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Although the literature on individual job crafting has proliferated over the past decade, research on the collaborative crafting efforts of organizational teams has lagged behind, which is surprising given the prominence of team-based arrangements in contemporary work and the importance of team proactivity in today's business environment. Drawing on proactive motivation theory and the literature on proactive performance in teams, this article presents a large-scale intervention study aimed at increasing team proactive motivation, including a pretest/posttest control group with 96 teams and 1,077 employees. We study the extent to which a team proactive motivation intervention is associated with changes in three dimensions of team crafting (task team crafting, relational team crafting, and cognitive team crafting) at both 6 months and 1 year after the intervention. We also examine the mediating role of change in the three team-level crafting dimensions in explaining the association between the intervention and change in team performance over time. Our results show that the intervention is positively associated with change in all three forms of team crafting. Furthermore, change in team crafting positively associates with change in team performance 6 months and 1 year after the intervention. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

The present study aims to test the impact of a self-leadership intervention on the work engagement, performance, and health of health care workers. By integrating self-determination theory and self-leadership theory, we propose that when employees are trained how they can autonomously influence own cognitions and behaviour, this will impact their work engagement, perceived performance, and general health. To test the hypotheses, a longitudinal field experiment with three measurement waves was conducted (pre-intervention, immediately after the intervention, and 2 months after the intervention). Health care professionals ( n  = 195) from five different organizations participated on voluntary basis and were randomly assigned to the intervention or control group. Results show that a self-leadership training positively impacts work engagement and performance of health care workers. Furthermore, the improved work engagement also mediates the effects of the training on health and performance 2 months later. No direct effect was found on general health. Theoretical and practical implications are discussed., Practitioners Points: The self-leadership intervention facilitates healthcare workers to develop self-determination and autonomous motivation, which will positively impact their work engagement, health, and performanceParticipation in the self-leadership intervention needs to be based on volition as this will contribute to the intrinsic motivation for actual self-leadership development through training., Competing Interests: All authors declare no conflict of interest., (© 2021 The Authors. Journal of Occupational and Organizational Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

In psychological contract research, the side of the supervisor is strongly underexposed. However, supervisors are responsible for maintaining relationships with both their subordinates and senior management and are likely to be influenced by events unfolding in these relationships. In this study, we state that supervisor well-being may be affected by subordinates who fail to meet their obligations. This study adds to psychological contract research by developing an understanding of how and when subordinate psychological contract breach (PCB) is associated with supervisor emotional exhaustion. Through a weekly diary survey among 56 Dutch supervisors, we test hypotheses about the relationships between subordinate PCB and the emotional exhaustion of the supervisor, the mediating role of perceptions of performance pressure by the supervisor in this relationship, and the moderating role of i-deals between the supervisor and senior management. Multilevel analyses support the first two hypotheses, but contradictory to our expectations show that the positive association between subordinate PCB and the emotional exhaustion of the supervisor is strengthened when the supervisor has high levels of i-deals with senior management. We discuss the findings in relation to their contribution to psychological contract theory., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Jong, Clinton, Bal and Van Der Heijden.)

Background: Spontaneous intracerebral hemorrhage may arise from underlying abnormalities, including aneurysms. Computed tomography angiography (CTA) is widely used for the detection of possible underlying causes, which is important because it may have immediate therapeutic consequences. In addition, CTA is used to detect the so-called spot sign, indicating active hemorrhage, which carries a worse prognosis. However, CTA is a snapshot in time. Four-dimensional (4D) CTA is a dynamic type of imaging and has emerged as a valuable imaging technique for different neurovascular disorders., Case Description: Two patients with intracerebral hemorrhage both showed an assumed spot sign on CTA, suggesting active hemorrhage. Additional 4D-CTA showed true active hemorrhage in one patient and a distal intracranial aneurysm in the other. This aneurysm was initially falsely interpreted as a spot sign on conventional CTA., Conclusions: Our case findings show how 4D-CTA can discern active bleeding from aneurysmal hemorrhage in cases with hemorrhagic stroke. This finding proves the additional value of this relatively new technique, because the detected underlying disorders have different therapeutic consequences in the acute setting., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Various factors pertaining to the social context (availability of plausible social contacts) as well as personality traits influence the emergence of social ties that ultimately compose one's personal social network. We build on a situational selection model to argue that personality traits influence the cognitive processing of social cues that in turn influences the preference for particular social ties. More specifically, we use a cross-lagged design to test a mediation model explaining the effects of need for cognition (NFC) on egocentric network characteristics. We used the data available in the LISS panel, in which a probabilistic sample of Dutch participants were asked to fill in surveys annually. We tested our model on data collected in three successive years and our results show that people scoring high in NFC tend to revolve in information-rich egocentric networks, characterized by high demographic diversity, high interpersonal dissimilarity, and high average education. The results also show that the effect of NFC on social network characteristics is mediated by non-prejudicial judgments.

Background: In this article we discuss the relationship between posttraumatic stress disorder (PTSD) and metabolic syndrome (MbS)., Aim: To assess the prevalence of MbS in patients with PTSD, establish which factors are involved and to consider what the implications are for clinical practice., Method: We performed a systematic search of the literature, using Medline, Embase Psychiatry and PsycINFO covering the period January 1990 up to and including October 2014., Results: We found 12 studies including one meta-analysis which showed large variations in the prevalence of MbS in patients with PTSD; these variations ranged between 7.7% to 73.0%. The PTSD and its severity as well as the comorbid depression and the use of antipsychotics all played a role in the wide discrepancies of the results. Furthermore, the reported results seem to indicate that many methodologies were used in these studies. The reasons for the large differences found in the prevalence of MbS in PTSD patients are complex: the variations are probably due mainly to the different methodologies that were used. The prevalence of MbS which stood out in a positive sense varied between 31.9% and 47.8%., Conclusion: To obtain greater clarity, more quantitative and descriptive studies are needed, in which the screening is performed on a PTSD-subgroup with severe PTSD, a severe comorbid depression and/or antipsychotic use. The studies should use method control for diagnoses of PTSD, depression, severity of both and of MbS.

Conditional marketing authorization (CMA) in the European Union (EU) is an early access pathway for medicines that show promising therapeutic effects, but for which comprehensive data are not available. Using a mixed quantitative-qualitative research design, we evaluated how CMA has been used in marketing authorization of oncology medicines in the period 2006 to 2013. We show that compared to full marketing authorization, CMA is granted based on less comprehensive data. However, this is accompanied by significantly longer assessment times and less consensus among regulators about marketing authorization. Moreover, development time from first-in-human testing to marketing authorization did not differ between full marketing authorization and CMA, but was significantly longer for CMA compared to accelerated approved products in the United States (US). Results indicate that CMA is not used by companies as a prospectively planned pathway to obtain early access, but as a "rescue option" when submitted data are not strong enough to justify full marketing authorization., (© 2015, The American Society for Clinical Pharmacology and Therapeutics.)

Purpose: The aim of this study is to provide a comprehensive overview of the outcomes of marketing authorisation applications via the mutual recognition and decentralised procedures (MRP/DCP) and assess determinants of licensing failure during CMDh referral procedures., Methods: All MRP/DCP procedures to the Co-ordination group for Mutual recognition and Decentralised procedures-human (CMDh) during the period from January 2006 to December 2013 were analysed. Reasons for starting referral procedures were scored. In addition, a survey under pharmaceutical companies was performed to estimate the frequency of licensing failure prior to CMDh referrals., Results: During the study period, 10392 MRP/DCP procedures were finalized. Three hundred seventy-seven (3.6%) resulted in a referral procedure, of which 70 (19%) resulted in licensing failure, defined as refusal or withdrawal of the application. The frequency of CMDh referrals decreased from 14.5% in 2006 to 1.6% in 2013. Of all referrals, 272 (72%) were resolved through consensus within the CMDh, the remaining 105 (28%) were resolved at the level of the CHMP. Most referrals were started because of objections raised about the clinical development program. Study design issues and objections about the demonstration of equivalence were most likely to result in licensing failure. An estimated 11% of all MRP/DCP procedures resulted in licensing failure prior to CMDh referral., Conclusion: Whereas the absolute number of MRP/DCP procedures resulting in a referral has reduced substantially over the past years, no specific time trend could be observed regarding the frequency of referrals resulting in licensing failure. Increased knowledge at the level of companies and regulators has reduced the frequency of late-stage failure of marketing applications via the MRP/DCP.

Background: Acute traumatic tendon injuries of the hand and wrist are commonly encountered in the emergency department. Despite the frequency, few studies have examined the true incidence of acute traumatic tendon injuries in the hand and wrist or compared the incidences of both extensor and flexor tendon injuries., Methods: We performed a retrospective population-based cohort study of all acute traumatic tendon injuries of the hand and wrist in a mixed urban and rural Midwest county in the United States between 2001-2010. A regional epidemiologic database and medical codes were used to identify index cases. Epidemiologic information including occupation, year of injury, mechanism of injury and the injured tendon and zone were recorded., Results: During the 10-year study period there was an incidence rate of 33.2 injuries per 100,000 person-years. There was a decreasing rate of injury during the study period. Highest incidence of injury occurred at 20-29 years of age. There was significant association between injury rate and age, and males had a higher incidence than females. The majority of cases involved a single tendon, with extensor tendon injuries occurring more frequently than flexor tendons. Typically, extensor tendon injuries involved zone three of the index finger, while flexor tendons involved zone two of the index finger. Work-related injuries accounted for 24.9% of acute traumatic tendon injuries. The occupations of work-related injuries were assigned to major groups defined by the 2010 Standard Occupational Classification structure. After assigning these patients' occupations to respective major groups, the most common groups work-related injuries occurred in construction and extraction occupations (44.2%), food preparation and serving related occupations (14.4%), and transportation and material moving occupations (12.5%)., Conclusions: Epidemiology data enhances our knowledge of injury patterns and may play a role in the prevention and treatment of future injuries, with an end result of reducing lost work time and economic burden.

Objectives: Although no universal consensus exists on treatment of cleft palates, early hard palate closure is commonly performed. The aim of the present study was to determine the influence of a vomer flap for early hard palate closure on residual palatal cleft width in patients with a unilateral complete cleft lip and palate (UCLP)., Materials and Methods: Forty-seven UCLP patients were retrospectively divided into two groups. Group A consisted of 25 patients who underwent early lip closure and simultaneous hard palate closure using a vomer flap. Group B included 22 patients who had lip closure only at first surgery. Palatal cleft widths of both groups were measured at two time points and were compared using the Mann-Whitney U test to examine the influence of vomerplasty in this very early stage., Results: No significant difference of baseline characteristics between the groups was found, and comparison of age at the time of surgeries was not significantly different. Mean age at the time of vomerplasty was 4.0 months. After the first surgery, a significantly greater total cleft width reduction of 5.0 mm average was found in group A compared to only 1.5 mm reduction in group B. This reduction took place after an average of 7.1 and 7.0 months, respectively., Conclusions: Lip closure accompanied by early hard palate closure using a vomer flap is associated with a significant postoperative reduction of the residual cleft when compared to lip closure only., Clinical Relevance: This study shows another great advantage of performing early hard palate closure using a vomer flap.

The study of negative relationships in teams has primarily focused on the impact of negative relationships on individual team member attitudes and performance in teams. The mechanisms and contingencies that can buffer against the damaging effects of negative relationships on team performance have received limited attention. Building on social interdependence theory and the multilevel model of team motivation, we examine in a sample of 73 work teams the team-level attributes that foster the promotive social interaction that can neutralize the adverse effect of negative relationships on team cohesion and, consequently, on team performance. The results indicate that high levels of team-member exchange as well as high task-interdependence attenuate how team cohesion and team performance suffer from negative relationships. Implications for research and practice are discussed., ((c) 2014 APA, all rights reserved.)

A quantum point contact (QPC) is a basic nanometre-scale electronic device: a short and narrow transport channel between two electron reservoirs. In clean channels, electron transport is ballistic and the conductance is then quantized as a function of channel width with plateaux at integer multiples of 2e(2)/h (where e is the electron charge and h is Planck's constant). This can be understood in a picture where the electron states are propagating waves, without the need to account for electron-electron interactions. Quantized conductance could thus be the signature of ultimate control over nanoscale electron transport. However, even studies with the cleanest QPCs generically show significant anomalies in the quantized conductance traces, and there is consensus that these result from electron many-body effects. Despite extensive experimental and theoretical studies, understanding these anomalies is an open problem. Here we report that the many-body effects have their origin in one or more spontaneously localized states that emerge from Friedel oscillations in the electron charge density within the QPC channel. These localized states will have electron spins associated with them, and the Kondo effect--related to electron transport through such localized electron spins--contributes to the formation of the many-body state. We present evidence for such localization, with Kondo effects of odd or even character, directly reflecting the parity of the number of localized states; the evidence is obtained from experiments with length-tunable QPCs that show a periodic modulation of the many-body properties with Kondo signatures that alternate between odd and even Kondo effects. Our results are of importance for assessing the role of QPCs in more complex hybrid devices and for proposals for spintronic and quantum information applications. In addition, our results show that tunable QPCs offer a versatile platform for investigating many-body effects in nanoscale systems, with the ability to probe such physics at the level of a single site.

In recent years, to protect the rights and welfare of human subjects, institutions in the USA have begun to set up programmes to monitor ongoing medical research. These programmes provide routine, onsite oversight, and thus go beyond existing oversight such as investigating suspected misconduct or reviewing paperwork provided by investigators. However, because of a lack of guidelines and evidence, institutions have had little guidance in setting up their programmes. To help institutions make the right choices, we used interviews and document analysis to study how and why 11 US institutions have set up their monitoring programmes. Although these programmes varied considerably, we were able to distinguish two general types. 'Compliance' programmes on the one hand were part of the institutional review board office and set up to ensure compliance with regulations. Investigators' participation was mandatory. Monitors focused on documentation. Investigators could be disciplined, and could be obliged to take corrective actions. 'Quality-improvement' programmes on the other hand were part of a separate office. Investigators requested to be monitored. Monitors focused more on actual research conduct. Investigators and other parties received feedback on how to improve the research process. Although both types of programmes have their drawbacks and advantages, we argue that if institutions want to set up monitoring programmes, quality improvement is the better choice: it can help foster an atmosphere of trust between investigators and the institutional review board, and can help raise the standards for the protection of human subjects.

Evaluating the practice of ethical review by Research Ethics Committees (REC) could help protect the interests of human participants and promote scientific progress. To facilitate such evaluations, we conducted an ethnographic study of how an REC reviews research proposals during its meetings. We observed 13 meetings of a Dutch REC and studied REC documents. We coded this material inductively and categorised these codes in two repertoires of evaluation: a repertoire of rules and a repertoire of production. In the repertoire of rules the REC applies rules, weighs scientific value and burdens to the participants and makes a final judgment on a research proposal in a meeting. In the repertoire of production, REC members check documents and forms and advise researchers on how to improve their proposals and can use informal communication. Based on these findings, we think that evaluations of the practice of ethical review should take into account the fact that RECs can use a repertoire of rules and a repertoire of production to evaluate research proposals. Combining these two repertoires can be a viable option so that the REC gives researchers advice on how to improve their proposals to prevent rejection of valuable research., (© 2012 The Authors. Sociology of Health & Illness © 2012 Foundation for the Sociology of Health & Illness/Blackwell Publishing Ltd.)

Radial longitudinal deficiency, also known as radial club hand, is a congenital deformity of the upper extremity which can present with a spectrum of upper limb deficiencies. The typical hand and forearm deformity in such cases consists of significant forearm shortening, radial deviation of the wrist and hypoplasia or absence of a thumb. Treatment goals focus on the creation of stable centralized and functionally hand, maintenance of a mobile and stable wrist and preservation of longitudinal forearm growth. Historically centralization procedures have been the most common treatment method for this condition; unfortunately centralization procedures are associated with a high recurrence rate and have the potential for injury to the distal ulnar physis resulting in a further decrease in forearm growth. Here we advocate for the use of a vascularized second metatarsophalangeal joint transfer for stabilization of the carpus and prevention of recurrent radial deformity and subluxation of the wrist. This technique was originally described by the senior author in 1992 and he has subsequently been performed in 24 cases with an average of 11-year follow-up. In this paper we present an overview of the technique and review the expected outcomes for this method of treatment of radial longitudinal deficiency.

Objective: To identify prognostic indicators of the publication rate of clinical studies, available to research ethics committees (RECs) during review., Study Design and Setting: Retrospective survival study of a random sample of 100 studies, approved by a Dutch academic REC, with follow-up information by questionnaire and bibliographic searches. Multivariate Cox regression analysis of the association between publication rate and seven factors available during review: six study characteristics and the number of letters sent by the committee during review representing the length of the review process., Results: Two factors were associated with publication rate: studies with possible therapeutic benefit to participants were less likely to be published than nontherapeutic studies (adjusted hazard ratio [AHR]: 0.16; 95% confidence interval [CI]: 0.03-0.54); with every letter sent, publication was less likely (AHR: 0.46 per letter; 95% CI: 0.17-0.98). Possibly, studies with more-than-minimal burdens to participants were more likely to be published than studies with minimal burdens (AHR: 3.90, 95% CI: 1.03-16.64)., Conclusion: We identified two prognostic indicators of publication rate. After suitable replication, RECs might explore using prognostic indicators, such as these, to target study protocols at high risk for nonpublication. Discussing the risk of nonpublication with investigators could help prevent nonpublication., (Copyright © 2010 Elsevier Inc. All rights reserved.)

A 29-year-old medical student suffered from vasovagal syncope triggered by blood and blood-related procedures, such as injections and injuries. Fainting was preceded by prodromal symptoms like light-headedness and altered vision. The patient consulted the Syncope Unit at the Academic Medical Centre, Amsterdam, the Netherlands, and received instructions on how to apply counterpressure manoeuvres. He was also successfully treated with psychological deconditioning, which consisted of desensitisation through exposure in vivo and cognitive behavioural therapy. Emotionally triggered vasovagal syncope is predominantly seen in young people and can lead to serious complications. It can be treated with simple interventions like drinking water and performing counterpressure manoeuvres. Psychological deconditioning is an effective additional therapy.

Objective: We examined the prevalence of mental health problems in refugees living in camps that emerged in Tanzania during the Rwanda crisis that started in 1994., Method: Using the 28-item version of the General Health Questionnaire (GHQ-28), we examined two samples: a random sample (n = 854) and a sample of clients of a psychosocial support programme in these camps (n = 23). Sensitivity, specificity and positive- and negative predictive values were estimated for several cut-off scores of the GHQ-28., Results: The prevalence of serious mental health problems was estimated at 50% (SE 12%). When using the GHQ-28 as a screener, a cut-off score of 14 is recommended., Conclusion: Given the high prevalence of mental health problems, psychosocial programmes for large refugee populations should aim at strengthening community structures and supporting groups instead of focusing at individuals. The screening capacity of the GHQ-28 could be used to identify mentally vulnerable groups.

We describe ER-HR3, a monoclonal antibody directed against bone marrow-derived haemopoietic reticulum cells. ER-HR3-positive cells have the electron-microscopic and enzyme-histochemical characteristics of macrophages. Additionally, they are able to phagocytoze. The ER-HR3 antigen is expressed by a majority of blood monocytes and is present on a subpopulation of resident macrophages in multiple organs. ER-HR3-positive cells are abundant in the bone marrow, the splenic red pulp, the mesenteric lymphoid paracortex and the interfollicular areas of the Peyer's patch. Few ER-HR3-positive cells have been observed in the thymic cortex and the connective tissues of the gastro-intestinal tract, the dermis and the renal medulla. Moreover, epidermal Langerhans cells express the antigen. No cross-reactivity with other cell types has been found. It is concluded that ER-HR3 has a unique distribution pattern distinct from other macrophage-specific antibodies.

We describe the purification and intracellular distribution of an antigen present on a subpopulation of murine macrophages and recognized by monoclonal antibody ER-HR3 against bone marrow-derived haemopoietic reticulum cells. Using the ER-HR3 antibody as an immobilizing ligand, two proteins were isolated as determined by SDS polyacrylamide gel electrophoresis. Under non-reducing conditions, there was a major band with an apparent molecular mass of 69 kDa and a minor band of 55 kDa. Under reducing conditions, the apparent molecular mass of each band was estimated as 76 kDa and 67 kDa, respectively. Intracellularly, these proteins occurred in close association with membranous structures, as demonstrated with gold-labelled protein A in an electron-microscopic study of the ER-HR3-positive cell line AP284. Some of the antigen was present in vesicles. To gain further insight into the possible function of the ER-HR3 antigen, its tissue distribution was investigated under distinct experimental conditions. In mice infected with Bacillus Calmette Gurèrin, ER-HR3-positive cells were observed in many, but not all, granulomata of the spleen, the lung and the liver. The ER-HR3 reactivity in these mice clearly differed from that of other antimacrophage monoclonal antibodies, such as F4/80, M5/114 and M1/70. Furthermore, phenylhydrazine-induced extramedullary erythropoiesis in the liver was accompanied by ER-HR3 expression on a subpopulation of macrophages. Finally, the addition of ER-HR3 to an antigen-specific T cell proliferation assay did not inhibit T cell proliferation.

In this study, a simple single-step fixation method for frozen tissue sections is introduced using the hexazotized salt of Pararosaniline as preservative agent. Tissue preservation by this method was shown to be superior to the commonly-used fixation with acetone. Fixation with hexazotized Pararosaniline caused a minimal loss of antigenicity as demonstrated using twenty-three monoclonal antibodies directed against lympho-haemopoietic and stromal cells.

We have studied the ability of subpopulations of hemopoietic stem cells, obtained from murine bone marrow using elutriation and multiparameter sorting, to establish and maintain hemopoiesis following their deposition on irradiated stromal layers of long-term bone marrow cultures. Two fractions were obtained that differed in their mitochondrial activity as indicated by the retention of Rhodamine-123 dye. The Rhodamine-bright cell fraction, containing the majority of day-8 and day-12 spleen colony-forming units (CFU-S) and in vitro clonable progenitors, showed hemopoiesis only in the first weeks. In contrast, the Rhodamine-dull fraction, which was depleted for day-8 CFU-S and which contained the majority of cells with marrow-repopulating ability, maintained hemopoiesis for a prolonged time after an initial week of delay. These data fully support and extend previously published in vivo data, indicating that CFU-S have low capability to generate new CFU-S and granulocyte-macrophage colony-forming units (CFU-GM), and that cells responsible for long-term generation of hemopoietic precursors and for maintenance of hemopoiesis both in vivo and in vitro are the precursors of CFU-S and of in vitro clonable progenitor cells. In addition, the present findings form the basis for an in vitro assay for a primitive precursor of CFU-S, namely the marrow-repopulating cell.

We have compared four assays to detect hemopoietic stromal damage induced by various cytostatic agents in young (4-week old) and adult (12-week old) mice. These assays included: (a) quantitation of the hemopoietic stem cell content of subcutaneously implanted spleens and femurs, (b) quantitation of fibroblastic colony-forming units per femur and spleen, (c) quantitation of the growth of normal hemopoietic progenitor cells in irradiated cytostatic drug-treated mice, and (d) measurement of splenic hemopoietic stem cell accumulation in response to bacterial lipopolysaccharide-induced hemopoietic stress. Busulfan caused a short- and long-term hemopoietic stromal defect. However, the four assays used showed different kinetics and severity of the stromal damage. Cyclophosphamide treatment resulted in a short-term stromal damage which was repaired within one week to three months, depending on the assay used. Methotrexate and vincristine did not cause long-term stromal damage as measured by the four assays used, whereas a short-term splenic stromal damage was detected using the subcutaneous implantation technique. No significant differences in stromal sensitivity to drug treatment were observed between young and adult mice. The presented data suggest that the four assays used to study stromal integrity measure different components of the hemopoietic microenvironment, and indicate that the use of a single assay may well lead to erroneous interpretations.

We investigated the in vitro effects of ASTA-Z-7595, ASTA-Z-7557, ASTA-Z-7654, and 4-hydroperoxycyclophosphamide (4HC) on murine stromal fibroblastoid colony-forming units, committed hemopoietic progenitors (erythroid burst-forming units and granulocyte/macrophage colony-forming units), and pluripotent hemopoietic stem cells assayed by the spleen colony-forming unit (CFU-s) assay. In general, the drugs showed a time-and dose-dependent effect on colony-forming unit survival, and the relative toxicities were in the order in which the drugs are listed above. We found a relative sparing of day 12 CFU-s compared with day 7 CFU-s and committed hemopoietic and stromal progenitors, although colony size of day 12 CFU-s was reduced. Our results support two possible mechanisms for delayed or inadequate hemopoietic reconstitution in clinical studies using bone marrow purged with 4-hydroperoxycyclophosphamide or ASTA-Z-7557, i.e., damage to (a) transplantable stromal cells or (b) the hemopoietic stem cells.

We studied the ability of the hemopoietic organ stroma to recover from damage inflicted by 5 or 7 Gy gamma radiation administered during a period of stromal growth in 4-week-old mice. Irradiation resulted in an immediate depletion of femoral colony-forming fibroblastic progenitors (CFU-F) down to 10-20% of age-matched control values. A full recovery to normal numbers occurred between 120 and 240 days after irradiation and was followed by a secondary decrease 1 year after irradiation. This secondary decrease was accompanied by a decrease in the femoral CFU-S and CFU-C content. Femoral CFU-F attained normal numbers and it was demonstrated to occur from surviving CFU-F and could not be enhanced or prolonged following infusion of unirradiated bone marrow cells after irradiation. During the transient CFU-F recovery the hemopoietic stroma remained severely damaged as judged by the regenerative capacity of spleen and femur stroma after subcutaneous implantation, and the ability of the spleen to accumulate CFU-S in response to lipopolysaccharide injection. We have reported earlier that in similarly irradiated adult mice, no restoration of femoral CFU-F was observed. This difference between 4-week-old and adult mice could not be explained by a difference in in vitro radiosensitivity of CFU-F or in their in vivo regeneration kinetics following irradiation and subsequent lipopolysaccharide injection. We conclude from these observations that the recovery kinetics of the CFU-F population is different in young and adult irradiated mice, infused CFU-F do not contribute to CFU-F regeneration in an irradiated femur, CFU-F are not the sole determinants of stromal regeneration in femur and spleen following irradiation.

Murine bone-marrow-derived reticular fibroblast cultures were tested for the ability to support hemopoiesis and release hemopoietic growth factors in vitro. The reticular fibroblast cultures employed in these studies were 95%-100% pure on the basis of Mac-1, F4/80, MIV-51, T200, antifactor VIII and ER-TR7 monoclonal antibody staining. Further support for the fibroblastic nature of these cells was obtained from collagen and laminin analyses. Addition of stromal cell-depleted bone marrow cell suspensions to flasks of confluent reticular fibroblasts resulted in production and release of granulocytes, monocyte-macrophages, and granulocyte-monocyte progenitors from the adherent layer for 4-8 weeks. Pluripotent spleen colony-forming units were detected during the first four weeks. Assay of reticular fibroblast conditioned medium for hemopoietic growth factors demonstrated production of granulocyte-macrophage colony-stimulating activity and stem-cell-activating factor. We did not detect any erythroid burst-promoting activity. These results suggest that reticular fibroblasts may play a role in the maintenance of pluripotent stem cells and in the proliferation and differentiation of cells committed to the granulocyte-monocyte lineage.

A murine macrophage cell line AP284 that appeared to be mature in phenotype was isolated. After repeated cloning, the cell line expressed the markers Mac-1, Mac-2, Mac-3, 2.4G2, F4/80 as well as Ia antigens. Moreover, it was positive for the enzymes nonspecific esterase and acid phosphatase, negative for alkaline phosphatase and was able to phagocytize latex beads. We studied whether this cell line was able to present antigen to cloned MT4+, Lyt-2- T cells specific for methylated bovine serum albumin (mBSA) or ovalbumin (OVA). The in vitro proliferative response of the cloned T cells specific for mBSA or OVA was found to be effectively supported by AP284. This proliferation could be blocked by monoclonal antibodies against Ia determinants. AP284 also effectively presented antigen in vivo as was shown in a foot swelling assay measuring delayed type hypersensitivity (DTH) to mBSA caused by specific cloned T cells with the helper phenotype. This offers a unique model system for studying the process of antigen presentation in which both the antigen presenting cells and the T cells are monoclonal.

We studied the short- and long-term effects of a fractionated injection of cis-diamminedichloroplatinum (II) (CDDP) upon the haemopoietic stroma and the haemopoietic precursor cell compartment of young and adult mice. The integrity of the stromal microenvironment was investigated using three different assays including quantification of (a) the fibroblastoid progenitor cell compartment, (b) the regenerative capacity after subcutaneous implantation of spleen and femur, and (c) the growth of normal bone marrow progenitors in lethally irradiated CDDP-treated mice. CDDP treatment induced a slight anaemia which lasted for the observation period of 1 year, and could not be restored by infusion of normal bone marrow cells. The population size of haemopoietic progenitors was severely decreased immediately after CDDP treatment and the CFU-S recovery in the bone marrow was slow and temporary. Stromal function was significantly decreased and normalization occurred within approximately 40 d, depending on the stromal parameter measured. Subsequently, the regenerative capacity of the stroma showed a second decrease which was still detected at 1 year. This pattern of stromal damage has not been reported for any other cystostatic agent. Since the other two assays did not detect a second decrement in stromal integrity it is implied that the three stromal assays used detect different stromal functions. We conclude that CDDP treatment of both young and adult mice results in severe short-term damage and a late occurring secondary regenerative defect of the haemopoietic organ stroma.

The blood supply to the femoral bed was studied in anaesthetised dogs before and after producing arterial stenoses. The blood supply system consisted of the vessels proximal to the site of measurement in the femoral artery and was characterised by a supply graph, which related mean perfusion pressure to mean flow. The different pressures and flows were obtained using an artificial periphery, the impedance of which was changed from beat to beat. The supply graph was approximated by a parabola with two parameters: the intercepts with the pressure and flow axes, the latter indicating the maximum mean flow. For constant aortic pressure the maximum mean flow appeared to be linearly related to the cross sectional area of the stenosed section (r = 0.98). Maximum mean flow was already considerably reduced before the stenosis became critical--that is, before physiological flow was measurably diminished. The change in maximum mean flow was therefore used to quantify the haemodynamic effects of stenoses that were less than critical. Blood supply graphs of the superficial femoral arteries were determined also in seven patients undergoing a femoropopliteal bypass operation. The maximum mean flow correlated well with the degree of obstruction determined from the preoperative angiograms (r = 0.90).