Selection for health professions education leads to increased inequality of opportunity and decreased student diversity in The Netherlands, but lottery is no solution: A retrospective multi-cohort study.

BACKGROUND: Concerns exist about the role of selection in the lack of diversity in health professions education (HPE). In The Netherlands, the gradual transition from weighted lottery to selection allowed for investigating the variables associated with HPE admission, and whether the representativeness of HPE students has changed. METHOD: We designed a retrospective multi-cohort study using Statistics Netherlands microdata of all 16-year-olds on 1 October 2008, 2012, and 2015 (age cohorts, N > 600,000) and investigated whether they were eligible students for HPE programs (n > 62,000), had applied (n > 14,000), and were HPE students at age 19 (n > 7500). We used multivariable logistic regression to investigate which background variables were associated with becoming an HPE student. RESULTS: HPE students with ≥1 healthcare professional (HP) parent, ≥1 top-10% income/wealth parent, and women are overrepresented compared to all age cohorts. During hybrid lottery/selection (cohort-2008), applicants with ≥1 top-10% wealth parent and women had higher odds of admission. During 100% selection (cohort-2015) this remained the case. Additionally, applicants with ≥1 HP parent had higher odds, those with a migration background had lower odds. CONCLUSIONS: Odds of admission are increasingly influenced by applicants' backgrounds. Targeted recruitment and equitable admissions procedures are required to increase matriculation of underrepresented students.

Ionic remodeling of sinoatrial node cells by heart failure.

BACKGROUND: In animal models of heart failure (HF), heart rate decreases as the result of an increase in intrinsic cycle length of the sinoatrial node (SAN). In this study, we evaluate the HF-induced remodeling of membrane potentials and currents in SAN cells. METHODS AND RESULTS: SAN cells were isolated from control rabbits and rabbits with volume and pressure overload-induced HF and patch-clamped to measure their electrophysiological properties. HF cells were not hypertrophied (capacitance, mean+/-SEM, 52+/-3 versus 50+/-4 pF in control). HF increased intrinsic cycle length by 15% and decreased diastolic depolarization rate by 30%, whereas other action potential parameters were unaltered. In HF, the hyperpolarization-activated "pacemaker" current (If) and slow component of the delayed rectifier current (IKs) were reduced by 40% and 20%, respectively, without changes in voltage dependence or kinetics. T-type and L-type calcium current, rapid and ultrarapid delayed rectifier current, transient outward currents, and sodium-calcium exchange current were unaltered. CONCLUSIONS: In single SAN cells of rabbits with HF, intrinsic cycle length is increased as the result of a decreased diastolic depolarization rate rather than a change in action potential duration. HF reduced both If and IKs density. Since IKs plays a limited role in pacemaker activity, the HF-induced decrease in heart rate is attributable to remodeling of If.

Reduced swelling-activated Cl(-) current densities in hypertrophied ventricular myocytes of rabbits with heart failure.

OBJECTIVE: Hypertrophied myocytes of failing hearts have prolonged action potential durations. It is unknown how the swelling-activated Cl(-) current (I(Cl,swell)) affects the abnormal AP configuration. METHODS: We studied I(Cl,swell) in ventricular myocytes isolated from failing and age-matched normal rabbit hearts. We applied whole-cell patch-clamp methodology and activated I(Cl,swell) by lowering tonicity of the superfusate. RESULTS: Neither with ruptured-patch nor with amphotericin B perforated-patch, whole-cell clamp we found I(Cl,swell) active under isotonic conditions in either the normal or the hypertrophied failing heart (HFH) myocytes. I(Cl,swell) caused AP shortening and resting membrane potential (V(m)) depolarization in an osmotic gradient-dependent fashion. However, in the HFH myocytes swelling-induced AP changes were significantly smaller, even though the cells underwent the same relative change in planar cell surface area. Voltage-clamp experiments revealed that in HFH myocytes I(Cl,swell) current density was approximately 50% reduced. CONCLUSION: Reduced I(Cl,swell) densities in HFH myocytes cause limited AP shortening and V(m) depolarization upon swelling of the cells.

Fifteen years medical information sciences: the Amsterdam curriculum.

OBJECTIVES: To inform the medical informatics community on the rational, goals, evolution and present contents of the Medical Information Sciences program of the University of Amsterdam and our achievements. METHODS: We elaborate on the history of our program, the philosophy, contents and organizational structure of the present-day curriculum. Besides, we describe the various didactic approaches in the program and the rational for these. Finally, we analyze the contents of our program in respect to the IMIA recommendations for dedicated programs in health and medical informatics. RESULTS AND CONCLUSIONS: Since its foundation in 1987, the program has undergone several major modifications. From a degree program following medical school it developed into a full-fledged, dedicated 4-year program on medical information sciences training high-school graduates for a master degree. The curriculum has been based from its outset within the University of Amsterdam-Faculty of Medicine. This organizational structure leaves ample opportunity for integration of the informatics-oriented components with the medical and health care-oriented components in the program. Student-centered approaches are heavily employed in the program, emphasizing students' critical appraisal and a style of life-long learning. Overall, our program follows the IMIA recommendations with slightly more focus on medicine and health care organization.

Increased sarcolemmal Na(+)/H(+) exchange activity in hypertrophied myocytes from dogs with chronic atrioventricular block.

Dogs with compensated biventricular hypertrophy due to chronic atrioventricular block (cAVB), are more susceptible to develop drug-induced Torsade-de-Pointes arrhythmias and sudden cardiac death. It has been suggested that the increased Na(+) influx in hypertrophied cAVB ventricular myocytes contribute to these lethal arrhythmias. The increased Na(+) influx was not mediated by Na(+) channels, in fact the Na(+) current proved reduced in cAVB myocytes. Here we tested the hypothesis that increased activity of the Na(+)/H(+) exchanger type 1 (NHE-1), commonly observed in hypertrophic hearts, causes the elevated Na(+) influx. Cardiac acid-base transport was studied with a pH-sensitive fluorescent dye in ventricular myocytes isolated from control and hypertrophied cAVB hearts; the H(+) equivalent flux through NHE-1, Na(+)-HCO(-) 3 cotransport (NBC), Cl(-)/OH(-) exchange (CHE), and Cl(-)/HCO(-) 3 exchange (AE) were determined and normalized per liter cell water and corrected for surface-to-volume ratio. In cAVB, sarcolemmal NHE-1 flux was increased by 65 ± 6.3% in the pH i interval 6.3-7.2 and NBC, AE, and CHE fluxes remained unchanged. Accordingly, at steady-state intracellular pH the total sarcolemmal Na(+) influx by NHE-1 + NBC increased from 8.5 ± 1.5 amol/µm(2)/min in normal myocytes to 15 ± 2.4 amol/µm(2)/min in hypertrophied cAVB myocytes. We conclude that compensated cardiac hypertrophy in cAVB dogs is accompanied with an increased sarcolemmal NHE-1 activity. This in conjunction with unchanged activity of the other acid-base transporters will raise the intracellular Na(+) in hypertrophied cAVB myocytes.

Dietary Omega-3 Polyunsaturated Fatty Acids Suppress NHE-1 Upregulation in a Rabbit Model of Volume- and Pressure-Overload.

BACKGROUND: Increased consumption of omega-3 polyunsaturated fatty acids (ω3-PUFAs) from fish oil (FO) may have cardioprotective effects during ischemia/reperfusion, hypertrophy, and heart failure (HF). The cardiac Na(+)/H(+)-exchanger (NHE-1) is a key mediator for these detrimental cardiac conditions. Consequently, chronic NHE-1 inhibition appears to be a promising pharmacological tool for prevention and treatment. Acute application of the FO ω3-PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) inhibit the NHE-1 in isolated cardiomyocytes. We studied the effects of a diet enriched with ω3-PUFAs on the NHE-1 activity in healthy rabbits and in a rabbit model of HF induced by volume- and pressure-overload. METHODS: Rabbits were allocated to four groups. The first two groups consisted of healthy rabbits, which were fed either a diet containing 1.25% (w/w) FO (ω3-PUFAs), or 1.25% high-oleic sunflower oil (ω9-MUFAs) as control. The second two groups were also allocated to either a diet containing ω3-PUFAs or ω9-MUFAs, but underwent volume- and pressure-overload to induce HF. Ventricular myocytes were isolated by enzymatic dissociation and used for intracellular pH (pH(i)) and patch-clamp measurements. NHE-1 activity was measured in HEPES-buffered conditions as recovery rate from acidosis due to ammonium prepulses. RESULTS: In healthy rabbits, NHE-1 activity in ω9-MUFAs and ω3-PUFAs myocytes was not significantly different. Volume- and pressure-overload in rabbits increased the NHE-1 activity in ω9-MUFAs myocytes, but not in ω3-PUFAs myocytes, resulting in a significantly lower NHE-1 activity in myocytes of ω3-PUFA fed HF rabbits. The susceptibility to induced delayed afterdepolarizations (DADs), a cellular mechanism of arrhythmias, was lower in myocytes of HF animals fed ω3-PUFAs compared to myocytes of HF animals fed ω9-MUFAs. In our rabbit HF model, the degree of hypertrophy was similar in the ω3-PUFAs group compared to the ω9-MUFAs group. CONCLUSION: Dietary ω3-PUFAs from FO suppress upregulation of the NHE-1 activity and lower the incidence of DADs in our rabbit model of volume- and pressure-overload.

Development of a test for evaluation of taste perception after tongue reduction.

When performing a tongue reduction a frequently asked question is how operation will influence taste of the patient. Different kinds of taste tests are designed, most of these being non-specific ways to determine taste sensation in which high concentration of taste solutions are used to detect if a person is able to taste. To be able to judge the influence of tongue reduction on taste we wanted to develop a validated test that could be used in early childhood. No specific tasting areas were found. This test can be used to evaluate tongue reduction procedures.

Contribution of NHE-1 to cell length shortening of normal and failing rabbit cardiac myocytes.

At the same intracellular pH (pHi) Na+/H+ exchange (NHE-1) fluxes of ventricular myocytes of hypertrophied failing hearts (HFH) are increased. We assessed how NHE-1 affected cell length shortening. pHi was measured fluorimetrically in resting and twitching (1-3 Hz) normal and HFH rabbit myocytes. In HEPES-buffered solutions, increased NHE-1 fluxes (P=0.001, n=14) made HFH resting pHi 0.2+/-0.03 units more alkaline than control (n=27). In CO2/HCO3--buffered solutions, HFH resting pHi was not different (7.05+/-0.02, n=30). Twitching myocytes of both groups shortened 15-16% less per 0.1 pH unit acidification. In HEPES-buffered solutions, cariporide depressed cell length shortening of normal myocytes (1-3 Hz) by 16+/-5.4% (n=9, P=0.005). In HFH myocytes cariporide restored the positive force-frequency relationship (n=7, P=0.009), by depressing twitch amplitudes at 1 Hz (16+/-11%, P=0.047) but not at 2 and 3 Hz. The depressions were all caused by pHi acidification. In CO2/HCO3- buffered solutions the cariporide-induced acidification was too small to explain the cell length shortening depression of normal (19+/-5.0%, n=11, P=0.006) and HFH myocytes (14+/-4.7%, n=11, P=0.001). When compared to HEPES-buffered solutions, HFH myocytes in CO2/HCO3--buffered solutions shortened 12+/-6.8% better than expected given the 0.16+/-0.02 units more acidic pHi's at which they twitched. We conclude that in CO2/HCO3--buffered solutions NHE-1 improved cell length shortening of unstretched normal and HFH myocytes via a pHi-independent mechanism. Although NHE-1 was increased in HFH myocytes, the magnitude of the pHi-independent effect of NHE-1 inhibition on cell length shortening was similar in both groups.

NHE-1 and NBC during pseudo-ischemia/reperfusion in rabbit ventricular myocytes.

Despite many studies into the pathophysiology of cardiac ischemia-reperfusion injury, a number of key details are as yet undisclosed. These include the timing and magnitude of the changes in both Na(+)/H(+) exchange (NHE-1) and Na(+) -- HCO(3)(-) -cotransport (NBC) transport rates. We fluorimetrically measured H(i)(+) fluxes (J(NHE-1) and J(NBC)) and Na(i)(+) fluxes in single contracting rabbit ventricular myocytes subjected to metabolic inhibition, pseudo-ischemia (i.e. metabolic inhibition and extracellular acidosis of 6.4), and pseudo-reperfusion. Metabolic inhibition and pseudo-ischemia inhibited NHE-1 by 43 +/- 3.1% and 91 +/- 3.6%, and NBC by 66 +/- 5.4% and 100%, respectively. Inhibition was due to both an acidic shift of the pH(i) at which NHE-1 and NBC become quiescent (set-point pH(i)) and a reduction of the steepness of the pH(i) -- H(i)(+) flux profiles. NHE-1 and NBC did not contribute to Na(i)(+) loading during metabolic inhibition (Na(i)(+) 18 +/- 1.7 mM) or pseudo-ischemia (Na(i)(+) 21 +/- 1.7 mM), because pH(i) acidified less than set-point pH(i)'s. Upon pseudo-reperfusion NBC recovered to 54 +/- 7.3% but NHE-1 to 193 +/- 11% of aerobic control flux, and set-point pH(i)'s returned to near neutral values. Metabolic inhibition and reperfusion caused an acid load of 18 +/- 3.2 mM H(+) 94% of which were extruded by the hyperactive NHE-1. At pseudo-reperfusion Na(i)(+) rose sharply to 31 +/- 5.8 mM within 1.5 min and that coincided with hypercontracture. Cariporide not only prevented the Na(i)(+) transient, but also inhibited pH(i) recovery and prevented hypercontracture. Our results are consistent with the view that NHE-1 is active during metabolic inhibition if, like in whole hearts, pH(i) is driven more acidic than NHE-1 set-point pH(i). Furthermore, either an acidic pH(i) or absence of additional Na(i)(+) loading during reperfusion, or both, limit ischemia-reperfusion injury.

Interleukin-4 and -13 promote basolateral secretion of H(+) and cathepsin L by glomerular epithelial cells.

Minimal change nephrosis (MCN) is characterized by massive proteinuria and ultrastructural alterations of glomerular visceral epithelial cells (GVEC). MCN has been associated with elevated production of interleukin (IL)-13 by circulating T lymphocytes and with T helper 2 lymphocyte-dependent conditions. We recently showed that GVEC express IL-4 and IL-13 receptors and that IL-4 and IL-13 increase transcellular ion transport over GVEC monolayers. We therefore hypothesized that IL-13 may directly injure GVEC. Here we demonstrate that IL-4 and IL-13 induce bafilomycin A1-sensitive basolateral proton secretion by cultured GVEC, indicating involvement of vacuolar H(+)-ATPase. The effects of IL-4 and IL-13 were accompanied by redistribution of the small GTPases Rab5b and Rab7, as shown by confocal immunofluorescence studies. Furthermore, Western blot analysis and assays for cysteine proteinase activity revealed basolateral secretion of the lysosomal proteinase procathepsin L by cultured GVEC, stimulated by IL-4 and IL-13. We speculate that IL-4 and IL-13 influence intracellular trafficking of proteins and promote proteolysis at the basolateral surface of GVEC, which may play a pathogenic role in altered glomerular permeability.

Ca(2+)-activated Cl(-) current in rabbit sinoatrial node cells.

The Ca(2+)-activated Cl(-) current (I(Cl(Ca))) has been identified in atrial, Purkinje and ventricular cells, where it plays a substantial role in phase-1 repolarization and delayed after-depolarizations. In sinoatrial (SA) node cells, however, the presence and functional role of I(Cl(Ca)) is unknown. In the present study we address this issue using perforated patch-clamp methodology and computer simulations. Single SA node cells were enzymatically isolated from rabbit hearts. I(Cl(Ca)) was measured, using the perforated patch-clamp technique, as the current sensitive to the anion blocker 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS). Voltage clamp experiments demonstrate the presence of I(Cl(Ca)) in one third of the spontaneously active SA node cells. The current was transient outward with a bell-shaped current-voltage relationship. Adrenoceptor stimulation with 1 microM noradrenaline doubled the I(Cl(Ca)) density. Action potential clamp measurements demonstrate that I(Cl(Ca)) is activate late during the action potential upstroke. Current clamp experiments show, both in the absence and presence of 1 microM noradrenaline, that blockade of I(Cl(Ca)) increases the action potential overshoot and duration, measured at 20 % repolarization. However, intrinsic interbeat interval, upstroke velocity, diastolic depolarization rate and the action potential duration measured at 50 and 90 % repolarization were not affected. Our experimental data are supported by computer simulations, which additionally demonstrate that I(Cl(Ca)) has a limited role in pacemaker synchronization or action potential conduction. In conclusion, I(Cl(Ca)) is present in one third of SA node cells and is activated during the pacemaker cycle. However, I(Cl(Ca)) does not modulate intrinsic interbeat interval, pacemaker synchronization or action potential conduction.