Improving Health Related Quality of Life and Independence in Community Dwelling Frail Older Adults through a Client-Centred and Activity-Oriented Program. A Pragmatic Randomized Controlled Trial.

INTRODUCTION AND AIM: In the ageing society, a considerable part of the older adults are frail. Frailty has a major impact on the individual's quality of life, independence and also on his environment. This study aimed to investigate - as a secondary prevention of disability - the effectiveness of a client-centred and activity-oriented intervention program for frail community living older adults. It was hypothesized that this program could be effective in improving basic Activities of Daily Living (b-ADL) and increasing Health Related Quality of Life (HRQoL). METHOD: This study was a single blind randomized controlled trial with an intervention and a control group (pre-test-post-test control group design). Analysis of covariance (ANCOVA) was used to compare the outcome across groups with post-test as outcome and baseline values as a covariate. Data were analysed using the intention-to-treat principle. RESULTS: The intervention group (n = 86) experienced more improvement on b-ADL and HRQoL compared with the control group (n = 82). These effects were statistically significant for the b-ADL index (p = 0.013) and the 'physical subscale pain' (p = 0.049). DISCUSSION AND CONCLUSION: These positive results can be seen as promising for further development of intervention strategies, although follow-up study should be conducted to determine long term effectiveness.

Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals.

Endocrine disrupting chemicals (EDCs) have the potential to interfere with the hormonal system and may negatively influence human health. Microarray analysis was used in this study to investigate differential gene expression in human peripheral blood cells (PBMCs) after in vitro exposure to EDCs. PBMCs, isolated from blood samples of four male and four female healthy individuals, were exposed in vitro for 18h to either a dioxin-like polychlorinated biphenyl (PCB126, 1µM), a non-dioxin-like polychlorinated biphenyl (PCB153, 10µM), a brominated flame retardant (BDE47, 10µM), a perfluorinated alkyl acid (PFOA, 10µM) or bisphenol (BPA, 10µM). ANOVA analysis revealed a significant change in the expression of 862 genes as a result of EDC exposure. The gender of the donors did not affect gene expression. Hierarchical cluster analysis created three groups and clustered: (1) PCB126-exposed samples, (2) PCB153 and BDE47, (3) PFOA and BPA. The number of differentially expressed genes varied per compound and ranged from 60 to 192 when using fold change and multiplicity corrected p-value as filtering criteria. Exposure to PCB126 induced the AhR signaling pathway. BDE47 and PCB153 are known to disrupt thyroid metabolism and exposure influenced the expression of the nuclear receptors PPARγ and ESR2, respectively. BPA and PFOA did not induce significant changes in the expression of known nuclear receptors. Overall, each compound produced a unique gene expression signature affecting pathways and GO processes linked to metabolism and inflammation. Twenty-nine genes were significantly altered in expression under all experimental conditions. Six of these genes (HSD11B2, MMP11, ADIPOQ, CEL, DUSP9 and TUB) could be associated with obesity and metabolic syndrome. In conclusion, microarray analysis identified that PBMCs altered their gene expression response in vitro when challenged with EDCs. Our screening approach has identified a number of gene candidates that warrant further study.

Tertiary syphilis presenting as hepatic bull's eye lesions.

We report a rare case of tertiary syphilis (hepatic gummata, asymptomatic neurosyphilis and iridocyclitis) in a 47 year old female patient. Our patient suffered from a troubled sight, pain in the right hypochondrium, one enlarged submandibular lymph node, an elevated sedimentation rate, disturbed liver tests and two hepatic lesions upon abdominal computed tomography. The diagnosis was based upon a liver biopsy and a positive Treponema Pallidum haemagglutination test. The patient was treated with doxycyclin. After treatment the sedimentation rate and liver tests normalised and the hepatic lesions disappeared leaving a small 'scar' on CT-scan; at the end she still complained of a decreased sight. We conclude that syphilitic gummata of the liver have a favourable prognosis when the diagnosis is made early. One has to differentiate with hepatic abscesses, primary tumours and metastases.

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin--induced diabetic rats is restored by 5-methyltetrahydrofolate.

AIMS/HYPOTHESIS: Endothelial dysfunction contributes to the development of diabetic vascular complications. A better understanding of the pathophysiology of endothelial dysfunction in diabetes could lead to new approaches to prevent microvascular disease. METHODS: Endothelium-dependent and endothelium-independent vasodilator responses were investigated in the renal microcirculation of streptozotocin-induced diabetic rats. We measured renal blood flow changes with an electromagnetic flow probe. In addition, the responses of the different segments of the renal microcirculation were evaluated with videomicroscopy using the hydronephrotic kidney technique. Because endothelial cells release different relaxing factors (nitric oxide, prostacyclin and an unidentified endothelium-derived hyperpolarizing factor), responses to acetylcholine were measured before and after treatment with the nitric oxide synthase inhibitor L-NG-nitroarginine methylester HCI (L-NAME) and the cyclooxygenase inhibitor indomethacin. We evaluated with the effect of 5-methyltetrahydrofolate, the active form of folate, on the responses. RESULTS: The L-NAME- and indomethacin-resistant vasodilation to intra-renal acetylcholine was significantly reduced in the diabetic compared with control rats, suggesting impaired endothelium-derived hyperpolarizing factor-mediated vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-i um-1,2-diolate (DETA-NONOate) and to the K+-channel opener pinacidil were similar in diabetics and controls, indicating intact endothelium-independent vasodilator mechanisms. The contribution of endothelium-derived hyperpolarizing factor to vasodilation induced by acetylcholine was greatest in the smallest arterioles. In diabetic rats, the response to acetylcholine was increasingly impared as vessel size decreased. Defective vasodilation in diabetic kidneys was rapidly normalized by 5-methyltetrahydrofolate. CONCLUSION-INTERPRETATION: Endothelium-derived hyperpolarizing factor-mediated vasodilation is impaired in the renal microcirculation of diabetic rats, in particular in the smallest arteries. Treatment with folate restores the impaired endothelial function in diabetes.

An organotypical in vitro model for vascular tissue remodelling and its application to study radiation effects.

An organotypic in vitro model, to study vascular tissueremodeling, was evaluated as a function of culture period. Inorder to validate the model as a tool for studying vascularresponses to damage, a dose-response analysis to ionizingirradiation was included.Rat aortic rings were explanted in vitro after being irradiatedwith single doses of (60)Co gamma-rays, namely 0, 5, 10, 15, 20or 25 Gy. Irradiated and sham-irradiated aortic rings werecultured for 3 weeks. Explant outgrowth on an adhesivesubstrate was evaluated by macroscopical scoring, and ringsderived from each irradiation group together with theoutgrowths were fixed and embedded in paraffin after 2, 7, 14and 21 days. Bromodeoxyuridine incorporation, alpha smoothmuscle actin and collagen types I and III were scored onimmunohistochemically stained sections. For each studiedparameter, irradiated and sham-irradiated rings were compared.In cultures of sham-irradiated rings, alterations from acontractile towards a synthetic/migratory smooth muscle cellphenotype were confirmed. After 3 weeks, fullgrown cultures hadformed. Irradiation slowed down the phenotypical modifications.After 15 Gy, irradiation explant outgrowth was already retarded;after 25 Gy, the outgrowth was completely blocked. On the otherhand, a dose of 15 Gy or more induced an increased collagen Iproduction in the tunica media.In conclusion, the present organotypical in vitro model fits toanalyse dynamics in the original vascular tissues as well as inthe primary outgrowth. It enables to confirm features oftissular reorganization and effects of ionizing radiationdescribed in vivo.

Beneficial effect of serotonin 5-HT2-receptor antagonism on renal blood flow autoregulation in cyclosporin-treated rats.

Renal blood flow (RBF) autoregulation reappears in postischemic rat kidneys during serotonin (5-HT2) antagonism. The aim of the present study was to analyze whether 5-HT2 antagonism can ameliorate impaired RBF autoregulation in rats treated with 20 mg/kg per d cyclosporin A during 10 d. Autoregulation of RBF was assessed during stepwise lowering of renal perfusion pressure from 110 to 70 mmHg by gradual compression of the aorta. Autoregulation was lost in the cyclosporin A-treated rats. During administration of the 5-HT2 antagonist ritanserin (0.6 mg/kg intravenous bolus, followed by 1.2 mg/kg per h intravenous infusion during 1 h), autoregulation acutely reappeared. Intrarenal bolus injections of a selective 5-HT2-agonist, 2,5 dimethoxy-4-iodoamphetamine hydrochloride, elicited a significantly stronger renal vasocontraction in cyclosporin A-treated rats than in control rats. This finding was also observed with serotonin after nitric oxide-synthase blockade. These results (1) show the importance of 5-HT2-receptor-mediated vasoconstriction in the suppression of vasodilatory autoregulation of RBF in experimental cyclosporin A-induced renal dysfunction and (2) demonstrate that the complete loss of RBF autoregulation is not due to damage of the vascular smooth muscle cells.

Influence of ketanserin on experimental loss of renal blood flow autoregulation.

Serotonin is important for effective renal blood flow (RBF) autoregulation in the normal rat and at two or seven days of reperfusion following renal ischemia. It has been suggested that after these reperfusion periods and during renal perfusion pressure (RPP) lowering, the vasodilatory autoregulation mechanism is not damaged but overwhelmed by increased 5-HT2-mediated vasoconstriction, resulting in complete loss of autoregulation. This study analyzes the influence of the 5-HT2-antagonist ketanserin on RBF autoregulation after two hours or one day of renal reperfusion following ischemia and in a model of cyclosporine (20 mg/kg.day for 10 days)-induced nephrotoxicity. Autoregulation was lost both after brief reperfusion periods and after cyclosporine. Similar to the two or seven days of reperfusion experiments, ketanserin in the cyclosporine model led to reappearance of autoregulation down to RPP 95 mm Hg. Despite an increased response to intrarenal serotonin after two hours of reperfusion, autoregulation was not restored by ketanserin. At one day of reperfusion and with ketanserin, autoregulation was present down to 105 mm Hg. Thus, during the early reflow period, other factors (of decreasing importance) most likely add to autoregulation loss.

Beneficial influence of ketanserin on autoregulation of blood flow in post-ischemic kidneys.

The influence of ketanserin, a S2-serotonergic receptor blocker, on the impaired renal hemodynamics in a clamp model of renal ischemia in rats was investigated in this study. Serotonin-induced vasoconstriction of the renal vascular bed was augmented after ischemia. This constriction is blocked by ketanserin (0.05 mg/kg i.v. bolus, followed by 0.1 mg/kg per h infusion). The influence of the same ketanserin treatment on the response of RBF versus a stepwise lowering of the renal perfusion pressure was studied in post-ischemic kidneys with an established loss of autoregulation of RBF. An almost perfect restoration of the autoregulatory response was apparent after the S2-serotonergic antagonism. Despite this beneficial effect on renal hemodynamics, renal function, judged by measurement of GFR and urinary sodium excretion rate, was not influenced by an acute infusion of ketanserin in post-ischemic kidneys. It is suggested that serotonin plays a pivotal role in the suppression of autoregulation of RBF by a S2-serotonergic receptor-mediated vasoconstrictor effect in the post-ischemic kidney. It most likely masks the potential myogenic dilatory response of the smooth muscle cells in renal preglomerular microvasculature. Restoration of the renal autoregulatory capacity by S2-serotonergic receptor antagonism could be of clinical relevance in human post-ischemic acute renal failure.

Regional differences in vasculotoxic effects of cyclosporin in rats.

Studies on cyclosporin-induced vasculotoxicity often yielded discrepant results, possibly as a result of differences in study protocols. The aim of the present study was to analyse cyclosporin-induced vasculotoxicity in arteries of different size and origin. Therefore, rats were treated with cyclosporin, 20 mg.kg-1.day-1, by gastric gavage for 10 days. In our previous studies, this treatment schedule induced renal functional impairment in vivo and an impaired relaxation response of thoracic aortic rings in vitro. Relaxation of various arteries (thoracic and abdominal aorta and carotid, renal, and interlobar arteries) from cyclosporin-treated and control rats in response to endothelium-dependent and -independent vasodilators was analysed. The thoracic aorta showed diminished endothelium-dependent and -independent relaxations; in the abdominal aorta no impairment was observed. Moreover, the dysfunction of the thoracic aorta seemed to be homogeneous along its length and showed an abrupt termination at the level of the diaphragm. In all other segments studied, no impairment of the relaxation responses was found. A similar pattern of vascular damage was found in rats treated with a very toxic cyclosporin treatment (50 mg.Kg-1.day-1 s.c. x 7 days). The results indicate regional differences in cyclosporin-induced vasculotoxicity. The thoracic aorta, and in view of the fall of the renal blood flow, most likely also the renal resistance vessels, could be more susceptible than other vessels to cyclosporin-induced vascular dysfunction.

Functional analysis of vascular dysfunction in cyclosporin treated rats.

OBJECTIVE: The aim was to analyse vascular damage after chronic cyclosporin treatment (20 mg.kg-1 during 10 d) in rats. METHODS: The reactivity to different vasoactive agents was studied on thoracic aortic rings from control rats, and from rats subjected to renal ablation or cyclosporin treatment. RESULTS: After cyclosporin treatment the endothelium dependent vasodilator responses to acetylcholine and to the endothelium independent NO donors were suppressed. These defects were restored after a 7 d recovery period. The contractile response after inhibition of basal endothelial NO synthesis was unaffected. Further analysis of the blunted vasodilatations not only points to impairments of cGMP mediated mechanisms but shows that other pathways are possibly involved as well. Renal insufficiency induced by renal mass reduction did not influence the aortic reactivity. CONCLUSIONS: Cyclosporin induced vasculotoxicity is a reversible phenomenon, and is not due to renal dysfunction as such. It seems to provoke a defect in the vasodilator mechanisms at the level of the vascular smooth muscle cells and most likely no impairment of endothelial nitric oxide production.

Light and electron microscopical study of two types of endocrines cell in the midgut of the adult worker honeybee (apis mellifera).

The occurrence, development and ultrastructure of two types of gut endocrine cell have been studied in the midgut of adult honeybees. These cells, one of a basal granular type and one of a vesicular type, are evenly distributed throughout the posterior three-quarters of the midgut. Each crypt complex contains one of each cell type, both of which may be derived from the same stem cells as the enterocytes. They already contain their respective secretory product while still in the nidus. Both reach the midgut lumen by a narrow apex and are therefore of the open type. The granular cells release their secretory granules at the cell base in a typical endocrine way. In young vesicular cells the secretory vesicles are released at the cell base and in the intercellular spaces. Old cells are still filled with vesicles when they are shed in the midgut lumen. This seems to indicate that these cells have both an endocrine (or paracrine) and an exocrine function, the latter apparently by holocrinc release.

Organisation and ultrastructure of the regenerative crypts in the midgut of the adult worker honeybee (L. Apis mellifera).

The midgut epithelium of the adult honeybee consists of columnar and endocrine cells, both originating from regenerative crypt cells. The regenerative crypt is composed of stem cells and differentiating cells. The stem cells generate two forms of endocrine cells along with differentiating enterocytes of two distinct stages. At first they can be seen as light crypt cells which are not secretory active; they then develop into more electron dense, active secretory crypt cells. The developing enterocytes are arranged as tetrads, each composed of cells with the same degree of differentiation. This can be explained by the occurrence of cytoplasmic bridges between the cells of each tetrad. These fusomes are probably responsible for the apparent intercellular coordination. This is a new example of intercellular bridges between somatic cells and, as far as we know the first description of fusomes in the insect midgut epithelium. The microvilli on top of the crypt cells develop within a spherical extracellular space where glycosaminoglycans are secreted. This occurs by the coordinated activity of the four surrounding electron dense crypt cells. Microvilli formation therefore seems to be the first in a series of successive functions of honeybee enterocytes during their ontogeny.

Manual or automatic nulling DC offset for physiological DC amplifier.

An inexpensive circuit to compensate for DC offset is presented. The circuit may be connected in a straightforward manner to any currently existing DC isolation amplifier and causes no deterioration in the performance of the system. The offset voltage is measured at discrete time intervals and then subtracted from the input signal. A switch is provided to bypass the offset compensation when the latter is not required.

Computer-controlled portable stimulator for paraplegic patients.

A six-channel lightweight, portable and computer-controlled stimulator for the functional activation of paraplegic patients is described. To enable programming of the various functions, the stimulator was designed to work in a remote-control mode hosted by an IBM PC or compatible computer, in addition to its normally used local mode. The stimulus parameters, including current intensity, stimulus frequency and pulse width, are individually adjustable and programmable for each channel. The power source is 12 V 500 m Ah-1, from 10 rechargeable nickel cadmium batteries, with a run time of 1.5 h for a load of 200 mA in four channels. Various training programmes for the activation of paraplegics in the sitting, standing and walking positions are described. The final design of the stimulator is based on experience gained from 25 patients, treated and evaluated during the course of development. Ongoing work including clinical, biomechanical and physiological studies is carried out to evaluate performance of the activated patients and to optimize stimulation.