Placebo Tests for Causal Inference

Placebo tests are increasingly common in applied social science research, but the methodological literature has not previously offered a comprehensive account of what we learn from them. We define placebo tests as tools for assessing the plausibility of the assumptions underlying a research design relative to some departure from those assumptions. We offer a typology of tests defined by the aspect of the research design that is altered to produce it (outcome, treatment, or population) and the type of assumption that is tested (bias assumptions or distributional assumptions). Our formal framework clarifies the extra assumptions necessary for informative placebo tests; these assumptions can be strong, and in some cases similar assumptions would justify a different procedure allowing the researcher to relax the research design's assumptions rather than test them. Properly designed and interpreted, placebo tests can be an important device for assessing the credibility of empirical research designs

Thaumatin-like proteins are differentially expressed and localized in phloem tissues of hybrid poplar

<p>Abstract</p> <p>Background</p> <p>Two thaumatin-like proteins (TLPs) were previously identified in phloem exudate of hybrid poplar (<it>Populus trichocarpa </it>× <it>P. deltoides) </it>using proteomics methods, and their sieve element localization confirmed by immunofluorescence. In the current study, we analyzed different tissues to further understand TLP expression and localization in poplar, and used immunogold labelling to determine intracellular localization.</p> <p>Results</p> <p>Immunofluorescence using a TLP antiserum confirmed the presence of TLP in punctate, organelle-like structures within sieve elements. On western blots, the antiserum labeled two constitutively expressed proteins with distinct expression patterns. Immunogold labelling suggested that TLPs are associated with starch granules and starch-containing plastids in sieve elements and phloem parenchyma cells. In addition, the antiserum recognized TLPs in the inner cell wall and sieve plate region of sieve elements.</p> <p>Conclusions</p> <p>TLP localization in poplar cells and tissues is complex. TLP1 is expressed predominantly in tissues with a prominent vascular system such as midveins, petioles and stems, whereas the second TLP is primarily expressed in starch-storing plastids found in young leaves and the shoot apex.</p

Defects of the Broad Ligament of the Uterus

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74780/1/j.1572-0241.1986.tb01505.x.pd

Augmenter of liver regeneration enhances the success rate of fetal pancreas transplantation in rodents

Background. Treatment of fetal pancreas (FP) isografts with insulin- like growth factor-I greatly improves the rate of conversion to euglycemia in diabetic rats. Complete knowledge of other factors that may facilitate the engraftment and function of FP in vivo is still embryonic. Augmenter of liver regeneration (ALR) is a newly described polypeptide growth factor found in weanling rat livers. ALR has trophic effects on regenerating liver. We studied the effects of in situ administration of this agent on FP isografts in rats. Methods. Streptozotocin-diabetic Lewis rats (blood glucose >300 mg/dl) received 16 FP isografts transplanted intramuscularly. ALR was delivered from day 1 through day 14, in doses of 40 or 400 ng/kg/d. Animals were followed for 3 months with serial weights and blood glucose monitoring. These animals were compared with those treated with vehicle alone. Results. Of the group treated with ALR at 40 ng/kg/day for 14 days, 89% (eight of nine) were euglycemic (P=0.0003). Of the group treated with ALR at 400 ng/kg/day for 14 days, 88% (seven of eight) were euglycemic (P=0.0007). Of the group treated with vehicle alone, none of the six were euglycemic. Euglycemia is defined here as glucose<200 mg/dl for 3 days. Pathology of the intramuscular transplant site showed patches of islet tissue embedded in fat. These patches demonstrated insulin immunoreactivity. Conclusions. Diabetes was reversed in a significantly greater proportion of FP + ALR-treated recipients than those animals treated with vehicle alone. Local delivery of growth factors my be used as an adjunct to FP transplantation to improve the rate of success. This in situ model may be useful to further evaluate other soluble factors

Current Management of Patients With Acquired Solitary Kidney.

Persons with acquired solitary kidney, including those who have had a unilateral nephrectomy for living kidney donation, renal malignancies, or trauma, have decreased renal mass that leads to increased intraglomerular pressure and glomerular hyperfiltration. These physiologic adaptations of solitary kidney may exacerbate other preexisting and genetic conditions that could create a predisposition to or worsen glomerular pathologies, leading to unfavorable renal outcomes. Hence, these persons may benefit from special care and lifestyle modifications, including nutritional interventions. There is a lack of consensus and evidence for proper surveillance and management after nephrectomy, and misconceptions in both directions of having a "normal" versus "abnormal" kidney status may cause confusion among patients and healthcare providers pertaining to long-term kidney health monitoring and management. We have reviewed available data on the impact of lifestyle modifications, particularly nutritional measures, and pharmacologic interventions, on short- and long-term outcomes after nephrectomy. We recommend avoidance of excessively high dietary protein intake (&gt;1 g/kg per day) and high dietary sodium intake (&gt;4 grams/d), adequate dietary fiber intake from plant-based foods, a target body mass index of&nbsp;&lt;30 kg/m2 (in non-athletes and non-bodybuilders), and judicious management of risk factors of progressive chronic kidney disease (CKD), and future studies should help to better determine optimal care practices for these persons

Influence of breast feeding on subsequent reactivity to a related renal allograft

In a previous report the hypothesis that exposure of the neonate to maternal allogeneic cells via the process of breast feeding would result in hyporesponsiveness to a subsequent maternal donor-related renal transplant was examined. Support for this hypothesis was obtained after correlating results of maternal donor-related renal transplantation with the breast feeding status of the transplant recipient. In the present report this observation has been expanded upon and it was asked if a history of breast feeding was associated with improved results in a different patient population (HLA semi-identical sibling donors). Breast-fed patients showed dramatic improvements in graft function rates compared to non-breast-fed counterparts at all intervals studied (P [les] 0.001). Because a history of breast feeding correlated with improved results after sibling donor as well as maternal donor transplantation, it was concluded that the breast feeding effect is not entirely specific for maternal antigens. These observations underscore the importance of breast feeding as a variable in clinical-related renal transplantation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24730/1/0000152.pd

Preparation of islets of Langerhans from the hamster pancreas

We describe a method for the preparation of viable islets from the pancreas of normal 8-week-old female Syrian golden hamster, based on the injection of the pancreatic duct with collagenase and on mechanical dissociation which liberates islets that maintain their normal morphological appearance and physiologic function. In a series of 11 animals, we examined the dose response of intraductal collagenase on islet yield. The mean number of isolated islets was 423 with a range from 130 to 873 per pancreas. Islet yield was most dependent on the concentration of collagenase solution used to inject the duct. The optimal concentration was determined to be 3.5 mg/ml when a total volume of 3.0 ml was injected. Islets responded to glucose stimulus in a normal biphasic pattern. Mesh filtration, rather than Ficoll, can be performed rapidly and results in a high yield of functional islets with minimal contamination by acinar tissue.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27386/1/0000417.pd

Peripheral blood catalase in patients undergoing renal transplantation

Oxygen free radicals are mediators of tissue injury and catalase is an enzyme which is involved in limiting this process. We examined peripheral blood catalase activity (PBCA) to assess its value as a marker in detecting tissue injury related to renal allograft rejection. Thirty-one consecutive recipients of kidney (n = 29) or simultaneous kidney/pancreas (n = 2) transplants and 10 normal volunteers were studied. Catalase activity, measured by the disk-flotation method, was expressed as Sigma units x 10-3/ml (SU/ml) of whole blood. Normal PBCA was determined to be greater than 76 SU/ml. Twenty-nine episodes of renal allograft rejection (diagnosed by clinical criteria +/- biopsy [79%]) were observed in 26 patients. PBCA (mean +/- SEM) was found to be low (64 +/- 1 SU/ml) in 28/29 episodes ([chi]2 = 46.3, P &lt; 0.001), and the decrease (at least two consecutive daily catalase values &lt; 76 SU/ml) occurred 2 days prior to the clinical/biopsy diagnosis of rejection in 26/28 episodes. The sensitivity of PBCA as a discriminant of rejection was 97%, specificity was 96%, and test accuracy was 96%. PBCA less than 50 SU/ml on two or more occasions occurred in five cases and transplant nephrectomy was required in four of these because of uncontrollable rejection. Nine episodes of cyclosporine nephrotoxicity occurred in 7 patients and none of these episodes was associated with a decreased PBCA. Our data suggest that decreased PBCA is a sensitive and specific indicator of renal allograft rejection. PBCA remains normal during episodes of cyclosporine nephrotoxicity and therefore provides a rapid and inexpensive discriminant from allograft rejection.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27320/1/0000343.pd

Quantitative scintigraphy with deconvolutional analysis for the dynamic measurement of hepatic function

A mathematical technique known as deconvolutional analysis was used to provide a critical and previously missing element in the computations required to quantitate hepatic function scintigraphically. This computer-assisted technique allowed for the determination of the time required, in minutes, of a labeled bilirubin analog (99mTc-disofenin) to enter the liver via blood and exit via bile. This interval was referred to as the mean transit time (MTT). The critical process provided for by deconvolution is the mathematical simulation of a bolus injection of tracer directly into the afferent blood supply of the liver. The raw data required for this simulation are obtained from the intravenous injection of labeled disofenin, a member of the HIDA family of radiopharmaceuticals. In this study, we perform experiments which document that the simulation process itself is accurate. We then calculate the MTT under a variety of experimental conditions involving progressive hepatic ischemia/reperfusion injury and correlate these results with the results of simultaneously performed BSP determinations and hepatic histology. The experimental group with the most pronounced histologic findings (necrosis, vacuolization, disorganization of hepatic cords) also have the most prolonged MTT and BSP half-life. However, both quantitative imaging and BSP testing are able to identify milder degrees of hepatic ischemic injury not reflected in the histologic evaluation. Quantitative imaging with deconvolutional analysis is a technique easily adaptable to the standard nuclear medicine minicomputer. It provides rapid results and appears to be a sensitive monitor of hepatic functional disturbances resulting from ischemia and reperfusion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26699/1/0000247.pd

Endothelial Cells in Co-culture Enhance Embryonic Stem Cell Differentiation to Pancreatic Progenitors and Insulin-Producing Cells through BMP Signaling

Endothelial cells (ECs) represent the major component of the embryonic pancreatic niche and play a key role in the differentiation of insulin-producing β cells in vivo. However, it is unknown if ECs promote such differentiation in vitro. We investigated whether interaction of ECs with mouse embryoid bodies (EBs) in culture promotes differentiation of pancreatic progenitors and insulin-producing cells and the mechanisms involved. We developed a co-culture system of mouse EBs and human microvascular ECs (HMECs). An increase in the expression of the pancreatic markers PDX-1, Ngn3, Nkx6.1, proinsulin, GLUT-2, and Ptf1a was observed at the interface between EBs and ECs (EB-EC). No expression of these markers was found at the periphery of EBs cultured without ECs or those co-cultured with mouse embryonic fibroblasts (MEFs). At EB-EC interface, proinsulin and Nkx6.1 positive cells co-expressed phospho-Smad1/5/8 (pSmad1/5/8). Therefore, EBs were treated with HMEC conditioned media (HMEC-CM) suspecting soluble factors involved in bone morphogenetic protein (BMP) pathway activation. Upregulation of PDX-1, Ngn3, Nkx6.1, insulin-1, insulin-2, amylin, SUR1, GKS, and amylase as well as down-regulation of SST were detected in treated EBs. In addition, higher expression of BMP-2/-4 and their receptor (BMPR1A) were also found in these EBs. Recombinant human BMP-2 (rhBMP-2) mimicked the effects of the HMEC-CM on EBs. Noggin (NOG), a BMP antagonist, partially inhibited these effects. These results indicate that the differentiation of EBs to pancreatic progenitors and insulin-producing cells can be enhanced by ECs in vitro and that BMP pathway activation is central to this process