CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells

Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T cell depletion increases the risk of graft rejection. In this study, two strategies are used to overcome rejection: (1) use of high doses of stem cells obtained from peripheral blood (PBSC), (2) admixture with a CD52 monoclonal antibody in order to deplete both donor and residual recipient lymphocytes. Two antibodies are compared: CAMPATH-1G (rat IgG2b) and its humanized equivalent CAMPATH-1H (human IgG1). A total of 187 consecutive patients at six centers received PBSC transplants from HLA-matched siblings between 1997 and 1999. A wide spectrum of diseases, both malignant and non-malignant, was included. The recovery of CD34+ cells after antibody treatment was close to 100%. The risk of acute GVHD (grade 2 to 4) was 11% in the CAMPATH-1G group and 4% in the CAMPATH-1H group (P = NS). The risk of chronic GVHD (any grade) was 11% in the CAMPATH-1G group and 24% in the CAMPATH-1H group (P = 0.03) but the risk of extensive chronic GVHD was only 2%. The overall risk of graft failure/rejection was 2%, not significantly different between the two antibodies. Antibody treatment was equally effective at concentrations between 10 microg/ml and 120 microg/ml and it made no significant difference to the outcome whether the patients received post-transplant immunosuppression or not (87% did not). Transplant-related mortality in this heterogenous group of patients (including high-risk and advanced disease) was 22% at 12 months. It is proposed that treatment of peripheral blood stem cells with CAMPATH-1H is a simple and effective method for depleting T cells which may be applicable to both autologous and allogeneic transplants from related or unrelated donors. Special advantages of this approach are the simultaneous depletion of donor B cells (which reduces the risk of EBV-associated lymphoproliferative disease) and the concomitant infusion of CAMPATH-1H to deplete residual recipient T cells and thus prevent graft rejection.     

Implementation of cancer prevention guidelines in clinical practice

Data from several sources, including consumer surveys, physician surveys, and medical record audits, indicate that consumers do not receive cancer screening tests as recommended by the National Cancer Institute, the American Cancer Society, and the U.S. Preventive Services Task Force. Performance rates are consistently below published standards for all tests except Pap tests. Major reasons physicians do not perform the recommended tests include physician forgetfulness, disagreement with recommendations, lack of time, and patient refusal. Physicians also tend to overestimate their own performance rates. Barriers to screening test performance can be categorized into patient factors, physician factors, test factors, and health care delivery system factors. Interventions, such as computerized reminder systems, physician audits with feedback, and patient education and reminders, can be effective in promoting performance of such screening. Interventions that target both physician and patient may be particularly effective. Presented at the conference, Frontiers in Disease Prevention, The Johns Hopkins University, June 5–6, 1989.     

From the Cover: A global carbon and nitrogen isotope perspective on modern and ancient human diet

Stable carbon and nitrogen isotope analyses are widely used to infer diet and mobility in ancient and modern human populations, potentially providing a means to situate humans in global food webs. We collated 13,666 globally distributed analyses of ancient and modern human collagen and keratin samples. We converted all data to a common “Modern Diet Equivalent” reference frame to enable direct comparison among modern human diets, human diets prior to the advent of industrial agriculture, and the natural environment. This approach reveals a broad diet prior to industrialized agriculture and continued in modern subsistence populations, consistent with the human ability to consume opportunistically as extreme omnivores within complex natural food webs and across multiple trophic levels in every terrestrial and many marine ecosystems on the planet. In stark contrast, isotope dietary breadth across modern nonsubsistence populations has compressed by two-thirds as a result of the rise of industrialized agriculture and animal husbandry practices and the globalization of food distribution networks.

Homo sapiens are the most widely distributed terrestrial mammal on the planet. Over the course of the Holocene, modern human range has extended to all continents, to the farthest islands of every ocean, and above the polar circles. The ability to rapidly adapt to newly encountered environments via technological and cultural innovation, that manifested ultimately in changes to our own genome, enabled this breath-taking range of expansion (1). Our capacity for successful innovation is tightly coupled to our ability to consume as “extreme opportunistic omnivores,” that is, across multiple trophic levels, from the base of a food web to filling the niche of apex predator (2–4). The development of agriculture, animal husbandry, urbanized societies, and commercial trade progressively allowed us to engage in niche construction of increasing complexity and extent (5, 6). As we permanently extended our range to above the Antarctic Circle in the 20th century, we progressively extended our capacity for advanced ecosystem engineering, thereby achieving a high degree of control over the production and distribution of our food supply across the globe (6, 7).The archaeological record documents our expansion into new habitats, our technological and social innovations, changing cultural practices, and the food that sustained us (8). While the physical remains of our diets, such as bones and charred plant remains, provide direct evidence of diet, not all foodstuffs are well-preserved. Moreover, such direct evidence does not indicate the proportion of different components that were consumed. A challenge in recreating past dietary components lies in accounting for taphonomic processes that may impact different dietary items at different rates, leading to underrepresentation of some important taxa (2). In contrast, the stable carbon and nitrogen isotope composition of human tissue (mostly collagen and keratin) has been investigated over the last several decades as a proxy for the proportions of different potential dietary components enabling an accounting for taphonomy (9). Carbon isotope composition (δ¹³C value) provides an indication of relative contributions of aquatic and/or terrestrial sources of carbon in the diet. Nitrogen isotope composition (δ¹⁵N value) is used to draw inferences regarding both the protein source and trophic level of an individual in the months or years before their death (10).To date, studies involving patterns in the stable isotope composition of ancient human remains (mostly bone collagen that can be well-preserved) have tended to focus on regional-scale variations during the Holocene, with the intent of determining wholesale changes in subsistence strategies (e.g., agriculture and pastoralism) and changing technological innovation, as well as social practices and structures (11–13). Although interpretation can sometimes be straightforward when observed differences are large, smaller differences are complicated by the complexities associated with disentangling the ecosystem processes driving C and N isotope fractionation within the food webs supporting human diet (13, 14).A parallel body of research has been conducted on the stable isotope composition of the tissues of contemporary humans (15–18). This research has mostly focused on noninvasive nail and hair keratin to examine the physiological processes in the human body, to deduce the recent movements of individuals (19), or to identify locations for repatriation of human remains (20). Substantial effort has been directed toward developing a spatial understanding of the controls on the stable isotope composition of modern human tissues, mostly as a consequence of the potential forensic application of this type of research (18, 21).Archaeological and modern stable isotope results on human tissues are not readily comparable for multiple reasons (Materials and Methods), hence there has been no attempt to interrogate the full record of dietary breadth and change for a globally distributed, omnivorous species, from the prehistoric to recent times. To address this gap, we collated isotope compositions of collagen as well as hair and nail keratin from three worldwide populations: modern urban (dates AD 1910 to 2020; Materials and Methods), modern subsistence (dates AD 1910 to 2020), and material dating to before the manufacture of industrial fertilizer (before AD 1910; pre-Haber–Bosch; hereafter, PHB). We calibrated all isotope compositions to their modern diet equivalent in order to directly compare modern and PHB distributions on a common scale. We show that the industrialized food system is vastly compressed in niche space and vastly less resilient compared with modern subsistence and PHB diets that are underpinned by complex food webs.We systematically collated (n = 6,879) globally distributed analyses of PHB archaeological bone collagen (pre-1910), with the majority of the data derived from samples of mid-Holocene or later age. We further collated analyses from studies of modern (post-1910) hair and nail keratin from populations of subsistence foragers, fishers, agriculturalists and pastoralists (n = 1,167), and urban populations (n = 5,610). In order to compare populations, we adjusted all measured values onto a common frame of reference; this being the equivalent δ¹³C and δ¹⁵N values of hair keratin in 2010 or modern keratin equivalent. We then used the accepted fractionations between human hair keratin and diet to calculate the modern diet equivalent (δ¹³C_MDE value) and (δ¹⁵N_MDE) values for all samples in 2010 (Materials and Methods).This approach has the advantage of allowing direct comparison of all results against the framework of our much more detailed contemporary understanding of stable isotope systematics in the modern biosphere. Exploiting this link between PHB and modern samples requires the assumption that the environmental conditions that drive the food webs that humans rely upon, wherever they are, have remained stable and that the past can be mapped onto the present. While there have been changes in climate and environment during the Holocene, these have been relatively muted, with most larger-scale landscape change resulting from human intervention beginning at varying times across the world in the Holocene and accelerating rapidly with the rise of industrial agriculture in the 20th Century (22).     

Metformin increases insulin sensitivity and basal glucose clearance in Type 2 (non-insulin dependent) diabetes mellitus

Abstract The effects of metformin on glycaemia, insulin and c-peptide levels, hepatic glucose production and insulin sensitivity (using the euglycaemic, hyperinsulinaemic clamp) were evaluated at fortnightly intervals in 9 Type 2 diabetic patients using a stepwise dosing protocol: Stage 1 - no metformin for four weeks; stage 2 - metformin 500mg mane; stage 3 - metformin 500mg thrice daily; stage 4 – metformin 1000mg thrice daily. Results are expressed as Mean ± SEM. Fasting blood glucose decreased from basal values (9.7 ±1.0 mmol/L) by 13% at stage 2, 34% at stage 3 and 41% at stage 4 (p<0.02 vs basal for all stages; p<0.02 stage 2 vs stage 3). Post-prandial glycaemia was significantly improved only with metformin 3000mg/day (p<0.05). Fasting, meal-stimulated and total insulin and c-peptide levels showed no change. Hepatic glucose output did not change significantly with metformin. Insulin sensitivity, measured as total glucose utilisation during hyperinsulinaemia, increased from stage 1 (10.3 ± 2.1 μmoL/kg/min) by 23% at stage 3 (p < 0.05) and by 29% at stage 4 (p < 0.02). Basal metabolic clearance of glucose increased compared to stage 1 (1.69 ±0.16 mL/kg/min) by 30% at stage 2, 53% at stage 3 and 44% at stage 4 (all p <0.02). This study demonstrates that improved efficiency of glucose utilisation, both basally and under conditions of euglycaemic hyperinsulinaemia, is the basis of metformin's antihyperglycaemic action.     

Genome scan in familial late‐onset Alzheimer's disease: A locus on chromosome 6 contributes to age‐at‐onset

Alzheimer's disease (AD) is a common, genetically complex, fatal neurodegenerative disorder of late life. Although several genes are known to play a role in early‐onset AD, identification of the genetic basis of late onset AD (LOAD) has been challenging, with only the APOE gene known to have a high contribution to both AD risk and age‐at‐onset. Here, we present the first genome‐scan analysis of the complete, well‐characterized University of Washington LOAD sample of 119 pedigrees, using age‐at‐onset as the trait of interest. The analysis approach used allows for a multilocus trait model while at the same time accommodating age censoring, effects of APOE as a known genetic covariate, and full pedigree and marker information. The results provide strong evidence for linkage of loci contributing to age‐at‐onset to genomic regions on chromosome 6q16.3, and to 19q13.42 in the region of the APOE locus. There was evidence for interaction between APOE and the locus on chromosome 6q and suggestive evidence for linkage to chromosomes 11p13, 15q12‐14, and 19p13.12. These results provide the first independent confirmation of an AD age‐at‐onset locus on chromosome 6 and suggest that further efforts towards identifying the underlying causal locus or loci are warranted. © 2013 Wiley Periodicals, Inc.