Correlations between peripheral blood Coxiella burnetii DNA load, interleukin-6 levels, and C-reactive protein levels in patients with acute Q fever.

From 2007 to 2010, the Netherlands experienced the largest reported Q fever outbreak, with >4,000 notified cases. We showed previously that C-reactive protein is the only traditional infection marker reflecting disease activity in acute Q fever. Interleukin-6 is the principal inducer of C-reactive protein. We questioned whether increased C-reactive protein levels in acute Q fever patients coincide with increased interleukin-6 levels and if these levels correlate with the Coxiella burnetii DNA load in serum. In addition, we studied their correlation with disease severity, expressed by hospital admission and the development of fatigue. Interleukin-6 and C-reactive protein levels were analyzed in sera from 102 patients diagnosed with seronegative PCR-positive acute Q fever. Significant but weak negative correlations were observed between bacterial DNA loads expressed as cycle threshold values and interleukin-6 and C-reactive protein levels, while a significant moderate-strong positive correlation was present between interleukin-6 and C-reactive protein levels. Furthermore, significantly higher interleukin-6 and C-reactive protein levels were observed in hospitalized acute Q fever patients in comparison to those in nonhospitalized patients, while bacterial DNA loads were the same in the two groups. No marker was prognostic for the development of fatigue. In conclusion, the correlation between interleukin-6 and C-reactive protein levels in acute Q fever patients points to an immune activation pathway in which interleukin-6 induces the production of C-reactive protein. Significant differences in interleukin-6 and C-reactive protein levels between hospitalized and nonhospitalized patients despite identical bacterial DNA loads suggest an important role for host factors in disease presentation. Higher interleukin-6 and C-reactive protein levels seem predictive of more severe disease.

Status epilepticus caused by a myxoedema coma.

The case of a 63-year-old woman who presented with status epilepticus, coma and hypoventilation is reported. A primary neurological cause was considered. Hypothermia led to further investigations and a diagnosis of severe hypothyroidism. The neurological complications of hyperthyriodism include alteration in mental status with slowness, decreased concentration and lethargy, headache, cranial nerve palsies, dysarthria, hoarseness, myopathy, neuropathy, reflex changes, ataxia, and psychotic episodes. Our patient suffered from a rare consequence of severe hypothyroidism presenting with status epilepticus and she died despite treatment. To our knowledge this is the second patient to be reported with myxoedema coma with this kind of presentation. Despite therapeutic options, there is a high mortality rate.

Prevalence and clinical characteristics of insulin-treated, anti-GAD-positive, type 2 diabetic subjects in an outpatient clinical department of a Dutch teaching hospital.

BACKGROUND: In clinical practice, type 1 and type 2 diabetic patients are sometimes difficult to distinguish. Type 1 diabetes has an immune-mediated pathogenesis, resulting in a loss of insulin-secreting beta-cells. Type 2 diabetes mellitus is characterised by a relative insulin insufficiency, without the presence of an autoimmune aetiology, initially due to insulin resistance and later also accompanied by defective insulin release. Latent autoimmune diabetes of the adult (LADA) is a subgroup of diabetes, somewhere on the borderland between type 1 and type 2 diabetes. LADA is characterised by a late-age onset and relatively mild progression, but with unmistakable signs of autoimmunity, such as the presence of the autoimmune antibodies anti-GAD65, anti-insulin antibodies, or anti-Ia-2ab. OBJECTIVE: To establish the prevalence of anti-GAD ina diabetic outpatient clinic of a Dutch, non-university,teaching hospital and to describe these patients clinical and laboratory features, especially of the metabolic syndrome. METHODS: We evaluated GAD65 antibodies and other parameters in 244 selected diabetic patients, who had been on oral therapy for at least three months before becoming insulin-dependent. RESULTS: Twenty-six patients (11.6%) were positive for GAD65 antibodies. These patients had a significantly lower BMI (27.8 +/- 4.5 vs 31.1 +/- 4.9; p<0.01); less often cerebrovascular accidents (19.2 vs 34.9%; p<0.01) and a higher HDL cholesterol (1.73 +/- 0.53 vs 1.21 +/- 0.38; p<0.05). In contrast, anti-GAD patients had a significantly higher prevalence of hypothyroidism (23.0 vs 6.6%; p<0.05). CONCLUSION: Anti-GAD-positive patients represent a sizable proportion of type 2 diabetes in a second-line outpatient clinic, and they are characterised by lower parameters of the metabolic syndrome, but higher prevalence of other autoimmune phenomena such as hypothyroidism.

[Diagnostic image (95). A man with a greyish blue complexion]. / Diagnose in beeld (95). Een man met een leiblauw gelaat. Diffuse melanose bij een gemetastaseerd maligne melanoom.

An 80-year-old man with anorexia and brown-coloured urine presented with a typical complexion due to diffuse melanosis caused by malignant melanoma.

Microcirculatory effects of KATP channel blockade by sulphonylurea derivatives in humans.

BACKGROUND: Recent investigations have shown that glibenclamide inhibits the opening of vascular ATP-sensitive potassium channels during ischemia. This observation may implicate cardiovascular effects of sulphonylurea derivatives when used under conditions of ischemia in patients with Type 2 diabetes mellitus. In addition to resistance arteries, the (pre) capillary vessels also contain ATP-dependent potassium channels. Closure of these channels by sulphonylurea derivatives might affect the development of microvascular disease in Type 2 diabetes mellitus. Therefore, we investigated the microcirculatory effects of sulphonylurea derivatives in Type 2 diabetic patients as compared with healthy volunteers. MATERIALS AND METHODS: Arteriovenous blood flow (skin temperature and laser Doppler flux) and capillary blood cell velocity were measured before and during infusion of four doses of glibenclamide (0.1, 0.3, 1.0 and 3.0 microg min-1 dL-1) into the brachial artery of 14 Type 2 diabetic patients and 13 healthy controls. The experiments included appropriate time control studies. RESULTS: Both skin temperature and laser Doppler flux decreased in response to glibenclamide in healthy volunteers (-7 +/- 2%, P < 0.0005 and -31 +/- 11%, P = 0.001, respectively), but did not change in Type 2 diabetic patients (1 +/- 3%, P = 0.29 and 4 +/- 14%, P = 0.97). However, capillary blood cell velocity decreased in Type 2 diabetic patients (-38 +/- 18%, P = 0.04), but did not change in healthy volunteers (-1 +/- 11%, P = 0.28). CONCLUSIONS: The results of the present study indicate that glibenclamide indeed affects microvascular blood flow. Glibenclamide may induce redistribution of the microvascular skin flow from nutritive flow to arteriovenous shunt flow in Type 2 diabetic patients. Therefore, closure of ATP-dependent potassium channels by glibenclamide possibly plays a role in the development of microangiopathy in Type 2 diabetic patients.

Consequences of asymptomatic bacteriuria in women with diabetes mellitus.

BACKGROUND: Women with diabetes mellitus (DM) have asymptomatic bacteriuria (ASB) more often than women without DM. It is unknown, however, what the consequences of ASB are in these women. OBJECTIVE: To compare women with DM with and without ASB for the development of symptomatic urinary tract infections (UTIs), renal function, and secondary complications of DM during an 18-month follow-up period. METHODS: In this multicenter study we monitored women with DM with and without ASB for the development of symptomatic UTIs, renal function, and secondary complications (ie, retinopathy, neuropathy, microvascular, or macrovascular diseases). Data on the first 18-month follow-up period are presented. RESULTS: At least 1 uncontaminated urine culture was available from 636 women (258 with type 1 DM and 378 with type 2 DM). The prevalence of ASB at baseline was 26% (21% for those with type 1 DM and 29% for those with type 2 DM). Follow-up results were available for 589 (93%) of the 636 women. Of these 589 women, 115 (20%) (14% with type 1 DM and 23% with type 2 DM) developed a symptomatic UTI. Women with type 2 DM and ASB at baseline had an increased risk of developing a UTI during the 18-month follow-up (19% without ASB vs 34% with ASB, P =.006). In contrast, there was no difference in the incidence of symptomatic UTI between women with type 1 DM and ASB and those without ASB (12% with ASB vs 15% without ASB). However, women with type 1 DM and ASB had a tendency to have a faster decline in renal function than those without ASB (relative increase in serum creatinine level 4.6% vs 1.5%, P = 0.2). CONCLUSION: Women with type 2 DM and ASB have an increased risk of developing a symptomatic UTI than those without ASB.

Reproducibility of skin microcirculatory measurements in humans, with special emphasis on capillaroscopy.

The reproducibility of capillaroscopic measurements of capillary blood cell velocity (CBV) in human nailfolds was investigated by use of the computerized system CapiFlow. Therefore, CBV measurements of two capillaries of each of three fingers together with laser Doppler fluxmetry (LDF) and skin temperature measurements were performed three times in five healthy volunteers. Short-term (1.5 h) intra-individual coefficient of variation (CV) of CBV was 18.4%. Long-term (7 days) CV amounted to 55.8%. Inter-individual CV was 55.9%. Short- and long-term intra-individual CVs of LDF were 25.4% and 37.3%. Inter-individual variation was 36.0%. Skin temperature showed short- and long-term CVs of 3.7% and 5.5% and inter-individual CV of 5.8%. In conclusion, measurement of CBV using CapiFlow is a suitable method to assess acute effects, but has limited value in investigating long-term effects. Because of the wide interindividual variability in both CBV and LDF, power calculations will reveal large numbers to investigate. Skin temperature has a relatively small intra- and inter-individual variation and is more suitable for long-term studies.

Risk factors for symptomatic urinary tract infection in women with diabetes.

OBJECTIVE: Women with diabetes have urinary tract infections (UTIs) more often than women without diabetes. The aim of the present multicenter study was to evaluate which clinical characteristics are associated with the development of a symptomatic UTI during an 18-month follow-up period. RESEARCH DESIGN AND METHODS: Patients with either type 1 or type 2 diabetes who were between 18 and 75 years of age were included. Follow-up results were available for 589 of the 636 women included in this study. All patients were interviewed, their medical history was noted, and at least one uncontaminated urine culture was collected at the moment of study entry. RESULTS: Of the 589 women, 115 (20%) developed a symptomatic UTI, 96 (83%) of whom were prescribed antimicrobial therapy A total of 34 women (14%) with type 1 diabetes developed a UTI. The most important risk factor for these women was sexual intercourse during the week before entry into the study (44% without vs. 53% with sexual intercourse, relative risk [RR] = 3.0, P = 0.01). A total of 81 (23%) women with type 2 diabetes developed a UTI. The most important risk factor for these women was the presence of asymptomatic bacteriuria (ASB) at baseline (25% without vs. 42% with ASB, RR = 1.65, P = 0.04). CONCLUSIONS: Risk factors for developing a UTI are the presence of ASB for women with type 2 diabetes and sexual intercourse during the week before entry into the study for women with type 1 diabetes.

Asymptomatic bacteriuria may be considered a complication in women with diabetes. Diabetes Mellitus Women Asymptomatic Bacteriuria Utrecht Study Group.

OBJECTIVE: To study the prevalence of and risk factors for asymptomatic bacteriuria (ASB) in women with and without diabetes. RESEARCH DESIGN AND METHODS: A total of 636 nonpregnant women with diabetes (type 1 and type 2) who were 18-75 years of age and had no abnormalities of the urinary tract, and 153 women without diabetes who were visiting the eye and trauma outpatient clinic (control subjects) were included. We defined ASB as the presence of at least 10(5) colony-forming units/ml of 1 or 2 bacterial species in a culture of clean-voided midstream urine from an individual without symptoms of a urinary tract infection (UTI). RESULTS: The prevalence of ASB was 26% in the diabetic women and 6% in the control subjects (P < 0.001). The prevalence of ASB in women with type 1 diabetes was 21%. Risk factors for ASB in type 1 diabetic women included a longer duration of diabetes, peripheral neuropathy, and macroalbuminuria. The prevalence of ASB was 29% in women with type 2 diabetes. Risk factors for ASB in type 2 diabetic women included age, macroalbuminuria, a lower BMI, and a UTI during the previous year. No association was evident between current HbA1c level and the presence of ASB. CONCLUSIONS: The prevalence of ASB is increased in women with diabetes and might be added to the list of diabetic complications in these women.

A man with a mysterious hypogammaglobulinaemia and skin rash.

We have observed a 26-year-old diabetic male who had been treated with carbamazepine because of seizures. After two months of treatment, he developed a severe illness with skin rash, fever, hepatomegaly and hypogammaglobulinaemia. Since hypogammaglobulinaemia is a rare side effect of carbamazepine treatment, a stop order was given for carbamazepine. The abnormalities (skin, fever, hypogammaglobulinaemia) remained until it appeared that the patient had secretly continued taking the drug. When drug administration was stopped the skin abnormalities improved and serum immunoglobulin levels became normal. The etiology of this transient carbamazepine-induced hypogammaglobulinaemia is unknown.

[Diabetes mellitus in connection with a hereditary disease]. / Diabetes mellitus in samenhang met een erfelijke aandoening.

Diabetes mellitus is usually subdivided into type I (insulin-dependent) and type II (relative insulin shortage and reduced sensitivity to insulin). Diabetes may also be related to pregnancy, malnutrition, pancreatic disease, pharmaceuticals, endocrine diseases and hereditary disorders. The hereditary diseases which may be associated with diabetes mellitus or impaired glucose tolerance can be subdivided into syndromes (such as maternally inherited diabetes and deafness, Down, Turner and Klinefelter syndrome), metabolic diseases (like cystic fibrosis and haemochromatosis) and endocrine diseases (like polyglandular autoimmune insufficiency syndrome and familial phaeochromocytoma). Although diabetes mellitus as part of a hereditary disorder is infrequent, the possibility should be kept in mind with a view to a correct diagnosis. In patients with diabetes mellitus a hereditary disorder may be involved, while patients with a hereditary disorder run a higher risk of developing diabetes mellitus.

Skin vasomotor reflexes during inspiratory gasp: standardization by spirometric control does not improve reproducibility.

Arteriovenous anastomoses (AVA) in skin microcirculation are mediated by the sympathetic stimuli. The inspiratory gasp test (IG test) triggers the sympathetic nervous system, resulting in a decrease in AVA skin blood flow, as measured by laser Doppler fluxmetry (LDF). We studied the reproducibility of the IG test under carefully standardized respiratory conditions. In each of 19 healthy (young) volunteers with a mean skin temperature during the experiment above 28 degrees C 13 IG tests were performed, either under spirometric control or uncontrolled and by using a negative pressure transducer. Starting the IG test end-inspiratory results in the most pronounced absolute LDF decrease [140 PU (70-490)], median (minimum-maximum) as compared to starting end-expiratory [100 PU (40-260)] and during inspiration [110 PU (50-350)], respectively, p < 0.001 and p < 0.001. Inspiration as fast as possible results in a larger absolute LDF decrease [150 PU (40-450)], compared to inspiration in 5 s [120 PU (60-340); p < 0.02] and in 10 s [130 PU (40-350); p < 0.05]. Continuously sucking negative mouth pressure results in a larger LDF decrease [140 PU (30-420)] in comparison with taking one deep breath and holding it for 10 s [110 PU (30-270); p < 0.01]. However, standardization of the IG test did not improve its reproducibility.

Skin microcirculation of the foot in diabetic neuropathy.

1. In the feet of patients with diabetic neuropathy, total skin blood flow is increased due to an increased shunt flow. The question is, does this increased anastomotic shunt flow lead to either under- or overperfused nutritive capillaries. 2. To solve this question, skin microcirculation tests of the left big toe were performed in 20 healthy control subjects and in 40 insulin-dependent diabetic patients without macroangiopathy, 20 without and 20 with neuropathy. Skin temperature measurements and laser Doppler fluxmetry were performed to record mainly shunt flow and capillaroscopy to study nailfold capillary blood flow. 3. The insulin-dependent diabetic patients with neuropathy had a higher baseline skin temperature (mean +/- SEM; 30.0 +/- 0.6 degrees C) and laser Doppler fluxmetry [26.2 +/- 2.2 perfusion units (pu)] than patients without neuropathy (27.2 +/- 0.8 degrees C, P < 0.01; 16.1 +/- 2.0 pu, P < 0.01) and healthy control subjects (27.9 +/- 0.7 degrees C, P < 0.05; 18.6 +/- 2.8 pu, P < 0.05). Sympathetic stimulation (inspiratory gasp) resulted in a smaller laser Doppler fluxmetry decrease in the neuropathic patients (31.4 +/- 4.6%) compared with non-neuropathic patients (48.2 +/- 5.1%, P < 0.05) and control subjects (49.0 +/- 3.8%, P < 0.05), while no difference between the three groups was seen in the laser Doppler fluxmetry decrease during a postural vasoconstriction test. The number of visible capillaries was highest in the neuropathic patients (10.2 +/- 0.6/0.5 mm2), when compared with non-neuropathic patients (8.7 +/- 1.2/0.5 mm2, P < 0.05) and control subjects (8.3 +/- 0.3/0.5 mm2, P < 0.001). Capillary blood-cell velocity was significantly higher in the neuropathic patients (0.32 +/- 0.05 mm/s) compared with non-neuropathic patients (0.23 +/- 0.03 mm/s, P < 0.05) and control subjects (0.23 +/- 0.02 mm/s, P < 0.01). 4. We conclude that there is an overperfused nutritive capillary circulation in the feet of patients with diabetic neuropathy. This is in contradiction to the capillary steal phenomenon and favours the hyperdynamic hypothesis to explain the decreased healing potential in diabetic neuropathic foot ulceration.

Microcirculation in the footsole as a function of mechanical pressure.

OBJECTIVE: In this study an experimental set-up for measuring skin microvascular responses of the footsole to changes in externally applied pressure was analysed. DESIGN: A clinical study. Skin microvascular blood flow was measured in healthy volunteers, during and after external mechanical pressure of different magnitudes. BACKGROUND: During standing and walking the footsole is commonly exposed to high static and dynamic mechanical pressure, resulting in changes in the microcirculation of the footsole. In diabetic patients a disturbed interaction between externally applied pressure and skin microvascular response seems to be involved in the development of a foot ulcer. METHODS: Eleven volunteers participated in the study. Static loads were applied to the heel part of the footsole with the person in a supine position. Contact pressure and skin blood flux, based on the laser Doppler technique, were simultaneously monitored. The pressure used was varied in five discrete steps between 10 and 160 kPa and applied during a period of 5 min each. The microcirculation was measured during as well as after pressure loading. RESULTS: Pressures of 40 kPa and higher do stop the blood flow in the skin microcirculation. Releasing the applied pressure resulted in a hyperaemic response. This response appears to increase in amplitude at increasing pressures up to 800% of the baseline laser Doppler fluxmetry level. Beyond a pressure level of 80 kPa the hyperaemic response seems not to be influenced by the pressure level. The time needed to achieve the maximal laser Doppler fluxmetry level decreased when the pressure was raised from 10 to 80 kPa, but increased again when higher pressures were applied (P = 0.051). An intraindividual variation of 11-50% was observed for the parameters describing the blood flux before, during, and after pressure application. CONCLUSION: Simultaneously measuring changes in contact pressure and laser Doppler flux of the footsole is a useful method to study the interaction of external mechanical pressure and skin microvascular reactions. Pressures above 40 kPa stop skin microvascular blood flow. Releasing the applied pressure results in a hyperaemic response, which increases when the applied pressure increases from 40 to 80 kPa. Higher pressures do not influence the amplitude in skin microvascular response, but result in a longer delay to maximal hyperaemia.

Evaluation of two sympathetic cutaneous vasomotor reflexes using laser Doppler fluxmetry.

Disturbances in sympathetic cutaneous vasomotor reflexes may be of pathogenetic importance in several microvascular problems. Laser Doppler fluxmetry (LDF) enables one to study the influence of sympathetic reflexes on skin blood flow. A matter of concern is the high variability of skin blood flow and its reactivity to sympathetic reflex test resulting in a poor reproducibility. In this study we evaluated two sympathetic stimulation tests, distant cooling and inspiratory gasp, and their influence on LDF-measured skin blood flow of the pulp of the big toe in 63 healthy volunteers. No age or sex dependency of the LDF test results was found. Absolute and relative LDF decrease during distant cooling was highly variable between the subjects (LDF decrease, mean +/-SD: 0.7 +/- 5.3%) compared to an LDF decrease of 46.5 +/- 3.1% during an inspiratory gasp test. The reproducibility, however, was better for the distant cooling test [coefficient of variation (CV): distant cooling: 5.8%, inspiratory gasp test: 35.4%]. With the use of a thermostatically controlled LDF probe holder fixed at a temperature of 36 degrees C, the short-term reproducibility of the two sympathetic vasomotor tests did not improve, probably because of a steady increase in baseline skin blood flow during the test. Surprisingly long-term variability of the percentage LDF decrease during the inspiratory gasp test, performed with the heated LDF probe, was lower compared to the short-term variability (CV 19.2 vs. 39.0%, p < 0.05). In conclusion to study sympathetic skin vasomotor reflexes with LDF, vasoconstriction during the inspiratory gasp test was more uniform compared to the distant cooling test, although the latter was more reproducible. Measuring skin blood flow reactivity with a heated LDF probe (36 degrees C) did not improve reproducibility.

The influence of ulnar nerve blockade on skin microvascular blood flow.

Microvascular research is seriously hampered by the great temporal and spatial variability of the measured skin blood flow and variation in sympathetic vasomotor reflexes within and between persons. Therefore skin vasomotor reflexes were studied before and after ulnar nerve blockade within the same person, resulting in a temporal complete denervation of the fifth finger and partial denervation of the fourth finger. Skin temperature and laser Doppler flux (LDF) were registrated to measure predominantly arteriovenous shuntflow. Measurements were performed on the palmar tip of the second and fifth finger in nine healthy volunteers, at baseline, and during a sympathetic reflex test (i.e. inspiratory gasp) and postural response test. Beat-to-beat digital blood pressure was recorded from the third and fourth finger by a Finapres device. Baseline capillary blood cell velocity (CBV) was measured at the nailfold of the second and the fifth finger. After ulnar blockade baseline skin temperature, LDF and CBV increased significantly, with respectively (mean +/- SE) 3.2 +/- 0.9 degrees C, 20.9 +/- 5.9 relative perfusion units and 0.79 +/- 0.40 mm-1 s. The percentage LDF decrease of the fifth finger during inspiratory gasp was 48.2 +/- 5.3% before and 3.1 +/- 0.9% after blockade. The postural response test showed a decrease in LDF of the fifth finger with no significant difference before and after blockade, respectively 12.3 +/- 14.7% and 8.0 +/- 2.7%, while no difference was found in the increase in digital blood pressure in the denervated fourth finger compared to both the same finger before blockade and to the third non-blocked finger.(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic dysfunction in Parkinson's disease, tested with a computerized method using a Finapres device.

An automated program using a Finapres device and a personal computer, using a battery of five cardiovascular reflex tests has been developed. This has been used to study cardiovascular autonomic dysfunction in 23 ambulant patients with Parkinson's disease, without disabling fluctuations, and 23 age-matched healthy controls, as a screening method to detect autonomic dysfunction. In one patient only a Finapres signal of insufficient quality due to the tremor excluded subsequent analysis. Heart rate response to forced breathing was abnormal (below the fifth percentile of 124 normals) in six (26.1%) of parkinsonian patients and in one (4.3%) healthy age- and sex-matched control, to standing up four (17.4%) versus none, and to the Valsalva manoeuvre seven (30.4%) versus two (8.7%) respectively. The blood pressure response to standing up was abnormal in two (8.7%) parkinsonian patients and in none of the controls, while the response to sustained handgrip was abnormal in five (21.7%) patients versus one (4.3%) control. Autonomic dysfunction is commonly defined as an abnormal score on two or more of the five tests. Using this arbitrary definition, five patients with Parkinson's disease (= 23%) had cardiovascular autonomic dysfunction, and none of the controls were abnormal.