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Nerve functions require phosphatidylinositol-4,5-bisphosphate (PIP2) that binds to ion channels, thereby controlling their gating. Channel properties are also attributed to serotonin transporters (SERTs); however, SERT regulation by PIP2 has not been reported. SERTs control neurotransmission by removing serotonin from the extracellular space. An increase in extracellular serotonin results from transporter-mediated efflux triggered by amphetamine-like psychostimulants. Herein, we altered the abundance of PIP2 by activating phospholipase-C (PLC), using a scavenging peptide, and inhibiting PIP2-synthesis. We tested the effects of the verified scarcity of PIP2 on amphetamine-triggered SERT functions in human cells. We observed an interaction between SERT and PIP2 in pull-down assays. On decreased PIP2 availability, amphetamine-evoked currents were markedly reduced compared with controls, as was amphetamine-induced efflux. Signaling downstream of PLC was excluded as a cause for these effects. A reduction of substrate efflux due to PLC activation was also found with recombinant noradrenaline transporters and in rat hippocampal slices. Transmitter uptake was not affected by PIP2 reduction. Moreover, SERT was revealed to have a positively charged binding site for PIP2. Mutation of the latter resulted in a loss of amphetamine-induced SERT-mediated efflux and currents, as well as a lack of PIP2-dependent effects. Substrate uptake and surface expression were comparable between mutant and WT SERTs. These findings demonstrate that PIP2 binding to monoamine transporters is a prerequisite for amphetamine actions without being a requirement for neurotransmitter uptake. These results open the way to target amphetamine-induced SERT-dependent actions independently of normal SERT function and thus to treat psychostimulant addiction.

Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed disorder of school-age children. Although genetic and brain-imaging studies suggest a contribution of altered dopamine (DA) signaling in ADHD, evidence of signaling perturbations contributing to risk is largely circumstantial. The presynaptic, cocaine- and amphetamine (AMPH)-sensitive DA transporter (DAT) constrains DA availability at presynaptic and postsynaptic receptors following vesicular release and is targeted by the most commonly prescribed ADHD therapeutics. Using polymorphism discovery approaches with an ADHD cohort, we identified a hDAT (human DAT) coding variant, R615C, located in the distal C terminus of the transporter, a region previously implicated in constitutive and regulated transporter trafficking. Here, we demonstrate that, whereas wild-type DAT proteins traffic in a highly regulated manner, DAT 615C proteins recycle constitutively and demonstrate insensitivity to the endocytic effects of AMPH and PKC (protein kinase C) activation. The disrupted regulation of DAT 615C parallels a redistribution of the transporter variant away from GM1 ganglioside- and flotillin1-enriched membranes, and is accompanied by altered CaMKII (calcium/calmodulin-dependent protein kinase II) and flotillin-1 interactions. Using C-terminal peptides derived from wild-type DAT and the R615C variant, we establish that the DAT 615C C terminus can act dominantly to preclude AMPH regulation of wild-type DAT. Mutagenesis of DAT C-terminal sequences suggests that phosphorylation of T613 may be important in sorting DAT between constitutive and regulated pathways. Together, our studies support a coupling of DAT microdomain localization with transporter regulation and provide evidence of perturbed DAT activity and DA signaling as a risk determinant for ADHD.

Abnormal function of NMDA receptors is believed to be a contributing factor to the pathophysiology of schizophrenia. NMDAR subunits and postsynaptic-interacting proteins of these channels are abnormally expressed in some patients with this illness. In mice, reduced NMDAR expression leads to behaviors analogous to symptoms of schizophrenia, but reports of animals with mutations in core postsynaptic density proteins having similar a phenotype have yet to be reported. Here we show that reduced expression of the neuronal RasGAP and NMDAR-associated protein, SynGAP, results in abnormal behaviors strikingly similar to that reported in mice with reduced NMDAR function. SynGAP mutant mice exhibited nonhabituating and persistent hyperactivity that was ameliorated by the antipsychotic clozapine. An NMDAR antagonist, MK-801, induced hyperactivity in normal mice but SynGAP mutants were less responsive, suggesting that NMDAR hypofunction contributes to this behavioral abnormality. SynGAP mutants exhibited enhanced startle reactivity and impaired sensory-motor gating. These mice also displayed a complete lack of social memory and a propensity toward social isolation. Finally, SynGAP mutants had deficits in cued fear conditioning and working memory, indicating abnormal function of circuits that control emotion and choice. Our results demonstrate that SynGAP mutant mice have gross neurological deficits similar to other mouse models of schizophrenia. Because SynGAP interacts with NMDARs, and the signaling activity of this protein is regulated by these channels, our data in dicate that SynGAP lies downstream of NMDARs and is a required intermediate for normal neural circuit function and behavior. Taken together, these data support the idea that schizophrenia may arise from abnormal signaling pathways that are mediated by NMDA receptors.

This report describes a 26 year old woman, of Pakistani origin, who presented five months postpartum with severe megaloblastic anaemia as a result of nutritional folate deficiency. This case was unusual in that a small number of myeloblasts were present in the peripheral blood at presentation, and this circulating population temporarily increased in size when folate replacement was begun. We also highlight the need to recognise the non-linear relation between haematocrit and red blood cell folate concentration when the haematocrit is very low (< 0.15) and emphasise the importance of the clinical history.

Aims: To evaluate the incidence and outcome of acute myeloid leukaemia (AML), FAB M6 (erythroleukaemia)., Methods: A demographic study in the Northern Health Region of England between 1983 and 1999., Results: Thirty three cases were diagnosed and registered prospectively. The overall incidence was 0.077 cases/100,000/year. There was a pronounced rise in incidence in patients aged 56 years or more: 6.6 times higher than that in younger patients. Overall survival was poor; median survival was 11 months for those aged less than 56 years, and three months for patients aged 56 years and above (p = 0.045). Acquired karyotypic abnormalities were found in 17 of 27 patients where analysis was attempted. When classified according to the criteria of the Medical Research Council AML trials, karyotype predicted survival, with a median overall survival of 14 months for those with "standard risk" cytogenetic results and two months for "poor risk" results (p = 0.005)., Conclusion: This study demonstrates a worse survival for patients with erythroleukaemia than that reported in some published trials of selected patients.

The management of acute massive blood loss is considered and a template guideline is formulated, supported by a review of the key literature and current evidence. It is emphasized that, if avoidable deaths are to be prevented, surgeons, anaesthetists, haematologists and blood-bank staff need to communicate closely in order to achieve the goals of secure haemostasis, restoration of circulating volume, and effective management of blood component replacement.

We report the development of a high titre antibody to factor VIII in a patient with previous high grade B cell non-Hodgkin's lymphoma treated with fludarabine. Unlike previous reports of factor VIII inhibitors and lymphoproliferative disease this patient's lymphoma was in remission. We speculate that the occurrence of the inhibitor is another manifestation of the increasingly recognized autoimmune side-effects of fludarabine.

Thromboembolic disease, as a complication of ovarian stimulation and assisted conception techniques, is generally considered to be a rare complication of ovarian hyperstimulation syndrome and, by implication, lower limb in origin. Sporadic cases of unusually sited thromboses, both venous and arterial, have been reported. This paper aims to draw attention to the relatively large number of such thromboses reported in the world literature compared with those cited in previous commentaries, and to emphasize how little is known about their pathogenesis. It is believed that this is an issue which requires to be addressed in order to understand the background pathology to such incidents and if possible to identify women at greatest risk from such potentially debilitating or fatal complications, such that appropriate prophylactic measures can be taken.

Three cases of upper limb deep venous thrombosis occurring in association with assisted conception treatment are presented. The accepted argument that lower limb thrombosis occurring in cases of complicated or severe hyperstimulation syndrome represents the likeliest thrombo-embolic disorder in this situation is questioned.

We describe the Alder-Reilly morphological abnormality in an elderly man with a myelodysplastic syndrome (MDS). The literature pertaining to abnormal neutrophil hypergranulation is reviewed and the possible role of myelodysplasia in its causation is discussed.

The aim of this study was to collect prospectively unselected, population-based data on young adults with acute myeloid leukaemia (AML) over a 9-year period and to evaluate the impact on survival of the introduction of allogeneic transplantation performed in first remission. The population within the Northern Region of England is 3.09 million. During the study period a total of 149 de novo patients between 15 and 55 years old presented. The incidence of AML was 0.79 per 10(5) (age-specific population) in the 15-24-year-old group, 0.85 per 10(5) in the group 25-39 years old and 1.35 per 10(5) in the 40-55-year-old group. Remission induction success varied with age (74% for patients < 40 years and 58% for patients 40-55 years). In the 15-40 year old group 28 patients had an HLA-matched donor, 22 patients had a transplant (one syngeneic) and 24 patients in the 15-40-year-old group in remission at 6 months did not have a transplant. The allogeneic group < 40 years old had an event-free survival (EFS) at 4 years of 62%, whereas patients of the same age who received chemotherapy alone had an EFS at 4 years of 24%. A small heterogeneous group of 14 patients who had intensification with autotransplant are not included in this analysis. The population study approach demonstrates the difficulties of introducing uniform treatment strategy in this disease group. The study confirms the view that allogeneic transplant in first remission in the 15-40-year-old group is the treatment of choice. Unfortunately the overall impact of transplant on the population is not great since only 22 of 149 patients (14%) were able to receive an allograft in first remission.

Skin and rectal biopsy tissue from 34 allogeneic and 23 autologous BMT recipients was prospectively analysed for CMV using immunohistochemistry and PCR to investigate the hypothesis that target organ infection with CMV initiates and/or exacerbates GVHD. Biopsies were obtained prior to and at 3, 8 and 26 weeks after BMT and whenever GVHD was suspected. Surveillance specimens of peripheral blood leucocytes (PBL), urine and throat swabs were obtained every 2 weeks until 12 weeks after BMT, and whenever CMV was suspected. Cryostat sections were analysed immunohistochemically for CMV antigens and PBL and biopsies for CMV DNA by PCR. Of the 31 patients who engrafted, 28 (90%) developed GVHD clinically, confirmed histologically in 56 biopsies. GVHD proved clinically severe in 14 patients, 4 of whom had treatment-resistant GVHD. CMV was detected in PBL more frequently in patients with severe GVHD than in those with mild/moderate GVHD (29% vs. 7%). However, in all but one patient the onset of GVHD preceded detection of CMV. In biopsy specimens, CMV was detected in only 2 patients, 1 of whom had an exacerbation of GVHD temporally associated with CMV. Thus, despite a high incidence of GVHD in this series, with 56 episodes of GVHD in 28 patients, only 1 patient had CMV in biopsy tissue temporally associated with GVHD. This suggests that biopsy infection with CMV is not a major factor in initiating or exacerbating GVHD in this cohort. This study thus does not support a role for target organ infection with CMV in the pathogenesis of GVHD.

A 4-year prospective study of de novo acute myeloid leukaemia in patients aged 56 years and over was undertaken in the Northern Region of England (population 3.09 million). The study was conducted to assess the incidence and outcome of treatment in all elderly patients diagnosed between January 1, 1988 and December 31, 1991. Two hundred cases de novo AML were confirmed, giving an incidence of 6.05/10(5) per annum (age specific population) (95% Cl, 5.2-6.9). Acute promyelocytic leukaemia was rare. Erythroleukaemia, monocytic leukaemia and AML with trilineage myelodysplasia were more common than in younger patients. Karyotypic abnormalities classically associated with response to therapy were present in only six of 91 patients where cytogenetic data was available. Treatment was at the discretion of the physician in charge: if given, specific treatment was recorded and clinical outcome assessed. Only 84 (42%) of patients received treatment with curative intent. Forty-four of 84 achieved a complete remission, usually of brief duration. A normal karyotype in leukaemic cells was associated with a survival advantage in this group (p < 0.05). Actuarial overall survival at 4 years for the entire group was 2.5%. Even with aggressive treatment, the outcome is poor. The pattern of disease and its lack of response to conventional treatment would support the hypothesis that AML in the elderly may differ biologically from that observed in younger patients. Karyotyping appears to predict those patients likely to benefit from intensive therapy and decisions about management in otherwise fit patients should, if possible, be delayed until a result is obtained. Every effort should be made to give such patients optimal treatment. However, most patients are unsuitable for aggressive treatment and, since long-term survival is rare, cure should not be offered as an inducement to accept such treatment and improving quality of life outside hospital should be the aim of treatment in this group.

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare but serious complication of blood component therapy in patients with haematological malignancies. B-chronic lymphocytic leukaemia (B-CLL), however, has rarely been associated with TA-GVHD. We report three patients with advanced B-CLL who developed TA-GVHD. All these had been treated with fludarabine. Suppression of T cells by fludarabine may have contributed to an increased susceptibility to TA-GVHD. The use of irradiated blood products to prevent this complication should be considered for patients with advanced B-CLL treated with fludarabine or other purine analogues.

Lymphoblasts were separated from the peripheral blood or bone marrow of 19 children (age 1-15, median 4 years) and 13 adults (age 18-59, median 47 years) with acute lymphoblastic leukaemia (ALL). Twenty-one samples were examined at presentation (16 from children and five from adults) and 13 at relapse (three children and ten adults). Glutathione (GSH) levels in leukaemic blasts were compared with in vitro sensitivity to a variety of cytotoxic drugs assessed using 3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) as an indicator of cell viability. There was a statistically significant positive correlation between GSH levels and in vitro sensitivity to daunorubicin (Spearman's rank correlation coefficient rs = 0.38, p < 0.04), melphalan (rs = 0.39, p < 0.04) and prednisolone (rs = 0.48, p < 0.01), but not mitozantrone, etoposide or 6-thioguanine. There was no statistically significant difference in median GSH levels between blasts from children and adults or between samples taken at presentation or relapse. The sample median GSH levels in blasts from patients who responded to therapy (n = 21) and those who did not (n = 7) were 1.05 fmol/cell (97.3% confidence interval (CI) 0.78-1.52) and 2.66 fmol/cell (98.4% CI 0.53-5) respectively, and this difference was statistically significant (p < 0.02, Mann-Whitney U test). In two patients for whom paired samples were available, GSH levels in blasts on relapse were greater than 2-fold higher than on presentation. These results provide evidence that elevation of GSH in leukaemic blasts may be associated with resistance to drugs used in the treatment of children and adults with ALL.

Immunocytochemistry was used to assess bcl-2 expression in blasts obtained from the bone marrow of 28 patients with acute lymphoblastic leukaemia (ALL) (16 children and six adults at presentation and three children and three adults on relapse) and 20 with acute myeloid leukaemia (AML) (19 adults and one child, 13 with de novo AML, 11 at presentation and two on relapse, and seven secondary to myelodysplasia or chronic myeloid leukaemia). Slides were examined both for the percentage of positive cells and for the intensity of staining using a five-point scale. There was a statistically significant increase in both the percentage of positive cells seen (P < 0.002) and the intensity of staining (P < 0.01) between samples obtained at relapse and those at presentation in ALL. There was a significantly greater intensity of staining in cells from patients with ALL (P < 0.05) and AML (P < 0.05) who failed to achieve remission after chemotherapy than in those who responded. The intensity of staining in cases of secondary AML was lower than that in de novo disease (P < 0.01). These results suggest that expression of bcl-2 may be an important prognostic feature in both de novo AML and in ALL, but not in secondary AML.

Iron deficiency severely limits the efficacy of recombinant human erythropoietin (EPO). In order to determine how best to identify and monitor children at risk of developing iron deficiency, we serially measured several parameters of iron status in nine children before and during a 24-week period of EPO therapy. Serum ferritin was the best predictor of development of iron deficiency, five of the nine children developed iron deficiency, characterised by a poor haemoglobin response or evidence of microcytosis and hypochromia; all had a serum ferritin of 60 micrograms/l or less at the start of EPO. Haemoglobin response was also related to change in mean red cell volume (MCV); a falling MCV, irrespective of absolute value, accompanying a poor response to EPO. Iron treatment in five children resulted in significant improvements in haemoglobin and iron status parameters. Although MCV remained low, there was a marked increase in red cell volume distribution width after iron, which may be of value in monitoring the response to iron therapy. We suggest that children with a serum ferritin of 60 micrograms/l or less and those who develop a falling MCV during EPO treatment should receive high-dose oral iron supplementation before and during treatment with EPO.

An in vitro skin explant model has been used to predict the severity of acute graft-versus-host disease (GVHD) in 34 HLA-identical bone marrow transplant recipients (correlation coefficient 0.6 p < 0.001). Supernatants from HLA-matched patient/donor mixed lymphocyte cultures (MLCs) were analysed for levels of tumour necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma). High levels of both cytokines correlated with the development of GVHD grades II or above (p < 0.05). The supernatants were also tested for induction of class II MHC antigen expression on third party skin and results correlated with clinical outcome in 17 of 22 cases (77%) (correlation coefficient 0.65, p < 0.001). The results suggest that measurement of both TNF alpha and IFN gamma in HLA-matched MLC supernatants is of predictive value and that the skin explant model is a useful model for studying the aetiology of GVHD in humans.

Failure to obtain sufficient material from marrow aspiration (dry tap) posed a diagnostic problem in two patients with pancytopenia. By using collagenase digestion of the trephine biopsy specimen, a precise diagnosis was reached. This technique is very useful because it permits flow cytometric and immunocytochemical analyses of cell suspensions obtained after collagenase digestion of the trephine biopsy specimen core. Acute leukaemia presenting with a dry tap can therefore be accurately immunophenotyped. The technique is easy to perform and merits wider use.

Skin and rectal biopsies from patients with GVHD were examined histologically and immunopathologically before and after treatment for the disease. The patients were divided into two groups: those showing a good response to treatment and those showing a poor or no response. The aims of the study were to assess the possibility of predicting the response to treatment and to compare good and poor responders after treatment. The results show that there are no features on either skin or rectal biopsy that could identify those patients with early GVHD who would respond to treatment. Following treatment with steroids there was no change histologically in the grading of the skin biopsy whereas the rectal biopsy showed improvement in six of nine good responders and no improvement in the poor responders. There was an increase in infiltrating lymphocytes in both the skin and rectum of patients showing a poor response and this is most likely due to the ongoing immune reaction. The pre-treatment biopsy did not show any features that would predict this development and was therefore of no prognostic value. However, examination of skin and rectal biopsies may aid in determining whether patients are responding to the treatment given for GVHD.

The immunopathological appearances of skin and rectum in 64 autologous and allogeneic recipients were determined before and after bone marrow transplantation. Patients who developed acute graft-versus-host disease were biopsied as soon as a clinical diagnosis was made. At the same time peripheral blood samples were collected for comparative analysis. Immunohistological and morphometric techniques were employed using a panel of monoclonal antibodies to T lymphocytes and subsets, B lymphocytes, natural killer cells, macrophages, and Langerhans cells. A reduction in the CD4/CD8 ratio after BMT was seen in skin and rectal biopsies from both autologous and allogeneic recipients with or without GVHD. The same pattern was observed in blood samples taken at the same time. Langerhans cells were reduced in the skin in all patients after BMT, probably by the conditioning regimen. Only a few cells expressing activation or natural killer cell markers were present and there were no changes observed in the macrophage population. This study has provided no evidence to implicate either CD4- or CD8-positive T lymphocytes as the initiators of the cellular damage in acute GVHD. The distribution of lymphocyte subsets in the blood was similar to that in the tissues, suggesting that the tissue changes reflect the pattern of lymphocyte repopulation after BMT and may have little bearing on the pathogenesis of GVHD.

Forty-one patients who had undergone bone marrow transplantation were examined. Nineteen (63%) of the 30 who had received fractionated total body irradiation (TBI) had cataracts in comparison with only 1 (9%) of the 11 non-irradiated patients. No significant differences in steroid therapy were demonstrated between these groups of patients. Dry eyes were observed in eight irradiated patients, seven of whom had preceding graft-versus-host disease. Superficial punctate staining of the bulbar conjunctiva was observed in 25 (83%) of the irradiated group and, in milder form, in five (45%) of the non-irradiated group. Our data suggest that the incidence of cataract following fractionated TBI is influenced not only by the total dose of radiation but also by its rate of administration (defined by midline tissue dose rate and fractionation schedule). In addition dry eyes and conjunctival staining may be exacerbated by TBI, though other aspects of conditioning may also be implicated.

The ionic monomer, sodium diatrizoate at 150 mg I/ml (726 mosmol/kg) and the non-ionic monomer, iopamidol, diluted to the same iodine concentration but at 324.3 mosmol/kg, were randomly allocated to patients undergoing transfemoral intra-arterial digital subtraction angiography for lower limb peripheral vascular disease. The agents produced images of comparable quality and diagnostic efficacy. There were no significant differences between the media regarding sensations of pain and warmth. Minor neurological symptoms (headache and dizziness) occurred 7 times more frequently with the ionic monomer. There was a slight but temporary rise in plasma potassium one hour after injection of the ionic monomer but no evidence of appreciable intravascular haemolysis. The non-ionic monomer caused a slight fall in haemoglobin and haematocrit one hour after injection which is attributed to osmotic haemodilution. It is concluded that a diluted high osmolar contrast agent is an acceptable alternative to a low osmolar agent in transfemoral digital subtraction lower limb aortography.

Over three years 81 consecutive bone marrow transplant recipients (32 allogeneic and 49 autologous) who received prophylaxis with acyclovir, were studied for symptomatic virus infection. Thirty nine infections were documented in a total of 28 patients. Thirty two infections were mild, five were moderately severe, and two were severe. Cytomegalovirus infection occurred in only six allogeneic recipients. Herpes simplex virus and varicella zoster virus infections occurred infrequently. Seven patients who were considered at the time of death to have died due to an infectious cause were studied virologically at necropsy. In only one patient was a virus infection thought to have been the cause of death. Prophylaxis with acyclovir may have influenced the rate and clinical prominence of herpes virus infections. In this study viruses were considered to have had a relatively minor role in causing morbidity and mortality.

In a total of 1977 males aged 5 years and over examined in 21 cluster samples on the coast of Tanzania, the overall rate for microfilariae of Wuchereria bancrofti was 32%. Hydrocoele and elephantiasis rates were 39% and 3%, respectively. The rates and severity of these 2 clinical manifestations increased in the older age groups. Both the microfilarial density and prevalence increased rapidly in the early age groups, followed by a levelling off and then a slight fall in old age. There was no association between microfilarial densities or rates and the overall prevalence of hydrocoele, but a negative association was demonstrated between microfilaraemia and hydrocoeles and elephantiasis. A comparison between the length of residence in an endemic area and the microfilarial and clinical sign rates showed evidence for the long incubation period for W. bancrofti and for the slow development of hydrocoeles and elephantiasis.

The examination of 250 cases of onchocerciasis from the Sudan-savanna of northern Cameroon showed a strong association between microfilarial invasion of the eye and microfilarial skin concentrations at the outer canthus. It was also shown that the presence of a head nodule was associated with a high microfilarial skin concentration around the eye. It is suggested that these findings are of practical importance in the field for the early detection of cases at risk of developing serious ocular lesions.

An in vitro skin explant model for graft-versus-host disease (GVHD) in humans has been used to study the role of effector T cells in the histological pathogenesis of GVHD. In 11 of 12 experiments clear GVHD changes of grades II-IV were induced in HLA-mismatched skin explants cultured with allogeneic T cells sensitized by in vitro mixed lymphocyte culture. The role of effector T cells was investigated by comparing results before and after removal of CD3 positive cells, and CD4 positive and CD8 positive T cell-subsets by antibody and complement cytolysis from responder populations. Only total removal of CD3 positive T cells prevented histopathological lesions of GVHD in the skin biopsy specimens. The results also demonstrated that the CD4 positive population caused the greatest degree of GVHD in vitro in skin biopsy specimens and direct infiltration into skin by cells is not required for changes to become evident. These results confirm the early results on animal models and demonstrate the use of the skin explant model as a tool for studying the biology of GVHD in humans.

A five-year follow-up of 18 403 male British civil servants between the age of 40 and 64, who had been the subject of an earlier clinical survey found 277 deaths from coronary heart-disease (C.H.D.). After adjusting for age, current cigarette smoking, systolic and diastolic blood-pressure, and blood-cholesterol were shown to be related to both the prevalence of one or more indices of cardiac ischaemia and to the risk of cardiac death. Neither blood-glucose two hours after a 50 g load nor weight/height showed any such simple linear association with mortality. Multivariate analysis confirmed that the main risk factors were independently related to cardiac morbidity and mortality. Irrespective of blood-pressure or plasma-cholesterol, current cigarette smokers thus had a higher risk of C.H.D. death than those not smoking cigarettes.

A comparative study of radionuclide bone scanning and skeletal radiology in patients with multiple myeloma revealed four principal findings: (i) There were no cases of negative bone scans with positive skeletal radiographs. (ii) Lytic bone lesions were seriously underestimated by bone scans. (iii) Bone scans tended to pick up lesions in ribs missed on the skeletal surveys. (iv) Patients with bone pain were more likely to have positive bone scans and skeletal radiographs than asymptomatic patients.

Factors V, VII, VIII, X, XI, and XII of the coagulation system, platelet count, and antithrombin III levels were assayed in 20 healthy volunteers aged 20-40 years and 61 elderly subjects aged 66-96 years whose skinfold thickness was also measured. Factors XI, XII, and antithrombin III levels tended to increase in women and decrease in men while factors X, VII, and V tended to increase in both males and females with advancing years. No age or sex differences were found in platelet counts or factor VIII levels. Factor VIII levels were inversely correlated with obesity in elderly males (r = -0.56, p < 0.005).

Combined neodymium and strontium isotope studies on Tertiary volcanics from northwest Scotland indicate that their parental mantle isotopic compositions have been substantially modified in many instances by contamination with the Precambrian continental crust through which they were erupted. The occurrence of samarium-neodymium and rubidium-strontium "pseudoisochrons" of different ages in these contaminated continental volcanics indicates that they are artifacts of the contamination processes and have no temporal significance with respect to mantle fractionation events.

With the advent of electronic particle counters of the Coulter S type the mean cell volume (MCV) has become an integral and useful feature of the red cell profile. Abnormally high values, often of minor degree, are particularly common but their precise clinical significance may be difficult to establish. This study defines the normal range and determines the incidence and distribution of the high MCV in routine hospital practice. Two hundred consecutive adult patients with an MCV of 100 fl or more were identified from the Coulter S analysis of 6542 blood samples and the underlying cause was established in 80%. Some of the clinical and economic implications of these findings are presented and briefly discussed.

Comparison is made of the advantages, in terms of benefit to patients and salary costs, of employing a consultant paediatrician and non-specialist physicians in clinical work, management activities, research, and education. Comparisons are based on data derived by a simple method from inpatient records of 10 125 children aged 0-5 years admitted over a 23-month period to Mbale Hospital, Uganda. Benefits to inpatients were assessed from the quarterly death and failure rates and the proportion of failures occurring within 24 h of admission to hospital. The relative costs of the various items of medical work were based on the salary costs that they incurred. The advantages of one activity compared with another are demonstrated, and the results clearly indicate that greater benefit at lower cost was obtained by the use of physicians in management and supervisory work than by employing them in the routine care of inpatients.

Health sciences librarians established a statewide medical information network in South Dakota to provide rural physicians with database access and rapid document delivery. A private grant funded equipment for interactive simultaneous remote searching (ISRS) and telefacsimile transmission, as well as for a coordinator for training and follow-up support. In less than one year, telefacsimile technology has become an integral part of library information transfer among sixteen network sites, and ISRS is gaining acceptance among physicians who lack local access to online databases.

A survey for schistosomiasis in a village in the Gezira area of the Sudan in 1973 showed that there has probably been a great increase in the incidence of S. mansoni infection in the last 25 years. Severe morbidity was uncommon in this sample but overt infection was associated with the symptoms of bloody diarrhoea, tiredness, and possibly abdominal pain, and with a reduced level of haemoglobin. Hepatosplenomegaly was common and schistosomiasis is considered to have contributed to this, although hyperendemic malaria must also have been important in its causation.

Since the description in 1974 of the 5q--syndrome, only 29 cases have been reported. Over a 3 1/2 year period cytogenetic culture of bone marrow submitted from 344 patients being investigated for a blood disorder revealed nine patients with anomalies of chromosome 5. In five of these patients (samples arising from 37 patients being investigated for refractory macrocytic or aplastic anaemia) the 5q-syndrome was diagnosed. The clinical and haematological findings of this syndrome are reviewed and attention is drawn to the importance of reviewing megakaryocytic numbers and morphology in refractory macrocytic anaemia if the diagnosis is to be considered. The diagnosis is compatible with prolonged survival and establishing it prevents repeated and unnecessary investigation.

One hundred and eighty bone marrow trephine biopsies obtained during 68 staging procedures before and during treatment of 20 children with Stage IV neuroblastoma were reviewed. A primitive cell infiltrate with prominent fibrous stromal reaction and increased reticulin characterized the marrow at presentation. Once treatment had begun, primitive cells became difficult to find but fibrosis and a marked increase in reticulin persisted in most cases. Distortion in marrow architecture and the continuation of abnormal stromal reactions may reflect failure to eradicate tumour despite absence of detectable primitive cells. If current therapeutic options are to be assessed properly, uniformly accepted criteria to define continuance of marrow infiltration in children with neuroblastoma are needed. A scheme for classifying marrow histological appearances is presented which may prove to be of more value than a simple distinction between 'involved' and 'uninvolved'.