‘Saviour Siblings’? The Distinction between PGD with HLA Tissue Typing and Preimplantation HLA Tissue Typing

One of the more controversial uses of preimplantation genetic diagnosis (PGD) involves selecting embryos with a specific tissue type so that the child to be born can act as a donor to an existing sibling who requires a haematopoietic stem cell transplant. PGD with HLA tissue typing is used to select embryos that are free of a familial genetic disease and that are also a tissue match for an existing sibling who requires a transplant. Preimplantation HLA tissue typing occurs when parents select embryos that are not at risk of a familial genetic disease to be a match for an existing sibling who requires a transplant. In Victoria, Australia, applications to use PGD with HLA tissue typing are reviewed by the Infertility Treatment Authority on a case by case basis. Preimplantation HLA tissue typing is prohibited prima facie because the embryo to be tested would not be at risk for a genetic abnormality or disease. Arguments for or against the use of PGD/HLA tissue typing are based on several key issues including the commodification and welfare of the donor child. This essay aims to show that that the same arguments apply to both PGD with HLA tissue typing and Preimplantation HLA tissue typing, and that the policy distinction between the two procedures is therefore ethically inconsistent.     

Infections and human tissue transplants: review of FDA MedWatch reports 2001–2004

Background More than 1.5 million tissue allografts are transplanted annually in the U.S. As part of the federal effort to improve tissue safety, FDA’s May 2005 Current Good Tissue Practices (CGTP) Rule requires tissue establishments to report to FDA serious infectious adverse events following allograft transplantation. To provide baseline data, we summarize reports of such infections received by FDA prior to the CGTP Rule. Methods We reviewed reports received by FDA’s MedWatch adverse event reporting system during 2001–2004. Our case definition was a reported infection in a human tissue transplant recipient within 1 year of transplantation. We examined demographics, tissue type, clinical outcomes and interventions, infectious organism(s), time from transplant to infection and reporter characteristics. Results We identified 83 reports of infections following allograft transplantations. Median patient age was 40 years (range: 1 month–87 years). The allografts included heart valves (42%), tendons (33%), bones (8%), blood vessels (6%), ocular tissues (5%), and skin (4%). Commonly reported outcomes and interventions were hospitalization (72%), antibiotic therapy (46%) and graft removal (42%). Nine of 11 patients who expired had received heart valves. In 65 reports that identified suspected organisms, bacteria were most common (42), followed by fungi (25) and prions (1). The median time from transplant to infection was 5.5 weeks (range: 3 days–52 weeks). Tissue manufacturers submitted 26% of reports. Among the remaining 74%, the reporters were quality assurance staff, infection control or risk management personnel (45%); physicians (15%); consumers (15%); nurses (13%); and surgical staff (12%). Conclusion This is the first review of reports to FDA for infections following allograft tissue transplantations. Infections led to serious outcomes and involved many tissue types. Although we were unable to confirm that reported infections were caused by the suspected tissue product, required reporting by tissue establishments and improvements in adverse event investigation will help to improve tissue safety surveillance.     

Scleritis and associated disease.

One hundred patients (66 women and 34 men) who presented consecutively to Moorfields Eye Hospital with scleral disease underwent medical examination. Thirteen were found to have seropositive rheumatoid arthritis and another 16 also had rheumatoid factor present (Rheumaton test). Autoantibodies were present in 35% of patients, being most common in the elderly and most frequent in cases of necrotising and diffuse scleritis. Although scleral disease is uncommon, it is associated with connective-tissue disorders. Scleritis may be severe and destructive locally, and one series showed that 27% of patients who develop necrotising scleritis are dead from systemic complications within five years. It is therefore important for it to be correctly diagnosed and effectively treated at an early stage.     

Computed tomography in the Multidisciplinary Science and Technology Complex "Eye Microsurgery"

The paper is devoted to analysis of the results of CT in 1000 patients examined in the Multibranch Research and Technology Complex "Eye Microsurgery". The specific feature of CT in this institution is that 52% of all investigations of ophthalmological patients fall to the share of eyeball abnormality and 40%--to a study of the other parts of the organ of vision. CT indications are extended for low tension glaucoma, complicated high myopia, and for monitoring the position of microsurgical implants. The use of CT in such a highly specialized medical institution as the MRTC "Eye Microsurgery" is considered indispensable.     

Impact of left ventricular assist device (LVAD) support on the cardiac reverse remodeling process

With improved technology and expanding indications for use, left ventricular assist devices (LVADs) are assuming a greater role in the care of patients with end-stage heart failure. Following LVAD implantation with the intention of bridge to transplant, it became evident that some patients exhibit substantial recovery of ventricular function. This prompted explantation of some devices in lieu of transplantation, the so-called bridge-to-recovery (BTR) therapy. However, clinical outcomes following these experiences are not always successful. Patients treated in this fashion have often progressed rapidly back to heart failure. Special knowledge has emerged from studies of hearts supported by LVADs that provides insights into the basic mechanisms of ventricular remodeling and possible limits of ventricular recovery. In general, it was these studies that spawned the concept of reverse remodeling now recognized as an important goal of many heart failure treatments. Important examples of myocardial and/or ventricular properties that do not regress towards normal during LVAD support include abnormal extracellular matrix metabolism, increased tissue angiotensin levels, myocardial stiffening and partial recovery of gene expression involved with metabolism. Nevertheless, studies of LVAD-heart interactions have led to the understanding that although we once considered the end-stage failing heart of patients near death to be irreversibly diseased, an unprecedented degree of myocardial recovery is possible, when given sufficient mechanical unloading and restoration of more normal neurohormonal milieu. Evidence supporting and unsupporting the notion of reverse remodeling and clinical implications of this process will be reviewed.     

Advances in umbilical cord blood transplantation

The first successful cord blood transplant was reported in 1989. In the last sixteen years, there has been a substantial increase in the use of cord blood as an alternative stem cell source for patients without matched related or unrelated bone marrow donors. Approximately 5000 cord blood transplants have been performed worldwide. Recently, the results in adult cord blood transplantation appear promising. In this review, the preclinical background, cord blood banking, and ethical issues will be briefly addressed. Outcome data for both pediatric and adult transplantation will be reviewed, with an emphasis on new strategies for adult cord blood transplantation. New indications for cord blood use outside of hematology/oncology will also be explored.     

Medical errors related to inappropriate genetic testing in liver transplant patients

Genetic testing of genes that encode proteins expressed by liver hepatocytes (clotting factors, alpha 1-antitrypsin, cytochrome P450 enzymes) is common in clinical practice. These tests use DNA extracted from peripheral blood lymphocytes (PBL) and are based on the assumption that PBL DNA can be used as a surrogate for hepatocyte DNA. However, in individuals who have undergone liver transplantation, hepatocyte DNA is that of the donor while PBL DNA remains that of the recipient. It follows that in liver transplant patients, genetic testing of the recipient's PBL DNA does not provide accurate results for proteins expressed by donor hepatocytes. Therefore, genetic testing of clotting factors, alpha 1-1-antitrypsin, cytochrome P450 enzymes, and other proteins expressed by hepatocytes is unreliable and inappropriate in liver transplant patients (inappropriate genetic testing). A review of the records of 215 consecutive liver transplant patients at our institution identified: one medical error and one near-miss medical error related to inappropriate genetic testing, 14 cases of inappropriate genetic testing, and 21 unnecessary duplicate genetic testing requests. We recommend laboratories performing genetic testing create systems to prevent inappropriate and duplicate genetic testing and that physicians be cognizant of the appropriate indications for genetic testing in liver transplant patients.     

Does increasing access-to-care delay accessing of care? Evidence from kidney transplantation

Policies increasing healthcare availability might decrease the cost of delaying accessing of care, leading to potential negative consequences if patients delay treatment. We analyze a policy designed to increase access to kidney transplantation through the use of time since dialysis inception to prioritize patients for transplant, which was piloted at 26 of the 271 kidney transplant centers in the United States in 2006 and 2007. We model the patient’s optimization problem comparing the benefits and costs of early waitlisting and predict that the policy change will lead to delayed waitlisting. To empirically test this prediction, we use difference-in-differences fixed effects panel regression techniques to analyze data on patients who began dialysis between 1/1/2000 and 12/31/2009. The results support the model’s prediction; patients on dialysis who waitlist for kidney transplantation increase pre-waitlist dialysis duration by 11.6 percent or approximately 76 days from a pre-policy mean of 652 days (SD = 654). With regard to waitlist outcomes, the policy is associated with a 4.5 percentage point decrease in the probability of receiving a deceased donor transplant, somewhat offset by a 3.0 percentage point increase in the probability of receiving a live donor transplant. On the extensive margin, patients on dialysis decrease their likelihood of ever waitlisting by 1.5 percentage points. We find an increase in pre-waitlist dialysis time and a decrease in the likelihood of waitlisting at all, especially among populations likely to have experienced increased access to transplantation through the policy change: patients self-identifying as Black or Hispanic rather than Non-Hispanic White, and patients without private insurance. These results suggest that some individuals may not benefit if their access to care increases, if the increase in access sufficiently decreases the penalty of delaying accessing of care.     

Social responsibility, personal responsibility, and prognosis in public judgments about transplant allocation

Background: Some members of the general public feel that patients who cause their own organ failure through smoking, alcohol use, or drug use should not receive equal priority for scarce transplantable organs. This may reflect a belief that these patients (1) cause their own illness, (2) have poor transplant prognoses or, (3) are simply unworthy. We explore the role that social acceptability, personal responsibility, and prognosis play in people's judgments about transplant allocation.
Methods: By random allocation, we presented 283 prospective jurors in Philadelphia county with one of five questionnaire versions. In all questionnaires, subjects were asked to distribute transplantable hearts between patients with and without a history of three controversial behaviors (eating high fat diets against doctors' advice, cigarette smoking, or intravenous drug use). Across the five questionnaire versions, we varied the relative prognosis of the transplant candidates and whether their behavior caused their primary organ
Results: Subjects were significantly less willing to distribute organs to intravenous drug users than to cigarette smokers or people eating high fat diets (p le; 0.0005), even when intravenous drug users had better transplant outcomes than other patients. Subjects' allocation decisions were influenced by transplant prognosis, but not by whether the behavior in question was causally responsible for the patients' organ failure.
Conclusion: People's unwillingness to give scarce transplantable organs to patients with controversial behaviors cannot be explained totally on the basis of those behaviors either causing their primary organ failure or making them have worse transplant prognoses. Instead, many people believe that such patients are simply less worthy of scarce transplantable organs.     

Video Capsule Endoscopy in Patients with Chronic Abdominal Pain with or without Associated Symptoms: A Retrospective Study

Background

Chronic abdominal pain (CAP) is a common indication for gastroenterology referrals. More insidious causes of CAP isolated to the small bowel, such as malignancies and Crohn’s disease, are rising in incidence and causing more gastroenterologists to evaluate their patients with video capsule endoscopy (VCE). However, the role of VCE in patients with CAP is still unclear.

Aims

We assessed the efficacy of VCE in patients with CAP and whether it led to findings that contributed to disease management and meaningful interventions.

Methods

This retrospective study evaluated 607 capsule endoscopy studies at an open referral endoscopy unit. Ninety of the studies were for CAP. These studies were compared to those performed for other indications to compare diagnostic yield. In addition, we investigated whether VCE led to an intervention that improved clinical outcomes.

Results

Overall, the number of abnormal findings in CAP patients was significantly lower than VCE performed for other indications (24.4% vs 39.0%, respectively p = 0.009). When patients with CAP presented with other pertinent clinical findings (e.g. nausea, weight loss, anemia, history of in inflammatory bowel disease, etc.), the likelihood of an abnormal finding increased to a level that was not different from those who received VCE for other indications (27.1%, p = 0.10). The findings from VCE lead to changed management and improved outcomes in 16.2% of CAP patients with associated symptoms. However, the subgroup that benefited the most were those who had a prior history of Crohn’s disease. Patients with CAP who did not have any associated symptoms continued to have a significantly lower abnormal finding rate compared to those who received VCE for other indications (19.4%, p = 0.03) and VCE rarely led to a change in management that would improve outcomes (5.6%).

Conclusions

VCE for CAP has a lower rate of abnormal findings than other indications. However, VCE is a useful diagnostic tool that can help provide a possible etiology of CAP in patients with associated symptoms. However, a change in management from VCE is likely to be limited to those with a history of Crohn’s disease.     

Developmental and morphological variation in the teleost craniofacial skeleton reveals an unusual mode of ossification

We investigated the morphology and development of the scleral ossicles within the eyes of three species from three basal teleost orders, namely, the alewife (Alosa pseudoharengus; Clupeiformes), the surface morph of the Mexican tetra (Astyanax mexicanus; Characiformes) and zebrafish (Danio rerio; Cypriniformes). Two morphologies, circular and elongated, and one variation, fused elements, were identified. Zebrafish have small circular ossicles, whereas the alewife and the Mexican tetra have elongated ossicles. Surprisingly in the Mexican tetra these elements fuse at one end forming a continuous element with an antero-ventral opening; this may be typical for the Order Characiformes. Regardless of morphology, the ossicles develop via unilateral perichondral ossification of the scleral cartilage from two centers opposite one another in the eye. This unilateral type of ossification, in which only the perichondrium furthest from the retina contributes to the ossicles, has not previously been reported in any vertebrate. Because either the perichondrium and/or an extension of the perichondrium can transform into the scleral ossicle, we refer to the transitional tissue as periskeletal. Although the functional significance of the different shaped ossicles is unclear, skeletal muscle attaches directly to these bones, implying voluntary control. The morphological and developmental variation of teleost scleral ossicles makes them an ideal system for determining the genetic basis underlying phenotypic variation as well as for studying mechanisms underlying osteogenic and chondrogenic processes in teleosts. These data support our previous finding that scleral ossicles in teleosts may not be homologous to those in other vertebrates, such as reptiles.     

Implementation of Organ Culture storage of donor corneas: a 3 year study of its impact on the corneal transplant wait list at the Lions New South Wales Eye Bank

Organ Culture corneal storage offers an extended storage time and increased donor pool and tissue assessment opportunities. In September 2011, the Lions New South Wales Eye Bank (LNSWEB) moved from hypothermic storage to Organ Culture corneal storage. This study evaluates the impact of implementation of Organ Culture on donor eye retrieval and the corneal transplant waiting list over a 3 year period in NSW, Australia. Retrospective review of the LNSWEB data from September 2011 to August 2014. Tissue collection, waiting list and tissue utilization data were recorded. The data from September 2008 to August 2011 for Optisol-GS storage was used for comparison. The annual donor and cornea collection rate increased 35 % and 44 % respectively with Organ Culture compared to Optisol-GS storage. The utilization rate of corneal tissue increased from 73.4 % with hypothermic storage to 77.2 % with Organ Culture storage. The transplant wait list decreased by 77.3 % from September 2011 to August 2014 and correlated with the increased rate of corneal transplantation (r = ?0.9381, p < 0.0001). No other factors impacting the wait list changed over this period. Corneas not used from either storage method were due to unacceptable endothelial cell density/viability. The contamination rate of corneas stored in Organ Culture medium was low at 1.74 %. The Organ Culture storage method increases the corneal donor pool available to Eye banks. The practical benefits of the extended storage time and increased donor assessment opportunities have directly led to an increase in corneal utilization rate and a significant decrease in recipient wait list time.     

Corneal donor tissue preparation for endothelial keratoplasty

Over the past ten years, corneal transplantation surgical techniques have undergone revolutionary changes. Since its inception, traditional full thickness corneal transplantation has been the treatment to restore sight in those limited by corneal disease. Some disadvantages to this approach include a high degree of post-operative astigmatism, lack of predictable refractive outcome, and disturbance to the ocular surface. The development of Descemet's stripping endothelial keratoplasty (DSEK), transplanting only the posterior corneal stroma, Descemet's membrane, and endothelium, has dramatically changed treatment of corneal endothelial disease. DSEK is performed through a smaller incision; this technique avoids 'open sky' surgery with its risk of hemorrhage or expulsion, decreases the incidence of postoperative wound dehiscence, reduces unpredictable refractive outcomes, and may decrease the rate of transplant rejection. Initially, cornea donor posterior lamellar dissection for DSEK was performed manually resulting in variable graft thickness and damage to the delicate corneal endothelial tissue during tissue processing. Automated lamellar dissection (Descemet's stripping automated endothelial keratoplasty, DSAEK) was developed to address these issues. Automated dissection utilizes the same technology as LASIK corneal flap creation with a mechanical microkeratome blade that helps to create uniform and thin tissue grafts for DSAEK surgery with minimal corneal endothelial cell loss in tissue processing. Eye banks have been providing full thickness corneas for surgical transplantation for many years. In 2006, eye banks began to develop methodologies for supplying precut corneal tissue for endothelial keratoplasty. With the input of corneal surgeons, eye banks have developed thorough protocols to safely and effectively prepare posterior lamellar tissue for DSAEK surgery. This can be performed preoperatively at the eye bank. Research shows no significant difference in terms of the quality of the tissue or patient outcomes using eye bank precut tissue versus surgeon-prepared tissue for DSAEK surgery. For most corneal surgeons, the availability of precut DSAEK corneal tissue saves time and money, and reduces the stress of performing the donor corneal dissection in the operating room. In part because of the ability of the eye banks to provide high quality posterior lamellar corneal in a timely manner, DSAEK has become the standard of care for surgical management of corneal endothelial disease. The procedure that we are describing is the preparation of the posterior lamellar cornea at the eye bank for transplantation in DSAEK surgery (Figure 1).     

Verifying surgical results and risk factors of the lateral thoracodorsal flap

In 1986, the combined use of the lateral thoracodorsal flap and an implant was introduced as an alternative method of delayed reconstruction of small to medium-size breasts for postmastectomy patients who are reluctant or unable to consider reconstruction by tissue expansion or by more extensive autologous tissue transplantation. So far, the technique has only been proven reproducible in Sweden. Postmastectomy radiotherapy has been proven to increase the risk of wound-healing complications after lateral thoracodorsal transplantation, and additional risk factors such as advanced age, obesity, smoking, and some general health characteristics have been indicated. The authors initiated a prospective study to assess the reproducibility of this technique outside Sweden and to confirm the proven risk factor, prove or refute the alleged ones, and possibly identify additional factors. Additionally, they applied the technique for immediate breast reconstruction and tried to expand the indications and applications of the lateral thoracodorsal flap even further. The authors report on their initial experience with 60 lateral thoracodorsal flaps and conclude that the use of this flap is a well-reproducible technique for breast reconstruction, with few complications leading to failure. Using the lateral thoracodorsal flap in combination with tissue expanders allows for reconstruction of breasts of larger than medium size. Moreover, the authors successfully applied fully deepithelialized lateral thoracodorsal flaps for additional indications. The statistical significance of postmastectomy radiotherapy as a risk factor could not be confirmed, but some general health characteristics were found to be significant patient-related risk factors. Out of five procedure-related characteristics, only increased flap length was proven to negatively influence the outcome of the procedure.     

Ethics of fetal tissue transplantation.

Now that the Clinton Administration has overturned the ban on federal funding for fetal tissue transplantation, old ethical issues renew their relevance and new ethical issues arise. Is fetal tissue transplantation necessary and beneficial? Are fetal rights violated by the use of fetal tissue in research? Is there a moral danger that the potential of fetal tissue donation will encourage elective abortions? Should pregnant women be allowed to designate specific fetal transplant recipients? What criteria should be used to select fetal tissue transplants? Whose consent should be required for the use of fetal tissue for transplantation? We review the current state of clinical research with fetal tissue transplantation, the legal history of fetal tissue research, the major arguments against the use of fetal tissue for transplantation, and the new postmoratorium ethical dilemmas. We include recommendations for guidelines to govern the medical treatment of fetal tissue in transplantation.     

Do CD4+ Foxp3+ Treg cells correlate with transplant outcomes: a systematic review on recipients of solid organ transplantation

Regulatory T cells (Tregs) are considered to be critical for the induction of transplant tolerance. Tregs counts were measured in blood, biopsy and urine sample after transplantation in many studies. Although not unanimous, some studies have suggested that Tregs is associated with better outcome and can also serve as an immune marker to predict the individual risk of rejection and identify tolerant patients. In this study, we systematically reviewed the correlation between Tregs and transplant outcomes, identifying if Tregs can predict transplant rejection and tolerance. A total of 22 articles were included and assessed, the results showed that Tregs in recipients are helpful to maintain a stable graft function, reduce acute/chronic rejection rate. And the Tregs in graft and urine, rather than in PBL, may have a better diagnostic value for transplant outcomes. However, since the low quality of included studies, results may be influenced by bias. More high quality studies with bigger sample size are still needed in future.     

Toward an understanding of the epithelial requirement for osteogenesis in scleral mesenchyme of the embryonic chick

Explants of scleral tissue from chick embryos of H.H. stage 29-36 (6-10 days of incubation) were used to determine if the epithelial-mesenchymal interaction which initiates scleral bone formation is cell contact, extracellular matrix, or diffusion mediated. Transfilter tissue recombinations, in which explanted interacting tissues are associated across interposing Nuclepore filters of various pore sizes and thicknesses, were performed with scleral mesenchyme and epithelium. When filters with pore sizes which would allow the passage of cell processes and diffusible substances were used, osteogenesis was initiated in the scleral mesenchyme. When cell processes were blocked with thicker filters or smaller pore sizes, bone formation still occurred, indicating that a diffusible substance mediates this tissue interaction. Further support for a diffusion-mediated interaction came from transfilter experiments using dialysis membranes to discriminate the size of the molecule(s), and Millipore filters to determine the distance over which these molecules travel. These experiments revealed that the scleral epithelial diffusible factor has a molecular weight of between 3500 and 6000 daltons, and acts over distances between 150 and 300 microns.     

Arguing by analogy in the fetal tissue debate

In the debate over fetal tissue use, an analogy is often drawn between removing organs from the body of a person who has been murdered to use for transplantation, and collecting tissue from an aborted fetus to use for the same purpose. The murder victim analogy is taken by its proponents to show that even if abortion is the moral equivalent of murder, there is still no good reason to refrain from using the fetal tissue, since as a society we do not see any problem about using organs from murder victims. However, I argue that the analogy between murder victims and aborted fetuses does not hold — the two situations are not the same in all morally relevant respects. Thus the murder victim analogy does not provide an argument in favour of fetal tissue transplant. In conclusion, I point to some of the potential pitfalls of using analogies in ethical argument.     

Confocal Laser Scanning Microscopy Evaluation of an Acellular Dermis Tissue Transplant (Epiflex?)

The structure of a biological scaffold is a major determinant of its biological characteristics and its interaction with cells. An acellular dermis tissue transplant must undergo a series of processing steps, to remove cells and genetic material and provide the sterility required for surgical use. During manufacturing and sterilization the structure and composition of tissue transplants may change.The composition of the human cell-free dermis transplant Epiflex® was investigated with specific attention paid to its structure, matrix composition, cellular content and biomechanics.We demonstrated that after processing, the structure of Epiflex remains almost unchanged with an intact collagen network and extracellular matrix (ECM) protein composition providing natural cell interactions. Although the ready to use transplant does contain some cellular and DNA debris, the processing procedure results in a total destruction of cells and active DNA which is a requirement for an immunologically inert and biologically safe substrate. Its biomechanical parameters do not change significantly during the processing.