Cardiorespiratory fitness is impaired and predicts mid-term postoperative survival in patients with abdominal aortic aneurysm disease.

NEW FINDINGS: What is the central question of this study? To what extent cardiorespiratory fitness is impaired in patients with abdominal aortic aneurysmal (AAA) disease and corresponding implications for postoperative survival requires further investigation. What is the main finding and its importance? Cardiorespiratory fitness is impaired in patients with AAA disease. Patients with peak oxygen uptake of <13.1 ml O2  kg-1  min-1 and ventilatory equivalent for carbon dioxide at anaerobic threshold ≥34 are associated with increased risk of postoperative mortality at 2 years. These findings demonstrate that cardiorespiratory fitness can predict mid-term postoperative survival in AAA patients, which may help to direct care provision. ABSTRACT: Preoperative cardiopulmonary exercise testing is a standard assessment of cardiorespiratory fitness (CRF) and risk stratification. However, to what extent CRF is impaired in patients undergoing surgical repair of abdominal aortic aneurysm (AAA) disease and the corresponding implications for postoperative outcome requires further investigation. We measured CRF during an incremental exercise test to exhaustion using online respiratory gas analysis in patients with AAA disease (n = 124, aged 72 ± 7 years) and healthy sedentary control subjects (n = 104, aged 70 ± 7 years). Postoperative survival was examined for association with CRF, and threshold values were calculated for independent predictors of mortality. Patients who underwent preoperative cardiopulmonary exercise testing before surgical repair had lower CRF [age-adjusted mean difference of 12.5 ml O2  kg-1  min-1 for peak oxygen uptake ( V ̇ O 2 peak ), P < 0.001 versus control subjects]. After multivariable analysis, both V ̇ O 2 peak and the ventilatory equivalent for carbon dioxide at anaerobic threshold ( V ̇ E / V ̇ C O 2 - AT ) were independent predictors of mid-term postoperative survival (2 years). Hazard ratios of 5.27 (95% confidence interval 1.62-17.14, P = 0.006) and 3.26 (95% confidence interval 1.00-10.59, P = 0.049) were observed for V ̇ O 2 peak  < 13.1 ml O2  kg-1  min-1 and V ̇ E / V ̇ C O 2 - AT ≥ 34, respectively. Thus, CRF is lower in patients with AAA, and those with a V ̇ O 2 peak  < 13.1 ml O2  kg-1  min-1 and V ̇ E / V ̇ C O 2 - AT ≥ 34 are associated with a markedly increased risk of postoperative mortality. Collectively, our findings demonstrate that CRF can predict mid-term postoperative survival in AAA patients, which may help to direct care provision.

The cardiopulmonary exercise test grey zone; optimising fitness stratification by application of critical difference.

BACKGROUND: Cardiorespiratory fitness can inform patient care, although to what extent natural variation in CRF influences clinical practice remains to be established. We calculated natural variation for cardiopulmonary exercise test (CPET) metrics, which may have implications for fitness stratification. METHODS: In a two-armed experiment, critical difference comprising analytical imprecision and biological variation was calculated for cardiorespiratory fitness and thus defined the magnitude of change required to claim a clinically meaningful change. This metric was retrospectively applied to 213 patients scheduled for colorectal surgery. These patients underwent CPET and the potential for misclassification of fitness was calculated. We created a model with boundaries inclusive of natural variation [critical difference applied to oxygen uptake at anaerobic threshold (V˙O2-AT): 11 ml O2 kg-1 min-1, peak oxygen uptake (V˙O2 peak): 16 ml O2 kg-1 min-1, and ventilatory equivalent for carbon dioxide at AT (V̇E/V̇CO2-AT): 36]. RESULTS: The critical difference for V˙O2-AT, V˙O2 peak, and V˙E/V˙CO2-AT was 19%, 13%, and 10%, respectively, resulting in false negative and false positive rates of up to 28% and 32% for unfit patients. Our model identified boundaries for unfit and fit patients: AT <9.2 and ≥13.6 ml O2 kg-1 min-1, V˙O2 peak <14.2 and ≥18.3 ml kg-1 min-1, V˙E/V˙CO2-AT ≥40.1 and <32.7, between which an area of indeterminate-fitness was established. With natural variation considered, up to 60% of patients presented with indeterminate-fitness. CONCLUSIONS: These findings support a reappraisal of current clinical interpretation of cardiorespiratory fitness highlighting the potential for incorrect fitness stratification when natural variation is not accounted for.

Supervised exercise training improves cardiorespiratory fitness and reduces perioperative risk in peripheral artery disease patients with intermittent claudication.

INTRODUCTION: This study examined to what extent supervised aerobic and resistance exercise combined with continued unsupervised exercise training improves cardiorespiratory fitness and corresponding perioperative risk in peripheral artery disease (PAD) patients with intermittent claudication. METHODS: A total of 106 patients (77% male) were enrolled into the study, alongside 155 healthy non-PAD control participants. Patients completed supervised exercise therapy (aerobic and resistance exercises of the upper and lower limbs) twice a week for 10 weeks. Thereafter, 52 patients completed 12 weeks of an unsupervised tailored home-based exercise. Pain-free walking distance (PWD), maximum walking distance (MWD), peak oxygen uptake ([Formula: see text]) and perioperative risk were assessed before and after both exercise interventions. RESULTS: Patients were highly unconditioned relative to healthy controls ([Formula: see text]=11.9 vs 24.2ml/kg/min, p=<0.001) with 91% classified as high perioperative risk (peak oxygen uptake <15ml/kg/min). Supervised exercise increased PWD (+44±81m, p=<0.001), MWD (+44±71m, p=<0.001) and [Formula: see text] (+1.01±1.63ml/kg/min, p=<0.001) and lowered perioperative risk (91% to 85%, p=<0.001). When compared with supervised exercise, the improvements in PWD were maintained following unsupervised exercise (+11±91m vs supervised exercise, p=0.572); however, MWD and [Formula: see text] decreased (-15±48m, p=0.030 and -0.34±1.11ml/kg/min, p=0.030, respectively) and perioperative risk increased (+3%, p=<0.001) although still below baseline (p=<0.001). CONCLUSIONS: Supervised aerobic and resistance exercise training and, to a lesser extent, unsupervised tailored exercise improves walking capacity and cardiorespiratory fitness and reduces perioperative risk in PAD patients with intermittent claudication.

Debridement, antibiotics and implant retention (DAIR) following hip and knee arthroplasty: results and findings of a multidisciplinary approach from a non-specialist prosthetic infection centre.

INTRODUCTION: Prosthetic joint infection (PJI) is a catastrophic complication following arthroplasty surgery. Recently a debridement, antibiotics and implant retention (DAIR) procedure has gained popularity for PJI where a thorough debridement, irrigation and modular component exchange is undertaken. METHOD: We present the outcome for DAIR, data collected prospectively, in a busy orthopaedic unit but not one specialising in PJI. All patients with PJI were included without loss of data or patients from 2012 to 2018 with a minimum follow-up of 5 years. RESULTS: Four total knee replacements, 17 total hip replacements, one revision total hip replacement and three hip hemiarthroplasties are included with an average duration from onset of symptoms to the DAIR procedure of 11 days (range 1-22 days). Staphylococcus aureus (24%) and Staphylococcus epidermidis (32%) were the most common causative organisms, and the most common antibiotic regimens included intravenous teicoplanin and flucloxacillin. Average follow-up was 67 months (range 9-104 months). Only four patients went on to require revision surgery. An analysis of midterm patient outcome measures for 6 of the total hip replacement (THR) DAIR patients were compared with a database of 792 THRs (with a minimum two-year follow-up) carried out by the same surgeon revealed no significant difference in Oxford hip scores at one-year post-surgery (OHS DAIR 36.2 vs 39 for control group). CONCLUSION: This study includes 25 consecutive patients treated with DAIR with only one reinfection, with a mean follow-up period of 5 years. Using a strict protocol, DAIR appears to offer a successful treatment strategy for the management of early PJI.

Abnormal repetitive behaviours: shared phenomenology and pathophysiology.

BACKGROUND: Self-injurious behaviour (SIB) is a devastating problem observed in individuals with various neurodevelopmental disorders, including specific genetic syndromes as well as idiopathic intellectual and developmental disability. Although an increased prevalence of SIB has been documented in specific genetic mutations, little is known about the neurobiological basis of SIB. This makes vulnerability assessment and pharmacological treatment incredibly challenging. METHOD: Here we review evidence that SIB and other repetitive, invariant behaviours, such as stereotypy, compulsions and tics, share many phenotypic similarities, are often co-morbidly expressed and have common inducing conditions. This argues for shared or overlapping pathophysiology. As much more is known about the neurobiology of these related disorders, this should make the neurobiology of SIB a more tractable problem. RESULTS: Stereotypy, compulsions and tics are diagnostic for disorders that have received focused neurobiological investigation (autism, obsessive compulsive disorder, Tourette syndrome, respectively). In addition, animal models of these repetitive behaviours have been well characterised. Collectively, these studies have found that cortical basal ganglia circuitry dysfunction mediates repetitive behaviour. Moreover, these studies provide more detailed information and potentially testable hypotheses about specific aspects of the circuitry that may be operative in SIB. CONCLUSIONS: We can use available information from clinical and animal models to make more precise hypotheses regarding the particular pathophysiology driving SIB. The results of testing such hypotheses should generate pharmacological strategies that may prove efficacious in reducing SIB.

Self-injurious behaviour: limbic dysregulation and stress effects in an animal model.

BACKGROUND: Self-injurious behaviour (SIB) is prevalent in neurodevelopmental disorders, but its expression is highly variable within, and between diagnostic categories. This raises questions about the factors that contribute to aetiology and expression of SIB. Expression of SIB is generally described in relation to social reinforcement. However, variables that predispose vulnerability have not been as clearly characterised. This study reports the aetiology and expression of self-injury in an animal model of pemoline-induced SIB. It describes changes in gross neuronal activity in selected brain regions after chronic treatment with pemoline, and it describes the impact that a history of social defeat stress has on the subsequent expression of SIB during pemoline treatment. METHODS: Experiment 1--Male Long-Evans rats were injected on each of five consecutive days with pemoline or vehicle, and the expression of SIB was evaluated using a rating scale. The brains were harvested on the morning of the sixth day, and were assayed for expression of cytochrome oxidase, an index of sustained neuronal metabolic activity. Experiment 2--Male Long-Evans rats were exposed to a regimen of 12 daily sessions of social defeat stress or 12 daily sessions of handling (i.e. controls). Starting on the day after completion of the social defeat or handling regimen, each rat was given five daily injections of pemoline. The durations of self-injurious oral contact and other stereotyped behaviours were monitored, and the areas of tissue injury were quantified. RESULTS: Experiment 1--Neuronal metabolic activity was significantly lower in a variety of limbic and limbic-associated brain structures in the pemoline-treated rats, when compared with activity in the same regions of vehicle-treated controls. In addition, neuronal activity was low in the caudate-putamen, and in subfields of the hypothalamus, but did not differ between groups for a variety of other brain regions, including nucleus accumbens, substantia nigra, ventral tegmentum, thalamus, amygdala, and cortical regions. Experiment 2--All the pemoline-treated rats exhibited SIB, and whereas the social defeat regimen did not alter the total amount of self-injurious oral contact or other stereotyped behaviours, it significantly increased the severity of tissue injury. CONCLUSIONS: A broad sampling of regional metabolic activity indicates that the pemoline regimen produces enduring changes that are localised to specific limbic, hypothalamic and striatal structures. The potential role of limbic function in aetiology of SIB is further supported by the finding that pemoline-induced self-injury is exacerbated by prior exposure to social defeat stress. Overall, the results suggest brain targets that should be investigated further, and increase our understanding of the putative role that stress plays in the pathophysiology of SIB.

Doctors' knowledge of radiation -- a two-centre study and historical comparison.

AIM: To investigate knowledge of the use of ionizing radiation in 2010 and whether there has been any change in this knowledge since the study was first undertaken over 7 years ago. MATERIALS AND METHODS: In both studies a single chest x-ray was classed as one unit of radiation. Doctors from all grades were asked to evaluate the average radiation dose incurred with 13 commonly undertaken radiological procedures, including magnetic resonance imaging (MRI), computed tomography (CT), etc. Answers within 20% of the actual dose were marked as correct. RESULTS: Two hundred and forty-two questionnaires were completed (130 in 2003; 112 in 2010). Equal numbers of juniors, middle grades, and consultants were questioned, and scores were comparable (23.3% in 2003; 29.4% in 2010). The majority of doctors (92% in 2003; 86% in 2010) correctly noted that ultrasound and MRI involve no radiation. Doctors underestimated the radiation doses of all investigations by a smaller margin in 2010 compared to 2003 (i.e., more accurately), with only one exception: CT of the abdomen. CONCLUSION: Despite evidence of some improvement, doctors of all grades still have a very poor knowledge of radiation exposure even with the most common investigations. The worsening appreciation of the radiation involved in CT scanning is especially worrying considering its increasing use in practice today.

Cardiorespiratory fitness fails to predict short-term postoperative mortality in patients undergoing elective open surgery for abdominal aortic aneurysm.

INTRODUCTION: Preoperative cardiopulmonary exercise testing aids surgical risk stratification and is an established predictor of mid- to long-term survival in patients undergoing elective open abdominal aortic aneurysm repair. Whether cardiopulmonary exercise testing also predicts 30-day mortality in this population remains to be established. MATERIALS AND METHODS: Data for 109 patients (mean age 72 years) who underwent cardiopulmonary exercise testing to assess risk for surgical abdominal aortic aneurysm repair was analysed. Patients were classified according to cardiopulmonary fitness as fit (peak oxygen uptake ≥ 15ml O2.kg-1.min-1) or unfit (peak oxygen uptake less than 15ml O2.kg-1.min-1) and further stratified according to clamp position (infrarenal or suprarenal). Between-group postoperative outcomes were compared for in-hospital 30-day mortality, postoperative morbidity scale scores (day 5) and hospital length of stay. RESULTS: Seventy-nine patients underwent open surgery and 30 patients were treated conservatively. No deaths were recorded at 30 days post-surgery. Unfit patients with infrarenal clamping exhibited higher postoperative morbidity scale scores (64% vs 26%) and longer length of stay (four days) than fit patients (p < 0.05). Conversely, with suprarenal clamping, postoperative morbidity scale scores were similar and length of stay longer (three days) in fit compared with unfit patients (p < 0.05). DISCUSSION AND CONCLUSION: Preoperative fitness level defined by peak oxygen uptake failed to identify patients at risk of 30-day mortality when undergoing elective abdominal aortic aneurysm repair. Postoperative morbidity and length of stay in patients with suprarenal clamping was high independent of cardiopulmonary fitness. These findings suggest that cardiopulmonary exercise testing may be a useful predictor of complications following infrarenal rather than suprarenal clamping but may not be a good predictor of 30-day mortality.

Prioritisation of vascular outpatient appointments cannot be based on referral letters alone.

BACKGROUND: Vascular referrals include patients with conditions varying from varicose veins of cosmetic nuisance to patients with critical ischaemia, transient ischaemic attacks and abdominal aortic aneurysms. A large number of such referrals are received each week from general practitioners. It is important to prioritise patients with conditions that need to be dealt with quickly. OBJECTIVE: We prospectively reviewed referral letters to two vascular units, one in South Wales and one in the Oxford region to assess whether prioritisation can be made on the basis of referral letters. MATERIAL AND METHODS: All GP referral letters were studied for four months. Only patients with lower limb ischaemic symptoms were included. Degree of urgency requested by the GP was also noted. RESULTS: Of 174 referrals for potential lower limb ischaemia analysed, 145 (83%) proved to be due to peripheral vascular disease. Of these 145 referrals, 72% were referred for claudication. Only 37% and 13% respectively mentioned claudication distance and/or rest pain. Risk factors with reference to diabetes, hypertension, hyperlipidaemia, ischaemic heart disease, atrial fibrillation, cerebrovascular disease and smoking were made in 19%, 43%, 23%, 23%, 10%, 14%, 31% of letters respectively. Clinical signs were poorly documented, with 90% of referrals failing to mention presence or absence of critical ischaemic signs. The GP's own assessment of urgency was not stated in 66% of letters, without which only 3% of patients were seen in the clinic within four weeks, compared with 22% in those in whom urgency was stated. Six per cent of patients when reviewed in outpatients were found to have sufficiently severe symptoms to warrant immediate admission. Regional variation was observed with 57% of Royal Glamorgan Hospital referral letters documenting degree of urgency compared with only 23% of Royal Berkshire Hospital letters (p = < 0.0001). CONCLUSION: Most referral letters were poorly documented with regard to key symptoms, risk factors and clinical signs. The degree of urgency was often not stated. The creation of referral protocols is now being considered.

Management of cardiovascular risk factors by primary care physicians in patients with peripheral arterial disease.

BACKGROUND: Patients with significant coronary artery disease (CAD) are now intensively treated by primary care physicians predominantly because of government pressure and remuneration to prescribe anti-platelet and anti-hyperlipidaemic drugs. Peripheral arterial disease (PAD) with the identical risk factors appeared to us to be less intensively investigated and treated by primary care physicians. OBJECTIVE: To review the treatment of risk factors in all patients referred to two vascular clinics with a diagnosis of suspected PAD. DESIGN: Cross-sectional survey. SETTING: Vascular outpatient clinic in two district general hospitals. PARTICIPANTS: 124 consecutive new patients were studied to determine risk factors and appropriate treatment. RESULTS: Of the 124 patients, 85 (68%) were confirmed to have PAD without evidence of symptomatic CAD. In the PAD alone group, less than 25% received anti-smoking advice (p < 0.0001) and only 36% were prescribed anti-platelet drugs (p = 0.016). Seventy-three per cent of the overall referred patients with hypertension had been treated for this condition and the blood pressure was normal in 71% of the patients with PAD. In patients with hyperlipidaemia, statins had been prescribed in 92% of patients with coexistent symptomatic CAD, but only in 64% of patients with PAD alone (p = 0.009). In the patients with diabetes, only 66% of the PAD alone group had adequate control of their blood sugar (p = 0.185). CONCLUSIONS: It would appear that patients with CAD and PAD are being treated successfully for their risk factors, but patients with PAD alone, sharing the same common risk factors, are being less than optimally treated.

Atherosclerotic axillary artery aneurysm.

True aneurysms of the axillary artery are rare, most pulsatile masses in the region being pseudoaneurysms. The present study reports a case of a true atherosclerotic axillary artery aneurysm arising in a 65 year old lady which presented with a short history of a painless pulsatile mass and sensory defecit in the hand in the absence of limb trauma. Following preoperative imaging to determine the anatomic details, she underwent repair of the aneurysm and made an excellent symptomatic recovery.

The neural circuitry of restricted repetitive behavior: Magnetic resonance imaging in neurodevelopmental disorders and animal models.

Restricted, repetitive behaviors (RRBs) are patterns of behavior that exhibit little variation in form and have no obvious function. RRBs although transdiagonstic are a particularly prominent feature of certain neurodevelopmental disorders, yet relatively little is known about the neural circuitry of RRBs. Past work in this area has focused on isolated brain regions and neurotransmitter systems, but implementing a neural circuit approach has the potential to greatly improve understanding of RRBs. Magnetic resonance imaging (MRI) is well-suited to studying the structural and functional connectivity of the nervous system, and is a highly translational research tool. In this review, we synthesize MRI research from both neurodevelopmental disorders and relevant animal models that informs the neural circuitry of RRB. Together, these studies implicate distributed neural circuits between the cortex, basal ganglia, and cerebellum. Despite progress in neuroimaging of RRB, there are many opportunities for conceptual and methodological improvement. We conclude by suggesting future directions for MRI research in RRB, and how such studies can benefit from complementary approaches in neuroscience.

Subthalamic nucleus pathology contributes to repetitive behavior expression and is reversed by environmental enrichment.

Repetitive motor behaviors are common in neurodevelopmental, psychiatric and neurological disorders. Despite their prevalence in certain clinical populations, our understanding of the neurobiological cause of repetitive behavior is lacking. Likewise, not knowing the pathophysiology has precluded efforts to find effective drug treatments. Our comparisons between mouse strains that differ in their expression of repetitive behavior showed an important role of the subthalamic nucleus (STN). In mice with high rates of repetitive behavior, we found significant differences in dendritic spine density, gene expression and neuronal activation in the STN. Taken together, these data show a hypoglutamatergic state. Furthermore, by using environmental enrichment to reduce repetitive behavior, we found evidence of increased glutamatergic tone in the STN with our measures of spine density and gene expression. These results suggest the STN is a major contributor to repetitive behavior expression and highlight the potential of drugs that increase STN function to reduce repetitive behavior in clinical populations.

Can carotid ultrasound predict plaque histopathology?

AIM: European and North American studies have confirmed the benefits of carotid endarterectomy for patients with symptomatic carotid artery stenoses >70%. However, the management of asymptomatic patients and those with lesser degrees of stenosis is less certain. Several studies have suggested that, for these subgroups, the targeting of potentially unstable plaques, may help to identify those most at risk of cerebrovascular accidents and thus most likely to benefit from surgery. The aim of this study was to correlate the ultrasound features of carotid artery stenosis with the histopathological findings of the carotid endarterectomy specimens in order to identify features which will allow preoperative identification of clinically unstable plaques. METHODS: Sixty consecutive patients with symptomatic, critical carotid stenosis were prospectively studied. Plaques were classified preoperatively into one of five types based on their echogenicity and were also assessed for irregularity and ulceration. These findings were then compared with the histopathological findings of the endarterectomy specimen. RESULTS: Of 33 plaques considered on ultrasound to be uniformly or predominantly echolucent (unstable), 27 were found to be largely fatty or haemorrhagic (PPV =82%). Of 17 plaques considered to be predominantly echogenic (stable) on ultrasound, 11 were found to be predominantly fibrotic (PPV = 65%). Correlation between ultrasound irregularity or ulceration and histopathology was poor. CONCLUSION: In routine clinical practice, ultrasound can identify with reasonable accuracy, plaques that are predominantly haemorrhagic or fatty, and therefore potentially unstable. This may have future implications in selection of patients for surgery.

Recurrent haemarthrosis of knee joint due to arterio-venous malformation of the superficial femoral artery.

Recurrent haemarthrosis involving the knee joint is commonly due to bleeding, a coagulation disorder or previous surgery. We have recently encountered a case of recurrent haemarthrosis involving the left knee joint of a 72 year old man due to arterio-venous malformation of the superficial femoral artery. Vascular malformations in patients with recurrent haemarthrosis without previous history of operation and a normal bleeding and clotting screen, should be considered a possible cause.

The European Working Time Directive: One for all and all for one?

BACKGROUND: The European Working Time Directive (EWTD) became law in Britain on October 1, 1998. As a result, the maximum period that may be spent as a resident in hospitals is 56 hours per week and after August 2009, 48 hours per week. The aim of this study was to determine the views of senior house officers (SHOs), specialist registrars (SpRs), and general consultant surgeons (CONs) in Wales on the influence of the EWTD on surgical training and clinical experience. METHODS: In this cohort study, a postal questionnaire was sent to 150 SHOs in surgical specialties, 50 general surgical SpRs, and all 84 CONs in the Welsh Deanery. RESULTS: The response rates were 81%, 78%, and 71% for SHOs, SpRs, and CONs, respectively. The vast majorities at all grades (88% SHOs, 100% SpRs, and 96% CONs) were unhappy with the introduction of EWTD legislation to clinical medicine. Most felt that EWTD legislation will have a negative effect on clinical experience (96% SHOs, 97% SpRs, 96% CONs); patient care (83% SHOs, 85% SpRs, 96% CONs); and training (94% SHOs, 100% SpRs, 93% CONs). Furthermore, a large proportion felt surgical training should be exempt from EWTD regulations (76% SHOs, 87% SpRs, 89% CONs). A significant proportion at each grade was opposed to the introduction of shifts in order to comply with regulations (78% SHOs, 87% SpRs, 89% CONs), and an alarming number have considered leaving the National Health Service when the regulations are enforced (29% SHOs, 41% SpRs, 33% CONs). CONCLUSION: This study shows that, in Wales at least, a vast majority of surgical trainees and consultants alike are opposed to the introduction of the EWTD and believe it will have a detrimental effect on training, patient care, and doctors' lives outside of medicine.

Early social deprivation in nonhuman primates: long-term effects on survival and cell-mediated immunity.

BACKGROUND: Early differential social experience of non-human primates has resulted in long-term alterations in behavior and neurobiology. Although brief maternal separation has been associated with changes in immune status, the long-term effects on survival and immune function of prolonged early social deprivation are unknown. METHODS: Survival rates were examined in rhesus monkeys, half of which had been socially deprived during their first year of life. Repeated measures of immune status were tested in surviving monkeys (18-24 years old). Peripheral blood T, B, and natural killer lymphocytes, macrophages, and monocytes were measured by flow cytometry. Functional cellular immune activity measures included T-cell proliferative responses to mitogens (concanavalin and phytohemagglutinin), T-cell memory response to tetanus toxoid antigen, T-cell-dependent B-cell proliferative responses to mitogen (PWM) and natural killer cell cytotoxic activity. RESULTS: Despite identical environments following isolation, early social deprivation resulted in a significantly decreased survival rate, males being particularly vulnerable to early death. Early social deprivation was associated with a decrease in the ratio of helper to suppressor T cells, and a significant increase in natural killer cell number and in natural killer cell activity in the surviving monkeys. No differences in T- or B-lymphocyte proliferation following mitogen or tetanus toxoid antigen stimulation were observed. CONCLUSIONS: Prolonged early social deprivation of non-human primates profoundly affected mortality and resulted in lifelong effects on cell-mediated immune status.

Thioridazine and the neuroleptic radioreceptor assay.

When the neuroleptic radioreceptor assay (NRRA) has been used to monitor total neuroleptic-like activity (NLA) in the blood of patients taking thioridazine, the NLA values obtained from the NRRA are much lower than values calculated in the same sample by measuring the actual concentrations of parent drug and active metabolites and multiplying these values by the relative potency of each compound. The present report demonstrates that in the NRRA for thioridazine or its active metabolites, the normal displacement of [3H]-spiperone from striatal membranes by thioridazine is altered in the presence of sera. The inclusion of serum (50 microliter/ml) distorts the sigmoidal displacement curves, such the resulting log-logit (or Hill) slope is markedly decreased. Similar serum-induced changes in the log-logit slope are seen for two active metabolites of thioridazine, but not for chlorpromazine or haloperidol. As a consequence, when one of these latter drugs is used as a standard, the NRRA substantially underestimates the actual NLA (chlorpromazine equivalents) values for patients treated with thioridazine. Moreover, because of differences in the magnitude of the effect with serum from different individuals, it is not possible to control completely for this effect. Thus, these data reconcile discrepancies that have been reported for data from the NRRA versus that from direct analytical measurements, and demonstrate that the use of the NRRA as a quantitative tool in the clinical pharmacology of thioridazine may lead to erroneous estimations of active drug and metabolites in the blood.

Error analysis of the double-integral method for calculating brain blood perfusion from inert gas clearance data.

A single-photon dynamic computer-assisted tomograph (DSPECT) has been built and is currently being used to evaluate regional cerebral blood perfusion in patients and volunteers. A computer simulation of the system was created to analyze the effects of data collection, Poisson noise, attenuation compensation, and the reconstruction technique now employed in the DSPECT. Several methods of attenuation compensation were used to generate perfusion images from both ideal and noisy data. The results indicate that the mean perfusion is calculated to within 10.4% accuracy for all perfusion rates in a region of interest if attenuation correction is used. Without attenuation correction, perfusions are underestimated by as much as 27%. The three correctors tested have different effects on the calculated perfusion value, depending on the location of the region of interest in the picture. The algorithm introduces random noise that is proportional to both the random error in the input data and the perfusion rate. Air-curve delay errors result in inaccuracies in the final perfusion picture that are proportional to perfusion rate. Physiological values (0.8-1.5) of the partition coefficient cause overestimation of both gray (0-34%) and white (7-67%) matter perfusion values. Compton scatter and collimator effects were not addressed in this study.