Geriatric rehabilitation care after hip fracture.

PURPOSE: After acute hospital admission, patients with a hip fracture are frequently discharged to skilled nursing homes providing geriatric rehabilitation (GR). There are few evidence-based studies regarding specific treatment times and assessments during GR. This study aims to provide a description of care for hip fracture patients during GR in the Netherlands. METHODS: Descriptive study analyzing the care pathways from GR facilities, regarding healthcare professionals involved, allocated treatment time per profession, total length of rehabilitation stay, and assessment instruments. Based on the reimbursement algorithm (diagnostic treatment combination = DBCs), of 25 patients, the registered actual treatment time per profession was calculated. RESULTS: The care pathways pivoted on three groups of health care professionals: medical team (MT), physiotherapy (PT), and occupational therapy (OT). There was some discrepancy between the allocated time in the care pathways and the calculated mean actual treatment time from the DBCs. First week: MT 120-180 min, DBC 120 (SD: 59) minutes; PT 120-230 min, DBC 129 (SD: 58) minutes; and OT 65-165 min, DBC 93 (SD: 61) minutes. From week two onwards, MT 15-36 min, DBC 49 (SD: 29) minutes; PT 74-179 min, DBC 125 (SD: 50) minutes; and OT 25-60 min, DBC 47 (SD: 44) minutes. Dieticians, psychologists, and social workers were sporadically mentioned. There was heterogeneity in the assessment and screening tools. CONCLUSIONS: It is difficult to define current standard care in GR after hip fracture in the Netherlands due to the diversity in care pathways and large practice variation. This is a problem in conducting randomized effectiveness research with care provided as control. TRIAL REGISTER AND DATE OF REGISTRATION: NL7491 04-02-2019.

Glycosphingolipids and Infection. Potential New Therapeutic Avenues.

Glycosphingolipids (GSLs), the main topic of this review, are a subclass of sphingolipids. With their glycans exposed to the extracellular space, glycosphingolipids are ubiquitous components of the plasma membrane of cells. GSLs are implicated in a variety of biological processes including specific infections. Several pathogens use GSLs at the surface of host cells as binding receptors. In addition, lipid-rafts in the plasma membrane of host cells may act as platform for signaling the presence of pathogens. Relatively common in man are inherited deficiencies in lysosomal glycosidases involved in the turnover of GSLs. The associated storage disorders (glycosphingolipidoses) show lysosomal accumulation of substrate(s) of the deficient enzyme. In recent years compounds have been identified that allow modulation of GSLs levels in cells. Some of these agents are well tolerated and already used to treat lysosomal glycosphingolipidoses. This review summarizes present knowledge on the role of GSLs in infection and subsequent immune response. It concludes with the thought to apply glycosphingolipid-lowering agents to prevent and/or combat infections.

[Death after a fall in patients with advanced dementia: cause of death natural or unnatural?] / Overleden na een val bij gevorderde dementie.

OBJECTIVE: This article describes and discusses the viewpoints of elderly care physicians and municipal coroners regarding the qualification of natural or unnatural deaths of nursing home residents with advanced dementia who fall. DESIGN: A digital questionnaire was sent to all elderly care physicians-in-training and their trainers in the Netherlands, and to all 23 municipal coroners in the Mid-Holland region. METHOD: As well as questions on knowledge of the Dutch law and prognostic figures concerning dementia-related death, the questionnaire described two cases with minimal differences. The respondents were asked if they would issue a certificate of natural death in each case, and if not, would they have preferred to do so. They were also asked to explain their answers. RESULTS: Of the 405 elderly care physicians who responded, 68% and 49%, respectively, would have issued a certificate stating the cause to be natural death in each case, or if they did not they would have preferred to do so. All 15 coroners who filled in the questionnaire came to the conclusion of unnatural death. CONCLUSION: The majority of the elderly care physicians feel that a certificate of natural death can be issued if a fall in a nursing home results in a fracture, as this can be considered as part of the disease process of dementia.

Impact of obesity on taste receptor expression in extra-oral tissues: emphasis on hypothalamus and brainstem.

Sweet perception promotes food intake, whereas that of bitterness is inhibitory. Surprisingly, the expression of sweet G protein-coupled taste receptor (GPCTR) subunits (T1R2 and T1R3) and bitter GPCTRs (T2R116, T2R118, T2R138 and T2R104), as well as the α-subunits of the associated signalling complex (αGustducin, Gα14 and αTransducin), in oral and extra-oral tissues from lean and obese mice, remains poorly characterized. We focused on the impact of obesity on taste receptor expression in brain areas involved in energy homeostasis, namely the hypothalamus and brainstem. We demonstrate that many of the GPCTRs and α-subunits are co-expressed in these tissues and that obesity decreases expression of T1R3, T2R116, Gα14, αTrans and TRPM5. In vitro high levels of glucose caused a prominent down-regulation of T1R2 and Gα14 expression in cultured hypothalamic neuronal cells, leptin caused a transient down-regulation of T1R2 and T1R3 expression. Intriguingly, expression differences were also observed in other extra-oral tissues of lean and obese mice, most strikingly in the duodenum where obesity reduced the expression of most bitter and sweet receptors. In conclusion, obesity influences components of sweet and bitter taste sensing in the duodenum as well as regions of the mouse brain involved in energy homeostasis, including hypothalamus and brainstem.

Prostaglandin profiling reveals a role for haematopoietic prostaglandin D synthase in adipose tissue macrophage polarisation in mice and humans.

BACKGROUND/OBJECTIVES: Obesity has been associated with both changes in adipose tissue lipid metabolism and inflammation. A key class of lipid-derived signalling molecules involved in inflammation are the prostaglandins. In this study, we aimed to determine how obesity affects the levels of prostaglandins within white adipose tissue (WAT) and determine which cells within adipose tissue produce them. To avoid the effects of cellular stress on prostaglandin levels, we developed a multivariate statistical approach in which metabolite concentrations and transcriptomic data were integrated, allowing the assignment of metabolites to cell types. SUBJECTS/METHODS: Eicosanoids were measured by liquid chromatography-tandem mass spectrometry and mRNA levels using real-time PCR. Eicosanoid levels and transcriptomic data were combined using principal component analysis and hierarchical clustering in order to associate metabolites with cell types. Samples were obtained from C57Bl/6 mice aged 16 weeks. We studied the ob/ob genetically obese mouse model and diet-induced obesity model. We extended our results in mice to a cohort of morbidly obese humans undergoing bariatric surgery. RESULTS: Using our modelling approach, we determined that prostglandin D2 (PGD2) in adipose tissue was predominantly produced in macrophages by the haematopoietic isoform of prostaglandin D synthase (H-Pgds). Analysis of sub-fractionated WAT confirmed that H-Pgds was expressed in adipose tissue macrophages (ATMs). Furthermore, H-Pgds expression in ATMs isolated from lean and obese mice was consistent with it affecting macrophage polarisation. Functionally, we demonstrated that H-PGDS-produced PGD2 polarised macrophages toward an M2, anti-inflammatory state. In line with a potential anti-inflammatory role, we found that H-PGDS expression in ATMs was positively correlated with both peripheral insulin and adipose tissue insulin sensitivity in humans. CONCLUSIONS: In this study, we have developed a method to determine the cellular source of metabolites within an organ and used it to identify a new role for PGD2 in the control of ATM polarisation.

The revised role of TGF-ß in aortic aneurysms in Marfan syndrome.

BACKGROUND: Recently, we demonstrated that losartan reduced the aortic root dilatation rate (AoDR) in adults with Marfan syndrome (MFS); however, responsiveness was diverse. The aim was to determine the role of transforming growth factor-ß (TGF-ß) as therapeutic biomarker for effectiveness of losartan on AoDR. METHODS: Baseline plasma TGF-ß levels of 22 healthy controls and 99 MFS patients, and TGF-ß levels after 1 month of losartan treatment in 42 MFS patients were measured. AoDR was assessed by magnetic resonance imaging at baseline and after 3 years of follow-up. RESULTS: Patients with MFS had higher TGF-ß levels compared with healthy controls (121 pg/ml versus 54 pg/mL, p = 0.006). After 1 month of therapy, losartan normalised the TGF-ß level in 15 patients (36%); the other 27 patients (64%) showed a significant increase of TGF-ß. After 3 years of losartan therapy, patients with a decrease in TGF-ß had significantly higher AoDR compared with patients with increased TGF-ß (1.5 mm/3 years versus 0.5 mm/3 years, p = 0.04). Patients showing a decrease in TGF-ß after losartan therapy had significantly elevated baseline TGF-ß levels compared with patients with increased TGF-ß (189 pg/ml versus 94 pg/ml, p = 0.05). CONCLUSION: Patients responding to losartan therapy with a reduction of the plasma TGF-ß level had higher baseline TGF-ß levels and a higher AoDR. Most likely, TGF-ß levels may be considered to be a readout of the disease state of the aorta. We propose that increased angiotensin II is the initiator of aorta dilatation and is responsible for increased TGF-ß levels in MFS. The concept of TGF-ß as initiator of aortic dilatation in MFS patients should be nuanced.

[Stroke rehabilitation in nursing homes: intensity of and motivation for physiotherapy]. / CVA-revalidatie in het verpleeghuis: therapie-intensiteit van en motivatie voor fysiotherapie.

INTRODUCTION: Stroke is a frequent and potential invalidating disease, of which recovery can be improved by rehabilitation. In The Netherlands old and frail stroke patients are rehabilitated in nursing homes. Probably, the intensity of and motivation for physiotherapy are important for successful discharge. The aim was to determine (1) therapy intensity of and motivation for physical therapy of geriatric stroke patients (2) its correlates and (3) the effect on discharge destination. METHODS: Data were obtained from the 'GRAMPS'-study, a longitudinal observational study of stroke rehabilitation in 15 Dutch nursing homes. Direct time spent on physiotherapy was registered during admission. Motivation was measured by the Pittsburgh Rehabilitation Participation Scale (PRPS). Data of 84 patients were analysed using uni- and multivariate regression analysis. RESULTS: Patients received an average 109 min of physiotherapy per week. 69 patients (82%) were good motivated for physiotherapy (had all PRPS scores 4 or higher). Therapy intensity was positively associated with the presence of a partner and good motivation. No significant independent variables of motivation were found. Therapy-intensity was positively related to discharge to prior living situation. CONCLUSION: Intensity of physiotherapy of stroke rehabilitation is an independent variable of successful discharge and is higher when the patient has a partner or is better motivated. These findings stress the importance of high motivation and therapy intensity in geriatric stroke rehabilitation.

Sleep monitoring by actigraphy in short-stay ICU patients.

Sleep deprivation is common in intensive care unit (ICU) patients. The criterion standard for sleep monitoring, polysomnography, is impractical in ICU. Actigraphy (a wrist watch indicating amount of sleep) proved to be a good alternative in non-ICU patients, but not in prolonged mechanically ventilated patients, probably due to ICU-acquired weakness. Short-stay ICU patients do not suffer from ICU-acquired weakness. However, the accuracy of actigraphy is unknown in these patients. Therefore, we compared actigraphy to polysomnography in short-stay ICU patients. Sleep measurements were conducted in 7 postcardiothoracic surgery patients. The sensitivity (percentage of actigraphy data that agreed with sleep determined using polysomnography) and specificity (percentage of actigraphy data that agreed with awake determined using polysomnography) were calculated. The result showed that actigraphy underestimated the amount of wake time and overestimated the amount of sleep. The median specificity for actigraphy was always less than 19% and sensitivity more than 94%. Therefore, actigraphy is not reliable for sleep monitoring in short-stay ICU patients.

Systematic validation of specific phenotypic markers for in vitro polarized human macrophages.

BACKGROUND: Polarization of macrophages by specific micro-environmental conditions impacts upon their function following subsequent activation. This study aimed to systematically validate robust phenotypic markers for in vitro polarized human macrophages in order to facilitate the study of macrophage subsets in vivo. METHODS: Human peripheral blood monocytes were polarized in vitro with IFN-γ, IL-4, or IL-10. Similar experiments were performed with TNF, IL-13, dexamethasone, M-CSF and GM-CSF as polarizing stimuli. Phenotypic markers were assessed by flow cytometry and qPCR. RESULTS: IFN-γ polarized macrophages (MΦ(IFN-γ)) specifically enhanced membrane expression of CD80 and CD64, IL-4 polarized macrophages (MΦ(IL-4)) mainly upregulated CD200R and CD206, and downregulated CD14 levels, and IL-10 polarized macrophages (MΦ(IL-10)) selectively induced CD163, CD16, and CD32. The expression profiles of the most specific markers were confirmed by qPCR, dose-response experiments, and the use of alternative polarizing factors for each macrophage subset (TNF, IL-13, and dexamethasone, respectively). GM-CSF polarized macrophages (MΦ(GM-CSF)) upregulated CD80 but not CD64 expression, showing a partial phenotypic similarity with MΦ(IFN-γ), and also upregulated the expression of the alternative activation marker CD206. M-CSF polarized macrophages (MΦ(M-CSF)) not only expressed increased levels of CD163 and CD16, resembling MΦ(IL-10,) but also displayed high levels of CD64. The phenotype of MΦ(M-CSF) could be further modulated by additional polarization with IFN-γ, IL-4, or IL-10, whereas MΦ(GM-CSF) showed less phenotypic plasticity. CONCLUSION: This study validated CD80 as the most robust phenotypic marker for human MΦ(IFN-γ), whereas CD200R was upregulated and CD14 was specifically downregulated on MΦ(IL-4). CD163 and CD16 were found to be specific markers for MΦ(IL-10). The GM-CSF/M-CSF differentiation model showed only a partial phenotypic similarity with the IFN-γ/IL-4/IL-10 induced polarization.

Delirium in intensive care unit patients.

Delirium is defined as a disturbance of consciousness with cognitive changes or perceptual disturbances, which has developed over a short period of time, and is caused by a medical condition or a postsurgical state. Although historically dismissed as an inconvenient and transient problem, recent studies have reported that delirium is associated with more complications, increased length of hospital stay, and higher mortality. Although delirium is a prevalent condition after cardiothoracic surgery and in the intensive care unit (ICU), the condition appears to be largely underdiagnosed. Several detection tools have been developed for routine monitoring of delirium by nonpsychiatric personnel in the ICU, such as the Confusion Assessment Method for the Intensive Care Unit and the Intensive Care Delirium Screening Checklist. Management includes treatment of underlying disorders, nonpharmacological measures and symptomatic drug therapy. There is a need for well-designed randomized, double-blind, placebo-controlled trials on drug treatment.

Rational design of a classical swine fever C-strain vaccine virus that enables the differentiation between infected and vaccinated animals.

The C-strain of the classical swine fever virus (CSFV) is considered the gold standard vaccine for the control of CSF. This vaccine, however, does not enable the serological differentiation between infected and vaccinated animals (DIVA). Consequently, its use can impose severe trade restrictions. The immunodominant and evolutionarily conserved A-domain of the E2 structural glycoprotein is an important target in CSFV-specific ELISAs. With the ultimate aim to render the C-strain suitable as a DIVA vaccine, mutations were introduced that were expected to dampen the immunogenicity of the A-domain. In the first of two approaches, the feasibility of shielding the A-domain by N-linked glycans was evaluated, whereas in the second approach C-strain mutants were created with targeted deletions in the A-domain. Analysis of the antibody responses elicited in rabbits suggested that shielding of the A-domain by an N-linked glycan had a minor effect on the immune response against the A-domain, whereas a targeted deletion of only a single amino acid severely dampened this response. C-strain mutants with larger deletions were highly debilitated and incapable of sustained growth in vitro. By providing the viruses with the opportunity to increase their fitness by mutation, a mutant was rescued that found a way to compensate for the imposed fitness cost. Most of the identified mutations occurred in several independently evolved viruses, demonstrating parallel evolution. By virtue of this compensatory evolution, a well replicating and genetically stable C-strain mutant was produced that can be serologically differentiated from wildtype CSFV. The findings provide the molecular basis for the development of a novel, genetically stable, live attenuated CSF DIVA vaccine.

Assessment of AFLP marker behaviour in enriching STS radiation hybrid maps.

Radiation hybrid (RH) mapping provides a powerful tool to build high-resolution maps of genomes. Here, we demonstrate the use of the AFLP technique for high-throughput typing of RH cell lines. Cattle were used as the model species because an RH panel was available to investigate the behaviour of AFLP markers within the microsatellite- and STS-based maps of this species. A total of 747 AFLP markers were typed on the TM112 RH radiation panel and 651 of these were assigned by two-point analysis to the 29 bovine autosomes and sex chromosomes. AFLP markers were added to the 1222 microsatellite and STS markers that were included in earlier RH maps. Multipoint maps were constructed for seven example chromosomes, which retained 248 microsatellite and STS markers, and added 123 AFLP markers at LOD 4. The addition of the AFLP markers increased the number of markers by 42.1% and the map length by 10.4%. The AFLP markers showed lower retention frequency (RF) values than the STS markers. The comparison of RF values in AFLP markers and their corresponding AFLP-derived STSs demonstrated that the lower RF values were due to the lower detection sensitivity of the AFLP technique. Despite these differences, AFLP and AFLP-derived STS markers mapped to identical or similar positions. These results demonstrate that it is possible to merge AFLP and microsatellite markers in the same map. The application of AFLP technology could permit the rapid construction of RH maps in species for which extensive genome information and large numbers of SNP and microsatellite markers are not available.

[Delirium in the intensive care unit]. / Delirium op de intensive care.

Delirium is a common condition in the intensive care unit (ICU). Between 16-89% of all ICU patients experience an episode of delirium during admission. Several detection tools have been developed for use specifically in the ICU. The Confusion Assessment Method for the intensive care unit (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) combine high sensitivity with high specificity. Treatment consists of treatment of underlying disorders, nonpharmacological measures and symptomatic drug therapy. The prognosis for ICU patients who experience delirium is worse than for those who do not. Delirious patients are more likely to develop complications, spend longer in hospital and have a higher mortality rate. In view of the high frequency, poor prognosis, high costs and lack of studies into the treatment of ICU delirium, research into the possibilities for prevention, early detection and treatment of the condition is essential.

Application of AFLP technology to radiation hybrid mapping.

We have investigated the use of AFLP technology as a tool for the high throughput enrichment of Radiation Hybrid (RH) maps. The 3000 rad TM112 bovine RH panel was assayed with 37 EcoRI/TaqI AFLP primer combinations. The number of selective nucleotides used during PCR was increased to seven, to reduce the complexity of the AFLP profile and minimise the overlap between hamster and bovine bands co-amplified from hybrid cell clones. Seven-hundred-forty-seven bovine AFLP bands were amplified that could be distinguished following electrophoresis. Repeatability was tested within and between laboratories on independent template preparations and an error rate of 1.3% found. Two-point linkage analysis clustered 428 AFLP fragments in 39 linkage groups of at least 4 markers. Multi-point maps were constructed for 5 sample linkage groups. The study demonstrated that the AFLP approach could be used to rapidly screen for the most informative clones during panel construction and to increase the number of markers on RH maps, which could be useful for joining linkage groups formed by other markers. The use of AFLP markers as anchor points between existing RH maps and other physical maps, such as BAC contigs, is also discussed.

Discrimination between selected lines of pigs using AFLP markers.

Amplified fragment length polymorphic (AFLP) markers were used to discriminate between lines of pigs, divergently selected over seven generations for components of efficient lean growth rate. A total of 270 animals with 30 animals per line were genotyped for 239 polymorphic AFLP markers. Canonical variate analysis identified linear combinations of the AFLP marker scores that grouped animals by selection line with no overlap between selection lines. Cluster analysis of AFLP marker scores identified 10 groups of animals with 226 of the 270 animals clustered into nine groups, each consisting of animals from only one selection line. AFLP marker genotyping, using the EcoRI and TaqI restriction enzymes, provided an effective means of discriminating between animals of different selection lines that have arisen from one base population.

Evaluation of patient outcomes in an area where prescribing of anticholinergic antidepressants was influenced by academic detailing.

OBJECTIVE: To evaluate, on a patient level, the effect of a "physician-level intervention" that successfully reduced the incidence of anticholinergic antidepressant prescribing. DESIGN: Cross-sectional surveys with questionnaires sent before and after intervention. SETTING: Additional study in an RCT to reduce the prescribing of highly anticholinergic antidepressants in the elderly in the South Holland Islands. PARTICIPANTS: Elderly patients (age 60-95 years) who used antidepressants in 1995 and 1996 in our research area according to a health insurance prescription database. MAIN OUTCOME MEASURES: Prevalence of adverse events related to antidepressant use, severity of depression and quality of life were compared in users living in the intervention and control areas. RESULTS: Prior to our intervention we sent 2,359 questionnaires of which we could use 827 (35%) for analysis. At baseline, there were no statistically significant differences between the intervention and control areas. After the intervention 3,375 questionnaires were sent, of which 939 (28%) could be used. The occurrence of "dry mouth" and "coughing" and the "amount of pain" were lower in the intervention area compared to the control area (p < 0.05). CONCLUSION: We found no indications that adverse events, severity of depression or quality of life were changed in an unfavourable direction, when comparing patients inside and outside the intervention area.

Association behaviour of glucitol amine gemini surfactants : Self-consistent-field theory and molecular-dynamics simulations.

The association behaviour of a number of glucitol amine gemini surfactants has been investigated by means of molecular dynamics and self-consistent-field calculations. We have shown that the titratable head group of the surfactant is responsible for a micelle-to-membrane transition when changing the pH. Furthermore, the association structure of this group of surfactants is shown to be very sensitive to ionic strength. The combination of a charged head group, a spacer, and the hydrophilic glucitol side chains is responsible for the possible structural transitions in the associates as a function of ionic strength and pH.

Death-receptor contribution to the germinal-center reaction.

Both helper T cells and follicular dendritic cells play crucial roles in the germinal-center (GC) reaction. One of their key functions is to provide GC B cells with anti-apoptotic signals during their growth, diversification of antibody repertoire and positive selection. Dysregulation of the mechanisms that control B-cell apoptosis in the GC could cause hyperplasia, endanger self-tolerance or impair dramatically the efficiency of the humoral response. This article discusses how the death receptor Fas and components of its signaling machinery contribute to the GC reaction.