The effect of a goal-setting strategy with integrated feedback on goal attainment in inflammatory arthritis patients: a mixed method study.

Patients with Inflammatory Arthritis (IA) often experience difficulties in daily life as a result of their disease. Unfortunately, outpatient consultations in daily practice tend to focus on medical topics, thereby ignoring the impact of the disease on patients' daily lives. Patient-Reported Outcomes (PROs) can be used to understand this impact, but they are not enough for offering person-centered care. Because the patient's true values and goals can only be ascertained during a proper conversation, which should include both medical as well as patient goals. Therefore, the aim of the study is to evaluate the effect of a goal management strategy with integrated feedback on goal attainment and Health-Related Quality of Life(HRQoL) in IA patients. IA patients with an active disease were given the opportunity to set and follow-up goals. In addition to goal setting, patients were asked to complete online questionnaires on various PROs, including HRQoL. Ninety-two IA patients participated in the study. The mean age was 51 years and most of them had rheumatoid arthritis. A total of 302 patient goals were set, of which 32% were achieved. In the entire population, HRQoL did not change over time, but patients who did not meet their goals tended to report a lower HRQoL. Incorporating a feedback mechanism in a goal-setting strategy has a positive effect on goal attainment. Yet no effect was seen on HRQoL, but this may due to the fact that general HRQoL measurement are not sensitive or specific enough to detect changes that are accompanied with goal setting and attainment.

Comparative pharmacokinetic, immunologic and hematologic studies on the anti-HIV-1/2 compounds aconitylated and succinylated HSA.

Charge modification by succinylation or cis-aconitylation of the terminal epsilon NH2 functions of the amino acid lysine in human serum albumin, resulted in polyanionic compounds with an anti-HIV-1 activity in the low nanomolar concentration range. After iv injections in rats of the negatively charged albumins (NCAs), a dose dependent elimination pattern was observed indicating a saturable eliminations pathway. The Michaelis-Menten parameters Vmax and K(m) were 62 +/- 8 micrograms.min-1.kg-1 and 16 +/- 4 micrograms.ml-1 (Clintr 3.9 +/- 1.1 ml.min-1.kg-1) and 74 +/- 6 micrograms.min-1.kg-1 and 11 +/- 2 micrograms.ml-1 (Clintr 6.7 +/- 1.2 ml.min-1.kg-1) for aconitylated-HSA (Aco-HSA) and succinylated-HSA (Suc-HSA) respectively, using 125I-labelled proteins. The volume of distribution (V) of both compounds was approximately 60 ml.kg-1. Coadministration of poly-inosinic acid and formaldehyde treated albumin showed a marked inhibition of blood clearance indicating that the compounds are mainly cleared from the bloodstream by scavenger receptors on liver and spleen endothelial cells and macrophages. The Michaelis-Menten constant K(m) was remarkably higher when the hydrophobic flurophore fluorescein was covalently linked to the protein, indicating that the affinity for the scavenger receptors is largely decreased by FiTC conjugation. The latter observation may have implications for the kinetic behavior of drug-carrier preparations if antiviral drugs like AZT or PMEA are linked to these intrinsic active carriers. In contrast to other polyanionic compounds like heparins and dextran sulfate, these NCAs did not exhibit acute toxicity and had no effect on blood coagulation. They neither had an effect on the lymphocyte proliferation. Studies on immunogenicity of the homologous derivatized albumins in rats did not show a significant response. The present pharmacokinetic and toxicologic data of Suc-HSA and Aco-HSA show that both compounds are interesting preparations for studies in SIV infected monkeys and AIDS patients.

Glycol methacrylate embedding of alginate-polylysine microencapsulated pancreatic islets.

A method for processing and embedding alginate-polylysine microencapsulated pancreatic tissue in glycol methacrylate resin (GMA) is described. Fixation in 4% phosphate buffered formaldehyde, processing in ascending concentrations of glycol methacrylate monomer and embedding in Technovit 7100 results in well preserved morphological details of hydrogels, hydrogel-cell interfaces, and encapsulated pancreatic tissue. Routine staining with Loeffler's methylene blue, hematoxylin and eosin, and Romanovsky-Giemsa gave excellent images of the GMA embedded alginate polylysine membrane and tissues allowing cells on the outside of the capsule to be analyzed effectively as part of the foreign body reaction against the capsule membrane.

The capsular overgrowth on microencapsulated pancreatic islet grafts in streptozotocin and autoimmune diabetic rats.

This study investigates whether capsular overgrowth on alginate-polylysine microencapsulated islets is influenced by (1) the presence of islet tissue, (2) MHC incompatibility between donor and recipient, or (3) the presence of autoimmune diabetes. Encapsulated Albino Oxford (AO, n = 6, isografts) and Lewis (n = 6, allografts) rat islets, and encapsulated human islets (n = 5, xenografts) were implanted intraperitoneally into streptozotocin-diabetic AO rats. Also, encapsulated AO islets were implanted into autoimmune diabetic Bio Breeding/Organon (BB/O) rats (n = 5, allografts). Five isografts, five allografts, and three xenografts in AO recipients and five allografts in BB/O recipients resulted in normoglycemia. Two weeks after implantation, islets containing capsules were retrieved by peritoneal lavage, after which all animals that had become normoglycemic after transplantation returned to a state of hyperglycemia. Recovery rates of the capsules of these successful grafts, expressed as percentages of the initially implanted graft volume, varied from 72% +/- 7% to 80% +/- 9%. The associated pericapsular infiltrates (PCI) were similar in all groups and varied from 3.2% +/- 1.4% to 8.3% +/- 2.6%. Similar recovery rates and PCI were also found with empty capsules. However, the recovery rates of recipients with graft failures were lower and showed more PCI. Immunohistological staining of PCI showed no differences in the types of cells in the PCI on capsules with or without islets. We conclude that this early PCI is a capsule-induced foreign body reaction that is not influenced by MHC incompatibility or by the presence of autoimmune diabetes, and it should be avoided by improving the biocompatibility of the capsules.

Glucose-induced changes in histochemically determined Ca2+ in B-cell granules, 45Ca uptake, and total Ca2+ of rat pancreatic islets.

Rat pancreatic islets contain an ionized or readily ionizable calcium fraction that can be determined by the metallochromic indicator glyoxal-bis-(2- hydroxyanil ) ( GBHA ). This calcium fraction is mainly localized in the secretory granules. The relationship between the effects of glucose on 45Ca uptake and on this ionized calcium fraction was investigated. In addition, the effects of glucose on total islet calcium content were also studied. Stimulation of isolated islets for 30 min with 15 mM glucose in the presence of 2.5 mM CaCl2 increased the 45Ca uptake but decreased the GBHA -Ca content, while the total calcium content was not affected. Deletion of CaCl2 caused, at 2.5 mM glucose, an abrupt decrease of GBHA -Ca, which did not occur at 15 mM glucose. Total islet calcium content decreased slowly at 2.5 mM glucose, but this was not significantly affected by glucose stimulation. Islet GBHA -Ca can be reduced by 70% and total islet calcium by 30% by means of washing with calcium-free buffer. Reintroduction of calcium at 2.5 mM glucose partly restored, but glucose 15 mM completely restored, the GBHA -Ca level within 5 min. The total calcium content was restored within 15 min independent of the glucose concentration. The increase of the islet calcium content equalled the 45Ca uptake at 2.5 mM glucose. The 45Ca uptake at 15 mM glucose was higher than the increase of the islet calcium content. The results indicate that the intragranular Ca2+ pool, as measured by GBHA , is rapidly and dramatically altered by glucose stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased response of mobile calcium in pancreatic islets of fasted rats to glucose stimulation and calcium manipulation.

The effect of fasting on mobile calcium in the B-cells of rat pancreatic islets was investigated in view of a possible role of calcium in the fasting-induced impairment of insulin secretion. Mobile calcium (GBHA-Ca), an ionized or readily ionizable calcium fraction, was determined histochemically with glyoxal bis (2-hydroxyanil). Fasting (24-72 h) strongly decreased the GBHA-Ca content of islets in situ (55-60%). Incubation of isolated islets at 2.5 mM glucose in the presence of 2.5 mM Ca2+ resulted after 15 min in stable GBHA-Ca levels, which were 25% lower in fasted than in fed islets. Glucose (15 mM) caused the GBHA-Ca content of fed islets to decrease rapidly and to rise again after 30 min. These changes did not occur after 24 or 72 h of fasting. GBHA-Ca appeared not to be displaceable with La3+. At 2.5 mM glucose, withdrawal of Ca2+ rapidly reduced GBHA-Ca in fed and fasted islets. Glucose (15 mM) inhibited this rapid fall, and this inhibitory effect was particularly evident in fed islets. Washing and preincubation in the absence of Ca2+ (2.5 mM glucose) largely depleted fed and fasted islets of GBHA-Ca. Reintroduction of Ca2+ at 2.5 mM glucose only partially restored the GBHA-Ca levels of fed and fasted islets. By contrast, 15 mM glucose restored the characteristic pattern of GBHA-Ca in fed islets as seen in nondepleted islets, but in fasted islets at lower levels as previously seen. Thus, fasting decreased the GBHA-Ca content and its response to glucose stimulation. It is suggested that GBHA-Ca, which is presumably mainly localized in the secretory granules, plays a role in the initiation of insulin secretion.

Changes in histochemically detectable calcium and zinc during tolbutamide-induced degranulation and subsequent regranulation of rat pancreatic islets.

Secretory granules of pancreatic B-cells contain high concentrations of zinc and calcium. The effect of gradual degranulation (induced by tolbutamide over a period of 3 days) and the subsequent regranulation (over a period of 4 days) on the histochemically detectable zinc (Zn) and calcium (Ca) content of B-cells was investigated. Zn was stained by dithizone, Ca by glyoxal-bis-(2-hydroxyanil), (GBHA), and B-granules by aldehyde fuchsin (AF). The staining intensities were determined cytophotometrically. A decrease of the granulation by 50% causes a comparable decrease of the Zn content. Almost complete degranulations, however, hardly further diminished the Zn content. Regranulation restores the Zn content parallel to the granulation. The presence of 40% of the initial Zn content in degranulated B-cells suggests the existence of a non-granular Zn fraction. The Zn content of B-cells may be partly involved in the storage of insulin as a Zn-insulin complex in the secretory vesicles. A-cells, however, contain even more (+ 30%) Zn than B-cells. Degranulation of B-cells is accompanied by a moderate decrease of the zinc content of the A-cells. The function of Zn in A-cells is completely unknown. Degranulation of B-cells causes the GBHA-Ca content to decrease to a very low level parallel to the AF-positive granulation. During regranulation the GBHA-Ca content restores parallel to the granulation and reaches after complete regranulation a slightly higher level than in untreated control rats. Almost complete disappearance of CBHA-Ca in the B-cells is accompanied by a decrease of the total islet calcium content of 33%. The results indicate that GBHA stains a Ca fraction which is mainly localized to the secretory granules. The stainability of granular Ca by GBHA is probably based on: a) the high Ca concentration in the granules, b) the presence of ionized Ca in the granules, due to the low intragranular pH, and c) on the properties of GBHA, which stains, under conditions used, only ionized (possibly also readily ionizable) Ca.

Effects of calcium manipulation and glucose stimulation on a histochemically detectable mobile calcium fraction in isolated rat pancreatic islets.

Pancreatic B-cell calcium as histochemically detectable with glyoxal bis (2-hydroxyanil) = GBHA was studied in isolated islets of fed rats. GBHA has previously been shown by us to detect an ionized or readily ionizable Ca-fraction (GBHA-Ca). In the presence of Ca++ (2.5 mM), high glucose (15 mM) induced a rapid decrease (30%) of islet GBHA-Ca followed by a rise between 30 and 60 min to levels above the initial value. At low glucose (0 or 2.5 mM) GBHA-Ca showed a slight and gradual decline under these conditions. Omission of Ca++ at low glucose rapidly decreased (30%) islet GBHA-Ca. This decrease was markedly inhibited by high glucose, although glucose did not induce insulin secretion under these conditions. Preincubation in the absence of Ca++ (15 min) depleted islet GBHA-Ca, but partial restoration occurred during subsequent incubation with Ca++ at low glucose. By contrast, high glucose completely restored GBHA-Ca within 5 min, followed by a decline and a subsequent rise. Reintroduction of Ca++ also rapidly restored the glucose-induced insulin secretion. These results indicate that islet GBHA-Ca represents a mobile Ca-fraction which is dependent on extracellular Ca++ and which responds very rapidly to glucose stimulation. It is suggested that changes of GBHA-Ca in the B-cells may reflect changes in the Ca pool involved in the insulin secretory mechanism.

Evaluation of the glyoxal-bis-(2-hydroxyanil)-method for staining of calcium in model gelatin films and pancreatic islets.

The nature of tissue calcium, detectable with glyoxal-bis-(2-hydroxyanil), (GBHA), was investigated using gelatin films as model. The results indicate that in the films the procedure detects only the calcium fraction which was ionized in the original gelatin solution. The GBHA staining intensity (absorbance) appeared to be linear with the amount of ionized calcium in the range from 0 to 2 micrograms/cm2. The method allows detection of amounts of ionized calcium as low as 0.15 micrograms/cm2 or 0.0015 pg/mu2. For the measurement of calcium in pancreatic tissue of fed rats, the tissue was subjected to freeze-substitution at -80 degree C in acetone containing 1% oxalic acid. Adjacent sections were stained with either GBHA or aldehyde-fuchsin (AF). Exocrine tissue hardly stained with GBHA whereas islet tissue stained intensely. For GBHA as well as for AF a variation in staining intensity (visual evaluation) between islets was observed. Islet GBHA- and AF-staining intensities did not correlate. The AF-staining intensity but not the GBHA-staining intensity decreased with increasing islet diameter. Also in pancreatic islet tissue the GBHA method appears to be very sensitive and reproducible and small differences in islet GBHA-staining intensity can be detected. The results indicate that between islets differences in ionized calcium content exist. These differences do not correlate with the degree of B-cell granulation.

Calcium, zinc and other elements in islet and exocrine tissue of the rat pancreas as measured by histochemical methods and electron-probe micro-analysis, Effects of fasting and tolbutamide.

Fasting for 24 or 72 h causes a strong decrease of pancreatic islet calcium content as detected by glyoxal-bis-(2-hydroxyanil), (GBHA). There is strong evidence that GBHA only detects ionized calcium and not total calcium (Wolters et al., 1979). Fasting does not influence the zinc content as detected by dithizone (DZN), and aldehyde-fuchsin (AF) staining intensity is only slightly decreased. After degranulation of islets by tolbutamide (which reduced the insulin content of the pancreas to 10% of the control value) the staining intensities of GBHA, DZN and AF were strongly depressed. Calcium (as well as other elements) were also measured by electron-probe micro-analysis (EPMA). It appeared that 24 or 72 h of fasting did neither affect the total content of Ca nor of Na, P, S, and K of the islets significantly. In exocrine tissue the Ca content increased gradually as a result of fasting. Thus, after 72 h of fasting the Ca content was 25% higher than in fed controls. On the other hand after 72 h of fasting the K content appeared to be decreased. EPMA revealed that after degranulation of islets the Ca content decreased markedly (35%). S appeared to be decreased by only 14%, whereas the content of the other elements was not changed. The results show that GBHA-detectable Ca is only a part of EPMA-detectable Ca. The GBHA-Ca "pool" which contains ionized Ca, is subjected to changes when the animals are fasted, the total Ca content as measured by EPMA does not change. Thus, at least two distinguishable pools of Ca exist within the islets (GBHA-detectable and not-GBHA-detectable). It is suggested that as a result of fasting Ca passes from one pool to another.

Quantitative analysis of pancreatic islet development and insulin storage in the foetal and newborn rat.

Pancreatic islet development and insulin storage were studied in foetal rats during the last 4 days of gestation (day 19 to 22 post-coitum (p.c.)) and in 1 and 5 days old neonatal rats. Adult female virgin rats were also studied. The percentage of granulated B-cells per islet, the degree of B-cell granulation and the islet insulin concentration rose from low levels on day 19 to adult levels on day 22 and remained stable after birth. This indicates that the qualitative maturation of the pancreatic islets as insulin producing units is completed on the last day of gestation. The percentage of islet tissue slowly rose from 0.7% at day 19 to 1.5% on day 22. A further and much more rapid rise occurred during the first day of birth. At the 5th postnatal day the islets comprised 3.6% of the pancreas versus 1.1% in adult rats. Likewise, the neonatal pancreatic insulin concentration was about 3 times higher than in the adult pancreas. The foetal pancreas as a whole showed rapid exponential growth between day 18 and 21 p.c., but a sudden decline in growth rate occurred from day 21 onward. The total mass of islet tissue, on the other hand, continued to expand at its high initial rate up to the first day after birth, whereafter this high rate also declined. The high concentration of insulin in the neonatal rat pancreas therefore appears to be due to differential growth rates of the endocrine and exocrine tissue during the last day of pregnancy and the first day after birth.