[Persistent subjective cognitive decline in middle age: diagnosis and treatment]. / Persisterende subjectieve geheugen-klachten op middelbare leeftijd: diagnostiek en behandeling.

A 47-year-old highly educated man without psychiatric history was referred for psychiatric evaluation because of persistent subjective cognitive decline after repeated and extensive diagnostic evaluation in an outpatient memory clinic. The patient developed increasing preoccupation and anxiety with memory complaints and concerns, despite repetitive negative findings from clinical investigations. This clinical case is coined as ‘neurocognitive hypochondria’, a syndrome interfacing with cogniform and illness anxiety disorders, in which obsessions and concerns about progression of unexplained memory deficits are indicated for specialized treatment. This case study provides more insight into differential diagnosis, classification according to the current DSM-5 criteria and discussion on potential treatment approaches.

What influences contracture formation in lower motor neuron disorders, severity of denervation or residual muscle function? An analysis of the elbow contracture in 100 children with unilateral Brachial Plexus Birth Injury.

PURPOSE: As in other neuromuscular disorders, both denervation and muscle paresis/imbalance are implicated as aetiological factors for contractures in children with a Brachial Plexus Birth Injury (BPBI). Although both factors are related, it is unclear which factor is dominant. The aim of this study is to assess whether contracture formation in children is predominantly related to denervation or to residual muscle function/imbalance. This might be relevant for understanding contracture formation in other neuromuscular disorders. METHODS: A total of 100 children (61 boys; mean age 10.4 years, 4 to 18) with unilateral BPBI were included in this cross-sectional study. Severity of the denervation was classified according to Narakas. Muscle function of flexors and extensors of both elbows was measured (in Newtons) using a hand-held dynamometer and flexion contractures were measured with a goniometer. The relation between denervation, muscle function/muscle balance and flexion contracture was assessed using univariate and multivariate analysis. RESULTS: Of the children, 57 were Narakas class I, 13 class II and 30 class III. Mean flexion contracture was 25° (90° to -5°). At the affected side the forearm flexion force was 47% and extension force was 67% of the force of the unaffected side. Contractures were more severe in children with higher Narakas classifications (p = 0.001), after neurosurgery (Mann-Whitney U test, p = 0.009) and were related to age (Spearman's Rho = -0.3, p = 0.008) and to paresis of the extensors (Rho = 0.4, p = 0.000). Flexor paresis as a percentage of unaffected side (Rho = 0.06, p = 0.6) and muscle balance had no influence. CONCLUSION: In BPBI, elbow contractures are related to the severity of the neurological lesion, not to residual muscle function. LEVEL OF EVIDENCE: Level II - prognostic study.

Individual Differences in Heparin Sensitivity and Their Effect on Heparin Anticoagulation During Arterial Vascular Surgery.

OBJECTIVES: To investigate whether a fixed heparin dose results in adequate heparinisation levels and consequent inhibition of haemostatic activation in all patients. METHODS: This prospective clinical pilot study included 24 patients undergoing arterial vascular surgery. Individual heparin responsiveness was assessed using the Heparin Dose Response (HDR) test, while the activated clotting time (ACT) and heparin concentration were measured to monitor the peri-procedural degree of anticoagulation. Finally, peri-operative haemostasis was evaluated with rotational thromboelastometry (ROTEM). RESULTS: Eight patients were identified with reduced heparin sensitivity (RS group) and 16 patients with normal heparin sensitivity (NS group). Compared with the NS group, the RS group showed less prolonged ACTs after heparinisation with heparin concentrations below the calculated target heparin concentration. ROTEM revealed shorter clot formation times in the intrinsically activated coagulation test (INTEM) 3 min (114 ± 48 s vs. 210 ± 128 s) and 30 min after the initial heparin bolus (103 ± 48 s vs. 173 ± 81 s) in the RS group compared with the NS group. In the RS group, one patient developed a major thromboembolic complication. CONCLUSIONS: This study shows that a third of the study population had reduced heparin sensitivity, which was associated with lower levels of heparinisation, and lower inhibition levels of clot initiation and clot formation. Identifying patients with reduced heparin sensitivity by monitoring the anticoagulant effect of heparin could decrease the risk of thrombotic complications after arterial vascular surgery.

Transplacental transmission of BTV-8 in sheep: BTV viraemia, antibody responses and vaccine efficacy in lambs infected in utero.

Bluetongue virus (BTV) is an insect vector transmitted virus which causes an economically important disease in ruminants. BTV infection during pregnancy can result in infection of the foetus, which may lead to the birth of persistently infected or immunotolerant offspring. Since persistently infected animals continuously produce large amounts of virus they could be a source of infection for the insect vector. This could significantly influence the epidemiology of the virus and hence might require additional measures to control a BTV outbreak. Therefore, we investigated the potential of BTV-8 to induce persistent infection or immunotolerance in lambs in an experimental setting. Infection of eighteen 70-75 days pregnant ewes with wild type BTV-8 led to the birth of 25 out of 44 BTV RNA positive lambs (foetal infected, FI). All 23 FI lambs born alive also had anti BTV antibodies at birth; infectious virus could be recovered from 5 out of 25 FI lambs. Viral RNA loads decreased rapidly after birth; 19 out of 20 FI lambs that remained in the experiment until week 14 after birth, were RNA negative at that time. Since persistence of BTV-8 infection could not be demonstrated, we investigated whether foetal infection had an effect on protection against a field virus infection and on efficacy of vaccination. To this end, 5 FI lambs and 5 foetal non-infected (FNI) lambs were vaccinated with the inactivated Bovilis(®) BTV-8 vaccine, five months after birth. Three weeks after the vaccination, all lambs were infected with wild type BTV-8. The foetal infection did not interfere with vaccination efficacy. In contrast, foetal BTV-8 infection induced an immune response which afforded protection against BTV challenge comparable to the level of protection induced by vaccination.

Scaling from challenge experiments to the field: Quantifying the impact of vaccination on the transmission of bluetongue virus serotype 8.

Bluetongue (BT) is an economically important disease of ruminants caused by bluetongue virus (BTV) and transmitted by Culicoides biting midges. The most practical and effective way to protect susceptible animals against BTV is by vaccination. Data from challenge studies in calves and sheep conducted by Intervet International b.v., in particular, presence of viral RNA in the blood of challenged animals, were used to estimate vaccine efficacy. The results of the challenge studies for calves indicated that vaccination is likely to reduce the basic reproduction number (R(0)) for BTV in cattle to below one (i.e. prevent major outbreaks within a holding) and that this reduction is robust to uncertainty in the model parameters. Sensitivity analysis showed that the whether or not vaccination is predicted to reduce R(0) to below one depended on the following assumptions: (i) whether "doubtful" results from the challenge studies are treated as negative or positive; (ii) whether or not the probability of transmission from host to vector is reduced by vaccination; and (iii) whether the extrinsic incubation period follows a realistic gamma distribution or the more commonly used exponential distribution. For sheep, all but one of the vaccinated animals were protected and, consequently, vaccination will consistently reduce R(0) in sheep to below one. Using a stochastic spatial model for the spread of BTV in Great Britain (GB), vaccination was predicted to reduce both the incidence of disease and spatial spread in simulated BTV outbreaks in GB, in both reactive vaccination strategies and when an incursion occurred into a previously vaccinated population.

Effect of vaccination with an inactivated vaccine on transplacental transmission of BTV-8 in mid term pregnant ewes and heifers.

The effect of vaccination with a commercial inactivated Bluetongue virus serotype 8 (BTV-8) vaccine on the ability of BTV-8 to cross the ruminant placenta was investigated in two experiments. Ten pregnant ewes (Experiment 1) or heifers (Experiment 2) were vaccinated according to the manufacturer's instructions. Three weeks after the completion of the vaccination schedule, all vaccinated animals were infected with BTV-8 together with ten non-vaccinated pregnant animals that served as challenged controls. Four additional pregnant animals received a mock challenge at the same time point. Three weeks after the challenge, the foetuses were collected. In the sheep experiment, the lambs of the vaccinated ewes and the mock infected ewes were negative in the virus isolation, whereas BTV-8 could be isolated from 11/23 lambs of 6/10 ewes in the BTV-8 challenged control group. The incidence and severity of BTV associated lesions, such as haemorrhages, meningitis/encephalitis and necrosis in the placentomes was significantly higher in the BTV-8 challenged control group. The rate of transplacental transmission was less in the cattle experiment: BTV-8 could be detected in 2/10 calves in the BTV-8 challenged control group. All other calves were negative. Vaccination clearly reduced transplacental transmission of BTV-8 in the sheep experiment, whereas in the cattle experiment, the incidence of transmission was too low to demonstrate a significant reduction of transmission by vaccination. However, the vaccine very effectively blocked viraemia, which suggests that the vaccine might prevent transmission in cattle as well. Transplacental transmission of BTV has serious economical consequences, due to the loss of progeny to the livestock industry. Vaccination can be an important aid in the reduction of these economic losses.

Transplacental transmission of Bluetongue virus serotype 8 in ewes in early and mid gestation.

The ability of Bluetongue virus serotype 8 (BTV-8) originating from the 2006 European outbreak to cross the ovine placenta during early and mid gestation was investigated in two separate experiments. In the first experiment, 16 ewes were infected with BTV-8 at 70-75 days gestation. The foetuses were collected at 18-19 days after infection (dpi). BTV-8 could be isolated from at least two organs of 19 out of 40 lambs and from 11 out of 16 infected ewes. In the second experiment, 20 BTV-8 infected ewes in early gestation (day 40-45) were euthanized at 10 days (10 ewes) or 30 days (10 ewes) after infection. The presence of BTV could be demonstrated in two foetuses from two ewes at 10 dpi and in 4 foetuses from four ewes at 30 dpi. The main pathological findings in the foetuses in mid gestation were meningo-encephalitis and vacuolation of the cerebrum. In the foetuses early at gestation, haemorrhages in various foetal tissues and necrosis and haemorrhages in the placentomes were found. These experiments demonstrate for the first time the presence of infectious BTV in lamb foetuses at different stages of gestation, combined with a difference in transmission rate depending on the gestation stage. The high transmission rate found at mid term gestation (69%) makes our model very suitable for further research into the mechanisms of transplacental transmission and for research into the reduction of this route of transmission through vaccination.

Ventilatory and cerebrovascular responses in normocapnic and hypercapnic COPD patients.

This study investigated the hypothesis that hypercapnia in some chronic obstructive pulmonary disease (COPD) patients may be related to a high cerebrovascular response to carbon dioxide (CO2). The relationship between responses of ventilation and of cerebral blood volume (CBV) to acute changes in carbon dioxide tension in arterial blood (Pa,CO2) was measured in 17 chronic hypercapnic (Pa,CO2 >6.0 kPa) and 16 normocapnic (Pa,CO2 < or = 6.0 kPa) COPD patients, who were matched for degree of airway obstruction (forced expiratory volume in one second 27% predicted). Results were compared with 15 age-matched healthy subjects. CBV was measured using near infrared spectroscopy during normo- and hypercapnia and related to inspired minute ventilation (V'I) and mouth occlusion pressure (P0.1). Hypercapnia (end-tidal pressure of carbon dioxide (deltaPET,CO2) > 1 kPa) was induced by giving adequate amounts of CO2 in the inspired air. During normocapnia, CBV (mL x 100 g(-1)) was 2.41+/- 0.66 and 2.90 +/- 0.60 (mean +/- SD) in the normocapnic and chronic hypercapnic patients, respectively, which was significantly lower compared to healthy subjects (3.53 +/- 0.77). All slopes of CO2 responsiveness (deltaCBV/deltaPa,CO2, deltaV'I/deltaPa,CO2, deltaP0.1/deltaPa,CO2) were significantly lower in both COPD groups relative to healthy subjects, but were not significantly different between the COPD groups. A poor but positive correlation between ventilatory and cerebrovascular CO2 responsiveness (deltaCBV/deltaPa,CO2 and deltaV'I/deltaPa,CO2) was found in COPD patients and healthy subjects. The findings do not support the hypothesis of abnormal cerebrovascular responses to carbon dioxide in hypercapnic chronic obstructive pulmonary disease patients.

Nonuniform quadriceps O2 consumption revealed by near infrared multipoint measurements.

Single location muscle monitoring does not reflect the heterogeneous activation of the muscle group(s) during a given exercise. Vastus lateralis and rectus femoris O2 consumption (VO2) was investigated, noninvasively, at rest and during maximal voluntary contractions (MVC) using a 12-channel near-infrared continuous wave spectroscopy (NIR(CWS)) system (0.1 s acquisition time). VO2 either at rest or during MVC was found to be nonuniform in the 11 out of 12 measurement sites over a surface of 8 x 8 cm2. As expected, VO2 during exercise was significantly higher than VO2 at rest (P < 0.01). However, at each muscle measurement site no difference was found between the mean values (n = 12) of VO2 measured during a 5-s intermittent MVC and the VO2 values measured during 30-s continuous MVC (P = 0.25). These results strengthen the role of NIR(CWS) as a powerful tool for investigating the spatial and temporal features of muscle oxygenation changes as well as muscle VO2.

Can cerebral blood volume be measured reproducibly with an improved near infrared spectroscopy system?

In some circumstances, cerebral blood volume (CBV) can be used as a measure for cerebral blood flow. A new near infrared spectroscope was used for determining the reproducibility of CBV measurements assessed by the O2-method. Twenty-seven healthy subjects were investigated. An intrasubject coefficient of variation (CV) was calculated, based on four identical episodes of desaturation-resaturation (O2-method) procedures for CBV measurements. Two trials were performed, with (trial 1) and without (trial 2) disconnecting the equipment. A mean CV of 12.6% and 10.0% was found in trial 1 and 2, respectively. Cerebral blood volume values yield 3.60+/-0.82 mL 100 g(-1). Cerebral blood volume could be measured reproducible in adults using near infrared spectroscopy, if the arterial desaturation is limited to approximately 5% from baseline level.

Simultaneous near-infrared spectroscopy monitoring of left and right occipital areas reveals contra-lateral hemodynamic changes upon hemi-field paradigm.

In this study we have shown that in humans it is possible to monitor non-invasively and simultaneously both hemispheres revealing cortical oxygenation changes in the occipital area in response to a contra-lateral hemi-field paradigm. A novel multi-channel near infrared spectroscopy approach with a high temporal resolution was used. The results confirm previous findings obtained by functional magnetic resonance imaging and positron emission tomography with the advantage to measure directly not only concentration changes in deoxyhemoglobin as measured by functional magnetic resonance imaging (MRI), but also in oxyhemoglobin with low cost instrumentation potentially useful to investigate the pathophysiology of vision.

Ventilatory response in metabolic acidosis and cerebral blood volume in humans.

The relationship between alterations in cerebral blood volume (CBV) and central chemosensitivity regulation was studied under neutral metabolic conditions and during metabolic acidosis. Fifteen healthy subjects (56+/-10 years) were investigated. To induce metabolic acidosis, ammonium chloride (NH(4)Cl) was given orally. CBV was measured using Near Infrared Spectroscopy during normo- and hypercapnia and related to inspired ventilation (V(i)). A mean acute metabolic acidosis of Delta pH - 0.04 was realized with a mean decreased arterialized capillary PCO(2) (P(c)CO(2)) of 0.20 kPa (1.5 mmHg) (both P<0.001). During normocapnia, CBV was 3.51+/-0.71 and 3.65+/-0.56 ml 100 g(-1) (mean+/-S.D.), measured under neutral metabolic conditions and during acute metabolic acidosis, respectively (ns). Corresponding values of V(i) were 7.6+/-1.4 and 10.0+/-2.4 l min(-1) (P<0.01), respectively. The slopes of the CO(2)-responsiveness (DeltaCBV/DeltaP(c)CO(2) and DeltaV(i)/DeltaP(c)CO(2)), were not significantly different during both metabolic conditions. A significant correlation between DeltaCBV/DeltaP(c)CO(2) and DeltaV(i)/DeltaP(c)CO(2) was found during metabolic acidosis (P<0.01), but not under neutral metabolic conditions. CBV does not contribute in a predictable way to the regulation of central chemoreceptors.

High electric field dielectric studies of aqueous myoglobin solutions.

High field dielectric measurements of the Piekara factor deltaepsilon/E2 have been carried out for a range of concentrations of horse heart myoglobin in water at 293K. Using the literature value for the dipole moment of myoglobin and the established theory for the classical orientational dipolar non-linear effect predicts a value of deltaepsilon/E2 one order of magnitude greater than that for water. The measured effect, however, was found to be one order of magnitude less than for water. This difference is explained as being most probably due to the existence of antiparallel molecular dipole pairs in the myoglobin solution. The possibility of a positive deltaepsilon due to a field induced conformational change of the myoglobin cannot, however, be ruled out.