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Over the years, a wide range of loneliness interventions for older adults have been developed. The majority of these interventions are not effective in reducing loneliness. In order to gain more insight into why many interventions do not achieve the desired goal, we examine active elements that are used in interventions into reduce loneliness. In order to achieve this goal, intermediate goals are needed: to have a social network, a sense of belonging, to experience intimacy, to experience meaning. In order to arrive at a division into active elements, a qualitative analysis was carried out of 119 loneliness interventions, described in 22 reviews of interventions. The result is a division into seven active elements: 'activities', 'meeting others', practical support', 'meaningful contact', 'interpersonal skills', 'realistic expectations' and 'meaningful role'. Most interventions combine several active elements. Some combinations of active elements are common. By mapping out the individual components of interventions, the effectiveness of each element can be evaluated. The use of a combination of active elements, and of general active elements such as good execution, may increase the effectiveness of interventions.In de loop der jaren is een breed aanbod aan eenzaamheidsinterventies voor ouderen ontwikkeld. Het merendeel van de interventies blijkt weinig effectief in het verminderen van eenzaamheid. Om meer inzicht te krijgen in waarom veel interventies niet het gewenste doel bereiken, gaan we in op de werkzame elementen die in interventies worden ingezet om eenzaamheid te reduceren, of waarmee subdoelen bereikt kunnen worden: een sociaal netwerk hebben, erbij horen, intimiteit ervaren, betekenis hebben. Om tot een indeling in werkzame elementen te komen is een kwalitatieve analyse uitgevoerd van 119 eenzaamheidsinterventies, beschreven in 22 reviews van interventies. Het resultaat is een indeling in zeven werkzame elementen: ‘bezigheden’, ‘ontmoeten’, praktisch ondersteunen’, ‘betekenisvol contact’, ‘sociale vaardigheden’, ‘realistische verwachtingen’ en ‘betekenisvolle rol’. De meeste interventies combineren verschillende werkzame elementen. Sommige combinaties van werkzame elementen komen vaak voor. Door afzonderlijke onderdelen van interventies in kaart te brengen, kan de werkzaamheid van elk element geëvalueerd worden. Het inzetten van een combinatie van werkzame elementen, en van algemene werkzame elementen zoals een goede uitvoering, kan de effectiviteit van interventies vergroten.

Dutch Abstract: Pensioenfondsen moeten hun Vereist Eigen Vermogen (VEV) berekenen als onderdeel van het financieel toetsingskader (FTK). De VEV wordt eenvoudig bepaald met de bekende wortelformule, maar daarbij moet worden uitgegaan van de evenwichtssituatie waarbij het Eigen Vermogen exact gelijk is aan de VEV. Dit betekent dat de VEV iteratief moet worden berekend, wat met name in ALM analyses bewerkelijk is. Dit artikel presenteert een directe formule voor de VEV zodat er niet geitereerd hoeft te worden. English Abstract: Dutch pension funds have to calulcate their Regulatory Capital Requirement (RCR) as part of the regulatory framework. The RCR is calculated by the well-kown square-root formula based on an equilibrium state where the equity of the pension fund equals the RCR. This implies an iterative procedure for calculating the RCR, which is demanding for ALM analyses. This paper presents a direct formula for calculating the RCR, whilst removing the need for iterations.

As a hedonic information system, a location-based social network (LBSN) is often seen as a promising innovative mobile service. However, research on LBSNs is still limited. Little is known about the factors influencing the intention to use LBSNs. Our study aims to explain the critical factors underlying the use of an LBSN, by developing a conceptual framework based on the technology acceptance model, the theory of diffusion of innovations and the five-factor model. To examine our proposed research model, we conducted an online survey among users of a Dutch LBSN. Our results demonstrate that perceived usefulness, perceived ease of use, perceived enjoyment and innovativeness predict the intention to use and the actual use of LBSNs, and hedonic information systems in general. We found no effect of extraversion. Our results suggest that developers of LBSNs should especially aim at pleasance and fun.

Real-time macroeconomic data are typically incomplete for today and the immediate past ('ragged edge') and subject to revision. To enable more timely forecasts the recent missing data have to be imputed. The paper presents a state-space model that can deal with publication lags and data revisions. The framework is applied to the US leading index. We conclude that including even a simple model of data revisions improves the accuracy of the imputations and that the univariate imputation method in levels adopted by The Conference Board can be improved upon. (C) 2011 Elsevier Inc. All rights reserved.

Hilling DE, Rijkelijkhuizen JK, Marang-van de Mheen PJ, Tons A, Terpstra OT, Bouwman E. Morphological changes of porcine islets of Langerhans after collagenase and HBSS infusion of the pancreas. Xenotransplantation 2010; 17: 413–417. © 2010 John Wiley & Sons A/S. Abstract: Background: A remarkable change in porcine islet morphology was observed after infusion of the pancreas with collagenase. The aim of the present study was to quantify these morphological changes and to assess whether these changes were due to the volume expansion caused by the collagenase entering the islet or the result of its digestive effects. Methods: This study was performed in pancreata of 28 crossbred pigs. First, eight pancreata were intraductally injected with collagenase by a continuous controlled pressure of 180 mmHg. Pancreas samples before collagenase infusion were used as controls. All tissue samples, both before and after infusion, were stained with anti-insulin. To quantify the morphological change of the islets, the mean beta cell/endocrine content ratio of the infused and not-infused tissue samples was compared. In a second experiment, 20 pancreata were similarly assessed after intraductal injection with Hank’s balanced salt solution (HBSS). Results: In both the collagenase- and HBSS-infused groups, mean beta cell/endocrine content ratio was lower than in the control samples. The observed decline in the beta cell/endocrine content ratio was not significantly different between collagenase- and HBSS-infused pancreata. This suggests that the lower beta cell/endocrine content ratio and thus the morphological change in the infused tissue samples is caused by volume expansion of the fluid entering the islet and that the digestive effect of collagenase plays no or only a minor role. Conclusion: Morphological changes of islets are observed after infusion of pancreata with collagenase and HBSS, most likely caused by volume expansion due to fluid entering the islets.

Hilling DE, Rijkelijkhuizen JKRA, Tons HAM, Terpstra OT, Bouwman E. Porcine islet isolation outcome is not affected by the amount and distribution of collagen in the pancreas. Xenotransplantation 2010; 17: 250–255. © 2010 John Wiley & Sons A/S. Abstract: Variable islet yields in porcine islet isolation may be caused by the collagen substrate within the pancreas. The aim of the present study was to determine the total amount and distribution of collagen within porcine pancreata and their relationship to islet isolation outcome. A total of 64 juvenile and 76 adult porcine pancreata of eight purebred breeds were histologically examined. The amount of collagen was quantitatively assessed in tissue samples stained with Sirius Red. Collagen distribution was semi-quantitatively determined by assessing the presence of collagen in the endocrine–exocrine interface and within the islet, in tissue samples stained with Sirius Red and anti-insulin. Islet isolation was performed in 58 pancreata of the adult group. Total collagen content and islet encapsulation ranged widely in both adult and juvenile pigs. However, the majority of islets in adult and juvenile pigs had no or only a limited collagen capsule. The difference in collagen content between adult and juvenile pigs could not be explained by age. Furthermore, no differences between adult and juvenile pigs were found in islet encapsulation or the amount of intra-islet collagen. In adult pigs, no significant relationships were found between obtained islet yield and total collagen content, islet encapsulation or amount of collagen within the islet. Considering the limitations in experimental design (staining method) and study material, isolation outcome does not seem to be affected by the total collagen content or collagen distribution. The influence of other matrix elements and collagen subtypes should be investigated.

Empirical modeling of the yield curve is often inconsistent with absence of arbitrage. In fact, many parsimonious models, like the popular Nelson-Siegel model, are inconsistent with absence of arbitrage. In other cases, arbitrage-free models are often used in inconsistent ways by recalibrating parameters that are assumed constant. For these cases, this paper introduces an arbitrage smoothing device to control arbitrage errors that arise in fitting a sequence of yield curves. The device is applied to the US term structure for the family of Nelson-Siegel curves. It is shown that the arbitrage smoothing device contributes to parameter stability and smoothness.

We present a comprehensive overview of derivative pricing in Gaussian affine asset pricing models. Gaussian affine asset pricing models are widely used in practice for pricing and scenario analysis due to their tractable pricing implications and easy estimation. This tractability is essential to efficiently evaluate portfolios of derivatives within many scenarios and time periods. We present efficient closed-form pricing formulas for the most common derivative instruments used by pension funds and insurance companies, such as interest rate swaps, swaptions, inflation-linked swaps, equity options, based on results from the literature. The pricing formulas are presented in a comprehensive computable form by utilising results based on the matrix exponential. Next, we show how some models commonly used in practice fit in the Gaussian affine framework, so that the pricing formulas can be applied to these cases. In particular, we discuss the KNW model by Koijen, Nijman and Werker (2010), which is widely used in the pension industry. Finally we discuss how our results can be applied to a time-inhomogeneous extension of the model that allows perfect calibration to the observed yield curve.

BIC is a primary microRNA (pri-miR-155) that can be processed to mature miR-155. In this study, we show the crucial involvement of protein kinase C (PKC) and nuclear factor-kappa B (NF-kappa B) in the regulation of BIC expression upon B-cell receptor triggering. Surprisingly, Northern blot analysis did not reveal any miR-155 expression upon induction of BIC expression in the Burkitt lymphoma-derived Ramos cell line, whereas other microRNAs were clearly detectable. Ectopic expression of BIC in Ramos and HEK293 cells resulted in miR-155 expression in HEK293, but not in Ramos cells, suggesting a specific block of BIC to miR-155 processing in Ramos. In line with the results obtained with Ramos, lack of miR-155 expression after induction of BIC expression was also observed in other Burkitt lymphoma cell lines, indicating a generic and specific blockade in the processing of BIC in Burkitt lymphoma. In contrast, induction of BIC expression in normal tonsillar B cells resulted in very high levels of miR-155 expression and induction of BIC expression in Hodgkin's lymphoma cell lines. It also resulted in elevated levels of miR-155. Our data provide evidence for two levels of regulation for mature miR-155 expression: one at the transcriptional level involving PKC and NF-kappa B, and one at the processing level. Burkitt lymphoma cells not only express low levels of BIC, but also prevent processing of BIC via an, as yet, unknown mechanism.

Background: In previous studies we have shown that pre-transplant hamster blood transfusion (HBT) can induce non-responsiveness in the T cell independent immunecompartment and result in tolerance towards hamster cardiac xenografts (Xgs) in T cell deficient athymic nude rats. In this study we test the combination of pre-transplant HBT with cyclosporin A (CSA) in immunocompetent Lewis rats. Methods: Before transplantation of a hamster cardiac Xg, 1 ml hamster blood was administered to nude rats or Lewis rats. CSA dissolved in olive oil was given orally at varying doses. Anti-hamster antibodies were measured by flowcytometry. Results: In nude rats HBT 3 days before transplantation resulted in 100% long-term survival >100 days (n = 9). In Lewis rats, HBT resulted in hyperacute rejection (HAR) (n = 6). Treatment of nude rats with CSA at doses varying from five to 20 mg/kg/day and treatment of Lewis rats with CSA five or 10 mg/kg/day did not effect Xg survival. However, treatment of Lewis rats with CSA 20 mg/kg/day led to long-term survival of five of nine Xgs (p

Background Transplantation of islets of Langerhans can restore insulin production in diabetic patients. Because of the shortage of human donor organs, transplantation of porcine islets may be an alternative solution. The present study was aimed at the characterization of rejection mechanisms of porcine islets transplanted into eight nondiabetic monkeys under the kidney capsule. Methods Cultured adult pig islets were used, which showed no expression of the galactose(alpha1,3)galactose epitope, major histocompatibility complex class II, or CD45, and no binding of antibodies or complement after exposure to monkey serum. Immunosuppression consisted of cyclophosphamide, cyclosporine A (CsA), and steroids (group 1); or antithymocyte globulin, anti-interleukin-2 receptor antibody, CsA, and steroids (group 2). In three animals of group 2, islets were also transplanted in the portal vein. Results Although all monkeys had preformed anti-pig antibodies, no correlation was found between antibody titers and rejection and no deposition of antibodies or complement was observed in the grafts. Group 1 showed islets up to day 11, followed by T-cell infiltration and rejection at approximately day 14. In group 2, two monkeys showed infiltrates consisting predominantly of T cells starting at approximately day 29, whereas two monkeys showed well-preserved islets without infiltration up to day 53. In the livers of the three monkeys that also received islets intraportally and were resectioned on days 21, 33, and 49, no islets could be detected. Conclusions This study demonstrates that cultured adult pig islets can survive in the monkey for more than 53 days without signs of rejection under standard immunosuppression.

The paper proposes a computationally convenient and parsimonious approach for creating a funding liquidity factor, building on work that relates the lack of funding of financial institutions to their ability to exploit arbitrage opportunities. Fontaine and Garcia (2012) propose a price-based funding liquidity factor from mispricing of bonds of similar characteristics but different ages. However, their arbitrage-free Nelson–Siegel framework requires the use of a non-linear Kalman filter, which is computationally intensive in practice. The novelty of this paper is to suggest an easier method for constructing an alternative liquidity factor that retains much of the same properties. Our proposed method for constructing this proxy liquidity factor relaxes the arbitrage-free assumption in the specification of the term structure model and bases it on a simple and flexible term structure specification. We demonstrate that this parsimonious liquidity factor fits the data well. The constructed factor is highly correlated with the Fontaine and Garcia (2012) liquidity factor and other funding liquidity measures, such as a liquidity factor by Hu et al. (2012), the TED-spread and the CP-spread.

Different factors have been reported to influence islet isolation outcome, but their importance varies between studies and are hampered by the small sample sizes in most studies. The purpose of this study was to perform a systematic review to assess the impact of donor-, pancreas-, and isolation-related variables on successful human islet isolation outcome. PubMed, Embase, and Web of Science were searched electronically in April 2009. All studies reporting on donor-, pancreas-, and isolation-related factors relating to prepurification and postpurification islet isolation yield and proportion of successful islet isolations were selected. Seventy-four retrospective studies had sufficient data and were included in the analyses. Higher pre- and postpurification islet yields and a higher proportion of successful islet isolations were obtained when pancreata were preserved with the two-layer method rather than University of Wisconsin solution in donors with shorter cold ischemia times (CITs) [1 h longer CIT resulted in an average decline of prepurification and postpurification yields and proportion of successful isolations of 59 islet equivalents (IEQs)/g, 54 IEQs/g, and 21%, respectively]. Higher prepurification yields and higher percentage of successful islet isolations were found in younger donors with higher body mass index. Lower yields were found in donation after brain death donors compared to donation after cardiac death donors. Higher postpurification yields were found for isolation with Serva collagenase. This review identified donor-, pancreas-, and isolation-related factors that influence islet isolation yield. Standardized reports of these factors in all future studies may improve the power and identify additional factors and thereby contribute to improving islet isolation yield.

The effects of pre-transplant blood transfusion vary from induction of antibodies and accelerated graft rejection, to prolonged survival and even tolerance. The beneficial 'transfusion effect' in allotransplantation is believed to be merely T-cell mediated. In xenotransplantation, T-cell independent mechanisms form a major hurdle. In this study we investigated the effects of pre-transplant hamster blood transfusion on the survival of hamster cardiac xenografts in T-cell deficient athymic nude rats. Nude rats rejected xenografts after 3.8 +/- 0.5 d (n = 8), and immunocompetent Lewis rats after 4.0 +/- 0.5 d (n = 8), following a similar IgM response (P = NS). Hamster blood transfusion 3 d before transplantation in nude rats led to an IgM response and long-term xenograft survival in 17/20. Timing was of importance: blood transfusion 7 d before transplantation resulted in 45% long-term xenograft survival (n = 20). Injection of purified hamster erythrocytes, leukocytes or minced heart also led to survival of xenografts for > 100 d in nude rats, but not in all cases. Second xenografts transplanted to long-term survivors did not provoke an IigM response, and were accepted for > 100 d (n = 4). Transfer of serum from long-term survivors to untreated nude rats resulted in survival of xenografts for > 100 d (n = 4). In Lewis rats pre-transplant blood transfusion induced hyperacute rejection of xenografts after 158 +/- 128 min (n = 8, P < 0.01). We conclude that pre-transplant hamster blood transfusion can induce long-term survival of hamster cardiac xenografts in T-cell deficient athymic nude rats. This blood transfusion effect is mediated by humoral factors and can be transferred by serum. Elucidation of underlying mechanisms might provide some insight into xenotransplantation nonresponsiveness of T-cell independent immunefactors.

Antibodies play a crucial role in the rejection of xenografts. We tested the hypothesis that xenografts are protected against antibody-mediated attack early after transplantation in a concordant model. We investigated the role of xenoreactive antibodies as a stimulus for protection and the effects of a total blockade of the antibody response by the leflunomide analog malononitrilamide 279. Hamster cardiac xenografts were transplanted to Lewis rat recipients. Second transplants and retransplants of xenografts were performed to untreated rats that had a xenograft in place for 3 d. Untreated rats rejected hamster cardiac xenografts after 4.0 +/- 0.0 d. Significant levels of anti-donor IgM, as measured by flowcytometry, were present on day 3 after transplantation (11.2% +/- 2.8 vs. 1.2% +/- 0.0 on day 0, P < 0.001). 'Fresh' second xenografts transplanted to rats that had a first xenograft in place for 3 d and had anti-hamster antibodies, underwent hyperacute rejection. The first xenografts remained functioning. Xenografts that were removed on day 3 from untreated rats and then retransplanted remained functioning. Xenografts that were removed on d 3 from rats that had been treated with malononitrilamide 279, 15 mg/kg/d and were retransplanted underwent hyperacute rejection. IgM levels at the time of removal were 1.1% +/- 0.5 in these rats and not different from baseline (P = 0.96). We conclude that xenografts are protected against antibody-mediated damage early after transplantation. The presence of anti-donor antibodies might be an essential stimulus for the induction of protection. There seems to be a delicate balance between the injurious and protective effects of antibodies. Treatment strategies that are designed to block antibody formation completely might prevent the induction of protection.

In the present study, attempts are made to improve posttransplant survival of intraportally transplanted hepatocytes in a syngeneic hepatocyte transplantation (HTX) model. Engrafted hepatocytes were detected and quantified after pretransplant labeling with 5'-bromo-deoxy-uridine. In order to enhance the survival percentage, three mechanisms that possibly influence cell survival were manipulated: (1) administration of Matrigel (extracellular-matrix components, Matrigel Basement Membrane Complex, Micronic BV, Lelystad, The Netherlands) in order to improve the environmental conditions of the transplanted hepatocytes; (2) immunosuppression of the recipients by 5 Gy total body irradiation and cyclosporin-A administration (25 mg/kg, 3 x weekly), and (3) Kupffer cell depletion by injection of dichloromethylene-diphosphonate-filled liposomes. The results were analyzed in relation to HTX without treatment. Cell survival was approximately 14% (10 days after HTX), and the transplanted hepatocytes were distributed equally throughout the various recipient liver lobes. However, no increase was attained by Matrigel coadministration, immunosuppression, or Kupffer cell depletion.

To explore the mechanism of rejection of vascularized xenografts, we performed discordant and concordant transplantation of aortic grafts. Forty-one guinea pig-to-rat and 50 hamster-to-rat aortic transplantations were performed successfully. Recipient rats were either untreated or treated three times per week with 10 mg/kg of cyclosporine (CsA) starting the day before transplantation. Recipients were sacrificed at various timepoints after transplantation and the grafts were processed for histology and immunohistochemistry. Guinea pig aortic grafts were rejected hyperacutely in both the control and CsA treated group. Four hours after transplantation all endothelial cells and some of the medial smooth muscle cells had disappeared. Seven days after transplantation the media were totally acellular, whereas the adventitia was enlarged due to infiltrating cells, consisting mainly of macrophages. At day 56, only traces of the original graft could be identified. Hamster aortic grafts developed signs of chronic rejection. In control rats, the intimal lesions could already be demonstrated in 17% of the rats at day 14, and in all rats from day 28. CsA treatment inhibited the development of the intimal lesions. At days 56 and 84 the difference in intimal thickness between the control group and the CsA treated group was statistically significant. The cellularity of the media of the hamster grafts remained constant during the first 21 days in both groups but declined sharply thereafter as a consequence of migration or necrosis of myocytes. The thickness of the adventitia in both groups increased after transplantation, due to infiltrating macrophages and T cells, reaching a peak at day 14. In conclusion, the aorta transplantation model provides useful information with regard to the development of chronic rejection in concordant grafts. Discordant aortic grafts are rejected hyperacutely just like discordant heart grafts.

The aims of this study were (1) to assess portal hemodynamics during intraportal hepatocyte transplantation (HTX) in dogs, (2) to evaluate a new method for the detection of transplanted hepatocytes using 5-bromo-2'-deoxyuridine (BrdU) incorporation, and (3) to determine the metabolic effects of HTX on an inborn error of the purine metabolism in dalmatian dogs. HTX was performed by intraportal infusion of freshly isolated allogeneic beagle hepatocytes. Portal flow and pressure were monitored continuously during HTX. For the detection experiments, beagles received hepatocytes that had been exposed to BrdU during regeneration of the donor liver, induced by partial hepatectomy. For metabolic studies, dalmatian dogs were used as recipients. Repetitive HTX was performed. As judged by the portal hemodynamics, the number of hepatocytes that could be infused safely varied from 5 x 10 8 to 8 x 10 8 in beagles, to 1 x 10 9 in dalmatians. Transaminase levels showed a 5- to 6-fold increase (P=0.05) after HTX, but normalized within 3 weeks. BrdU-positive cells were identified in the recipient livers 2 weeks after HTX and 5-10% of the total amount of transplanted hepatocytes was retrieved. A significant (P=0.05) decrease in serum uric acid was demonstrated after repeated HTX in dalmatians. In conclusion, (1) intraportal HTX is feasible, but portal hypertension limits the maximum amount of hepatocytes that can be infused in one HTX ; (2) BrdU labeling is an attractive method for the detection of transplanted hepatocytes in the recipient liver ; and (3) after two consecutive hepatocyte transplantations, a temporary correction of the purine metabolism was accomplished in the dalmatian dog.

The daily average price of electricity represents the price of electricity to be delivered over the full next day and serves as a key reference price in the electricity market. It is an aggregate that equals the average of hourly prices for delivery during each of the 24 individual hours. This paper demonstrates that the disaggregated hourly prices contain useful predictive information for the daily average price. Multivariate models for the full panel of hourly prices significantly outperform univariate models of the daily average price, with reductions in Root Mean Squared Error of up to 16%. Substantial care is required in order to achieve these forecast improvements. Rich multivariate models are needed to exploit the relations between different hourly prices, but the risk of overfitting must be mitigated by using dimension reduction techniques, shrinkage and forecast combinations.

We propose a tractable class of arbitrage-free models for the term structure of electricity prices, where spot and forward prices are a linear function of latent factors. The modeling approach offers much flexibility in the specification of the factor dynamics by only restricting their risk-neutral drift. We derive a canonical form where the parameters determining the factor loadings for the forward prices can be separated from the parameters describing the factor dynamics. The factor loading parameters can be consistently estimated by directly fitting the cross-section of forward prices. The modeling framework is applied to a panel of daily prices on forward contracts from the Nordpool electricity market, using affine factor dynamics. We find that forward prices (i) are mainly driven by changes in the level, slope and curvature of the forward curve; (ii) exhibit time-varying volatilities; and (iii) incorporate time-varying forward premia.

Winner 2014 Crowell Second Prize. We assess the effect of aggregate stock market illiquidity on U.S. Treasury bond risk premia. We find that the stock market illiquidity variable adds to the well established Cochrane-Piazzesi and Ludvigson-Ng factors. It explains 10%, 9%, 7%, and 7% of the one-year-ahead variation in the excess return for two-, three-, four-, and five-year bonds respectively and increases the adjusted R 2 by 3-6% across all maturities over Cochrane and Piazzesi (2005) and Ludvigson and Ng (2009) factors. The effects are highly statistically and economically significant both in and out of sample. We find that our result is robust to and is not driven by information from open interest in the futures market, long-run inflation expectations, dispersion in beliefs, and funding liquidity. We argue that stock market illiquidity is a timely variable that is related to "right-to-quality" episodes and might contain information about expected future business conditions through funding liquidity and investment channels.

When studying histological characteristics of porcine pancreata in relation to islet isolation, a remarkably high number of hyperemic islets (HIs) was encountered. The abnormalities observed in these HIs ranged from a single dilated vessel to hemorrhages extending into the surrounding exocrine tissue. The aim of the present study was to compare pancreata with and without HI on islet isolation outcomes. This study involved a histological examination of 143 purebred (74 juvenile and 69 adult) and 47 crossbred (only juvenile) porcine pancreata. Islet isolation was performed in 48 purebred adult pigs and in 25 crossbred pigs. Tissue samples were stained with Aldehyde Fuchsine. The presence of HIs was scored semi-quantitatively (HI-, HI+). We observed HIs in 48% of the purebred and in 68% of the crossbred pigs. However, only 3.3 +/- 3.1% and 3.1 +/- 4.7% of all assessed islets was hyperemic in HI+ pancreata in purebred and crossbred pigs, respectively. In both groups, significantly higher endocrine cell mass was found in the HI+ pancreata (p

When studying histological characteristics of human donor-pancreata, a remarkably high number of hyperemic islets (HIs) were encountered. The abnormalities in these HIs ranged from single/multiple dilated vessels to hemorrhages extending into the exocrine tissue. We aimed to determine the relevance of the presence of HIs in human donor-pancreata for isolation outcome and to identify donor and procurement factors associated with the occurrence of HIs. The presence of HIs was scored semi-quantitatively (HI-, HI+) in 102 human donor-pancreata. Islet isolation was performed in 40 cases. Donor and procurement factors were retrospectively analyzed in 94 donors. HIs were found in 54.6% of all donor-pancreata. However, only 4.5% of all islets in the affected pancreata was hyperemic. The affected pancreata contained slightly more endocrine tissue, but produced significantly lower yields. When corrected for other factors known to influence isolation outcome, the presence of HIs and endocrine content were the only factors significantly influencing isolation outcome. Prolonged ICU stay and pre-procurement hypertension were associated with the presence of HIs. This study is a first indication that the presence of HIs in human donor-pancreata are associated with reduced isolation outcomes and suggest an impact of the procurement procedure and pre-procurement hemodynamic status of the donor on the islet quality. It is tempting to speculate that this contributes to the generally experienced difficulties in obtaining sufficient amounts of human islets.

The paper presents an arbitrage-free yield model based on macro-portfolio dynamics. Apart from a level factor, detrended portfolio values serve as factors for the yield model. Using trend-balanced portfolios and parameters in terms of the instantaneous mean-variance frontier, risk premia and yield curve dynamics are modeled in a natural, integrated, parsimonious way. Positivity constraints on parameters and factors are formulated that guarantee the model is well posed. In an empirical analysis a four-factor model is applied to daily US Treasury yields. We estimate by quasi-maximum likelihood using the unscented Kalman filter. The model fits well, while the estimates of both parameters and factors satisfy the positivity constraints. The analysis reveals a strong link between business cycle variation in yields and risk premia.

To evaluate whether further improvement in porcine islet xenotransplantation is feasible, a number of questions were addressed. Earlier we showed significant improvement in the nude mouse of the porcine islets by selection through long-term culture. Now these islets were tested in the stringent pig-to-rat model. Islets were isolated from adult pigs, cultured for 1.5–3 weeks and transplanted to rats. Possible rejection mechanisms were assessed by interference of the cellular response with cyclosporine A (CsA), blocking macrophages with gadolinium chloride (GdCl), and suppressing the humoral response with cyclophosphamide. Modifications in graft size and condition were analyzed. Untreated control recipients showed primary nonfunction (PNF). CsA treatment could fully overcome PNF and resulted in graft survival from 10 to over 134 days. Rejection was the main cause of function loss. Although rejection could not be prevented by intensifying the induction therapy, increased maintenance immunosuppression effectively blocked rejection, albeit at the expense of toxicity. Blocking the humoral response was ineffective; all grafts showed PNF. In contrast, depletion of macrophages fully prevented PNF. Combination of GdCl and CsA gave no additional effect, and grafts were rejected between 57 and 162 days. Generally, graft survivals were similar to those reported in the literature; however, long-term cultured islets required much less maintenance immunosuppression. Cessation of graft function was not always due to rejection; in some cases “islet exhaustion” was found, possibly caused by discrepancy between the graft size and the rapidly growing recipient. Neither the presence of damaged islet tissue in the graft nor the size of the graft exerted any influence on graft survival. On rejection, no real infiltration of the graft was seen; destruction gradually processed from the outside. The good functional capability of the cultured islets was illustrated by disappearance of the clinical symptoms and increase in body weight, which almost doubled in the long-term survivors.

Motivated by yield curve modeling, we solve dynamic mean-variance efficiency problems in both discrete and continuous time. Our solution applies to both complete and incomplete markets and we do not require the existence of a riskless asset, which is relevant for yield curve modeling. Stochastic market parameters are incorporated using a vector of state variables. In particular for markets with deterministic parameters, we provide explicit solutions. In such markets, where no riskless asset need be present, we describe term-independent uniformly mean-variance efficient investment strategies. For constant parameters we show the existence of a unique, symmetrically distributed, trend stationary, uniformly MV efficient strategy.

The success of human islet isolation is hampered by the varied and unpredictable outcomes of the islet isolation procedure. Pancreata which meet well-defined criteria are no guarantee for success. Interindividual variations may contribute to the differences in isolation outcomes. The present study examined several structural elements in the anatomy of the human pancreas for possible relevance for islet isolation. Sixty pancreata were used for histochemical and immunochemical analyses. We assessed the total percentage of endocrine tissue and the size distribution of the islets. Sirius Red staining quantified total collagen content; the degree of islet encapsulation with collagen was correlated with total collagen. We analyzed the percentage of pancreatic edema and amount of intraparenchymal fat. The percentage of endocrine tissue varied 5-fold with wide variations in islet size distribution. A strong variation was observed for total collagen; its content increased slightly with age. The number of islets totally encapsulated with collagen varied strongly with no relation to age or to total collagen. Pancreatic edema and intraparenchymal fat also showed great differences. These differences justifies continued study to evaluate the correlation of these variables with isolation outcomes.

Low yield and insufficient purity limit the transplantation of human islets of Langerhans. In the rat, a new technique to isolate the islets of Langerhans was developed by intraarterial infusion of iron particles into the islet capillaries. After digestion the iron-loaded islets were purified with magnetic retraction (MR). In the present study, 10 human pancreata not suitable for clinical use were arterially injected with an iron-oxide suspension. After injection a small piece was used for histological analysis, and the tail was intraductally perfused with collagenase and manually digested. The yield was compared with 11 pancreata processed in the standard way. Nine of 10 pancreata were successfully injected with iron-oxide and digested. After MR, enrichment was achieved but the purity was not more than 50%. Similar results between the 2 groups were obtained regarding digestion times (23 ± 1.1 vs 22.7 ± 1.5 minutes) and purification yields (1749 ± 502.1 vs 2111 ± 501.8 IE/g, P = .6) for the MR vs control groups, respectively. Histological analysis revealed that 60% to 88% of the islets contained iron aggregations with substantially higher concentrations compared with the exocrine tissue. In conclusion, iron-oxide did not influence the isolation outcome before purification. Islet purification with MR gave enrichment but no pure fractions.

Most studies on the immunomodulating effects of interferon-gamma (IFN-gamma) have been performed in vitro, using recombinant mouse and human IFN-gamma preparations. Recently, recombinant rat IFN-gamma (rRIFN-gamma) became available, enabling extensive studies with this new preparation in vivo. In the present study a LEW rat model was used to determine the efficacy of rRIFN-gamma on immune functions in vivo. LEW rats were treated with rRIFN-gamma by continuous intravenous infusion at a dosage of 1.5 x 10(5) U/kg.h for 2 consecutive days. Twelve hours after cessation of rRIFN-gamma administration immune functions, including NK-cell activity, phagocytosis, and mitogen-induced blastogenesis, were assessed. All experimental animals displayed a marked reduction in the number of peripheral blood and bone marrow cells when compared with controls (p less than 0.005). Assessment of immune functions revealed a significant enhancement of NK-cell activity (p less than 0.001), phagocytosis (p less than 0.05), and mitogen-induced blastogenesis (p less than 0.05). These findings indicate that rRIFN-gamma, when given in high dosages, has a stimulatory effect on various immune functions, which substantiates its important immunological role in vivo.

OBJECTIVES The pig is generally considered a suitable alternative donor for clinical islet transplantation. However, adult pig islets are difficult to isolate and culture, often behave variably in in vitro assays, and do not consistently cure diabetic nude mice. In this study, we compared the in vivo function of freshly isolated and cultured adult porcine islets by transplantation in diabetic nude mice. METHODS Freshly isolated and cultured islets were transplanted in different doses to diabetic nude mice (N = 48). RESULTS Average islet yield was 1924 islet-equivalents per gram of pancreas, purity 96%, and the viability that was measured by acridine orange and propidium iodide was greater than 80% in all freshly isolated islet preparations. Grafts of freshly isolated islets failed to reduce hyperglycemia in 17 of 18 recipients. Although after 1 day of culture islet recovery was only 21%, grafts of these islets cured 12 of 17 mice. After 7 to 14 days of culture, the recovery had decreased to 11%; however, these islets reversed hyperglycemia in all mice (13/13) and showed shorter time-to-normoglycemia and more tightly regulated blood glucose. CONCLUSIONS Although freshly isolated adult porcine islets survive culture and transplantation poorly, islets selected by prolonged culture are of high potential.

Since 1921 and until recently, insulin by injection has been the only treatment for patients with diabetes mellitus type 1. After pancreas transplantation, which became possible in 1977, the next logical step to cure patients with diabetes mellitus type 1 is the transplantation of the islets of Langerhans. In the last few years, the results of islet transplantation are markedly improved thanks to developments in the isolation technique and better immunosuppressive protocols. Ongoing problems in islet transplantation are allo-immunity, auto-immunity and the growing shortage of donor pancreases. Alternatives to pancreas donation, be it post-mortem or from a living donor, could be: sources for islets are xenotransplantation with the aid of pig islets and beta-cell neogenesis from embryonic stem cells or pancreatic duct cells.

The effects of pre-transplant blood transfusion vary from induction of antibodies and accelerated graft rejection, to prolonged survival and even tolerance. The beneficial 'transfusion effect' in allotransplantation is believed to be merely T-cell mediated. In xenotransplantation, T-cell independent mechanisms form a major hurdle. In this study we investigated the effects of pre-transplant hamster blood transfusion on the survival of hamster cardiac xenografts in T-cell deficient athymic nude rats. Nude rats rejected xenografts after 3.8 +/- 0.5 d (n = 8), and immunocompetent Lewis rats after 4.0 +/- 0.5 d (n = 8), following a similar IgM response (P = NS). Hamster blood transfusion 3 d before transplantation in nude rats led to an IgM response and long-term xenograft survival in 17/20. Timing was of importance: blood transfusion 7 d before transplantation resulted in 45% long-term xenograft survival (n = 20). Injection of purified hamster erythrocytes, leukocytes or minced heart also led to survival of xenografts for100 d in nude rats, but not in all cases. Second xenografts transplanted to long-term survivors did not provoke an IigM response, and were accepted for100 d (n = 4). Transfer of serum from long-term survivors to untreated nude rats resulted in survival of xenografts for100 d (n = 4). In Lewis rats pre-transplant blood transfusion induced hyperacute rejection of xenografts after 158 +/- 128 min (n = 8, P0.01). We conclude that pre-transplant hamster blood transfusion can induce long-term survival of hamster cardiac xenografts in T-cell deficient athymic nude rats. This blood transfusion effect is mediated by humoral factors and can be transferred by serum. Elucidation of underlying mechanisms might provide some insight into xenotransplantation nonresponsiveness of T-cell independent immunefactors.

Antibodies play a crucial role in the rejection of xenografts. We tested the hypothesis that xenografts are protected against antibody-mediated attack early after transplantation in a concordant model. We investigated the role of xenoreactive antibodies as a stimulus for protection and the effects of a total blockade of the antibody response by the leflunomide analog malononitrilamide 279. Hamster cardiac xenografts were transplanted to Lewis rat recipients. Second transplants and retransplants of xenografts were performed to untreated rats that had a xenograft in place for 3 d. Untreated rats rejected hamster cardiac xenografts after 4.0 +/- 0.0 d. Significant levels of anti-donor IgM, as measured by flowcytometry, were present on day 3 after transplantation (11.2% +/- 2.8 vs. 1.2% +/- 0.0 on day 0, P0.001). 'Fresh' second xenografts transplanted to rats that had a first xenograft in place for 3 d and had anti-hamster antibodies, underwent hyperacute rejection. The first xenografts remained functioning. Xenografts that were removed on day 3 from untreated rats and then retransplanted remained functioning. Xenografts that were removed on d 3 from rats that had been treated with malononitrilamide 279, 15 mg/kg/d and were retransplanted underwent hyperacute rejection. IgM levels at the time of removal were 1.1% +/- 0.5 in these rats and not different from baseline (P = 0.96). We conclude that xenografts are protected against antibody-mediated damage early after transplantation. The presence of anti-donor antibodies might be an essential stimulus for the induction of protection. There seems to be a delicate balance between the injurious and protective effects of antibodies. Treatment strategies that are designed to block antibody formation completely might prevent the induction of protection.

IN a previous study we demonstrated that porcine islets of Langerhans transplanted to monkeys will not be hyperacutely rejected. In immunosuppressed monkeys (cycplophosphamide, cyclosporine [CyA], and prednisolone) rejection occurred in the second week posttransplantation. Rejection infiltrates were dominated by T cells. We therefore wanted to investigate whether a more T-cell-directed immunosuppressive regimen could improve graft survival. Our aim was to deplete recipients of T cells prior to transplantation (using ATG) and prevent rejection posttransplantation using a combination of CyA, prednisolone, and anti-IL-2R antibody (Zenapax).

Experiments were performed in accordance with the “Principles of Laboratory Animal Care” (NIH publication No. 85-23, revised 1985) and institutional guidelines. Four outbred cynomolgous monkeys (Macaca fascicularis; Biomedical Primate Research Centre, Rijswijk, The Netherlands) weighing 5 to 12 kg were used. Pancreata from large sows were obtained from a local slaughterhouse. Highly purified (.95%) islets were cultured 1 to 2 weeks in RPMI with 20 mmol/L HEPES and 10% porcine serum at 37°C in ambient air. These islets were grafted under the capsule of both kidneys of the monkeys, which received cyclophosphamide (day 21 40 mg/kg, day 11 10 mg/kg), cyclosporine (CyA) intramuscularly (IM) and orally, reaching at least 600 ng/mL trough levels, and prednisolone (1 mg/kg/d). Monkey anti-pig antibodies were assessed by a hemolytic complement-dependent assay.

Primary nonfunction (PNF) is seen very frequently after xenogeneic transplantation of islets of Langerhans. In a pig-to-rat model we recently observed that no PNF occurs when the islets are kept in culture at 37°C for 1–2 weeks prior to transplantation. In order to investigate the rejection mechanisms in a preclinical model, we transplanted cultured porcine islets under the capsule of both kidneys in four cynomolgous monkeys. Islets were isolated from adult sows by means of digestion with Liberase in University of Wisconsin solution (UWS). The digest was purified by a density gradient of OptiPrep in UWS. Highly purified (>95%) islets were cultured 1–2 weeks in RPMI. All monkeys showed significant titers of preformed anti-pig antibodies. The immunosuppression of the monkeys consisted of cyclophosphamide (Cy) (2 days), cyclosporin A (CsA), and prednisolone. Anticipating a fast rejection we carried out nephrectomies at different time points within 2 weeks after transplantation. Following unilateral nephrectomy, well-preserved islets with no signs of rejection were observed between 3 and 7 days posttransplant. Later, between days 11 and 15 posttransplant, histology in the first three animals demonstrated no islets. In the fourth monkey histology on day 11 showed islets with excellent morphology and some small focal infiltrates. The highest CsA blood levels (around 1000 ng/ml) were found in animals with the best graft survival. We conclude that cultured porcine islets can be grafted without hyperacute rejection in monkeys with preformed anti-pig antibodies. In the presence of high levels of CsA only marginal signs of a cellular immune response were observed 11 days after transplantation.

Xenotransplantation of porcine islets of Langerhans is considered to be a possible alternative for clinical islet transplantation. However, porcine islet isolation procedures have been shown to produce highly variable yields between pigs with similar backgrounds. One of the variables that could account for this is the collagen substrate within the pancreas. We determined the amount and distribution of collagen within porcine pancreata as they determined islet isolation outcomes. This study involved the histological examination of 140 porcine pancreata (64 juvenile and 76 adult) and islet isolation from 58 adult organs. To quantify the amount of collagen, tissue samples were stained with Sirius Red. Collagen distribution was determined by assessing the presence of collagen in the endocrine-exocrine interface (the "islet capsule"), in tissue samples double-stained with Sirius Red and anti-insulin. Strong variation in total collagen was observed in both adult and juvenile pigs. The mean collagen content in the juvenile group was significantly lower than that in the adult group. Apparently, the pancreas undergoes a process of fibrosis as pigs age. The vast majority of islets from both adult and juvenile pancreata had no or only a limited collagen capsule. However, islet encapsulation was highly variable between pancreata. We observed no significant correlation between total collagen content or the percentage islet encapsulation and islet yield. Although total collagen content and islet encapsulation show great variability between pancreata, neither the amount nor the distribution of collagen affected porcine islet isolation outcome.

In the near future, xenotransplantation of porcine islets of Langerhans might be an alternative in the treatment of patients with diabetes mellitus. However, xenotransplantation of islets of Langerhans in large animals has been shown to result in an exceedingly short graft survival, which suggests that a humoral immune response might play a major role in islet demise. This study was performed to assess binding human preformed antibodies to isolated porcine islet cells (PIC) and to determine the lysis of PIC using human sera in complement-mediated cytotoxicity (CMC) and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. Ten Dutch Landrace pigs were used for the isolation of PIC. Sera from 30 healthy blood donors (1/10 diluted) were used in a 51Cr release assay to assess CMC. Heat-inactivated normal human sera and fresh sera from patients with agammaglobulinemia were used as controls. Binding of human IgM IgG, and IgA antibodies to PIC was tested in an ELISA using isotype-specific secondary monoclonal antibodies ADCC was tested in a 51Cr release assay using normal human sera and sera from newly diagnosed type I diabetics with peripheral blood mononuclear cells as effector cells and PIC as targets. It was found that PIC were recognized by human IgM and IgG preformed antibodies and that fresh human sera had strong CMC activity inducing a percentage-specific PIC lysis of 61 +/- 10% (mean +/- SD) within 60 min. Agammaglobulinemic sera killed 42 +/- 12% of PIC. No significant cytotoxic activity was found in ADCC assays using normal sera or sera from diabetic patients. These results show that all tested human sera lyse PIC via CMC, even in the absence of human antibodies, as concluded from the use of agammaglobulinemic sera. In pig-to-human transplantation, islets may be hyperacutely rejected by antibody-dependent and antibody-independent activation of complement and not by antibody-dependent cell-mediated mechanisms.