The effects of antidiabetic agents on heart failure.

In the Netherlands, approximately 250,000 people are living with heart failure. About one-third of them have comorbid diabetes mellitus type 2. Until recently, the effects of antidiabetic agents on heart failure were largely unknown. This changed after an observed increased risk of heart failure and ischaemic heart disease associated with thiazolidinediones that prompted the requirement for cardiovascular outcome trials for new glucose-lowering drugs. In the past decade, three new classes of antidiabetic agents have become available (i.e. dipeptidyl peptidase­4 inhibitors, glucagon-like peptide­1 receptor agonists and sodium-glucose cotransporter­2 (SGLT2) inhibitors). Although the first two classes demonstrated no beneficial effects on heart failure compared to placebo in patients with diabetes mellitus type 2, SGLT2 inhibitors significantly and consistently lowered the risk of incident and worsening heart failure. Two recent trials indicated that these favourable effects were also present in non-diabetic patients with heart failure with reduced ejection fraction, resulting in significantly lower risks of hospitalisation for heart failure and presumably also cardiovascular and all-cause mortality. SGLT2 inhibitors have been shown to be benefit on top of recommended heart failure therapy including sacubitril/valsartan and may also prove beneficial for heart failure with preserved ejection fraction. In this review, we discuss the effects of antidiabetic agents on heart failure.

Integrated remotely tunable optical delay line for millimeter-wave beam steering fabricated in an InP generic foundry.

A compact and fabrication-tolerant integrated remotely tunable optical delay line is proposed for millimeter-wave beam steering and is fabricated in an InP generic foundry. The proposed delay line is based on a spectrally cyclic-arrayed waveguide grating feedback loop. Its major features include the tolerant architecture with reduced chip size, and bi-directional operation with simplified remote tuning. Moreover, its cyclic feature guarantees further cascaded operations either for 2D radio beam steering or for high-resolution delay generation. The experimental results show less than 6.5-dB insertion loss of the integrated delay line. Five different delays from 0 to 71.6 ps are generated with less than 0.67-ps delay errors.

Cyclic additional optical true time delay for microwave beam steering with spectral filtering.

Optical true time delay (OTTD) is an attractive way to realize microwave beam steering (MBS) due to its inherent features of broadband, low-loss, and compactness. In this Letter, we propose a novel OTTD approach named cyclic additional optical true time delay (CAO-TTD). It applies additional integer delays of the microwave carrier frequency to achieve spectral filtering but without disturbing the spatial filtering (beam steering). Based on such concept, a broadband MBS scheme for high-capacity wireless communication is proposed, which allows the tuning of both spectral filtering and spatial filtering. The experimental results match well with the theoretical analysis.

Phase modulation parallel optical delay detector for microwave angle-of-arrival measurement with accuracy monitored.

A novel phase modulation parallel optical delay detector is proposed for microwave angle-of-arrival measurement with accuracy monitored by using only one dual-electrode Mach-Zehnder modulator. A theoretical model is built up to analyze the proposed system including measurement accuracy monitoring. The spatial delay measurement is translated into the phase shift between two replicas of a microwave signal. Thanks to the accuracy monitoring, the phase shifts from 5° to 165° are measured with less than 3.1° measurement error.

Synchronized signaling delivery for broadband 60 GHz in-building optical wireless network based on digital frequency division multiplexing and digital Nyquist shaping.

A simple and low-cost synchronized signaling delivery scheme has been proposed for a 60 GHz in-building optical wireless network with 12.7Gbps throughput based on digital frequency division multiplexing and digital Nyquist shaping.

Cost optimization of optical in-building networks.

Optical fiber-based in-building network solutions can outperform in the near future copper- and radio-based solutions both regarding performance and costs. POF solutions are maturing, and can already today be cheaper than Cat-5e solutions when ducts are shared with electricity power cabling. We compare the CapEx and OpEx of in-building networks for fiber and Cat-5E solutions. For residential homes, our analysis shows that total network costs during economic lifetime are lowest for a point-to-point duplex POF topology.

Record high-speed short-range transmission over 1 mm core diameter POF employing DMT modulation.

We report multigigabit/second transmission capacity in 1 mm core diameter graded index plastic optical fiber (POF) exploiting off-the-shelf low-cost components and discrete multitone (DMT) modulation. Transmission capacities of 10.1 Gbits/s x 15 m and 12.7 Gbits/s x 3 m are achieved for average bit-error rates less than 10(-3).

Sustained changes in lipid profile and macrophage migration inhibitory factor levels after anti-tumour necrosis factor therapy in rheumatoid arthritis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) has recently emerged as an important cytokine possibly linking rheumatoid arthritis (RA) and atherogenesis. Because atherogenesis is accelerated in RA this study was conducted to investigate whether anti-tumour necrosis factor (TNF) therapy could lead to sustained downregulation of systemic MIF levels and improvement in lipid profiles. METHODS: Fifty RA patients with active disease (disease activity score in 28 joints (DAS28) >or=3.2), who started adalimumab therapy at 40 mg every other week, were included. At baseline, weeks 16 and 52 serum levels of MIF and lipids were assessed. In addition, the DAS28 and serum C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) were determined. RESULTS: After 16 weeks of adalimumab therapy, both DAS28 and MIF levels were significantly decreased (p<0.001 and p = 0.020, respectively). This was sustained up to week 52 (p<0.001 and p = 0.012, respectively). CRP levels and ESR were significantly reduced after 16 and 52 weeks of adalimumab therapy (p<0.001). High-density lipoprotein cholesterol levels increased at week 16 (p<0.001), but returned to baseline at week 52. Apolipoprotein (apo) A-I levels increased at week 16 (p<0.001) and remained stable (p = 0.005). This resulted in an improved apo B/A-I ratio. CONCLUSIONS: The results underline the sustained downregulation of MIF as a potential new mechanism by which anti-TNF therapy might reduce vascular inflammation, and as such perhaps cardiovascular morbidity in RA patients. This hypothesis is supported by an improved apo B/A-I ratio as well as reduced CRP levels in these patients.

Soft tissue infection after photoselective vaporization of the prostate: a life-threating complication.

Bladder outlet obstruction is a common aetiology of lower urinary tract symptoms in adult men and several treatment options are available. We report on a case of a 73-year-old man with a complicated soft tissue infection due to an urinoma after laser prostatectomy. He was treated by several surgical interventions and long-term antibiotic therapy.

A comparison of human jaw muscle cross-sectional area and volume in long- and short-face subjects, using MRI.

OBJECTIVE: In humans, the vertical craniofacial dimensions vary significantly with the size of the jaw muscles, which are regarded as important controlling factors of craniofacial growth. The functional relevance of the maximum cross-sectional area (CSA), indicating maximum muscle strength, is questionable since peak forces are generated only a fraction of the day. Alternatively, muscle volume (indicating the generated loads) might be a more meaningful functional variable. Therefore, the aim of this study was to investigate if jaw muscle volume is stronger related with vertical craniofacial dimensions than with jaw muscle CSA. DESIGN: Thirty-one adult healthy subjects with varying vertical craniofacial morphology participated in this study. Axial magnetic resonance imaging (MRI) scans were used for segmentation of the masseter (Mas) and medial pterygoid muscles (MPM). This enabled measurements of the muscle CSA and volume. Cephalometric analysis was performed using lateral radiographs. With factor analysis, the number of cephalometric variables was reduced into two factors that represented the anterior face height and the posterior face height (PFH), respectively. Subsequently, mutual relationships between these factors and muscular variables were assessed using a multiple regression analysis. RESULTS: It was found that vertical craniofacial dimensions were significantly better (up to 12%) related with muscle volume rather than with CSA. Furthermore, it was shown that especially the PFH factor was significantly correlated with the Mas and MPM. CONCLUSION: Vertical craniofacial dimensions are stronger related with jaw muscle volume than with CSA. Tentatively, it can be assumed that the generated muscle loads, rather than maximum forces, influence vertical craniofacial growth.

Diet-induced hyperlipoproteinemia and atherosclerosis in apolipoprotein E3-Leiden transgenic mice.

Apolipoprotein E3-Leiden (APOE*3-Leiden) transgenic mice have been used to study the effect of different cholesterol-containing diets on the remnant lipoprotein levels and composition and on the possible concurrent development of atherosclerotic plaques. On high fat/cholesterol (HFC) diet, the high expressing lines 2 and 181 developed severe hypercholesterolemia (up to 40 and 60 mmol/liter, respectively), whereas triglyceride levels remained almost normal when compared with regular mouse diet. The addition of cholate increased the hypercholesterolemic effect of this diet. In lines 2 and 181, serum levels of apo E3-Leiden also increased dramatically upon cholesterol feeding (up to 107 and 300 mg/dl, respectively). In these high expressing APOE*3-Leiden transgenic mice, the increase in both serum cholesterol and apo E3-Leiden occurred mainly in the VLDL/LDL-sized fractions, whereas a considerable increase in large, apo E-rich HDL particles also occurred. In contrast to the high expressing lines, the low expressing line 195 reacted only mildly upon HFC diet. On HFC diets, the high expresser APOE*3-Leiden mice developed atherosclerotic lesions in the aortic arch, the descending aorta, and the carotid arteries, varying from fatty streaks containing foam cells to severe atherosclerotic plaques containing cholesterol crystals, fibrosis, and necrotic calcified tissue. Quantitative evaluation revealed that the atherogenesis is positively correlated with the serum level of cholesterol-rich VLDL/LDL particles. In conclusion, with APOE*3-Leiden transgenic mice, factors can be studied that influence the metabolism of remnant VLDL and the development of atherosclerosis.

Modulation of very low density lipoprotein production and clearance contributes to age- and gender- dependent hyperlipoproteinemia in apolipoprotein E3-Leiden transgenic mice.

Apolipoprotein E3-Leiden (APOE*3-Leiden) transgenic mice have been studied to identify factors modulating chylomicron and VLDL remnant lipoprotein metabolism. Transient elevated levels of VLDL/LDL-sized lipoproteins occurred in these mice with maximal levels during the period of rapid growth (optimum at 45 d of age). After about 100 d of age, serum cholesterol and triglyceride levels stabilized to slightly elevated levels as compared to control mice. The expression of the APOE*3-Leiden transgene was not age-dependent. In young mice the in vivo hepatic production of VLDL-triglycerides was 50% increased as compared to older mice. This is sustained by in vivo VLDL-apo B turnover studies showing increased (75%) VLDL-apo B secretion rates in young mice, whereas the VLDL-apo B clearance rate appeared not to be age dependent. On a high fat/cholesterol diet, females displayed significantly higher cholesterol levels than males (10 versus 7.0 mmol/liter, respectively). Serum levels of VLDL/LDL sized lipoproteins increased upon administration of estrogens, whereas administration of testosterone gave the opposite result. As compared to male mice, in female mice the hepatic VLDL-triglyceride production rate was significantly elevated. Injection of estrogen in males also resulted in increased VLDL-triglyceride production, although not statistically significant. In vivo VLDL-apo B turnover experiments showed that the VLDL secretion rate tended to be higher in females. Although, the fractional catabolic rate of VLDL-apo B is not different between males and females, administration of estrogens in males resulted in a decreased clearance rate of VLDL, whereas administration of testosterone in females resulted in an increased clearance rate of VLDL. The latter presumably due to an inhibiting effect of testosterone on the expression of the APOE*3-Leiden transgene. We conclude that hyperlipidemia in APOE*3-Leiden transgenic mice is strongly affected by age via its effect on hepatic VLDL production rate, whereas gender influences hyperlipidemia by modulating both hepatic VLDL production and clearance rate.

Introduction of an in-house PCR for routine identification of M. tuberculosis in a low-income country.

SETTING: National Tuberculosis (TB) Treatment Centre, Makerere University Medical School and Joint Clinical Research Centre, Kampala, Uganda. OBJECTIVE: To evaluate the introduction of a polymerase chain reaction (PCR) based assay for identification of the Mycobacterium tuberculosis complex (MTC) into routine practice. DESIGN: Routine diagnostic specimens were processed and inoculated into Bactec 12B vials and monitored daily. At a growth index (GI) > or =10, 0.5 ml of the 12B broth was removed and assayed with PCR. The same 12B vial was analyzed using the Bactec NAP method at GI > or =500. Vials at various levels of GI were included. Recurrent cost and time required to perform PCR and NAP were compared. RESULTS: Initially, 71 specimens were analyzed; of these, 68 were NAP-positive while 69 were PCR-positive for MTC. PCR resulted in a 75% reduction in cost for a single test compared with Bactec NAP. PCR has been successfully incorporated into routine practice, and 432 samples have been analyzed. In addition, isolates from solid media were also well identified by PCR. With PCR, more samples can be analyzed at a time, it is faster and is less labor intensive. CONCLUSION: PCR is a reliable and cheaper alternative for the identification of MTC.

Acyl-CoA:cholesterol acyltransferase inhibitor avasimibe reduces atherosclerosis in addition to its cholesterol-lowering effect in ApoE*3-Leiden mice.

BACKGROUND: The present study investigated whether the ACAT inhibitor avasimibe can reduce atherogenesis independently of its cholesterol-lowering effect in ApoE*3-Leiden mice. METHODS AND RESULTS: Two groups of 15 female ApoE*3-Leiden mice were put on a high-cholesterol (HC) diet; 1 group received 0.01% (wt/wt) avasimibe mixed into the diet. The HC diet resulted in a plasma cholesterol concentration of 18.7+/-2.6 mmol/L. Addition of avasimibe lowered plasma cholesterol by 56% to 8.1+/-1.2 mmol/L, caused mainly by a reduction of and composition change in VLDL and LDL. In a separate low-cholesterol (LC) control group, plasma cholesterol was titrated to a level comparable to that of the avasimibe group (10.3+/-1.4 mmol/L) by lowering the amount of dietary cholesterol. After 22 weeks of intervention, atherosclerosis in the aortic root area was quantified. Treatment with avasimibe resulted in a 92% reduction of lesion area compared with the HC control group. Compared with the LC control, avasimibe reduced lesion area by 78%. After correction for the slight difference in cholesterol exposure between the LC control and avasimibe groups, the effect of avasimibe on lesion area (73% reduction) remained highly significant. In addition, monocyte adherence to the endothelium, free cholesterol accumulation, and lesion severity were reduced by avasimibe treatment. CONCLUSIONS: Treatment with avasimibe potently lowered plasma cholesterol levels in ApoE*3-Leiden mice and considerably reduced atherosclerotic lesion area in addition to its cholesterol-lowering effect. Because monocyte adherence to the endothelium and lesion severity were also reduced by avasimibe, treatment with avasimibe may result in higher plaque stability and therefore a reduced risk of plaque rupture.

Dietary plant stanol esters reduce VLDL cholesterol secretion and bile saturation in apolipoprotein E*3-Leiden transgenic mice.

Dietary plant stanols lower serum cholesterol levels in humans and in hyperlipidemic rodents, mainly by inhibition of the intestinal cholesterol absorption. We used female apolipoprotein E*3-Leiden transgenic mice to investigate the consequences of this effect on serum lipid levels and hepatic lipid metabolism. Five groups of 6 or 7 mice received for 9 weeks a diet containing 0.25% cholesterol and 0.0%, 0.25%, 0.5%, 0.75%, or 1.0% (wt/wt) plant stanols (sitostanol 88% [wt/wt], campestanol 10% [wt/wt]) esterified to fatty acids. Compared with the control diet, plant stanol ester treatment dose-dependently reduced serum cholesterol levels by 10% to 33% (P<0.05), mainly in very low density lipoproteins (VLDLs), intermediate density lipoproteins, and low density lipoproteins. Furthermore, 1.0% of the dietary plant stanols significantly decreased the liver contents of cholesteryl esters (-62%), free cholesterol (-31%), and triglycerides (-38%) but did not change the hepatic VLDL-triglyceride and VLDL-apolipoprotein B production rates. However, plant stanol ester feeding significantly decreased the amounts of cholesteryl esters and free cholesterol incorporated in nascent VLDLs by 72% and 30%, respectively, resulting in a net 2-fold decreased VLDL cholesterol output. Liver mRNA levels of low density lipoprotein receptors, 3-hydroxy-3-methylglutaryl coenzyme A synthase, cholesterol 7alpha-hydroxylase, and sterol 27-hydroxylase were not changed by plant stanol ester feeding. Nevertheless, the serum lathosterol-to-cholesterol ratio was significantly increased by 23%, indicating that dietary plant stanol esters increased whole-body cholesterol synthesis. Plant stanol esters also significantly decreased the cholesterol saturation index in bile by 55%. In conclusion, in apolipoprotein E*3-Leiden transgenic mice, plant stanol ester feeding dose-dependently lowered serum cholesterol levels as a result of a reduced secretion of VLDL cholesterol. This was caused by a decreased hepatic cholesterol content that also resulted in a lowered biliary cholesterol output, indicative of a reduced lithogenicity of bile in these mice.

The combined influence of the stimulus frequency of the vagal nerves and the atrial stimulus interval on the atrioventricular conduction time.

The way in which the A-V node adapts its conduction time to stepwise alterations of atrial stimulation rates was studied under different conditions of vagal nerve activity (open chest, anaesthetised rabbit). Increase of stimulation rate induced oscillatory adaptation to a longer conduction time. Decrease caused shorter conduction times without oscillation. The time constant did not differ. Oscillation amplitude and time constants were markedly influenced by vagal activity. The observed phenomena can be explained on the basis of a time and voltage dependent K+ conductance.

A note on the phase-plane technique representation of cardiac action potentials.

In this study the applicability of the phase-plane technique for interpreting membrane properties of cardiac cells in a two-dimensional structure is discussed. The conditions are derived for which the effects of two-dimensionality of a sheet can be neglected and for which the one-dimensional phase-plane technique for estimation of the membrane current densities remains valid. The usual phase-plane technique appears to be applicable to nodal and atrial tissue.

Melioidosis and renal failure in a Dutch man after a trip to Gambia.

Melioidosis is due to Burkholderia pseudomallei and is known to be endemic in South-East Asia, while epidemiology of disease in Sub-Saharan Africa is still unclear. Prompt recognition of infection is crucial for adequate antibiotic treatment. Infection can lead to visceral abcesses and awareness of this complication is important for proper management.

Food choice in hyperthyroidism: potential influence of the autonomic nervous system and brain serotonin precursor availability.

We explored energy and macronutrient intake in patients with Graves' hyperthyroidism. We specifically hypothesized that hyperthyroidism is associated with increased appetite for carbohydrates, because of enhanced sympathetic tone and diminished serotonin mediated neurotransmission in the brain. To test this hypothesis, we measured food intake by dietary history and food selected for lunch in the laboratory in 14 patients with Graves' hyperthyroidism. Twenty-four-hour catecholamine excretion was used as a measure of activity of the sympathetic nervous system (SNS) and the plasma [Trp]/[NAA] ratio was measured to estimate (rate limiting) precursor availability for brain 5-hydroxytryptamine synthesis. All measurements were repeated after the subjects had been treated to establish euthyroidism. In addition, the effects of nonselective beta-adrenoceptor blockade upon these parameters were studied to evaluate the influence of beta-adrenergic hyperactivity on food intake. Hyperthyroidism was marked by increased SNS activity and reduced plasma [Trp]/[NAA] ratio. Accordingly, energy intake was considerably and significantly increased in hyper vs. euthyroidism, which was fully attributable to enhanced carbohydrate consumption, as protein and fat intake were not affected. These results suggest that hyperthyroidism alters the neurophysiology of food intake regulation. Increased SNS activity and reduced Trp precursor availability for 5-hydroxytryptamine synthesis in the brain may drive the marked hyperphagia and craving for carbohydrates that appears to characterize hyperthyroid patients. Because propranolol did not affect food intake in hyperthyroidism, the potential effect of catecholamines on food intake might be mediated by alpha-adrenoceptors.

Triglyceride-rich lipoproteins of subjects heterozygous for apolipoprotein E2(Lys146-->Gln) are inefficiently converted to cholesterol-rich lipoproteins.

The APOE*2(Lys146-->Gln) allele behaves like a dominant trait in the expression of familial dysbetalipoproteinemia (FD) (Smit et al., J. Lipid Res. 1990; 31: 45-53). FD patients carrying the APOE*2(Lys146-->Gln) allele exhibit less elevated cholesterol to triglyceride ratios in the d < 1.019 g/ml lipoprotein density fraction as compared to classical FD patients displaying homozygosity for the APOE*2(Arg158-->Cys) allele (0.8 vs. 1.4). Upon treatment of complete serum with lipoprotein lipase (LPL), the mean cholesterol to triglyceride molar ratio of the d < 1.019 g/ml lipoprotein fraction in these FD patients increased only marginally (from 0.8 to 1.1), as compared with that of classical FD subjects (from 1.4 to 2.6) and non-FD control subjects (from 0.7 to 1.5). In order to obtain further evidence for an inefficient lipolysis of the d < 1.019 g/ml lipoprotein fraction in APOE*2(Lys146-->Gln) carriers, possibly in combination with a less efficient cholesteryl ester transfer protein (CETP) activity, blood samples of APOE*2(Lys146-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys149-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys146-->Gln) FD patients, the increase in plasma cholesterol was mainly confined to the very low density lipoprotein (VLDL) fraction, whereas in classical FD patients, the levels of cholesterol in the intermediate density lipoprotein (IDL) fraction was also dramatically increased (ratios of VLDL to IDL cholesterol are 4.7 and 2.6, respectively). Family analyses of the APOE*2(Lys146-->Gln) FD subjects showed that the apo E to apo B ratio in the d < 1.019 g/ml lipoprotein fraction of allele carriers is 3.5 times as high as that found in non-carriers (2.8 vs. 0.8, by wt.). Also, in the APOE*2(Lys146-->Gln) allele carrying family members, the ratio of cholesterol to triglyceride of the d < 1.019 g/ml lipoprotein fraction is less markedly elevated upon addition of LPL when compared to that in non-carrying controls (from 1.1 to 1.8 vs 0.7 to 1.6). The efficiency of the d < 1.019 g/ml lipoprotein fraction of APOE*2(Lys146-->Gln) FD patients to compete with low density lipoprotein (LDL) for binding to the LDL receptor is intermediate to that of controls and classical APOE*2(Arg158-->Cys) homozygous FD patients. These findings suggest that in APOE*2(Lys146-->Gln) allele carriers, the conversion of VLDL into IDL is impaired due to an inefficient lipolysis, possibly in combination with a retarded CETP activity.(ABSTRACT TRUNCATED AT 250 WORDS)