Search

Spiralling research costs combined with urgent pressures from the Coronavirus 2019 (COVID-19) pandemic and the consequences of climate disruption are forcing changes in drug discovery. Increasing the predictive power of in vitro human assays and using them earlier in discovery would refocus resources on more successful research strategies and reduce animal studies. Increasing laboratory automation enables effective social distancing for researchers, while allowing integrated data capture from remote laboratory networks. Such disruptive changes would not only enable more cost-effective drug discovery, but could also reduce the overall carbon footprint of discovering new drugs., Competing Interests: Declaration of Competing Interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.M.T. is a director of Talisman Therapeutics Limited and Ubiquigent Limited as well as a shareholder of Cellesce Limited. G.R.L. has no interests to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and non-governmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathways-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research. There is a pressing need for an approach that strategically implements advanced, human biology-based models and tools to understand disease pathways at multiple biological scales. We present recommendations to help achieve this., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human-based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and exciting tools to enhance and forward AD research. In particular, these methods are helping advance AD research by contributing multifactorial and multidimensional perspectives, especially considering the crucial role played by lifestyle risk factors in the determination of AD risk. In addition to research techniques, we also consider related pitfalls and flaws in the current research funding system. Conversely, we identify encouraging new trends in research and government policy. In light of these new research directions, we provide recommendations regarding prioritization of research funding. The goal of this document is to stimulate scientific and public discussion on the need to explore new avenues in AD research, considering outcome and ethics as core principles to reliably judge traditional research efforts and eventually undertake new research strategies., Competing Interests: CONFLICTS OF INTERESTS Gillian Langley is a consultant to Humane Society International. Francesca Pistollato, Ann Lam, Neal Barnard, Mei-Chun Lai, Ryan Merkley and P. Charukeshi Chandrasekera work at the Physicians Committee for Responsible Medicine, a non-profit medical advocacy organization. Thomas J. Novak is an employee of Cellular Dynamics International (CDI) and the PI on CDI's grant with the California Institute for Regenerative Medicine (CIRM) to generate 3000 patient-derived iPSC lines, including those from patients with late-onset AD.

Using Alzheimer's disease as a case study, this review argues that it might be time to consider a new paradigm in medical research and drug discovery. The existing framework is overly dependent on often unvalidated animal models, particularly transgenic mice. Translational success remains elusive and costly late-stage drug failure is common. The conventional paradigm tends to overlook species differences and assumes that animal-based findings are generally applicable to humans. Could pathways-based research using advanced human-specific models probed with new tools, including those of systems biology, take centre stage? The current transition in chemical toxicology to a 21st-century paradigm could be a model for health research, with probable medical and economic benefits., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Splenectomy is associated with increased risk for bacteremia, due to impaired clearance of bloodborne agents and to altered phagocytosis and humoral immunity. We conducted a retrospective cohort study of patients at risk for splenectomy for a 13-year period to determine immunization coverage, and outcomes of those with and without splenectomy, and with or without receipt of influenza or pneumococcal vaccine., Methods: Data were extracted from the provincial Medical Services Insurance database for insured services rendered by a physician for 1990-2002, and from the Vital Statistics Death database. The eligible cohort was selected based on diagnostic codes for hematologic conditions for which splenectomy might be considered, such as immune thrombocytopenia. Each patient was followed longitudinally from the date of first diagnosis until 31 Dec, 2002, or death, or relocation out-of province. In addition, persons with splenectomy and no hematologic condition were identified and followed for 6 months post-surgery. Infectious illness rates per 100 person-years of observation and death rates were calculated with and without splenectomy. Death rates were determined using splenectomy status as a time-dependent covariate. The relationship between splenectomy and death according to immunization status was examined using Cox proportional hazard ratios., Results: Of 38,812 persons in the cohort 427 subjects with a hematologic diagnosis had splenectomy and another 452 subjects without a hematologic diagnosis had this surgery. 72% were > 18 years of age. Pneumococcal immunization was recorded in 16.5% of asplenic patients overall, and was not associated with reduced risk of death in these persons (adjusted Hazard Ratio [HR] = 1.07, 95% CI 0.70 - 1.65). Influenza immunization was recorded in 53.1% of asplenic patients overall, and was associated with reduced risk of death (adjusted HR = 0.46, 0.33-0.62). No pneumococcal or influenza immunization was recorded in patients with a hematologic diagnosis without splenectomy. Infectious illness visits were higher among all patients who had a splenectomy than among those without a splenectomy (151 visits/100 person-years of observation in the post-splenectomy period vs. 120 visits/100 person-years; p < 0.0001)., Conclusions: In asplenic patients, influenza immunization is associated with a 54% reduced risk of death compared to unimmunized asplenic persons; no reduction in risk was demonstrated with (polysaccharide) pneumococcal vaccine. Vaccine coverage in the entire cohort was less than routinely recommended. Improved delivery of infection prevention programs to this population is warranted. Conjugate pneumococcal vaccines should be urgently studied in this immunocompromised population.

A patient was recently evaluated who had longstanding sarcoidosis with lymphadenopathy and multiple, small lung nodules, and who developed a new, 9 cm solitary pulmonary mass in the right lower lobe. After thoracotomy, this lesion was ultimately found to be lymphomatoid granulomatosis, a rare lymphoproliferative disorder. Radiographic evaluations of patients with this disorder characteristically show multiple, bilateral reticulonodular opacities that follow the bronchovascular bundles; however, presentation with a solitary, large pulmonary mass is rare. The present case illustrates the need for complete evaluation of new clinical and radiographic findings in the setting of chronic lung disease.

Background: High resolution Confocal Laser Scanning Microscopy (CLSM) may be applied to testing of drug resistance in vitro in clinical setting. Rapid analysis of DNA damage by precise quantitation of excised DNA in bone marrow samples exposed to potential treatment moieties directly after isolation but the relative sensitivity of the integrated method is as yet untested., Aims: To test the clinical applicability of SCGE/high resolution CLSM for differences in drug resistance in marrow cells., Methods: Cells from normal bone marrow samples were exposed for identical periods and at 4 concentrations to either 1 hour of standard Daunorubicin (.5, 1, 1.5, 2 micrograms/ml) or 8 hours DaunoXome (courtesy of NeXstar Inc, USA) (.05, .1, .15, .2 microgram/ml). After 2 and 6 hours recovery, cells were harvested for SCGE, randomization, analysis of tail length, total excised DNA and fragment size distribution using high resolution CLSM., Results: Tail length and fragment size distribution was not, but total excised DNA was significantly increased after 0.1 microgram/ml Liposomal Daunorubicin (DaunoXome) compared to 1.0 microgram/ml Daunorubicin., Conclusion: SCGE/high resolution CLSM effectively demonstrated differences in Daunorubicin resistance of human marrow cells to alternative formulations. The method has potential for use in clinical testing of neoplastic cell drug resistance.

Background: New analogues of DNA directed chemotherapy moieties are available for comparative efficacy testing in human neoplastic disease. In addition to MTT testing direct assessment of DNA excision repair activity after direct exposure of marrow cells may provide information on relative DNA effects in vitro., Aims: To assess the ability of SCGE/high resolution CLSM to detect differences in drug resistance between human neoplastic cell lines in the DNA excision repair response to chemotherapy., Methods: Eight human leukaemia samples (4 childhood, 4 adult) were exposed to 1 hour of single concentrations of daunorubicin, DaunoXome (courtesy NeXstar Pharmaceuticals Inc, USA), cyclophosphamide and 4-hydroperoxycyclophosphamide (4-HC, courtesy Dr. M. Colvin, Duke University, USA), followed by SCGE/high resolution CLSM with quantitation of total excised DNA. Differences between cases/drug moieties/exposures were analysed., Results: Although generally equal effect dose levels for DaunoXome were lower than for standard daunorubicin, patients/individual neoplastic cells differed considerably in optimal dose levels. Conventional cyclophosphamide in comparison to 4-HC showed inconsistent results indicating considerable differences in the level of drug resistance to the conventional product., Conclusions: Direct testing for drug resistance patterns in DNA directed drug moieties by SCGE/CLSM reveals individual variability of human malignant cell lines warranting comparison with results of MTT testing and in-vivo patient response.

Objectives: Acute intermittent porphyria (AIP) is caused by mutations in the porphobilinogen deaminase (PBGD) gene that disrupt the function of the enzyme. Many mutations that lead to decreased PBGD activity have been described. An Arg to Trp substitution at codon 173 (CGG-->TGG in exon 10) and designated R173W, which leads to a CRIM-negative phenotype, has been reported in Swedish, Finnish, Scottish, and South African kindreds, and in a Nova Scotian proband with fatal AIP. In this work, we investigated the presence of this mutation in a Nova Scotian patient population presenting with AIP., Design and Methods: Single-strand conformation polymorphism analysis and DNA sequencing by TA cloning and Sanger's dideoxy chain termination method, were used to confirm the maternal transmission of this mutation to the proband. The mutation also eliminates an Ncil (also Mspl) endonuclease restriction site, which allows for detection of the mutant allele by polymerase chain reaction amplification and restriction enzyme digestion., Results: The family of the Nova Scotian proband and four other AIP kindreds showed the presence of the same mutation. These five families are descendants of German, Swiss, and French immigrants historically known as the "Foreign Protestants," who were recruited to Nova Scotia in the 1750s., Conclusion: In all these families, descent from one couple that settled in Nova Scotia in 1751 has been identified by genealogy research, consistent with a founder effect within this population. This is the first identified mutation in PBGD causing AIP that has been linked to a founder effect in descendants of an immigrant population to North America, and which could be traced to such a distant background, similar to the South African variegate porphyria mutation.

Objective: To determine whether there is regional variation in environmental (non-medical) factors affecting referral decisions of family physicians (FPs)., Design: Cross-sectional interview survey., Setting: Nova Scotia., Participants: A random sample of 125 FPs grouped into 1 of 5 functionally defined geographic regions of Nova Scotia (25 in each group). Groupings were based on access to general hospital beds through active staff hospital appointments or to specialist consultants in the community, or both. Participants were personally interviewed on site. No physician refused an interview. In 9 cases the physician indicated that he or she did not fit the profile of the assigned group; the physician was excluded from the study and the next doctor on the list was substituted., Outcome Measures: The questionnaire was designed to test several hypotheses about factors known to potentially influence decisions about referral. Geographic differences in factors affecting referral and in decisions about 5 hypothetical cases were assessed with the use of significance tests for proportions that were sensitive to specific orders across groups., Results: Three factors affecting referral showed unequivocal variation across the 5 groups. Access to hospital facilities and remoteness from specialist care, leading to local styles of practice or treatment policies, and the FP's relationship with specialist consultants appeared to be important nonmedical factors affecting referral decisions. For similar case scenarios the physicians living in rural areas would refer only half as often overall as those living in urban areas with tertiary care hospitals; for some cases, such as a severe asthma attack, the difference was more than 7-fold., Conclusions: Significant differences in nonmedical factors affecting referral, and in referral decisions about hypothetical cases, were found between the groups of FPs. Differences in access to resources, creating local styles of practice, appeared to explain most of the variation. The results may account for previously observed differences in actual rates of referral for these particular groups.

Synopsis An established cytotoxicity test for plastic materials in medical devices has been adapted and used to assess the relative potential irritancy of cosmetic ingredients and formulations during product development. Serum-free medium containing a novel protein supplement supported growth in suspension of LS mouse fibroblast cells. Release of the vital dye Neutral Red from pre-loaded cells suspended in agar was the endpoint. Test substances and reference standards were applied to a central well cut into the agar, a sensitive method which allowed accurate dose application and yielded consistent results. Relative irritancy potential was measured quantitatively by comparing the diameters of the clear zones of damaged cells which surround the central well. The test has been used with raw materials such as surfactants, preservatives and herbal extracts, as well as finished products ranging from shampoos and conditioners to creams, lotions and coloured cosmetics. The method is practical, versatile, reproducible and economic to use. Résumé Un test de cytotoxicité utilisé pour la détection de toxines dans les plastiques des appareils médicaux a été adapté pour prévenir le potentiel d'irritation relative. Le point mesuré est la libération de la teinture vitale rouge neutre des cellules chargées au préalable, résultant de l'incubation avec des substances tests. La mesure des diamétres de la zone claire de dilutions sequentielles de substances tests permet de calculer l'irritation potentielle d'un produit testé par rapport à un standard. Parmi les modifications, on a pu constater à l'aide d'une ligne de cellules en suspension dérivées de fibroblastes de souris L-929, la pousse en milieu sans sérum pour éviter les produits d'abattoir. A la place du sérum de veau, on a ajouté au milieu une nouvelle protéine innovatrice supportant la pousse normale en suspension. Durant la procédure de test les cellules se trouvaient en suspension dans une solution agar et les substances tests ont été appliquées sur une cellule centrale bien délimitéc sur la gélose plutôt qu'à l'aide d'un disque de papier filtre. L'application par une cellule centrale était plus sensible qu'avec un disque, permettant l'application d'une dose précise et fournissant des résultats plus fiables. Le test modifié a été utilisé sur une période de 4 ans pour des matiéres premières telles que tensioactifs, conservateurs et extraits de plantes, ainsi que des formules de shampooings, savons, lotions hydratantes et cosmétiques colorés. Ces produits ont étéévalués sur des panels de volontaires, et les produits testés sont commercialisés depuis 2 ans au moins. Le test est un moyen pratique, versatile, reproductible et économique de calculer le potentiel d'irritation relative d'une gamme de produits et ingrédients cosmktiques.

Objectives: To identify nonmedical factors perceived by family physicians (FPs) and consultants as important influences on decisions about referral for consultation, to determine the relative frequency with which such factors are cited and to identify those factors ranked as most important by the FPs and consultants., Design: Survey with semistructured interview between July 1989 and April 1990., Participants: A total of 41 FPs and 20 consultants who were practising or had practised previously in Nova Scotia., Interventions: The questionnaire comprised 10 questions: 4 were nondirective "probes" designed to elicit responses without suggesting possible answers, 2 asked the participants to rank such responses in order of importance, and 4 were "prompts" that asked for comments about a list of factors based on a review of the literature., Results: A total of 4845 discrete items were mentioned as being capable of influencing FPs' decisions about referral for consultation. Aggregation of related items resulted in a list of 35 nonmedical factors, of which 11 were identified by at least half the respondents and 14 by less than half but more than 10. These 25 factors fell into three categories: patient and family factors (e.g., patient's wishes), FP and consultant factors (e.g., FP's capabilities), and other influences (e.g., style of practice). On the basis of both frequency of identification and priority scores "patient's wishes" emerged as the most important factor. Two medical factors that were consistently cited--type of problem and age of patient--were thought to interact with the other factors., Conclusion: Certain nonmedical considerations may substantially affect physicians' referral practices.

Autologous bone marrow transplantation (ABMT) is becoming increasingly prevalent for treatment of advanced malignant disease. In order to increase the availability and utility of this therapy, we assessed the feasibility of transferring patients to their regional referral centers on the day after marrow infusion (day 1), for management post-transplant. This prospective study compares the outcome of 77 patients either transferred the day after marrow transplant for subsequent management at one of six selected Canadian regional centers closest to their domicile, or treated entirely at The Toronto Hospital, according to a common protocol. Study end-points included frequency of complications during transfer, transplant-related morbidity and mortality and hematopoietic recovery. Assessment of eligibility for transplant, bone marrow harvesting, autograft cryopreservation, administration of intensive therapy and marrow infusion were conducted in all cases at The Toronto Hospital. Thirty patients received marrow transplants and were transferred on day 1. There were no complications during transfer. Compared with 47 consecutive patients treated entirely at The Toronto Hospital, there were no differences in treatment-related morbidity or mortality, use of intravenous antifungal therapy or total days of hospitalization. We conclude that day 1 transfer of patients after ABMT to designated centers is feasible and safe. The operation of a regional ABMT network appears to benefit patients, relatives, referring physicians, the transplant center and may also improve health care delivery.

Fifty-one patients with relapsed or refractory intermediate- or high-grade non-Hodgkin's lymphoma were referred for autologous bone marrow transplantation (ABMT). The primary criterion for eligibility was sensitivity to conventional-dose salvage chemotherapy. Of 47 patients who received salvage chemotherapy, 30 demonstrated chemotherapy-sensitive disease. Six eligible patients did not undergo ABMT for various reasons. A total of 24 patients underwent ABMT, with etoposide, melphalan ± total body irradiation as the intensive therapy regimen. There was one early treatment-related death and three non-responders. Of the remaining patients, 9 relapsed, while 11 remain in continuous complete remission (CR) at a median follow-up of 21 months after transplant (range 5-37 months). Two patients with chemosensitive disease and bone marrow involvement underwent allogeneic BMT with marrow from HLA-identical siblings. Both are in continuous CR at 6 and 12 months follow-up. Of the 25 patients who did not undergo ABMT, all have died (median survival 5 months). The results indicate that approximately one-half of relapsed or refractory aggressive histology lymphoma patients referred for ABMT eventually undergo transplantation, if chemotherapy-sensitive relapse is the major criterion for eligibility. Approximately 25% of the referred patients may become long-term disease-free survivors with this approach. Reports of marrow transplant series should include all patients referred for ABMT as the denominator for calculating disease-free survival in order to reduce the bias of patient selection.

The major purpose was to explore the use of written case scenarios to investigate factors associated with regional variations in referral for consultation. Data were collected in Nova Scotia, where extensive computer-based records of utilization of health services are kept, and the nine health care regions are in sufficient proximity to make visits and interviews feasible. Interviews with 9 x 25 = 225 randomly-selected family physicians, using scenarios analogous to ICD-9 codes, permitted testing of hypotheses about the effects of selected variables on referral rates for hypothetical cases. The family physicians' self-reported referral behavior for the written case scenarios was compared, region by region, with the actual referral of analogous cases by physicians in the same region, as determined from Nova Scotia Health Services and Insurance Commission records. The results indicated that written scenarios provide a useful tool for studies of such variables. Generally, the family physicians responded appropriately to the information that described the hypothetical patients ("case cues"). However, comparisons of hypothetical and actual referral rates indicated that appropriate information about the environment within which referral decisions take place ("environmental cues") may be needed to explain actual regional variations in referral rates.

Much attention has been paid to the use of ethical principles to guide the conduct of clinical trials. Less has been done to clarify and assess the "weights" assigned by clinicians (and others) to the values that come into conflict when patients are offered entry into trials. Quantitative techniques of value assessment were used to measure the relative importance of variables frequently identified as barriers to the entry of patients into clinical trials. Responses were obtained from 52 oncologists, 26 clinical trials and senior nurses, and 23 family physicians. The group of oncologists identified the scientific design of the trial as the most important factor. In contrast, the groups of nurses and family physicians gave higher weight to effects of the trial on the doctor-patient relationship. The results illustrate ways in which methods of value assessment may be used to clarify and rank values.

Chronic lymphocytic leukaemia peripheral blood mononuclear cells (CLL-PBMN) were separated into B, T and Null-enriched lymphocyte sub-populations using sequential mouse and sheep red blood cell rosetting depletions on Hypaque-Ficoll gradients. The procedure produced viable cell populations with mean percentage purities of 90, 87 and 75 for B, T and non-rosetting (Null-enriched) sub-populations, respectively. More than 80% of PBMN cells were generally accounted for by mouse and sheep rosetting. The purified lymphocyte sub-populations were examined with a panel of B-cell specific alloantisera obtained from kidney transplant recipients and a rabbit antiserum to B cell antigen isolated from a human B-lymphoblastoid line. The results illustrated that the antigens detected by these sera also have potential as a marker for characterizing the CLL population. Where conventional markers were weak or absent, B cell antigens were readily detected in both fluorescent and cytotoxic tests. The majority of the non-rosetting cells (less than 90%) in CLL followed similar patterns of reactivity to the purified B cells, suggesting they are a subset of B cells. A small residual population (0--5% of PBMN) did not react with the antisera, the significance of which is unknown.

Blast cells from patients with acute myelogenous leukemia (AML) grow exponentially in suspension culture and form colonies in cultures "stiffened" with methylcellulose; under both culture conditions, cells are generated which have the ability to adhere to plastic or glass. These adherent cells lack the capacity to form colonies, to proliferate in liquid culture or to support growth. Adherent cells are generated in parallel with changes in the frequency of clonogenic cells and express surface markers of AML blasts but with a higher frequency of an antigen recognized by the monoclonal MO1, a late stage marker associated with the macrophage differentiation lineage. While the appearance of adherent cells provides further evidence that blast cells follow differentiation programs in culture, the generation of adherent cells does not indicate that normal differentiation is occurring; rather the data is consistent with the view that components of normal monocytic differentiation programs are assembled abnormally in the programs of some blast progenitors.

T cell colony formation in normal individuals and untreated patients with chronic lymphocytic leukaemia (CLL) was studied to determine if there is a deficiency in the number of T cells capable of forming colonies in this disease. In normal individuals, assays using enriched T cells did not reveal the total number of potential colony forming cells, preventing accurate assessment in patients with B cell CLL where enriched T cells are mandatory. Conditions were therefore optimized to obtain the maximal number of colonies, so that accurate comparisons could be made between the potential of normal individuals and patients with CLL. Addition of normal autologous non-T cells to enriched T cells enhanced colony numbers in normal individuals to those seen in the whole mononuclear population. However, addition of normal non-T cells to CLL T cells would have caused a mixed lymphocyte reaction (MLR), which influences T cell colony numbers. Therefore the MLR was bypassed by adding to the enriched T cells, supernatants having characteristics of Interleukin-1 or commercially obtained Interleukin-2. The supernatants with Interleukin-1 activity enhanced T cell colony numbers comparably in both normal individuals and patients with CLL. Interleukin-2 did not increase T cell colony numbers in normal individuals and the increase seen in patients with CLL were not significant. Thus the effect of the lymphokines on T cell colony numbers was comparable in both normal individuals and untreated patients with CLL. We therefore concluded that there are normal numbers of cells which have the potential to form T cell colonies in untreated patients with CLL.

Available manpower data indicate that for the forseeable future there will be a continuing requirement in Canada for specialists in general internal medicine. While these specialists will be located predominantly in community hospitals, they will also be needed in university medical centres. The major roles of the general internist will be (a) to provide consultative service to primary care physicians and to other specialists, (b) to provide continuing care to patients with complex serious illness and (c) to participate in intensive care, particularly in community hospitals. Therefore training programs in this specialty must provide adequate experience in consultative medicine in both university and community hospitals, an opportunity to follow up patients with chronic serious illness over long periods, and experience in a variety of intensive care settings including surgical intensive care units. In some university departments the organization and supervision of training programs in this discipline have been carried out by a division of internal medicine that has equal status with other specialty divisions within the department. This seems to have been a salutory development.

Some patients with chronic lymphocytic leukemia (CLL) have a relatively stable clinical course without treatment, but many of these eventually develop progressive disease. We have followed 68 patients over 5 1/2 years by employing conventional surface markers and lymphocyte reactivity, including that of separate enriched T cells to their own leukemic B cells, to phytohemagglutinin (PHA), and to normal allogeneic B cells; we have observed an unusual response in each of the seven patients who developed progressive disease over this period of time. During the stable phase of the disease the T cells from 27 leukemic subjects did not respond to their own leukemic B cells in culture. In the seven patients who developed progressive disease, a significant reactivity of their enriched T cells to their own leukemic B cells occurred. There was no consistent change in T-cell reactivity to PHA or to allogeneic B cells, suggesting a change in the leukemic B-cell populations that was not detected morphologically. The change in reactivity of T cells to leukemic B cells occurred prior to evidence of clinical or laboratory deterioration in one of the seven cases; there was increasing lymphocytosis and lymphadenopathy in six and two instances, respectively; and anemia and thrombocytopenia in the three and one cases, respectively.

Cell-mediated immunity is depressed in elderly individuals compared to young individuals, and lymphocytes from elderly individuals have been reported to have impaired lymphocyte responsiveness to stimulation by PHA after 4 days of culture. We have confirmed this observation. However, after 8 days of culture, the lymphocyte responses were greater in elderly normal individuals than in young normal individuals. Responses of lymphocytes from young individuals decreased with time from 4 to 8 days in culture, while there were increased responses with time when lymphocytes from elderly individuals were studied. When adherent cells from lymphocytes of young individuals were removed by passage through protein-coated Degalan-bead columns, the lymphocyte responses to PHA were significantly increased at 8 days. Passage of lymphocytes from elderly individuals through coated Degalan bead columns did not alter the lymphocyte responses. Removal of macrophages from the mononuclear cells obtained from young individuals did not result in increased lymphocyte responses to PHA after 8 days in culture. Removal of adherent cells appeared to have the same effect regardless of the efficiency of removing B cells. The adherent cells removed by the protein coated columns, therefore, appear to be nonphagocytic mononuclear cells which are not B lymphocytes.

To identify the characteristics of exemplary family physicians and consultants, we interviewed 25 family physicians and 25 consultants (5 each in the specialties of internal medicine, obstetrics and gynecology, pediatrics, psychiatry and surgery) selected by their peers as being exemplary in their own practice setting. The results indicated that the participants had well-formulated concepts of exemplary practitioners, defining five main categories of performance: clinical competence, relationship with patients, availability, family physician-consultant relationship and a fifth category that included organizational ability and personality attributes. The family physicians and the consultants placed different values on these categories and indicated that these values might change under different clinical circumstances. Their concepts appear to be compatible with, but not restricted to, a model of contemporary medical practice based on an ethic specific to medicine.

Previously untreated patients with myeloma were randomized to initial treatment with melphalan and prednisone (and to cyclophosphamide or carmustine if relapse or progression occurred)(Group A, 125 patients), melphalan, cyclophosphamide, carmustine and prednisone in alternating (Group B, 123 patients) or concurrent (Group C, 116 patients) schedules. The groups were similar with respect to known prognostic factors. Response rates and survival were also similar. We were unable to identify a subgroup of patients who responded or survived better on melphalan-cyclophosphamide-carmustine and prednisone than on melphalan and prednisone. We conclude that the combination of the four drugs is not better than melphalen and prednisone for inducing responses or prolonging the survival of patients with myeloma. Myelomas producing only gamma chains have a poorer prognosis (P greater than 0.001) than IgG, IgA, or kappa myeloma. Acute leukemia has developed in 14 patients. The actuarial risk of developing acute leukemia, has increased rapidly to 17.4 per cent at 50 months.

Screening patients for anemia and determining its cause is challenging and rewarding. Ordinarily, the cause can be readily diagnosed and treatment is available. A clinical approach to the diagnosis of anemia is presented. After clinically determining whether the anemia is due to decreased production of red blood cells, increased destruction, or loss of blood, initial laboratory investigations are specifically chosen to confirm the clinical impression or to answer basic clinical questions. The clinical features and initial laboratory findings should direct subsequent diagnostic and/or treatment approaches.

Seven patients with a clinical diagnosis of infectious mononucleosis (IM) and detectable heterophil antibodies were found to have peripheral blood lymphocytes that were cytotoxic for lymphoid cells containing Epstein-Barr virus from a patient with Burkitt's lymphoma. The cytotoxic lymphocytes persisted in the peripheral circulation for up to 45 days. Patients who had had IM 1 to 5 years previously lacked such cytotoxic lymphocytes. Patients who had signs and symptoms of IM but no detectable heterophil antibodies lacked cytotoxic lymphocytes. The lymphocytes of one patient with IM showed progressive diminution of cytotoxic ability after prednisone treatment.

Previous studies have shown that lymphocytes from patients with chronic lymphocytic leukaemia have a diminished response to mitogens which stimulate T cells. Chronic lymphocytic leukaemia is most often a disease of accumulating B cells so that T lymphocytes are diluted by large numbers of leukaemic cells. Direct comparison with the responses of normal lymphocytes to mitogenic stimulation is therefore suspect. To circumvent this difficulty, a method of isolating T cells from normal individuals and patients with chronic lymphocytic leukaemia was developed. Lymphocytes containing an average of 16.1 per cent B cells from normal individuals were applied to IgG-anti-IgG-coated Degalan bead columns and held at 4 degrees for 2 hours. The eluted cells contained less than 2 per cent B cells. When chronic lymphocytic leukaemic lymphocytes, containing an average of 68.6 per cent B cells, were applied to IgG-anti-IgG columns, the eluted cells contained 36.4 per cent B cells. To improve the purification of T lymphocytes, columns of uncoated Degalan beads were used to remove non-specifically adherent cells. Eluted lymphocytes were then applied to IgG-anti-IgG columns. This resulted in the recovery of purified populations of T cells with less than 2 per cent contamination with B cells. Patients with chronic lymphocytic leukaemia were found to have lymphocytes with either a normal density or a low density of surface immunoglobulins. B cells were successfully removed from lymphocyte suspensions in all cases of chronic lymphocytic leukaemia with a normal density of lymphocyte surface immunoglobulins. In the three cases of chronic lymphocytic leukaemia with low density surface immunoglobulins, separation by this method was unsuccessful. However, an enriched T-cell population was obtained when leukaemic lymphocytes which had lost all detectable surface immunoglobulins were passed through a column coated with heat-aggregated IgG.

Osteolytic defects and osteoporosis are common in myeloma, while sclerotic lesions of bone are rare. Eighteen patients with increased bone density have been described in the literature and five patients are presented in this report. Diffuse increase in skeletal density, similar to that seen in the myelofibrosis-myelosclerosis syndrome, occurred in two patients, and progressive multiple focal areas of sclerosis with splenomegaly in a third. Two patients had solitary areas of sclerosis. Although there was increased cortical and trabecular bone, osteoblastic activity was normal on histological sections. Whether the sclerosis was due to new bone formation or interference with bone resorptive processes could not be determined. Patients with polycythemia, myelofibrosis and myelosclerosis have been found to have, or later develop, myeloma. This has led to the suggestion that myeloma be included among the myeloproliferative disorders. At present the evidence for this interrelationship is the frequency of the association of these diseases.

An increasing interest in educational science as applied to medical education is apparent in the past decade. Recently, a six-week teacher training program was held at the Center for the Study of Medical Education at the University of Illinois. Fifteen medical faculty members, including five Canadians, participated. During this period there was an opportunity to engage in discussions and independent study of several aspects of medical education, using the personnel from the Center's four major divisions as resource people. Training in educational science is important for all teachers, and a centre to provide this type of instruction should be available in Canada.

Thirteen Canadians with a mild hypochromic anemia were found to have beta thalassemia trait. The families of these individuals had resided in Canada for two to five generations and, where known, had not emigrated from areas with a high incidence for the thalassemia gene. A Negro family with abnormal erythrocyte morphology was suspected to be carrying the thalassemia gene although the hemoglobin A(2) concentration was normal and abnormal minor components were not detected. Thalassemia trait has been detected in practically every ethnic group, and its sporadic occurrence among Canadians without Mediterranean ancestry can be expected.