Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies.

CD47, a broadly expressed cell surface protein, inhibits cell phagocytosis via interaction with phagocyte-expressed SIRPα. A variety of hematological malignancies demonstrate elevated CD47 expression, suggesting that CD47 may mediate immune escape. We discovered three unique CD47-SIRPα blocking anti-CD47 monoclonal antibodies (mAbs) with low nano-molar affinity to human and cynomolgus monkey CD47, and no hemagglutination and platelet aggregation activity. To characterize the anti-cancer activity elicited by blocking CD47, the mAbs were cloned into effector function silent and competent Fc backbones. Effector function competent mAbs demonstrated potent activity in vitro and in vivo, while effector function silent mAbs demonstrated minimal activity, indicating that blocking CD47 only leads to a therapeutic effect in the presence of Fc effector function. A non-human primate study revealed that the effector function competent mAb IgG1 C47B222-(CHO) decreased red blood cells (RBC), hematocrit and hemoglobin by >40% at 1 mg/kg, whereas the effector function silent mAb IgG2σ C47B222-(CHO) had minimal impact on RBC indices at 1 and 10 mg/kg. Taken together, our findings suggest that targeting CD47 is an attractive therapeutic anti-cancer approach. However, the anti-cancer activity observed with anti-CD47 mAbs is Fc effector dependent as are the side effects observed on RBC indices.

Pregnancy outcomes of women with and without a history of anorexia nervosa.

BACKGROUND: When women have a history of anorexia nervosa (AN), the advice given about becoming pregnant, and about the management of pregnancies, has usually been cautious. This study compared the pregnancy outcomes of women with and without a history of AN. METHOD: Women with a confirmed diagnosis of AN who had presented to psychiatric services in North East Scotland from 1965 to 2007 were identified. Those women with a pregnancy recorded in the Aberdeen Maternal and Neonatal Databank (AMND) were each matched by age, parity and year of delivery of their first baby with five women with no history of AN. Maternal and foetal outcomes were compared between these two groups of women. Comparisons were also made between the mothers with a history of AN and all other women in the AMND. RESULTS: A total of 134 women with a history of AN delivered 230 babies and the 670 matched women delivered 1144 babies. Mothers with AN delivered lighter babies but this difference did not persist after adjusting for maternal body mass index (BMI) in early pregnancy. Standardized birthweight (SBW) scores suggested that the AN mothers were more likely to produce babies with intrauterine growth restriction (IUGR) [relative risk (RR) 1.54, 95% confidence interval (CI) 1.11-2.13]. AN mothers were more likely to experience antepartum haemorrhage (RR 1.70, 95% CI 1.09-2.65). CONCLUSIONS: Mothers with a history of AN are at increased risk of adverse pregnancy outcomes. The magnitude of these risks is relatively small and should be appraised holistically by psychiatric and obstetric services.

Feedback on doctors' performance from parents and carers of children: a national pilot study.

OBJECTIVES: To evaluate the reliability and validity of a children's carers' feedback tool, to explore the feasibility of delivering this nationally and to determine acceptability to doctors of this assessment. PARTICIPANTS: 122 UK paediatricians on the specialist register undertaking outpatient consultations. DESIGN: Participants were each sent 50 forms for distribution to carers. Mean scores for each question, and for the overall pilot cohort were returned to participants with verbatim free text comments. Participating paediatricians' views were sought before and after receiving feedback. RESULTS: 122 doctors returned 4415 forms (mean 36 per doctor). All doctors scored highly with scores across all returned forms having a median of 4.58 (IQ range 0.17) where the maximum score was 5. Differences were observed between scores from female compared to male carers (p<0.05), from consultations rated by carer and child compared to carer alone (p<0.05) and from carers who had previously met the doctor compared to those in their first consultation (p<0.001). 'White' doctors received higher ratings than 'non-white' doctors (p<0.05) and white patients rated both white doctors and non-white doctors more highly than non-white patients (p<0.01). A minimum of 25 consultations rated by children's carers are needed for acceptable reliability. 93.9% of participants would be happy to be assessed in this way for the purposes of revalidation. CONCLUSIONS: National delivery of a valid and reliable method of carer feedback is feasible. The scores received and acceptability in these self-selected doctors was high. Confounding variables may influence feedback, so guidance on interpretation may be needed.

Development of a health screening clinic.

Medical morbidity and mortality levels remain elevated in people with schizophrenia compared with the general population. Despite the increasing recognition of an excess of physical health problems in this population, health screening remains limited. Medical risk in this population can be related to a variety of sources. The disease process itself as well as poor diet and sedentary lifestyle contribute to the overall physical health problems. In addition antipsychotic medication can contribute to the risk of cardiovascular and metabolic problems. The Dundee Health Screening Clinic was developed to address the needs of this population by monitoring physical health and providing follow-up to ensure that patients received the necessary care. The Clinic demonstrates how a coordinated approach can be used to take simple steps to improve the overall well-being of these patients. It was set up by adapting the manpower resources and procedures of the community mental health team and local resource centre, without specific additional funding. Simple clinical measurements and tests were conducted in the Clinic and patients clearly demonstrated on a satisfaction questionnaire that they considered the health checks important. This Clinic is an example of how a holistic approach can impact on both the physical and mental well-being of patients and offer them improved care and therefore a better quality of life.

Management of physical health in patients with schizophrenia: practical recommendations.

Improved physical health care is a pressing need for patients with schizophrenia. It can be achieved by means of a multidisciplinary team led by the psychiatrist. Key priorities should include: selection of antipsychotic therapy with a low risk of weight gain and metabolic adverse effects; routine assessment, recording and longitudinal tracking of key physical health parameters, ideally by electronic spreadsheets; and intervention to control CVD risk following the same principles as for the general population. A few simple tools to assess and record key physical parameters, combined with lifestyle intervention and pharmacological treatment as indicated, could significantly improve physical outcomes. Effective implementation of strategies to optimise physical health parameters in patients with severe enduring mental illness requires engagement and communication between psychiatrists and primary care in most health settings.

Minimising metabolic and cardiovascular risk in schizophrenia: diabetes, obesity and dyslipidaemia.

People with schizophrenia are at greater risk of obesity, Type 2 diabetes, dyslipidaemia and hypertension than the general population. This results in an increased incidence of cardiovascular disease (CVD) and reduced life expectancy, over and above that imposed by their mental illness through suicide. Several levels of evidence from data linkage analyses to clinical trials demonstrate that treatment-related metabolic disturbances are commonplace in this patient group, and that the use of certain second-generation antipsychotics may compound the risk of developing the metabolic syndrome and CVD. In addition, smoking, poor diet, reduced physical activity and alcohol or drug abuse are prevalent in people with schizophrenia and contribute to the overall CVD risk. Management and minimization of metabolic risk factors are pertinent when providing optimal care to patients with schizophrenia. This review recommends a framework for the assessment, monitoring and management of patients with schizophrenia in the UK clinical setting.

Nonlinear isochrones in murine left ventricular pressure-volume loops: how well does the time-varying elastance concept hold?

The linear time-varying elastance theory is frequently used to describe the change in ventricular stiffness during the cardiac cycle. The concept assumes that all isochrones (i.e., curves that connect pressure-volume data occurring at the same time) are linear and have a common volume intercept. Of specific interest is the steepest isochrone, the end-systolic pressure-volume relationship (ESPVR), of which the slope serves as an index for cardiac contractile function. Pressure-volume measurements, achieved with a combined pressure-conductance catheter in the left ventricle of 13 open-chest anesthetized mice, showed a marked curvilinearity of the isochrones. We therefore analyzed the shape of the isochrones by using six regression algorithms (two linear, two quadratic, and two logarithmic, each with a fixed or time-varying intercept) and discussed the consequences for the elastance concept. Our main observations were 1) the volume intercept varies considerably with time; 2) isochrones are equally well described by using quadratic or logarithmic regression; 3) linear regression with a fixed intercept shows poor correlation (R(2) < 0.75) during isovolumic relaxation and early filling; and 4) logarithmic regression is superior in estimating the fixed volume intercept of the ESPVR. In conclusion, the linear time-varying elastance fails to provide a sufficiently robust model to account for changes in pressure and volume during the cardiac cycle in the mouse ventricle. A new framework accounting for the nonlinear shape of the isochrones needs to be developed.

Unraveling the role of mitochondria during oxidative stress in plants.

The sedentary habit of plants means that they must stand and fight environmental stresses that their mobile animal cousins can avoid. A range of these abiotic stresses initiate the production in plant cells of reactive oxygen and nitrogen species that ultimately lead to oxidative damage affecting the yield and quality of plant products. A complex network of enzyme systems, producing and quenching these reactive species operate in different organelles. It is the integration of these compartmented defense systems that coordinates an effective response to the various stresses. Future attempts to improve plant growth or yield must consider the complexity of inter-organelle signaling and protein targeting if they are to be successful in producing plants with resistance to a broad range of stresses. Here we highlight the role of pre-oxidant, antioxidant, and post-oxidant defense systems in plant mitochondria and the potential role of proteins targeted to both mitochondria and chloroplasts, in an integrated defense against oxidative damage in plants.

Season of birth in females with anorexia nervosa in Northeast Scotland.

OBJECTIVE: To determine whether patients with anorexia nervosa exhibit an abnormal pattern in their season of birth. METHOD: Case records of female patients presenting to secondary services in Northeast Scotland from 1965 to 1997 who received a clinical diagnosis of anorexia nervosa were examined. The months of birth of the 446 anorexic patients with a confirmed diagnosis were compared with 5,766 female control subjects born locally in 1951, 1961, 1971, and 1981. RESULTS: Patients with anorexia nervosa had an excess of births in the first 6 months of the year (p =.013). The greatest excess was from March to June. DISCUSSION: This provides further evidence that birth dates of anorexics peak in the late spring and early summer. There are parallels with the epidemiology of schizophrenia. The evidence suggests that a seasonally fluctuating factor, most plausibly an intrauterine effect of common infectious agents during the winter months, is of etiological significance.

Changes in the presenting features of females with anorexia nervosa in northeast Scotland, 1965-1991.

OBJECTIVE: Rates of anorexia nervosa among females presenting to specialist services in northeast Scotland had increased significantly between 1965 and 1991. We sought to elucidate possible causes of this change. METHOD: Hospital and primary care records were searched. Age, weight, and body mass index (BMI) were determined for 196 patients and duration of symptoms from onset to presentation was established in 190 cases. Changes in these parameters were investigated over the 27-year period of the study. RESULTS: There was no significant change in duration of illness or in age at presentation. BMIs increased significantly, but this arose because patients decreased in height, not because they increased in weight. There was no increase in seriously underweight patients with BMIs of < or =15. DISCUSSION: Anorexic females were not referred at an earlier stage of their illness, but primary care teams may be identifying and referring milder cases. Alternatively, the findings may reflect an increasing incidence of eating disorders coupled with changes in their presenting symptomatology.

Hyperamylasemia in bulimia nervosa and hyperemesis gravidarum.

OBJECTIVES: The exact causes of hyperamylasemia detected in bulimia nervosa are unknown but it is presumed to be due either to repeated binging or to vomiting. This study set out to investigate the importance of vomiting in producing the raised serum amylase and to clarify whether the amylase in pancreatic or salivary. METHODS: Patients suffering from hyperemesis gravidarum who were repeatedly vomiting in pregnancy but not binge eating had their total serum and pancreatic amylase measured. Bulimic patients and a control sample of nonvomiting pregnant women were similarly studied. An assessment of the frequency and duration of vomiting and binging was also made. RESULTS: Results show 45% (5) of bulimic patients had raised serum amylase, but none had a raised pancreatic amylase. Twenty-four percent (7) of the hyperemetic patients also had a raised serum amylase level, all with a normal pancreatic amylase level. None of the nonvomiting pregnant patients had a raised amylase. DISCUSSION: Of patients with hyperemesis gravidarum who repeatedly vomit but do not binge, a significant number had raised amylase. This suggests that it is the vomiting rather than the binge behavior that increases amylase in bulimic patients. This increased amylase probably comes from the salivary gland.

Technology and application of ultraminiature catheter pressure transducers.

After a brief historical account of the methods for pressure measurements in the cardiovascular system, the basic structural elements of a new generation of miniaturized catheter pressure transducers are described. These catheters have an outside diameter at the tip of 0.9 mm (3 French) and have been routinely applied in left and right heart catheterization in intact, anesthetized rats. Together with cardiac output measured by the thermodilution technique, a complete set of basal functional parameters can be obtained in vivo. The method of cardiac catheterization in rats is accurate, reliable and easy to perform. As to left heart function, changes occurring in several models of cardiac hypertrophy and heart failure have been recorded and correlated with morphological and metabolic alterations. In addition, the functional effects of catecholamines and thyroid hormones have been evaluated. In addition to the routine catheterization procedure, a double catheter method has been introduced recently, which allows measurement of left ventricular isovolumetric pressure in intact rats. Catheterization of the right ventricle requires a more refined catheter with a characteristic bend at the tip so that it can be comfortably slid from the right atrium into the right ventricle. With this method it was found that right ventricular systolic pressure was elevated markedly in rats with chronic myocardial infarction induced by ligation of the left anterior descending coronary artery, by pulmonary artery banding, by intermittent chronic hypoxia and by noradrenaline administration. The ultraminiature catheter pressure transducer has also been successfully applied in an isolated working rat heart preparation. Recent modifications of this kind of catheters also enabled the catheterization of the left ventricle in mice. Future applications of ultraminiature catheter pressure transducers may be directed to catheterization of the pulmonary artery in rats and to the in vivo and in vitro assessment of heart function of transgenic mice.

In vivo murine left ventricular pressure-volume relations by miniaturized conductance micromanometry.

The mouse is the species of choice for creating genetically engineered models of human disease. To study detailed systolic and diastolic left ventricular (LV) chamber mechanics in mice in vivo, we developed a miniaturized conductance-manometer system. alpha-Chloralose-urethan-anesthetized animals were instrumented with a two-electrode pressure-volume catheter advanced via the LV apex to the aortic root. Custom electronics provided time-varying conductances related to cavity volume. Baseline hemodynamics were similar to values in conscious animals: 634 +/- 14 beats/min, 112 +/- 4 mmHg, 5.3 +/- 0.8 mmHg, and 11,777 +/- 732 mmHg/s for heart rate, end-systolic and end-diastolic pressures, and maximum first derivative of ventricular pressure with respect to time (dP/dtmax), respectively. Catheter stroke volume during preload reduction by inferior vena caval occlusion correlated with that by ultrasound aortic flow probe (r2 = 0.98). This maneuver yielded end-systolic elastances of 79 +/- 21 mmHg/microliter, preload-recruitable stroke work of 82 +/- 5.6 mmHg, and slope of dP/dtmax-end-diastolic volume relation of 699 +/- 100 mmHg.s-1.microliter-1, and these relations varied predictably with acute inotropic interventions. The control normalized time-varying elastance curve was similar to human data, further supporting comparable chamber mechanics between species. This novel approach should greatly help assess cardiovascular function in the blood-perfused murine heart.

General practice consultation patterns preceding diagnosis of eating disorders.

OBJECTIVE: To see whether patients with eating disorders consult general practitioners more frequently than control subjects and, if so, to describe the pattern of consultation. METHOD: General practitioner case record review of patients with anorexia nervosa, bulimia nervosa, and partial syndromes referred to a specialist eating disorder service. RESULTS: Seventy-eight of 100 case records were available for analysis. Eating disorder patients consulted significantly more frequently than controls over 5 years prior to the diagnosis of the eating disorder. They presented to the general practitioners with a variety of symptoms including psychological, gastrointestinal, and gynecological complaints. DISCUSSION: The findings suggest that methods could be developed to enable earlier diagnosis of eating disorders in general practice. This will enable the earlier application of effective treatments with the prospect of improved outcome.

The impact on community benzodiazepine prescribing of hospitalization.

To assess the impact of both general and psychiatric hospitalization on the community prescribing of benzodiazepines, we carried out an observational study using record linkage of prescribing prior to and following hospitalization along with a review of hospital case records at four Tayside General Practices. In a population of 29,672 subjects, 2628 general hospital and 254 psychiatric hospitalizations were studied. The main outcome measure was the change in community benzodiazepine prescribing following hospitalization. We found that admission to a general hospital resulted in 59 of the 2628 subjects (2.2%) commencing and 45 subjects (1.7%) discontinuing benzodiazepines. Admission to a psychiatric hospital resulted in 17 of 254 subjects (6.7%) commencing and 40 (16.7%) discontinuing benzodiazepines. When compared to benzodiazepine prescribing in the study population these effects were trivial. We conclude that hospitalization in both general and psychiatric hospitals had a minor effect on total community prescribing of benzodiazepines. In this study general hospital admission resulted in a small net increase and psychiatric hospitalization a small net decrease in benzodiazepine prescribing.

Increasing incidence of anorexia nervosa in the female population of northeast Scotland.

OBJECTIVE: The aim of the study was to determine whether there has been an increase in the incidence of anorexia nervosa in the female population in the northeast of Scotland since the 1960s. METHOD: Standardized diagnostic criteria were applied to the case records of female subjects who had been diagnosed as suffering from anorexia nervosa and had presented for the first time to psychiatric services between 1965 and 1991 or had been admitted for the first time to a general hospital between 1970 and 1991. Age-standardized annual incidence rates were calculated from 1965 through 1991. As a broad measure of severity, the weights of patients in 3 early years of the study, 1970-1972, were compared with those of patients in the last 3 years, 1989-1991. RESULTS: Over the 27-year period studied, 287 patients received confirmed diagnoses of anorexia nervosa, and the mean annual increase in incidence was 5.3%. The rate of increase was highly statistically significant. Comparison of weights at presentation showed a trend for patients presenting in 1970-1972 to be lighter than those presenting in 1989-1991. CONCLUSIONS: Rates of referral for female subjects with anorexia nervosa have greatly increased since the 1960s. These rates likely reflect a genuine increase in incidence, but the data suggest that less severely ill patients are now being referred.

Craniofacial resection in the management of paranasal sinus cancer.

The prognosis for patients with cancer of the paranasal sinuses (PNC) has been very poor, mainly due to a high rate of local recurrence. We report a series of 46 patients with PNC treated by craniofacial resection at the Royal Melbourne Hospital between November 1983 and June 1991. There has been no operative mortality or serious morbidity in these patients. The importance of a pericranial flap in the reconstruction of the floor of the anterior cranial fossa is emphasized. All patients have been followed to death or to the present time. There was a five year survival of 73% for squamous cell carcinoma and 83% for adenocarcinoma. This appears to represent a significant improvement in the long term results over conventional surgery and radiotherapy. The strong association between adenocarcinoma of the ethmoid sinuses and occupational exposure to hardwood dusts is borne out in our series. A history of prolonged wood dust exposure was given by all the 16 patients with adenocarcinoma and by 12 of the 25 patients with squamous cell carcinoma.

The case against open neck biopsy.

Many patients present with lateral neck lumps due to benign or malignant conditions, and they may be difficult to differentiate clinically. It is detrimental to perform an open neck biopsy on a patient with a cancer originating from the head and neck region (upper aerodigestive tract or skin) prior to definitive treatment. The biopsy interferes with the assessment and management of the neck, increasing morbidity. It may also decrease curability and perhaps induce fungation. A protocol to avoid the need for an open biopsy, using fine needle aspiration cytology and a thorough examination of the upper aerodigestive tract is recommended. The authors also recommend combined radical radiotherapy and surgery for the patient who has had an open biopsy. A thoughtless biopsy is both needless and harmful.