous 133Xenon technique for measurement of cutaneous blood flow during reactive hyperemia and orthostatic pressure changes. The laser-Doppler flowmeter seems to measure blood flow in capillaries as well as in arteriovenous anastomoses, while the 133Xe method probably measures only capillary flow. A calibration of the laser-Doppler method against the 133Xe method would appear to be impossible in skin areas where arteriovenous anastomoses are present. The changes in blood flow during reactive hyperemia, orthostatic pressure changes, and venous stasis were found to be parallel as measured by the two methods in skin areas without shunt vessels. The laser-Doppler flowmeter would appear to be a useful supplement to the 133Xe washout method in cutaneous vascular physiology, but it is important to keep in mind that different parameters may be measured.

Distensibility of the vascular bed in subcutaneous tissue in generalized scleroderma.

Passive distensibility of resistance vessels in subcutaneous tissue of hand and leg was examined in 6 normals and 8 patients suffering from generalized scleroderma of the acrosclerosis type. Local paralysis of smooth muscle was obtained by injection of papaverine and increase in transmural pressure by lowering the limb. Blood flow was estimated by the local 133Xenon wash-out method. Distensibility of blood vessels in subcutaneous tissue in generalized scleroderma was not decreased to a significant degree, whereas, both in patients and normals, the blood vessels of the leg exhibited diminished distensibility compared to blood vessels of the hand. The findings suggest that the morphologic changes of vascular and extravascular tissue observed in sclerodermic skin do not affect distensibility of the vascular bed in subcutaneous tissue.

Quantitation of microcirculatory blood flow changes in human cutaneous tissue induced by inflammatory mediators.

The cutaneous microcirculation is a desirable model for pharmacologic and physiologic studies of inflammatory mediators. For exact measurements of the induced blood flow changes, two objective methods are introduced. The laser-Doppler flowmeter and the 133Xe washout technique have formerly been used for measurement of the undisturbed cutaneous blood flow. We have modified these methods to measure changes in the blood flow following intracutaneous deposition of a vasodilator, leukotriene D4. When compared with a metric estimate of the erythemal response, the two new methods were found to be more sensitive than the traditional estimate of cutaneous blood flow changes. Both methods exhibited a good sensitivity and reproducibility when applied simultaneously, although the 133Xe washout technique appeared to be able to separate interindividual differences that could not be recognized by the laser-Doppler technique. Even though the laser-Doppler technique is superior in simplicity of use, the 133Xe washout technique is recommended for exact measurements.

The local regulation of blood flow evaluated simultaneously by 133-xenon washout and laser Doppler flowmetry.

The laser Doppler flowmeter and the 133-Xenon washout techniques of measuring cutaneous blood flow were compared for measuring the vasoconstrictor response of the hand during orthostatic maneuvres. Important discrepancies were detected for the two methods. When the hand was lowered by 40 cm a 40% decrease in blood flow was detected by the 133-Xenon method, while a 60% decrease was seen by the laser Doppler technique. Lowering the hand by 50 cm resulted in no further blood flow decrease when using the 133-Xenon method, but an 80% blood flow decrease was recorded with the laser Doppler method. A marked decrease in blood flow was recorded by the laser Doppler technique in hands that were sympathectomized or a hand that was subjected to a nerve blockade, strategies which should eliminate the orthostatic vasoconstrictor response of superficial cutaneous vessels. The 133-Xenon technique did not detect any blood flow changes in hands without sympathetic tone. We found the laser Doppler flowmetry technique unsatisfactory for measurement of blood flow changes that occur in nutritional vessels as this method measures total skin blood flow including non-capillary vessels.

Leukotriene- and histamine-induced increases in vascular permeability and interstitial transport in the skin.

The aim of the present study was to investigate the edema induced by leukotriene D4 (LTD4). Edema is the gross effect of increased blood flow and capillary permeability. Our objective was to elucidate the effect of LTD4 on edema generation without the influence of the concomitantly increased blood flow induced by this potent vasodilator. A new method was outlined measuring the exudation through skin windows of a macromolecular tracer [( 131I]albumin) and a micromolecular tracer [( 99Tc]pertechnetat). Exudation of [131I]albumin is a function of enhanced vascular permeability and interstitial transport and blood flow, whereas that of [99Tc] pertechnetat is mainly a function of blood flow. Thus a ratio of the 2 exudate measurements gives a specific estimate of the changes in vascular permeability and interstitial transport. Histamine was employed to establish the method. A dose-response relation was found for histamine in the dose range of 10(-4) to 10(-7) M. The effect of 10(-5) M LTD4 on vascular permeability and interstitial transport of macromolecules was indistinguishable from that of histamine in the same concentration. This property together with their well-known vasodilatory capabilities indicate that the leukotrienes of the slow-reacting substance of anaphylaxis may play a role in the vascular changes in the allergic-inflammatory reaction.

A new technique for ranking vascular corticosteroid effects in humans using laser-Doppler velocimetry.

By combining laser-Doppler velocimetry with reactive hyperemia, induced by arterial occlusion of 4-min duration we have established a simple and atraumatic new ranking technique for assessing steroid potency. The experiments were performed in 19 healthy volunteers. Budesonide (Preferid) and placebo (vehicle) were applied under occlusion on the flexor aspect of the forearm for 2, 24, and 48 h. Blood flow was measured with a laser-Doppler flowmeter before and after arterial occlusion with a blood pressure cuff on the upper arm. The induced reactive hyperemia reaction was measured planimetrically on the registered curves. The steroid preparation caused a significant reduction of the hyperemia closely related to the application time. The reduction of the hyperemia was confirmed using the atraumatic 133Xe washout technique. In another group, hydrocortisone, hydrocortisone-butyrate (Locoid), budesonide (Preferid), and klobetasol (Dermovat) applied under occlusion for 1 h were compared. A significant dose-response relation corresponding to the expected rank-order efficacy was revealed. In 10 experiments, pretreatment with 50 mg indomethacin i.v. resulted in a significant reduction of the hyperemia reaction. As a hypothesis we therefore suggest that the reactive hyperemia reaction amplifies the vascular events and unmasks steroid-induced inhibition of the synthesis of arachidonic acid metabolites.

Microdialysis of the interstitial water space in human skin in vivo: quantitative measurement of cutaneous glucose concentrations.

The purpose of this study was to evaluate the usefulness of a microdialysis technique for measurement of substances in the interstitial water space in intact human skin. Glucose was selected to validate the method. The cutaneous glucose concentration was measured by microdialysis and compared to that in venous blood. Single dialysis fibers (length 20 mm, 2,000 Da molecular weight cutoff) were glued to nylon tubings and inserted in forearm skin by means of a fine needle. Dialysis fibers were inserted in duplicate. Seven subjects were investigated after an overnight fast. Intradermal position of the dialysis probes was established by C-mode ultrasound scanning. The implantation trauma lasted 90-135 min as measured by laser Doppler flowmetry. Each dialysis fiber was calibrated in vivo by perfusing it with four to five different glucose concentrations. The perfusion rate was 3 microliters/min. Regression analysis of the calibration curves yielded the relative in vivo recovery of glucose. The skin glucose concentration was calculated as that particular perfusate glucose concentration that resulted in no net glucose transport across the dialysis membrane. Correlation coefficient of the regression lines was 0.93 +/- 0.03 (mean +/- SEM). After the injection trauma had vanished, recovery was 20.5 +/- 0.7%. Coefficient of variation (CV) on recovery was 10.9%. The cutaneous glucose concentration was 99.1 +/- 1.8% of the glucose concentration in venous plasma water (CV 4.1%). These findings suggest that the microdialysis technique accurately and precisely can reflect biochemical events in the interstitial water space in human skin in vivo.

Local regulation of blood flow in subcutaneous tissue in generalized scleroderma.

The effect of orthostatic changes in vascular transmural pressure on blood flow in subcutaneous tissue was studied in 10 patients with the acrosclerotic type of generalized scleroderma. Blood flow was measured on the back of the hand by the local 133xenon washout technique. The blood flow remained constant when the hand was elevated 20 cm above the jugular notch, indicating that there is autoregulation of blood flow, When the hand was lowered 40 cm below by 50% observed in normals. Thus, intrinsic vascular reactions responsible for the autoregulator response are present, whereas the normal "vasoconstrictor response" to an increase in venous transmural pressure is almost abolished in tissues with sclerodermic changes. The abolition of the vasoconstrictor response is probably due to sympathetic neuropathy associated with the sclerodermic changes.

Subdermal penetration of topically applied clobetasol propionate in ointment base through intact human skin: lack of effect on subcutaneous adipose tissue blood flow.

Some data have demonstrated a substantial subdermal accumulation of topically applied drugs in animals. The aim of this study was to evaluate a possible effect of epicutaneously applied clobetasol propionate on blood flow in human subcutaneous adipose tissue. Nine healthy subjects were studied. The 133Xenon wash-out method was used for the measurement of subcutaneous blood flow. Resting blood flow and the local blood flow regulatory mechanisms, autoregulation of blood flow and the veno-arteriolar reflex, were assessed prior to treatment and were measured following 24, 48 and 72 h of treatment. The results demonstrated no effect of clobetasol propionate on resting subcutaneous blood flow or the local regulatory mechanisms.