A characteristic continuous wave Doppler signal in cor triatriatum? Continuous wave Doppler recordings of the turbulent jet through the restrictive orifice of a left atrial partition in a patient with corrected transposition of the great arteries and cor triatriatum showed alternate bands of high intensity diastolic and low intensity systolic signals with preservation of the normal configuration of the diastolic E and A peaks. It is thought that Doppler studies in cor triatriatum will provide useful complementary haemodynamic information in the echocardiographic diagnosis of this anomaly.


Cor triatriatum sinister, not mitral stenosis, in an adult with previous Sydenham's chorea: diagnosis and preoperative assessment by cross sectional echocardiography. In cor triatriatum sinister, one of the rarest congenital cardiac anomalies, a membrane divides the left atrium into a pulmonary venous component above and the vestibule below. The importance of the anomaly lies in the effects of the resultant pulmonary venous obstruction that usually present in the first year of life and can mimic obstructed total anomalous venous drainage or congenital mitral stenosis. A case presented as mitral stenosis in the third decade of life, ten years after a well documented episode of Sydenham's chorea. The diagnosis was made rapidly by transthoracic echocardiography and transoesophageal echocardiography was used for complete assessment. Cardiac catheterisation added nothing to the non-invasive diagnosis or the preoperative assessment. Uncomplicated corrective surgery was undertaken.


HIV-associated papulosquamous diseases.

HIV-associated papulosquamous diseases. Persons infected with the human immunodeficiency virus (HIV) can develop a variety of dermatoses in which the primary lesions are scaly papules or plaques. These dermatoses can be the presenting clinical manifestations of HIV infection. Depending on the degree of immune dysfunction, the clinical and histopathologic appearance may be typical or quite unusual.


Primary bacterial skin infections.

Primary bacterial skin infections. Bacterial infections are among the most frequent inflammatory skin disorders. This continuing education article describes certain aspects of bacterial infections and outlines the medical and the nursing management. A comprehensive nursing care plan is listed.


Sexuality and self-concept: issues in skin disease. Self-concept is closely tied to feelings of sexuality. Therefore, comprehensive nursing care of patients with skin disorders should include sexuality issues. This article addresses methods of assessment and a variety of interventions in dealing with sexuality and skin disease.


Reducing pain and anxiety in children.

Reducing pain and anxiety in children. Children faced with clinical procedures may become distressed in anticipation of the experience of pain. This article describes psychological interventions designed to minimise the trauma children associate with potentially distressing situations. Although time-consuming, the author suggests they are valid tools in the control of pain.


Genetic counselling. Alzheimer's disease: advances in genetics. Recent advances in DNA technology have allowed identification of those carrying the gene mutation for early onset Alzheimer's disease in some families, and provide the prospect of an effective treatment or cure in the future. While last week's article questioned the existence of late onset Alzheimer's as a distinct disease entity, this one illustrates how and why these scientific advances may have far-reaching psychosocial consequences for some family members. It suggests why there is likely to be an increase in demand for the kind of information and support which can be offered by a genetic counselling service.


Issues in nursing and health. Patient access to health records. The Access to Health Records Act was passed in 1990. To provide time for training to be given and procedures to be put in place, it did not come into effect until November 1 1991. The Act was promulgated as a result of pressure from people who wanted access to their notes and health professionals who recognised the benefits of open relationships with the people for whom they cared.


Quality assurance: using BS 5750 in health care settings. This article places the issue of standards within the arena of a quality service. It argues that standards of quality can only be turned into reality if they are developed through the discipline of a quality assurance system, combined with the motivation of a quality culture. A quality assurance system, British Standard (BS) 5750, is briefly outlined and attention is given to examining the mechanisms for defining the specific requirements necessary to develop quality assurance within residential care homes. This is based on the authors' experience of working with Napier House, the first caring enterprise in Europe working directly with patients or residents to obtain the BS 5750.


Sexual activity after myocardial infarction. The resumption of sexual activity after myocardial infarction can be an area of concern for patients, and one that may be difficult for nurses to address. Patients often fear that resuming sex will be dangerous to their perceived fragile health status, while nursing staff can be reluctant to broach a subject which may cause embarrassment to both parties. The author discusses the aims of the patient education process, and includes practical advice that can be given. He stresses the need to consider the circumstances of the individual patient, thereby avoiding vague and generalised advice that may be of little value.


The nursing process: Fijian experiences. The nursing process is almost taken for granted in the United Kingdom. Fijian nurses, when faced with its implementation, found it was poorly understood and uncommonly used. This study highlights some of the perceptions of Fijian nurses to the nursing process and how it is intended to overcome the challenges these pose.


Evaluating growth hormone treatment.

Evaluating growth hormone treatment. The consequences in later life for people whose growth in childhood has been restricted can be profound, often with severe emotional or psychological effects. The author defines the causes of short stature and describes clinical trials being undertaken to evaluate the use of growth hormone in children who do not appear to have growth hormone deficiency.


Is elderly care research-based?

Is elderly care research-based? Nurses working with elderly people, and students considering the specialty as a career option, may develop negative attitudes about the value of the work they do. These often derive from the perception that their efforts do not improve patients' problems, and a misconception that what they do is intuitive rather than based in research. Such tensions can lead to the development of 'burnout' and the rapid demoralisation of the workforce. Roger Watson shows how nursing elderly people, particularly those with dementia who live in continuing care settings, calls on high degrees of technical and interpersonal skills, and demonstrates how the roots of the specialty are deeply entrenched in research.


Incidence of bladder cancer in a cohort of workers exposed to 4-chloro-o-toluidine while synthesising chlordimeform. Between 1982 and 1990 seven cases of bladder cancer were detected in a group of 49 workers who were synthesising chlordimeform from 4-chloro-o-toluidine. Latency periods ranged from 15 to 23 years. The incidence of bladder tumours in this group was significantly higher than that of the cancer registers of the former GDR, Saarland, and Denmark by factors of 89.7, 53.8, and 35.0 respectively. This provides further evidence that monocyclic aromatic amines such as 4-chloro-o-toluidine may be carcinogenic in humans.


Morbidity study of extruder personnel with potential exposure to brominated dioxins and furans. I. Results of blood monitoring and immunological tests. The potential for exposure of employees to polybrominated dibenzofurans (PBDFs) and dibenzo-p-dioxins (PBDDs) during extrusion blending of resins containing decabromodiphenyl ether was established through previous air monitoring (area samples) and biomonitoring studies. The findings presented herein are further biomonitoring results for 42 employees and immunological tests for exposed and referent employees. Among potentially exposed men, 2,3,7,8-TBDF and 2,3,7,8-TBDD concentrations in blood lipid ranged from non-detectable to 112 parts per trillion (ppt) and from non-detectable to 478 ppt respectively. Biomonitoring results correlated well with assignments in the extruder work area when adjusted for process changes and engineering improvements and provided biological half life estimates of between 1.1 and 1.9 years for 2,3,7,8-TBDF and between 2.9 and 10.8 years for 2,3,7,8-TBDD. Results for 16 measures of the immune system were examined in relation to exposure (exposed v referent group) and in relation to the biomonitoring data. Some individual trends in immunological parameters with exposure and covariates such as age and cigarette smoking were found (for example, an increase in complement C4 with increasing concentrations of PBDFs and PBDDs, increased lymphocyte subpopulation counts with cigarette smoking); however, the overall clinical assessment was that the immune system of exposed employees was not adversely impacted at these burdens of PBDFs and PBDDs.


Effects of occupational exposure to mercury vapour on the central nervous system. Possible effects of mercury on the central nervous system (CNS) were examined in a group of chloralkali workers exposed to mercury (n = 89) and compared with a control group (n = 75), by registration of subjective symptoms, personality changes, forearm tremor, and performance on six computerised psychometric tests in the two groups. The groups were similar in age, education, verbal comprehension, and work tasks. In the chloralkali group, median blood mercury concentration (B-Hg) was 55 nmol/l, serum mercury concentration (S-Hg) 45 nmol/l, and urine mercury concentration (U-Hg) 14.3 nmol/mmol creatinine (25.4 micrograms/g creatinine). Corresponding concentrations in the control group were 15 nmol/l, 4 nmol/l, and 1.1 nmol/mmol creatinine (1.9 micrograms/g creatinine) respectively. The number of self reported symptoms, the scores for tiredness and confusion in the profile of mood states (POMS), and the degree of neuroticism in the Eysenck personality inventory (EPI), were significantly higher in the mercury exposed group compared with the controls. Performance on the psychometric tests and tremor frequency spectra did not differ significantly between the two groups. Dose-response calculations showed weak but statistically significant relations between symptom prevalence and current mercury concentrations in both blood and urine. The performance on three of the psychometric tests was negatively correlated with earlier peak exposures. The findings indicate a slight mercury induced effect on the CNS among the chloralkali workers.


Longitudinal studies of exposure to cadmium. Measurements of urinary proteins, blood and urinary cadmium, and in vivo kidney and liver cadmium have been made for a group of workers at several times between 1981 and 1990. The possibility of the introduction of measurement artifacts due to the use of different in vivo measurement systems has been assessed and is considered to be small. Changes in cadmium body burden with time have been studied in relation to kidney function. The results suggest several interesting patterns, although more data are needed to elucidate these further. They do, however, show the effectiveness of good hygiene in the workplace.


Peripheral markers of neurochemical function among workers exposed to styrene. A cross sectional study of biological markers of neurochemical function in peripheral blood cells, and self reported nervous system symptoms, was conducted among 60 workers exposed to styrene in three reinforced plastics plants and 18 reference workers not exposed to styrene or other solvents. Concentrations of styrene in the air at the plants ranged from less than 1 to 160 ppm. Biomarkers of neurochemical function measured were: sigma receptor binding in lymphocytes, monoamine oxidase type B (MAO-B) activity in platelets, and serotonin uptake by platelets. Blood styrene concentration was used as the exposure index to take account of the use of protective equipment and dermal uptake. Four blood styrene exposure groups were defined as: non-exposed (reference) and exposed to less than 0.05, 0.05-0.19, and greater than or equal to 0.20 micrograms/ml. The prevalences of headache, dizziness, light headedness, fatigue, irritability, memory loss, and feeling "drunk" at work increased with increasing blood styrene concentration. No effect on sigma receptor binding was seen. A slight positive correlation was found for uptake of serotonin, which has been used as an exposure related effect indicator in previous studies of workers exposed to solvents. The MAO-B activity decreased with increasing blood styrene concentration; the mean (SE) MAO-B values for the four groups were 34.2 (3.0), 28.1 (5.3), 20.1 (4.8), and 16.9 (7.7) pmol/10(7) cells/min. The MAO-B activity also correlated negatively with the number of reported nervous system symptoms, whereas no associations were seen between prevalence of symptoms and either serotonin uptake or sigma receptor binding. The findings for MAO-B activity are consistent with previously reported experimental data, and suggest that MAO-B may be a useful marker of styrene neurotoxicity.


Decline in spirometric variables in grain workers from start of employment: differential effect of duration of follow up. Prospective study of 164 young men from the start of employment in grain elevators showed that of those seen at the initial evaluation of respiratory state only 30% were available for a complete four year follow up. The drop out of subjects could represent a health related selection leading to the underestimation of respiratory effects of exposure to grain dust as assessed in the survivor group. This hypothesis was examined by comparisons of longitudinal changes in lung function in four groups defined by the duration of follow up involving the initial examination and periodic evaluations after one, two, and four years of work. Sixty four men were tested only on the initial examination (group I), 18 underwent two (group II), 31 underwent three (group III), and 51 (group IV) all four examinations. The groups had similar mean ages (range: 19.4-20.1 years), mean duration of previous exposure to grain dust (range: 8-13 weeks), smoking habits, lung function, and prevalences of respiratory symptoms evaluated on the initial occasion. The average decline in lung function over the first year was associated with duration of follow up. The annual decline in FVC (ml) was 58 in group II, 41 in group III and -55 (increase) in group IV; the decline in FEV1 (ml) was 224, 130, and 70 respectively. The differences for the annual declines of FEV1, FEF25-759 Vmax509 and Vmax25 were significant between groups II and IV, and the FEF25-759 Vmax509 and Vmax25 differed significantly between groups II and III. The results show that the restriction of analysis to the survivors may underestimate the relation between work and respiratory impairment.


Immune response to flour and dust mites in a United Kingdom bakery. In a study of 279 United Kingdom bakery workers a high prevalence of immunological response to storage mites was found. To determine whether this was the consequence of exposure to storage mites in bakery work, a population of salt packing workers was examined as a comparison group not at occupational risk of exposure to storage mites. Forty two per cent of both groups were atopic (had a positive skin prick response greater than negative controls to D pteronyssinus, grass pollen, or cat fur by 2 mm or more) and 33% had an immediate skin prick test response to at least one of four storage mites (L destructor, G domesticus, T putrescentiae, A Siro). A higher percentage of the salt packing workers than the bakery workers had a positive radioallergosorbent test (RAST) (greater than or equal to 0.35 PRU) to D pteronyssinus and to the four storage mites. Logistic regression analysis identified atopy as the most significant variable for a positive skin test and RAST response to storage mites in both groups of workers. RAST inhibition was used to analyse extracted area and personal air samples. Analysis of static area samples for aeroallergen showed immunological identity with flour but L destructor was found in only one of seven exposed filters. The concentration of airborne flour was related to exposure rank of perceived dustiness and gravimetric measurement of total dust. Nineteen out of 32 filters from workers in jobs with higher dust exposure (rank >/=6) had a level of > 10 microgram/m(3) flour whereas this concentrations was exceeded in only one of 23 filters from workers in low dust exposure (< rank 6). It is concluded that storage mites are not of special significance in allergic responses in bakery workers. The development of immunological (and airway) responsiveness to inhaled flour dust is increased in those exposed to higher concentrations of airborne allergen, which appears to be predominantly flour and not storage mites.


Radiographic osteoarthrosis in the acromioclavicular joint resulting from manual work or exposure to vibration. The hypothesis that manual work and exposure to vibration are antecedents to the development of osteoarthrosis was assessed employing a cross sectional study design. The frequency of osteoarthrosis in the acromioclavicular joint was studied in three groups of workers in the construction industry. Two groups were manual workers (54 bricklayers and 55 rock blasters); the third group consisted of 98 foremen. The radiographic appearance of the right and left acromioclavicular joints was classified into one of five grades of osteoarthrosis. A protocol was developed to assess exposure on the basis of job title, years of manual work, total weight lifted during working life, and total hours of exposure to vibrating tools. Odds ratios for job titles (manual worker v foreman) and for years of manual work as indicators of exposure were of similar magnitude of around 2.5. Construction workers who had lifted more than 709 tonnes had an increased risk of developing severe osteoarthrosis of the right acromioclavicular joint, odds ratio: 2.62 (95% confidence interval (95% CI), 1.13-6.06). The odds ratio for the left side was 7.67 (95% CI, 2.76-21.34). In the analysis of vibration exposure, workers who had been highly exposed to vibration had an odds ratio of 1.99 (95% CI, 1.00-3.92) on the right side and 2.20 (95% CI, 1.07-4.56) on the left. This effect almost disappeared after simultaneous adjustment for manual work. Occupational and ergonomic factors, such as the sum of lifted tonnes during working life, job title, and the sum of years of manual work seem to be risk factors for osteoarthrosis of the acromioclavicular joint, whereas vibration alone was a weaker risk factor.


The course of respiration and circulation in death due to typical hanging. Experiments were carried out on 15 dogs to investigate the course of respiration and circulation during the agonal period of death due to typical hanging. Animals were asphyxiated by a method simulating typical hanging. Electrocardiogram (ECG), electroencephalogram (EEG), blood pressure (BP) in the femoral artery and intrathoracic pressure (ITP) were registered. In typical hanging, the course of respiration was characterized by shorter stages of dyspnoea and initial apnoea and a longer stage of the terminal respiration when compared with obstructive asphyxia. However, the whole time of the course of respiration and circulation in typical hanging was almost the same as that in obstructive asphyxia. The BP increased rapidly, was maintained during the dyspnoea stage, and then decreased gradually. EEG disappeared with, or a short time after, the end of the dyspnoea stage. The increased heart rate in the dyspnoea stage remained until circulatory collapse. The analysis of the ECG complexes revealed that the heart muscle adapted to oxygen deficiency during typical hanging.


Polymorphism of coagulation factor XIII B subunit: further occurrence of FXIIIB*15 in Japanese and phenotyping in bloodstains. The polymorphism of FXIIIB was investigated in 555 unrelated Japanese individuals using isoelectric focusing and immunoblotting. Five common phenotypes and a rare variant type FXIIIB 15-3 were observed. The allele frequencies were FXIIIB*1 = 0.3063, FXIIIB*2 = 0.0162, FXIIIB*3 = 0.6766 and FXIIIB*15 = 0.0009. Phenotyping was also possible from bloodstains stored at 37 degrees C for up to 4 months and from bloodstains stored at room temperature and at 4 degrees C for over 6 months. The FXIIIB system can provide a new powerful genetic marker for the medicolegal grouping of bloodstains.


Glycyrrhizin and glycyrrhetinic acid determination from formalin-fixed tissue. Glycyrrhetinic acid (GA), the main metabolic product of glycyrrhizin (GLY), could be detected in formalin-fixed tissue from a man who died 6 hours after therapeutic administration of a GLY-containing agent. GA was extracted from homogenized formalin-fixed liver tissue and 3 ng GA/g could be detected by HPLC. The extraction from formalin-fixed liver tissue gave the same retention time peak as the GLY control. GA could also be detected by mass spectrometry in the blood sample. This confirms that the man had received a GLY-containing agent for therapeutic use prior to his death and that GA can be determined from formalin-fixed tissue.


Genetic polymorphism of orosomucoid (ORM1 and ORM2) in Lombardy (Italy). Orosomucoid subtypes have been analysed in 600 unrelated individuals from the Brescia Area (Lombardy-Italy) by the isoelectric focusing technique and immunoprinting. Five ORM1 phenotypes were observed. The ORM2 pattern was found to be virtually monomorphic, but one variant with an additional single band was found. The estimated allele frequencies were: ORM1*F1 = 0.5992, ORM1*F2 = 0.0150, ORM1*S = 0.3858.


Non-traumatic rupture of the superior mesenteric vein with hemoretroperitoneum. A case of rupture of the superior mesenteric vein with hemoretroperitoneum is described. The autopsy revealed the presence of an acute pancreatitis and thrombosis of the superior mesenteric artery. From the histological findings it appeared that the acute pancreatitis had damaged the venous wall from the outside and that the portal system overload, caused by the superior mesenteric artery thrombosis and the anomalous termination of the inferior mesenteric vein, acted from the inside of the vein causing its rupture. To our knowledge this is the first report of a rupture of the superior mesenteric vein caused by acute pancreatitis and resulting in hemoretroperitoneum.


The "Scandinavian Star" ferry disaster 1990--a challenge to forensic odontology. With 158 victims, the fire on board the "Scandinavian Star" was one of the world's worst ferry disasters. A team of identification experts, including dentists, were employed to secure evidence for identification and to remove the victims from the ferry. Four parallel teams, each with 2 dentists, examined and autopsied the victims at the Institute of Forensic Medicine, University of Oslo. Using the INTERPOL Disaster Victim Identification forms and aided by computers, all victims were identified within 17 days. Dental identity could be established in 107 cases (68%).


Postmortem toxico-kinetics of co-proxamol. Postmortem drug redistribution in suicidal poisonings by co-proxamol (dextropropoxyphene and paracetamol) has been studied. Analytical data for 8 tissue samples, including muscle and fat, up to 8 blood samples, and gastric and small bowel contents were obtained in 4 cases. Blood samples were taken from multiple sites at the start of autopsy and after 24 or 48 h. Concentrations of both drugs were site dependent with the lowest concentrations in peripheral blood. Paracetamol concentrations varied two to threefold and propoxyphene concentrations varied seven to tenfold. Pulmonary artery concentrations of paracetamol did not change significantly with time; propoxyphene concentrations typically increased twofold over 24 h and threefold over 48 h. Propoxyphene concentrations in the inferior vena cava increased unpredictably but occasionally significantly (up to sevenfold). For both drugs the most dramatic elevations of blood concentrations were seen in the aorta; in one case paracetamol rose to 1.9 g/l, 8 times the peripheral blood concentration and 4 times the liver level (454 mg/kg); propoxyphene rose to 191.5 mg/l, 55 times the peripheral blood concentration. This appears to reflect postmortem diffusion of unabsorbed drug from the gastric lumen. It is likely that markedly higher concentrations in the putrefactive fluid from the left pleural cavity as compared with the right also reflect diffusion from the stomach.


Tyre tread marks on the body without internal injuries. Two cases are presented involving a 5-year-old boy with tyre tread impressions on the back and right arm and a 4-year-old girl with tread marks on the head but both had no internal injuries. These cases suggest that injuries to internal organs do not always occur when the trunk or head is run over by the wheels of a vehicle.


Improved section bonding using silanated glass slides--application protocol. Silanated slides provide excellent tissue adhesion for routine histology, immunohistochemistry and in situ hybridization of frozen, paraffin embedded material or cell smears. An easy and inexpensive method of treating glass microscope slides with triethoxysilylpropylamine is reported.


DNA extraction from mixtures of body fluid using mild preferential lysis. A modification to the DNA extraction method "preferential lysis" (Gill et al. 1985) is proposed which can be applied to DNA mixtures of vaginal cells and spermatozoa. In mixtures with a low sperm content the further loss of sperm DNA caused by the extraction can be avoided by using "mild preferential lysis". Amplification by PCR (polymerase chain reaction) then yields sufficient DNA to be able to identify both components in the mixture.


Group-specific component (GC) polymorphism in Cádiz (southern Spain). The genetic polymorphism of group-specific component (GC) was analysed in a sample of 443 healthy unrelated subjects of both sexes resident in the province of Cádiz (Southern Spain). Isoelectric focusing was carried out in polyacrylamide gels followed by staining with coomassie blue R 250. The estimated gene frequencies were as follows: GC*1S = 0.6185; GC*1F = 0.1162; GC*2 = 0.2652.


Gene-specific DNA interstrand cross-links produced by nitrogen mustard in the human tumor cell line Colo320HSR. Genomic and gene-specific DNA interstrand cross-links produced by nitrogen mustard (HN2) were measured in the human tumor cell line Colo320HSR. Following exposures that produced greater than or equal to 1 log cell kill, it was found that HN2-induced DNA interstrand cross-links were produced and processed in a heterogeneous fashion within the genome. Cross-links were detected in the amplified, overexpressed c-myc oncogene, whereas in the weakly expressed N-ras gene and the nontranscribed, high copy number alpha-satellite sequence (of chromosome 20), cross-links were not detected. The cross-links in the c-myc oncogene disappeared more rapidly than total genomic cross-links. These results suggest that HN2-induced DNA interstrand cross-links are produced and processed in the genome in a nonrandom fashion.


Transcriptional control of epidermal growth factor receptor by retinoic acid. Retinoic acid (RA) and epidermal growth factor (EGF) regulate growth and differentiation of epithelial cells. RA has both direct and indirect effects on gene expression. Direct effects result from modulation of the transcriptional activity of genes, which contain RA response elements (RARE) recognized by trans-acting nuclear RA receptors (RARs). A second indirect mechanism for the modulatory effects of RA is by the induction or repression of growth factors and growth factor receptors. There is evidence for functional interactions between RA and the EGF receptor (EGFR). RA enhances the proliferative response of cultured keratinocytes to EGF, increases the number of EGFRs on the surface of some cells, and induces EGFR promoter activity in most cells. In contrast, immunoprecipitation, Northern blot, and nuclear run-on analysis described in this paper show that RA suppresses EGFR synthesis at the transcriptional level in human epidermoid carcinoma ME180 cells. Deletion analysis of EGFR gene promoter mutants linked to the chloramphenicol acetyltransferase gene revealed the existence of a region of the promoter, -771 to -384, which is responsive to RA. Gel retardation data indicated that a cell-type nuclear protein which binds to this novel element is suppressed by RA in a dose-dependent manner. This decrease coincides with a decreased steady-state level of RAR-gamma mRNA. These data strongly suggest that the EGFR promoter is regulated by RAR-gamma, which itself is under the control of RA. Other cell-specific trans-acting factors may be involved in this regulation.


Altered distribution of phospholipase C-gamma 1 in benign hyperproliferative epidermal diseases. Phospholipase C-gamma 1 (PLC-gamma 1) is a well characterized substrate for the epidermal growth factor receptor tyrosine kinase and has been implicated in the intracellular biochemical signaling cascade which occurs following stimulation of cells with epidermal growth factor. The in vivo localization of PLC-gamma 1 was examined by immunohistochemistry in sections of normal human skin and in skin sections from a diverse series of hyperproliferative epidermal conditions (psoriasis, seborrheic keratoses, acrochordons, and margins near second-degree burns). Immunoreactive PLC-gamma 1 was detected only in the basal compartment of normal skin but was readily detectable in both the basal and outer epidermal compartment in hyperproliferative skin conditions. In addition, immunoreactive PLC-gamma 1 colocalizes with immunoreactive epidermal growth factor receptor in both normal and hyperproliferative epidermis.


Adolescent developmental change in topography of EEG amplitude. EEGs were recorded from 32 channels in 30 normal males, ages 16-22. Delta activity decreased throughout this age range. This decrease was greatest in the left frontal and temporal regions; no occipital lead showed this pattern. Relative EEG amplitude analysis, based on normalized maps, revealed decreases with age across alpha, delta, and theta bands with beta staying the same or increasing. These changes were greatest in the left temporal and left frontal regions. Taken together, these findings suggest that these cortical areas are maturing in the second decade of life. Both delta and theta showed significantly greater decreases with age in the left parietal region than in the right.


Mortality in DSM-IIIR schizophrenia.

Mortality in DSM-IIIR schizophrenia. Mortality was investigated in 356 DSM-IIIR schizophrenics admitted to a university psychiatric hospital over a 12-year period. Determination of death was made through a record-linkage process and observed death was compared with the mortality experience of the general population of the State of Iowa. Schizophrenics had nearly a three-fold increase in overall mortality. Mortality was primarily attributable to unnatural causes of death, particularly suicide, which was more than twenty-three times greater than expected. Mortality was greater in schizophrenic patients younger than 40 years and during the early portion of follow-up. Studies of mortality in psychiatric patients continue to be important, particularly as diagnostic criteria become better refined.


Validity of the negative/positive dichotomy for schizophrenic disorders under long-term conditions. A total of 148 patients fulfilling the DSM-III symptomatological criteria of schizophrenia were classified according to Andreasen's criteria of positive, negative and mixed symptomatology. After excluding cases of permanent hospitalisation and patients with monoepisodic course the remaining 100 patients had a total of 458 episodes. Of these episodes, 213 were identified as positive, 134 as negative and 111 as mixed. During the course of illness the proportion of negative episodes increased and the proportion of positive episodes decreased. The great majority of the patients (76%) had a bimorphous course, i.e. one showing both types of schizophrenic symptomatology, positive and negative. Only 6% of the patients had only negative episodes, and only 18% had only positive episodes. The shift from one type of episode to another is dependent on the length of illness. Stability was not greater later during the course of illness than at the beginning.


Early parental death: relation to electrodermal orienting response and gender in schizophrenia. The aim of the present study was to examine age at parental loss by death and its relation to electrodermal orienting response and sex in schizophrenia. Forty-four DSM-III schizophrenic inpatients were exposed to a series of moderately intense tones in a standard orienting habituation paradigm, while skin conductance was recorded. The twenty-three patients who failed to respond to any of the first two tones were found to be younger when they lost their first parent compared to the 21 responders. When the 44 patients were divided according to sex, the females were found to be younger than the males when parental loss occurred. Finally, when multivariate analyses were performed, it was found that both responding/nonresponding and sex provided almost equally large independent contribution to the prediction of parental loss.


Gender and the familial risk for schizophrenia. Disentangling confounding factors. Recent studies of the effect of gender on the familial risk for schizophrenia have shown that relatives of females have a higher risk for schizophrenia than relatives of males. This study attempts to explain the effect by examining factors found to differentiate schizophrenic men and women and found to be related to the familial risk for schizophrenia. Cox proportional hazard regression model was used to examine the simultaneous effects of age at onset, season of birth, and premorbid history, controlled for symptoms that have been found to differ by gender (dysphoria, paranoia, and flat affect). Results showed that the effect of gender on the transmission of schizophrenia could not be explained by gender differences in age at onset, symptom expression, premorbid history, and winter birth. However, premorbid history had an effect on familial risk independent of gender, indicating that probands with a poor premorbid history had a lower familial risk for schizophrenia than those with a good premorbid history. Implications of the findings are discussed.


Prediction of employability in schizophrenic patients. This study, the third of a series of reports on employability and schizophrenia, investigated the effects of both interview and non-interview variables on employability. Data on 46 chronic schizophrenic inpatients included demographic and illness-related variables, measures of psychopathology and interview-based ratings of employment skill. Latent class analysis using linear structural relations (LISREL) modelling generated the main finding namely, that interview-based measures are the strongest determinants of employability. However, other variables pertaining to illness, prior functioning and negative symptoms, exert an effect on interview performance and hence indirectly influence employability ratings and judgements.


Covariance of personality, neurocognition, and schizophrenia spectrum traits in the community. Clinical researchers have observed in relatives of schizophrenic individuals abnormal personality traits resembling the psychopathology of schizophrenia. Further similarities have been observed in correlations between measures of brain function, including attention and executive abilities, and these personality psychopathologies. However, two methodologic factors might account for the covariation of these 'schizophrenia spectrum' personality traits and measures of brain function. Clinical selection bias (Berkson's bias) might result in subjects with overlapping conditions being more likely to be studied, and normal personality attributes could affect performance on neurobehavioral tasks. This study investigated relationships between neurobehavioral correlates of schizophrenia, clinical schizophrenia spectrum personality traits, and normal personality dimensions in the five-factor model of personality. To avoid Berkson's bias, subjects expected to have a high probability of spectrum traits were recruited from the Baltimore Epidemiologic Catchment Area Survey community sample. About 40% of the sample were found to have DSM-IIIR Schizotypal, Schizoid, or Paranoid Personality Traits or Disorders. Schizophrenia Spectrum traits showed significant associations with personality dimensions of the five factor model, particularly Openness to Experience and Neuroticism. In ordinary linear regression models, after adjustment for a number of normal personality characteristics, Schizotypal Personality Traits were still strongly associated with perseverative responses on the Wisconsin Card Sorting Test (WCST). In logistic regression models, subjects with Schizotypal, Schizoid, or Paranoid Traits differed in terms of normal personality profiles and WCST performance.


Scanning eye movements in schizophrenic patients. Relationship to clinical symptoms and regional cerebral blood flow using 123I-IMP SPECT. Eye movements during the Benton Visual Retention Test were examined using an eye-mark recorder in 32 schizophrenic patients and 32 normal controls. The patients had significantly fewer eye fixations, longer mean duration of fixation and shorter length of mean scan path than the controls. In the patients, these eye movement parameters were significantly correlated with the negative symptom score but not with the positive symptom score on the Positive and Negative Syndrome Scale. These parameters had a significant correlation with the composite score on the Scale for the Assessment of Negative Symptoms (SANS). In particular, they were highly correlated with avolition-apathy and affective flattening or blunting scores on SANS subscales. Thus, examination of scanning eye movements seemed to be a good objective index of negative symptoms. Secondly, regional cerebral blood flow (rCBF) was examined using N-isopropyl-p-[123I]iodoamphetamine (123I-IMP) and single photon emission computer tomography in 17 of 32 patients. With regard to the relationship between the eye movement parameters and rCBF, the mean duration of fixation was negatively correlated with 123I-IMP uptake in the left superior frontal area and left basal ganglia. The mean length of the scan path was correlated with uptake in the left superior frontal area. These findings suggest that the characteristic eye movements of schizophrenic patients are likely to be related with dysfunction of the frontal-basal ganglia neural circuit.


Wisconsin Card Sorting Test deficits in chronic paranoid schizophrenia. Evidence for a relatively discrete subgroup? Some, although not all, researchers have reported dramatically increased numbers of perseverative responses on the Wisconsin Card Sorting Test (WCST) in schizophrenic patients compared to normal comparison subjects. The current study was designed to further explore the nature of possible WCST deficits in a group of paranoid schizophrenic patients compared to normal and psychiatric comparison subjects. In the current study, schizophrenic patients had significantly greater numbers of perserverative responses on the WCST than the comparison groups. The sample of patients with schizophrenia appeared to be characterized by a non-Gaussian distribution of perseverative responses on the WCST. WCST-impaired and WCST-nonimpaired schizophrenic subgroups were compared on cognitive and symptom measures, and increased perseverative responding was associated with negative symptoms, slowed reaction time, and more hospitalizations. While additional research is necessary to further investigate hypotheses of frontal versus generalized brain dysfunction in schizophrenic patients, WCST impairment seems to be present in a clinically meaningful subgroup of paranoid schizophrenic patients.


Dichotic listening in monozygotic twins discordant and concordant for schizophrenia. Emotional and neutral word versions of the fused rhymed words dichotic listening test were administered to members of 18 pairs of monozygotic twins discordant for schizophrenia, 7 pairs concordant for schizophrenia, and 7 pairs of normal twins. In the discordant group, affected twins had smaller right ear advantages than did their unaffected cotwins for neutral words. The difference was completely attenuated with the presentation of emotional words or in less powerful between-group comparisons that included twins concordant for schizophrenia and normal twins. It is unlikely that this finding reflects an abnormality in the lateralized representation of language, both because we did not find a correlation between handedness scores and dichotic listening scores and because emotional stimuli normalized results. The finding may reflect abnormalities in the allocation of attention for priming language centers in the left hemisphere. 'At risk' subjects, i.e., the unaffected members of the discordant pairs, did not differ significantly from normal monozygotic twins on measures of dichotic listening.


Schizophrenic feature recognition deficits are independent of task criterion. The present study determined the minimal exposure time (i.e., critical stimulus duration (CSD) necessary for feature registration and recognition by normals and chronic schizophrenics. Our interest was whether the longer exposure times required by schizophrenics than by normals could be attributed to an inability of schizophrenics to maintain attention when the task criteria were stringent as opposed to 'loose'. The present findings support previous findings of impaired feature recognition by chronic schizophrenics. Chronic schizophrenics' and normals' CSDs were not affected by task criterion. The consistent performance by these groups on the 'loose' and 'rigid' task criteria suggest that if attentional lapses occur then they are as likely to occur for chronic schizophrenics as for normals and they are independent of the task's criterion. It is concluded that impaired feature registration for chronic schizophrenics is a consequence of a deficit at the earliest stage of encoding.


Association of schizophrenia and partial trisomy of chromosome 5p. A case report. A normal balanced chromosome 5 translocation carrier (5:14) (p14.1; q32.3) produced one offspring with a 5p deletion syndrome (cri du chat syndrome) and two with a partial trisomy (one with schizophrenia and the other with refractory epilepsy). We had hypothesized that the translocation might be complex and involve 5q, overlapping with a schizophrenia associated area described by Bassett et al., (1988). Cytogenetic study, however, indicated that there was no overlap in the involved chromosome 5 trisomy for this individual with schizophrenia and the trisomic region previously described. The probands with the trisomy and the cytogenetic findings are described in this report. Alternative interpretations are suggested to explain the association of schizophrenia and chromosomal abnormalities.


Chronotropic and inotropic effects of ropivacaine, bupivacaine, and lidocaine in the spontaneously beating and electrically paced isolated, perfused rabbit heart. The purpose of this study was to compare the inotropic and chronotropic effects of ropivacaine, bupivacaine, and lidocaine in an isolated, spontaneously beating rabbit heart preparation. The ability to electrically pace the heart in the presence of local anesthetic also was examined. Hearts were perfused with Krebs-Henseleit solution, then exposed to ropivacaine or bupivacaine at 1, 6, or 13 micrograms/ml or lidocaine at 6, 20, or 40 micrograms/ml (n = 6, each concentration). Left ventricular pressure, left ventricular dP/dt (rate of change derivation from analog waveform of the left ventricular pressure wave), pulmonary artery flow, oxygen consumption, and electrocardiogram were monitored throughout the studies. Drug exposure was for 30 minutes or until a 75% decrease in left ventricular pressure occurred. All preparations were exposed to 1 microgram/ml bupivacaine or ropivacaine and 6 micrograms/ml lidocaine for the full 30 minutes. At the intermediate concentrations, only one of six bupivacaine preparations (6 micrograms/ml) survived the full 30-minute exposure period, compared to six of six preparations for both ropivacaine (6 micrograms/ml) and lidocaine (20 micrograms/ml; p less than 0.05). Similar results were found with exposure to the highest concentrations of these local anesthetics. No electrocardiogram changes were observed with any of the three lidocaine concentrations or with the lowest ropivacaine and bupivacaine concentration. At the intermediate concentration, atrioventricular conduction changes were seen with bupivacaine in five of six preparations, compared to one of six ropivacaine preparations (p less than 0.05). With the high concentration, ventricular tachycardia occurred in four of six bupivacaine preparations, compared to zero of six with ropivacaine (p less than 0.05). In general, left ventricular systolic pressure, dP/dt, heart rate, and oxygen consumption were reduced during exposure to all concentrations of the three local anesthetics. The most profound effects (greater than 75% reduction) were seen with 13 micrograms/ml bupivacaine. All local anesthetics caused an increase in the voltage required to pace the hearts via the atria. With 6 micrograms/ml bupivacaine and 13 micrograms/ml ropivacaine, 50% of the preparations could not be paced via the atria; and with 13 micrograms/ml bupivacaine, none of the preparations could be paced via the atria. The depressant effects of 6 micrograms/ml bupivacaine approximated those seen with 13 micrograms/ml ropivacaine. The reductions in oxygen consumption and pulmonary artery flow were not significantly different between treatment groups. The results of this study indicate that bupivacaine is more cardiodepressant and arrhythmogenic than either ropivacaine or lidocaine.


Hemodynamic effects of continuous spinal anesthesia: a comparative study between low and high doses of bupivacaine. Arterial hypotension is a major side effect of spinal anesthesia. Continuous spinal anesthesia may allow titration of the amount of local anesthetic to obtain a level that is appropriate for the surgical procedure. This study compared the hemodynamic effects and the quality of analgesia of spinal anesthesia performed with 3 ml of either 0.125% (n = 12) or 0.5% (n = 13) plain bupivacaine in 25 elderly patients undergoing orthopedic surgery. The initial dose's duration of action (time elapsed between the end of injection and the first patient's complaint of pain during surgery) was shorter in the group receiving 3 ml of 0.125% plain bupivacaine than in the group receiving 0.5% plain bupivacaine: 80 +/- 31 minutes versus 114 +/- 37 minutes, respectively (mean +/- SD; p less than 0.05). In 6 (50%) of 12 patients of the 0.125% group and in 2 (15%) of 13 of the 0.5% group, analgesia became insufficient during the surgical procedure, necessitating injection of an additional 1 ml (top-up) of the previous solution. All subjects obtained good anesthesia for the entire procedure. The mean dose of bupivacaine necessary for the procedure was significantly lower in the 0.125% group (4.8 +/- 1.3 mg) compared with the 0.5% group (16.1 +/- 3 mg). For a similar maximal upper level of analgesia (T4-T12 in the 0.125% group versus T2-T10 in the 0.5% group), the decrease in systolic arterial pressure was more pronounced in the 0.5% group than in the 0.125% group during the period 15-40 minutes after induction of spinal anesthesia (p less than 0.05%). The mean dose of ephedrine was threefold larger in the 0.5% group than in the 0.125% group. Continuous spinal anesthesia with small amounts of 0.125% plain bupivacaine produces effective anesthesia for orthopedic procedures in elderly patients with minimal hemodynamic changes.


Failure of phenylephrine to prolong isobaric bupivacaine spinal anesthesia in elderly patients. The effects of phenylephrine on the duration of spinal anesthesia produced by plain bupivacaine were investigated in a double-blind study of 100 elderly patients. Each patient received a basic solution of 3 ml 0.5% plain bupivacaine to which was added either 1 ml physiologic saline, 0.2 ml (1 mg) 0.5% phenylephrine plus 0.8 ml normal saline, 0.4 ml phenylephrine plus 0.6 ml normal saline, 0.6 ml phenylephrine plus 0.4 ml normal saline, or 0.8 ml phenylephrine plus 0.2 ml normal saline. The duration of sensory block (measured by two- and four-segment regression times and times to regression to T12 and L2 dermatomes) was not statistically prolonged by addition of phenylephrine. It is concluded that, in an attempt to prolong plain bupivacaine spinal anesthesia, the addition of phenylephrine does not appear to be advantageous for routine clinical practice.


The addition of epinephrine to subarachnoid administered hyperbaric bupivacaine with fentanyl for cesarean delivery: the effect on onset time. This study examines the effect of epinephrine on the time to achieve a T4 sensory level when added to a hyperbaric bupivacaine-fentanyl mixture for spinal anesthesia. Sixty-nine healthy parturients scheduled for elective cesarean delivery were randomly assigned to three groups. All patients were given 9 mg hyperbaric 0.75% bupivacaine with 25 micrograms fentanyl. Group 1 received no epinephrine while Groups 2 and 3 received 100 micrograms and 200 micrograms epinephrine, respectively. Injection of the spinal anesthetic solutions was performed with the patient in the sitting position. Immediately after drug administration, patients were placed supine with their heads elevated on a pillow and 15 degrees of left uterine displacement was maintained. Vital signs and sensory levels were obtained every minute for 10 minutes. In Groups 2 and 3, the mean time to T4 sensory level was significantly longer (6.9 minutes and 6.6 minutes, respectively) than in Group 1 (4.6 minutes). As a subset, patients weighing more than 90.8 kg achieved a T4 sensory level faster than did those weighting less than 90.8 kg (3 minutes and 5.1 minutes, respectively), but in both groups epinephrine prolonged the onset time to T4 (5.8 minutes and 7.3 minutes, respectively). Three patients were excluded because of failure to obtain a T4 sensory level. The onset time to T4 is related inversely to patient weight, and epinephrine (100 micrograms and 200 micrograms) delays the onset of sensory block to T4 when administered with subarachnoid hyperbaric bupivacaine-fentanyl.


Effects of epidural bupivacaine or mepivacaine on somatosensory evoked potentials and skin resistance responses. The main purpose of this study was to compare the depth of neural block in lumbar epidural analgesia using either 20 mg/ml mepivacaine or 5 mg/ml bupivacaine. Sixteen healthy patients were randomly divided to receive blindly either 17.5 ml mepivacaine (median, 15-20) or 17.5 ml bupivacaine (median, 14-20) for lumbar epidural analgesia. Afferent block was assessed by somatosensory evoked potentials (SEPs) during electrical stimulation of cutaneous sensory nerves at the T10, L1, L4, and L5 dermatomes. Efferent block was assessed by skin resistance responses (SRRs) recorded from the hand (C6), T12-L1, and foot (L5). Upper level of analgesia (pin-prick, cold) was T4 (T1-11) in the mepivacaine group and T4-5 (T2-9) in the bupivacaine group. In the mepivacaine group, SEPs were abolished in seven of eight cases at the T10 stimulation level and in five of eight cases at the L1 level. In the bupivacaine group, SEPs were abolished in two of eight cases at the T10 level and in three of eight cases at the L1 level. At the L4 and L5 levels, SEPs were only slightly changed in both groups. In the mepivacaine group, SRRs were completely or almost completely blocked (0-35% of control values) in all of eight cases at both the T12-L1 level and in the foot. Corresponding values for bupivacaine were six of seven and five of eight, respectively. Skin resistance responses in the foot and hand were significantly (p less than 0.05) lower in cases with abolished SEPs at the T10 stimulation level compared with those cases with preserved (although reduced) SEPs. Twenty mg/ml mepivacaine produces a more complete neural block than 5 mg/ml bupivacaine. The responsiveness of the afferent and efferent limbs of the nervous system was blocked in a similar manner as was shown by depression of the SEPs and SRRs.


Analysis of human epidural pressures.

Analysis of human epidural pressures. During performance of epidural injection, entry into the epidural space has traditionally been determined by identification of negative pressure to the advancing needle by indirect means such as hanging drop; loss of resistance to air, saline, or water; or use of a MacIntosh balloon. Confusion in the literature regarding entry pressures versus postentry (baseline) pressures and zero reference pressure was noted. Baseline epidural pressure changes were examined using a closed system zeroed to the dorsal spine during and after injection of local anesthetics in 39 patients referred to the Pain Treatment Center, located at SUNY Health Science Center, Syracuse, New York, for epidural injections. The course of epidural pressure changes after injection and the temporal relation of epidural pressure waves to the arterial and venous wave forms were examined. In contrast to previous investigations, subatmospheric pressure was found in the epidural space in only one patient. Baseline pressure for all patients was 7.7 +/- 3.9 mmHg. There were significant differences in baseline pressure in patients who had undergone back surgery compared with patients who had not undergone such surgery: 11.8 +/- 3.4 as opposed to 7.0 +/- 3.5 mmHg, respectively (p less than 0.005). Three minutes after a 2-ml injection of local anesthetic into the epidural space, the pressure returned to baseline. This contrasted to the effects of a 6-ml injection, which resulted in the pressure remaining above baseline after 3 minutes. The epidural pressure wave forms more closely paralleled the radial artery wave form than the central venous pressure. Lumbar epidural pressure is greater than atmospheric pressure when referenced to zero at the dorsal spine level.


The resistance of the human dura mater to needle penetration. An aneroid manometer attached to a needle during lumbar puncture for spinal anesthesia was used to record the pressure in the epidural space, and an attempt was made to define the moment the needle contacted and indented the dura mater. By measuring the distance the needle travelled after contact with the dura and before its actual perforation, it was determined that the dura mater indents 2-6 mm. The finding indicated that the dura mater is relatively resistant to puncture.


Regional anesthesia for cataract surgery: comparison of retrobulbar and peribulbar techniques. METHODS. The features of retrobulbar and peribulbar blocks were compared prospectively in 300 patients undergoing elective, ambulatory cataract surgery. Both techniques were clinically applicable, but to achieve total akinesia of the eye muscles, an additional injection was needed in 13% of the patients with retrobulbar block and in 35% with periocular block. RESULTS. In younger patients (less than 65 years), the number of injections and the volume of the local anesthetic needed to produce a total akinesia of the eye were significantly higher when compared with the elderly.


Fentanyl and lidocaine versus lidocaine for Bier block. The present study was designed to assess the efficacy of fentanyl combined with dilute lidocaine solution for intravenous regional anesthesia of the arm. In ten volunteers, the nondominant arm was exposed to three treatments: 100 mg lidocaine, 42 ml; 100 mg lidocaine plus 100 micrograms fentanyl, 42 ml; and 100 micrograms fentanyl, 42 ml. Each subject was tested on three occasions with three or more days between experiments. Sensory and motor function was tested to determine whether the neural effects of the particular treatments differed. When lidocaine and lidocaine plus fentanyl results were compared, no significant differences were found. However, anesthesia, analgesia, and loss of motor function generally were less complete and slower in onset with the fentanyl alone treatment. Two subjects became nauseated after tourniquet cuff deflation when lidocaine plus fentanyl was tested, as did one subject when fentanyl was tested. Results of this and other studies indicate there is no value in adding fentanyl to local anesthetics for intravenous regional anesthesia.


Hemodynamic changes associated with tourniquet use under epidural anesthesia for total knee arthroplasty. Epidural anesthesia is administered commonly for total knee arthroplasty, a procedure using a thigh tourniquet. Tourniquet use has been associated with intraoperative hypertension and with occasional circulatory collapse after deflation. The purpose of this study was to define the hemodynamic changes in this setting. We prospectively studied 373 consecutive patients having a total knee arthroplasty performed under epidural anesthesia, with continuous electrocardiogram and radial artery pressure monitoring. Results were analyzed using Student's t-test, correlation coefficients, analysis of variance, or chi-square analysis. Alpha was set at 0.01. There was a 4 +/- 11 mmHg rise in mean arterial pressure throughout the period of tourniquet application (p less than 0.001); no clinically significant hypertension occurred. After tourniquet deflation, there was a 19.2 +/- 12% reduction in mean arterial pressure, occurring within one minute. The magnitude of mean arterial pressure reduction failed to correlate with any clinical parameter other than vasopressor use. There was a small subset of patients who had a fall in heart rate and a more profound degree of hypotension after tourniquet deflation, but these patients could not be identified before tourniquet release. In this setting, tourniquet-induced hypertension is rare. However, hypotension after deflation is common, occurs rapidly, and correlates poorly with clinical parameters.


Indirect sonographic guidance for epidural anesthesia in obese pregnant patients. Obesity and edema frequently obscure anatomic landmarks and result in technical difficulties during epidural anesthesia administration. However, the method of indirect sonographic guidance permits identification of the midline by sagittal scan of the laminae of lumbar vertebrae 2, 3, and 4. Thirty-six obese women scheduled for elective repeat cesarean delivery were prospectively studied. Use of a 5-MHz transducer positioned with the transducer center site over the second or third interspace allowed measurement of skin-to-lamina distance by the electronic calipers of a Toshiba SAL-32B or RT 3000 GE machine, prediction of needle depth for epidural puncture (EP), and skin marking of the site. After the transducer was removed, a 9.5- or 11.4-cm Tuohy needle was percutaneously advanced perpendicularly from the site until EP was achieved. Needle depth was measured by marker and measure, and epidural anesthesia was successfully administered to all patients. Simple linear regression analysis was performed with strong positive results. Indirect and continuous sonographic guidance studies designed to determine whether sonography reduces complications are planned.


Glucosamine oligomers: 4. Solid state-crystallization and sustained dissolution. When glucosamine oligomers are stored in the solid state they undergo a process of crystallization. The extent to which this occurs depends on whether the samples are isolated in the -NH3+ or -NH2 form, on the storage time, and on the degree of polymerization of the isolated oligomer. The allomorph obtained by this process seems to correspond to the so-called 'tendon-chitosan'. Dissolution of such aged oligomer samples gives rise to a process of dissociation of the associated chains in the crystal, leading to the establishment of a pseudo-equilibrium between single and associated oligomer chains and hence the simultaneous presence of the 'monomeric', 'dimeric', 'trimeric', etc., forms of the oligomer. The phenomenon cannot be attributed to a process of aggregation in solution. The effects of various parameters on this behaviour have been investigated.


Limited proteolysis of streptokinase and properties of some fragments. Limited proteolysis of streptokinase (Sk) by trypsin and thermolysin was performed under various incubation conditions and analysed by polyacrylamide gel electrophoresis. Several fragments (Sk1, Tr27, Tr17, Th26, and Th16) were isolated and characterized further. The N-terminal sequences of Tr27, Tr17, Th26, Th16 and the C-terminal sequences of Tr27 and Th26 were determined by partial sequencing. The evidence available allows the positioning of these fragments within the Sk sequence. Fragment Sk1 is obtained by carefully standardized tryptic digestion of Sk and gel chromatography under non-denaturing conditions. Sk1 is formed by a large polypeptide Ser60-Lys293 and non-covalently bonded smaller polypeptides composed of amino acids from the N-terminal region Ile1-Lys59 of Sk. Fragment Tr27 consists of the large polypeptide Ser60-Lys293 of Sk1, and can be obtained from Sk1 by removal of the smaller N-terminal polypeptides under denaturing conditions. Fragment Th26 is composed of amino acids Phe63-His291. The N-termini of fragments Tr17 and Th16 start with Glu148 and Ile151. From their electrophoretically-determined sizes it can be concluded that they most probably have the same C-terminal amino acids, Lys293 and His291, as fragments Tr27 and Th26, respectively. Secondary structure elements of similar composition were found in all the fragments studied using circular dichroism (c.d.) and infrared (i.r.) measurements. Differential scanning calorimetric (d.s.c.) measurements were performed in order to correlate the sequence regions of Sk to energetic folding units of the protein. Fragments Sk1, Tr27, Th26, Tr17, and Th16 show one melting peak in the temperature range from 42.8 to 46.1 degrees C (thermal unfolding stage). For fragment Sk1, this melting peak can be separated by deconvolution into two transitions at T1 = 46.1 degree C and T2 = 47.3 degrees C with delta H1 = 450 kJ/mol and delta H2 = 219 kJ/mol, respectively. Fragments Tr17 and Th16 show one two-state transition at T = 42.8 degrees C with delta H = 326 kJ/mol.


Biosynthesis of poly(3-hydroxyalkanoates) from threonine. A series of copolyesters of 3-hydroxybutyrate (3HB) and 3-hydroxyvalerate (3HV) was biosynthesized by Alcaligenes eutrophus from an amino acid, threonine. The 3HV content of these polyesters ranged from less than 0.1% to 30%.


Cross-linking and gel formation of water-soluble lysine polypeptides. An insolubilization model reaction for adhesive proteins. Insolubilizing studies of water-soluble synthetic polypeptides containing lysine residues were examined using organic aliphatic and aromatic cross-linking agents such as dialdehydes, diacyl chlorides and diactive ester, together with an enzyme tyrosinase, in water and simulated seawater systems. The cross-linking reaction was characterized by the viscosity and turbidity changes. Among the organic cross-linking agents used aliphatic glutaraldehyde and aromatic o-phthalaldehyde were the most effective. When excess organic cross-linking agents were added to the lysine polypeptide systems, the corresponding solid gels were formed. As a whole, the molecular weight of the samples, the amino acid compositions, the cross-linking agent used, the molar ratios between cross-linking agents and functional residues and system pH were found to have roles in the insolubilizing reaction and the gel formation. The cross-linking results obtained were compared with those of the polypeptide-tyrosinase systems, whose deep brownish red colour was decolorized by the addition of L-ascorbic acid.


Branched-chain analogues of linear polysaccharides: a spectroscopic and conformational investigation of chitosan derivatives. The solution properties and conformational features of 2-substituted propanoic acid (I) and 2-substituted pentanedioic acid (II) derivatives of chitosan were investigated over a wide range of pH by potentiometric, optical and chiroptical measurements, and by theoretical conformational analysis. No significant change is observed in the solution properties of I upon pH variations, in agreement with computational results showing that the conformational features of the polymer do not vary with respect to the charge state of the ionizable groups. In contrast, spectroscopic titration and preliminary 1H-n.m.r. data indicate that conformational equilibria in II are pH-dependent. Consistently, computed models show that both the charge state of the ionizable groups and the chirality of the carbon atom in the side chain control the structural features of the polymer.


Biosynthesis and n.m.r. studies of deuterated poly(3-hydroxybutyrate) produced by Alcaligenes eutrophus H16. Alcaligenes eutrophus H16 was grown on mixtures of 1H- and 2H-acetate as carbon sources. The accumulation of deuterated poly(3-hydroxybutyrate) (P(3HB)) was observed. The deuterium distributions in the isolated P(3HB)s were determined from 1H and 2H-n.m.r. spectra and confirmed by 13C-n.m.r. spectra. Although one would expect to synthesize P([2,2,4,4,4-2H5]3HB) when the cells were grown on 2H-acetate as the sole carbon source, the methyl, methylene and methine groups of the P(3HB) contained both deuterium and proton. This observation indicates some substitution from 2H to 1H during the P(3HB) synthesis. The 2H content in the methyl groups was larger than that in the methylene groups, which suggests a kinetic isotope effect in the P(3HB) synthesizing process. The deuterium distributions in the two magnetically non-equivalent methylene protons were determined to be different, which indicates stereoselectivity at the C2 site.


Molecular and crystal structure of (1----3)-alpha-D-glucan triacetate. A crystal and molecular structure for GTA I, the low temperature polymorph of (1----3)-alpha-D-glucan triacetate, is proposed on the basis of X-ray diffraction analysis of well-oriented films, combined with stereochemical model refinement. The unit cell is monoclinic with parameters a = 30.17 A, b = 17.42 A, c (fibre axis) = 12.11 A, and beta = 90 degrees C. The probable space group is P2(1) with b axis unique. Six molecular chains pass through the unit cell with alternating polarity and with three independent chains comprising the asymmetric unit. The chain axes are located in a hexagonal packing arrangement. The chain backbone conformation is a left-handed, three-fold helix, but all nine O(6) acetyl groups of the asymmetric unit are in non-equivalent rotational positions. The most probable structure is indicated by X-ray residuals R = 0.261 and R" = 0.283, based on 62 reflection intensities (41 observed and 21 unobserved).


The variability of cardiopulmonary adaptation to pregnancy at rest and during exercise. To examine the cardiopulmonary adaptation to normal pregnancy in sitting women during rest and bicycle exercise. A longitudinal study beginning early in pregnancy and ending 8-12 months after delivery. University Hospital, Zurich, Switzerland. 20 women were monitored every second week during pregnancy from 8 to 14 weeks gestation, twice in the puerperium and twice 6-8 weeks and twice 8-12 months after delivery. All the women finished the study, but not all of them participated in every visit. The results obtained 8-12 months after delivery are considered the non-pregnant data and are presented first so that any change in pregnancy will be more obvious. Values given below refer to the median except when stated otherwise. At rest: 1. Oxygen consumption increased significantly from a median of 182 ml/min in the non-pregnant state to 256 ml/min by 8-11 weeks gestation, and peaked at 300 ml/min at 32 weeks. At 6-8 weeks after delivery the value was 225 ml/min. 2. Oxygen consumption per kg increased significantly from 3.0 ml/min in the non-pregnant state to 4.3 ml/min by 8-11 weeks gestation and peaked at 5.0 ml/min soon after delivery. At 6-8 weeks after delivery the value was 3.4 ml/min. 3. Carbon dioxide production generally showed changes similar to those of oxygen consumption. 4. Respiratory quotient did not show any significant changes. 5. Ventilation increased from a median of 9.4 l/min in the non-pregnant state to 10.5 l/min by 8-11 weeks and then slowly increased to 12.6 l/min in late pregnancy. 6. Respiratory rate did not change significantly. 7. Tidal volume showed a median of 563 ml in the non-pregnant women and rose significantly to 632 ml in early pregnancy, peaking at 715 ml in late pregnancy. 8. Alveolar ventilation increased significantly from a non-pregnant value of 3.4 l/min to 6.2 l/min in early pregnancy, peaking at 6.7 l/min at term; 6-8 weeks after delivery the value was 4.5 l/min. 9. Ventilation equivalent for oxygen fell significantly from the median non-pregnant value of 52 to 42 in early pregnancy and remained at that level until 6-8 weeks after delivery when it was 44. 10. Ventilation equivalent for carbon dioxide showed similar changes to those for oxygen. 11. Alveolar carbon dioxide tension fell significantly from a median non-pregnant level of 4.6 kPa (34 mmHg) to 4.0 kPa (30 mmHg) in early pregnancy. It began to increase in the puerperium and was 4.3 kPa (33 mmHg) 6-8 weeks after delivery. 12. Mixed venous carbon dioxide tension fell significantly from a median of 5.9 kPa (44 mmHg) to 5.2 kPa (39 mmHg) during pregnancy. 13. Transcutaneous carbon dioxide tension decreased significantly in early pregnancy from 8.8 kPa (66 mmHg) in the non-pregnant women, and from 20 weeks gestation remained at 6.9 kPa (52 mmHg). 14. Transcutaneous oxygen tension showed a non-significant increase from 10.0 kPa (75 mmHg) in the non-pregnant women to 11.1 kPa (83 mmHg) during pregnancy. 15. Cardiac frequency increased gradually from a non-pregnant median of 80 b.p.m. to about 90 b.p.m. in the last 2 months of pregnancy. In the puerperium the median was 75 b.p.m. 16. Cardiac output increased significantly by almost 50% from the non-pregnancy level to that at 8-11 weeks gestation. 17. Cardiac output per kg also increased significantly by 50% from the non-pregnant level to that at 8-11 weeks gestation. From mid-pregnancy there was a gradual fall until delivery. 18. Stroke volume increased significantly from a median of 31 ml in the non-pregnant state to 51 ml in early pregnancy, and remained at this level until delivery. In the puerperium the stroke volume was 63 ml. 19. Oxygen pulse increased significantly from a median of 2.2 ml in the non-pregnant women to 3.1 ml in early pregnancy and remained at that level. 20. Individual curves.(ABSTRACT TRUNCATED AT 400 WORDS)


Assembly and transport of MHC class II molecules. At the surface of antigen-presenting cells MHC class I and class II molecules present peptides to respectively CD8+ and CD4+ T cells. MHC class I molecules acquire peptides right after synthesis in the endoplasmic reticulum. MHC class II molecules do not acquire peptides in the endoplasmic reticulum but instead associate with a third chain, the invariant chain which impedes peptide binding. Subsequently the invariant chain takes MHC class II molecules to the endosomal/lysosomal compartment thanks to a targeting signal retained in its cytoplasmic tail. It then dissociates from the MHC class II dimer to allow it to bind peptides.


Proline isomerases at the crossroads of protein folding, signal transduction, and immunosuppression. The immunosuppressants cyclosporin A (CsA), FK506, and rapamycin block T-cell activation by interfering with signal transduction. The institution of CsA therapy for prophylaxis against graft rejection revolutionized human organ transplants, and clinical trials with FK506 and rapamycin are in progress. The targets for these drugs, cyclophilin for CsA and FKBP for FK506 and rapamycin, are members of two unrelated families of ubiquitous, highly conserved, abundant proteins. Although unrelated, both cyclophilin and FKBP catalyze proline isomerization and may fold proteins. The structures of both cyclophilin and FKBP have been determined, in some cases in complex with drugs or substrates. The cyclophilin-CsA and FKBP-FK506 complexes prevent T-cell response to antigen, bind and modulate the activity of the protein phosphatase calcineurin, and prevent nuclear import of a subunit of NF-AT, a T-cell activation transcription factor. In contrast, rapamycin blocks T-cell responses to IL-2. Yeast genetic studies suggest that the FKBP-rapamycin target is a protein complex involved in cell cycle progression. Further studies should provide fundamental insights into T-cell activation, signal transduction, and protein folding, and hold the promise of more specific immunosuppressive therapies.


Dynamics of the Dictyostelium cytoskeleton during chemotaxis. Movement and chemotaxis are fundamental processes of cells and tissues and are based on the dynamics of the cytoskeleton. The cellular slime mold Dictyostelium discoideum is an excellent model system with which to study the molecular components and the key reactions that are required for a coordinated locomotion of single cells or a cell mass during development. The D. discoideum cytoskeleton relies mainly on the equilibrium between monomeric and filamentous actin and, like other nonmuscle cells, contains a large number of actin-binding proteins that either decrease or increase the rigidity of the microfilament system. The proteins themselves are regulated by phosphorylation, Ca2+, phospholipids, and/or pH and thus are targets for the intracellular changes that occur upon stimulation of a cell with chemoattractant. In a synopsis of the data published during the past years, the properties of numerous cytoskeletal components and the biochemical reactions of the signal transduction chain are combined here in a schematic model that attempts to explain how the directed movement of a cell could be coordinated at the molecular level.


Signal transduction cascade shared by epidermal growth factor and platelet-derived growth factor is a major pathway for oncogenic transformation in NRK cells. We have isolated two recessive, mutually complementary NRK cell mutants that are refractory to transformation by epidermal growth factor (EGF) and transforming growth factor-beta. Both mutants are defective in a signal transduction cascade shared by EGF and platelet-derived growth factor (PDGF). Analysis of the mutants suggests that transformation of NRK cells by the v-fms, v-erbB, activated erbB-2, v-ras, v-fos, v-mos, v-fes, v-src, SV40 large T, polyomavirus middle T, and human papillomavirus type 16 E6,E7 oncogenes is mediated by the EGF/PDGF signal cascade. The data also suggest that the EGF/PDGF cascade branches into mitogenic and oncogenic signals, the latter of which is required for soft agar growth and focus formation.


Oncogenic signal-induced ability to enter S phase in the absence of anchorage is the mechanism for the growth of transformed NRK cells in soft agar. Upon neoplastic transformation, cells acquire the ability to grow in soft agar. We investigated how this occurs by cell cycle analysis of a rat cell line NRK-49F and its transformation-deficient mutants. Rapidly growing NRK and mutants arrest in G1 when deprived of anchorage by suspending in methylcellulose. Addition of epidermal growth factor (EGF) together with transforming growth factor-beta (TGF-beta), which is highly oncogenic to NRK, induces the rapid progression of G1-arrested NRK cells into S phase. The time course and the extent of synchronization are very similar to the cell cycle progression in the presence of anchorage. EGF alone, which is highly mitogenic but only slightly oncogenic, fails to induce such progression. Both mutants remain arrested in G1. These data indicate that oncogenic signals confer on NRK the ability to enter S phase in the absence of anchorage and that this is the principal mechanism for its ability to grow in soft agar.


Analysis of the DNA binding and transcriptional activation properties of the Ets1 oncoprotein. The c-ets1 gene product (Ets1) is the prototype of a family of sequence-specific transcriptional activators which have been implicated in various developmental processes and in the response of cells to a variety of extracellular stimuli. We report here a structure-function analysis of the DNA binding and transcriptional activation properties of Ets1. The minimal region required for specific DNA binding is located at the carboxy-terminus of Ets1, a domain highly conserved in all known members of the Ets family. Transcriptional activation by Ets1 in mammalian cells requires an additional domain of 110 amino acids characterized by a high content of acidic residues and localized in the amino-terminal half of the protein. This domain also functions as a transcriptional activation domain in yeast cells when linked to the heterologous DNA binding domain of Gal4. In contrast to its conservation in Ets1 proteins across vertebrate species, this activation domain is not conserved in other members of the Ets family. These results indicate that an important level of specificity between different members of the Ets family may reside in the differential interactions of their respective activation domains with distinct general transcription factors or different associated coactivators.


Context rules of rightward overlapping reading. We have investigated the mechanism and sequence context rules governing ribosome frameshifting promoted by aminoacyl-tRNA limitation. In the case of one shifty sequence, frameshifting promoted by lysyl-tRNA limitation occurs at the sequence AAG C and is due to rightward movement of the ribosome so as to read the AGC triplet overlapping the hungry codon from the right. The frequency of this event is unaffected by sequence elements more than three bases to the left (upstream) or two bases to the right (downstream) of the hungry codon, and only slightly affected by the identity of the base two bases to the right. It is strongly affected by the base immediately to the right of the hungry codon, which becomes the wobble base of the shifted triplet; and by the third base of the hungry codon, even though the two synonyms (AAG and AAA) call for the same aminoacyl-tRNA; and by the identity of the base immediately to the left of the hungry codon. The latter result suggests that the aminoacyl-tRNA in the P site affects the maintenance of reading frame at the adjacent A site of the ribosome. However, the DNA sequence makes it seem unlikely that the P-site tRNA shifts to the right in concert with the A-site tRNA, a mechanism that can account for leftward frameshifting (in the opposite direction) in retroviral translation. The specificity of sequence determinants of leftwing versus rightwing frameshifting is discussed.


Regulation of HTLV-I gene expression by tax and AP-2. The HTLV-I transactivator protein tax activates expression of both viral and cellular genes. In addition it has been demonstrated to repress expression of the DNA beta-polymerase gene. We wished to investigate potential interactions between tax and the cellular transcription factor AP-2 which binds to distinct motifs in each of the three 21-bp repeat sequences in the HTLV-I LTR. First we demonstrate that AP-2 is capable of activating HTLV-I gene expression. Cotransfection experiments reveal that AP-2 and tax are capable of inhibiting each other's ability to activate HTLV-I gene expression. The mechanism of this inhibition was studied by gel retardation analysis using both bacterial and in vitro synthesized AP-2 and tax proteins. These results indicate that tax inhibits the ability of AP-2 to bind to the 21-bp repeat. Mutational analysis of both tax and AP-2 demonstrate that the amino termini of both proteins are potential sites of interaction. These results are consistent with a model in which AP-2 and tax can potentially form protein complexes resulting in an altered ability of each factor to modulate HTLV-I gene expression.


Activation in vivo of the minimal replication origin beta of plasmid R6K requires a small target sequence essential for DNA looping. The plasmid R6K contains three distinct origins of replication: alpha, beta, and gamma. The gamma sequence is essential in cis and acts as an enhancer that activates the distant alpha and beta origins. R6K therefore represents a favorable procaryotic model system with which to unravel the biochemical mechanisms underlying selective origin activation, particularly activation involving distant sites on the same chromosome. We have discovered that plasmids containing the origins alpha and gamma required the Escherichia coli DnaA initiator protein in addition to the R6K-encoded initiator protein, Pi, and other host replisomal proteins for their maintenance in vivo. Plasmids initiating replication from origin beta required only the Pi initiator protein and other host replisomal proteins. We have exploited the differential requirement for the DnaA protein by origins gamma and beta to selectively study and localize the minimal origin beta sequences by deletion analysis as one test of a looping model of origin activation. A 64-bp region spanning the extreme -COOH terminal coding sequence of the Pi protein was found to be essential for replication in vivo in the absence of DnaA protein, consistent with the approximate physical location of the beta origin. Replication emanating from origin beta could be abolished in vivo by deletion of the 9-bp target site for Pi protein-mediated DNA looping between the gamma origin/enhancer and the distant beta origin. Electron microscopy of nascent replication intermediates generated in vivo directly confirmed our genetic localization of the beta origin. Our results strongly suggest that activation of the beta origin by a distant replication enhancer element requires a small target sequence essential for initiator protein-mediated DNA looping.


In situ lacZ retrovirus-marked lymphocytes define a B cell microenvironment in the lymph node medulla. A recombinant nonreplicating retroviral vector bearing the Escherichia coli lacZ indicator gene was used to mark a population of B cells in situ in murine lymphoid tissue. The retrovirus was surgically injected into popliteal lymph nodes during the primary immune response to DNP-CGG when B cell proliferation in the germinal centers was maximal. LacZ+ cells were initially detected in the perivascular medullary interstitium, where they expanded and persisted up to 2 weeks following retrovirus injection. Migrant lacZ+ B cells were detected in the spleen 3-18 weeks following immunization and resided in the red pulp or marginal zones. Two-color flow cytometric analysis using a fluorogenic substrate for beta-galactosidase revealed that lacZ+ cells bear kappa light chains and that at least 50% of these cells bound the hapten, DNP. Based on their location, life span, migratory capacity, antigenic specificity, and surface immunoglobulin density, lacZ+ cells define a distinct nonfollicular B cell population associated with other late developmental stages of B lymphocytes, including memory and plasma cells.


Effects of recombinant human interleukin-1 alpha on clonogenic growth of primary human tumors in vitro. Interleukin-1 alpha (IL-1 alpha) is a low-molecular-weight cytokine that regulates proliferation and differentiation of lymphatic and myeloid cells. It also has pleiotropic activity on a variety of other target cells and acts as an important mediator of inflammation and septic shock. Recombinant human IL-1 alpha (rhIL-1 alpha) is undergoing clinical evaluation of its potential as an anticancer agent. We have studied the growth modulating effects of rhIL-1 alpha on a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. Final concentrations of 0.01-100 ng/ml were used in continuous incubation experiments. Of 139 specimens tested, 56 (40%) were evaluable for determination of tumor growth modulating activity. The most common tumor types examined included breast, nonsmall cell lung, ovarian, colorectal cancer, and melanoma. Stimulation of tumor colony-forming units (colony formation greater than or equal to 1.5 x controls) was observed in only 1/56 (2%) tumors. No evidence was found for increased size of individual colonies after incubation with rhIL-1 alpha. At a concentration of 100 ng/ml, colony formation of 9/56 (16%) tumor specimens was significantly inhibited (colony formation less than or equal to 0.5 x controls). We conclude that rhIL-1 alpha is not a major modulator of tumor colony formation in vitro. However, some antitumor effects may be observed at high concentrations.


In vitro and in vivo effects of recombinant human interleukin-2 in naive miniature swine. Recent data in mice have shown that early administration of recombinant human interleukin-2 (rIL-2) provides significant protection from lethal graft-versus-host disease. Because of the potential clinical importance of these findings, it will be important to assess the effectiveness of this therapy in a large animal preclinical bone marrow transplantation model. We report here our initial studies of the in vitro and in vivo effects of rIL-2 in miniature swine. In vitro 4-day cultures of pig peripheral blood lymphocytes (PBL) in complete medium containing rIL-2 at 1,000 U/ml resulted in optimal proliferation and generation of lymphokine-activated killer (LAK) cells. A pig-mouse hybridoma cell line was found to be highly sensitive as a LAK cell target. Two naive pigs received 20,000 U/kg and 2 pigs received 100,000 U/kg of rIL-2 intravenously twice a day for 4 days. No clinical symptoms were seen during or after administration at the lower dose while both high dose-treated animals showed generalized erythema from days 2 to 4, and one showed mild diarrhea during this period. The disappearance of IL-2 activity from the serum showed two components: (1) an initial fast component with a half-time of approximately 10 min and (2) a slow component with a half-time of approximately 60 min. LAK cell precursors disappeared from the peripheral circulation by 6 min after rIL-2 administration and began to recover by 6 h in the low dose recipients and only after 12 h in the high dose recipients.(ABSTRACT TRUNCATED AT 250 WORDS)


A Southwest Oncology Group Phase I study of the sequential combination of recombinant interferon-gamma and recombinant interleukin-2 in patients with cancer. Thirty-seven patients with advanced malignancies were treated sequentially with recombinant interferon-gamma (rIFN-gamma) and recombinant interleukin-2 (rIL-2) in an outpatient dose escalation clinical trial. rIFN-gamma (0.1 or 0.25 mg/m2/day) was administered by intramuscular injection, days 1-7 and rIL-2 (12, 18, or 24 x 10(6) IU/m2/day) was administered by a 15-min intravenous bolus, days 8-12. Common toxicities encountered included fever, chills, fatigue, neutropenia, and elevations of SGOT, bilirubin, or creatinine. Hypotension and cardiac and pulmonary toxicities were rare. With repeated cycles of therapy, nausea/vomiting and diarrhea associated with the administration of rIL-2 were seen in greater frequency. There were no treatment-related deaths, and no patient required intensive care unit admission for toxicity management. A complete response was observed in one of 11 patients with renal cancer and a partial response was observed in one of seven patients with malignant melanoma. Due to problems with drug supply, further dose escalation could not be continued, and maximum tolerated doses (MTD) were not determined by strict criteria. However, the combination of rIFN-gamma, 0.25 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day, appeared to be beyond the MTD, as three of six patients at this dose level could not complete one cycle of therapy due to toxicity. It is unlikely that higher doses of either agent would be tolerated, and for further study using this schedule, we recommend the doses: rIFN-gamma, 0.1 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day.


Renal cell carcinoma treated with continuous-infusion interleukin-2 with ex vivo-activated killer cells. High-dose recombinant interleukin-2 (rIL-2) results in tumor responses in patients with metastatic renal cell carcinoma ranging from 9 to 31%. Continuous infusion regimens of rIL-2 may be less toxic and may result in greater in vivo lymphokine-activated killer (LAK) cell production. The current trial used a continuous infusion of rIL-2 with ex vivo LAK cells. These cells were pretreated with phenylalanine methyl ester to remove monocytes to allow cell culture at higher concentrations. Twenty-three patients were entered into the trial. Two patients had complete responses (9%) lasting 15+ and 20+ months. Four patients had partial responses (17%) of 9+, 6+, 3, and 3 months, respectively. One partial responder at 9+ months had only minimal residual retroperitoneal disease that may represent scar tissue. All responders had prior nephrectomies. All but one of the responding patients completed a full cycle of rIL-2 at the highest (starting) dose, 6 x 10(6) U/m2. This rIL-2/LAK regimen appears to be an effective therapy for metastatic renal cell carcinoma.


Enhancement of lymphokine-activated killer activity induction in vitro by interleukin-1 administered in patients with urological malignancies. We have evaluated the synergistic effects of interleukin-1 (IL-1) and interleukin-2 (IL-2) on the induction of lymphokine-activated killer (LAK) activity. Subcutaneous injection of recombinant IL-1 beta at an initial dose of 1 x 10(4) U was given to nine patients (five with renal cell carcinoma, two with bladder carcinoma, one with renal pelvic tumor, one with testicular tumor) on days 1 and 2 weekly for 4 weeks. The dose was increased weekly up to 4 x 10(4) U, if it was well tolerated. Peripheral blood mononuclear cells (PBMC) were isolated from patients on day 3 in the 2nd and 4th weeks, and LAK activity of PBMC against Daudi cells was measured using a 4-h 51Cr-release assay at an effector:target cell ratio of 20:1, after incubation with 50 U/ml of recombinant IL-2 for 72 h. Proliferation of PBMC was measured by tritiated thymidine incorporation after incubation with IL-2 for 72 h. IL-2 receptor (IL-2R)-positive cells in PBMC were enumerated using monoclonal antibody and flow cytometry. Mean values of LAK activity induced by IL-2 were significantly augmented after administration of IL-1 beta (p less than 0.01). IL-1 beta, however, did not enhance proliferation of PBMC caused by IL-2, nor did it increase the number of IL-2R-positive cells in peripheral blood lymphocytes of the patients. Results suggest that combination of IL-1 and IL-2 has synergistic antitumor activity in treatment of malignant diseases.


Adoptive immunotherapy with activated macrophages grown in vitro from blood monocytes in cancer patients: a pilot study. Ninety-three collections of leucocytes by cytapheresis followed by separation of monocytes by centrifugal elutriation were undertaken in twelve metastatic cancer patients (four melanomas, six colon carcinomas, one ovarian carcinoma, and one lung cancer). The leucaphereses were performed aiming to collect a product, ready for introduction into the elutriation chamber, i.e., with low contamination by erythrocytes and granulocytes. The median collection of leucocytes was 7.3 x 10(9). After elutriation, purified monocytes (mean: 0.91 x 10(9)) were cultured with 3-5% autologous serum for 7 days in the presence of 250 IU/ml of recombinant human gamma-interferon (Rh-IFN gamma) for the last 18 h of culture. The median number of activated macrophages (MAK) available for reinfusion was 2.4 x 10(8) for each culture. The phenotypes and the antitumoral potentiality of MAK cells were documented. Reinfusions performed i.v. or i.p. were well tolerated with no major side effects. No complete tumor response was obtained. One partial response and two stabilizations of the disease were observed in one melanoma and two colon carcinomas.


Interleukin-2 in association with increasing doses of interferon-gamma in patients with advanced cancer. Twenty-seven patients with evaluable metastatic cancer were treated with recombinant interleukin-2 (rIL-2) and escalating doses of interferon gamma (IFN-gamma). rIL-2 was infused over a 15 min period at a constant dose (8 x 10(6) IU/m2/8 h x 5 days first cycle, and 8 x 10(6) IU/m2/12 h x 5 days second and third cycles, with 9 days rest between each cycle). IFN-gamma was started 4 days before each cycle of rIL-2 and was given every other day at a dosage of 1 x 10(6) U/m2 x 3/cycle (four patients), 5 x 10(6) U/m2 x 3/cycle (four patients), 5 x 10(6) U/m2 x 5/cycle (four patients) and 10 x 10(6) U/m2 x 5/cycle (15 patients). Common side effects were fluid retention and hepatic toxicity (27 and 15% grade greater than or equal to 2); one ischemic chest pains and one acute respiratory distress occurred. Toxicities were not greater than those described with high dose rIL-2 alone and were similar in each dose level of IFN-gamma. No patient died from the procedure. Four patients responded, one complete response and three partial responses; all were treated with 25 or 50 x 10(6) U/m2/cycle of IFN-gamma (melanoma, two patients; renal cell carcinoma, one patient; lymphoma, one patient). Further phase II studies at these dosages are justified to precisely define the antitumoral efficacy of this association.


Reversible cardiomyopathy after high-dose interleukin-2 therapy. We observed two patients who developed moderate global myocardial dysfunction during therapy with high-dose interleukin-2 (IL-2). Although cardiac enzymes became markedly elevated at the completion of a full course of IL-2, patients exhibited no ischemic symptoms. Serial echocardiography documented global myocardial dysfunction, which resolved in 5 days in one patient but persisted beyond 4 weeks in another. Asymptomatic reversible myocardial injury can occur with high-dose IL-2 and can persist beyond 4 weeks after stopping therapy. Review of the literature suggests an IL-2-associated myocarditis as an etiology.


Quality of nursing worklife issues--a unifying framework. This article describes a theoretical view of the many variables that influence nurses' worklife. It summarizes the national perspective and the provincial initiatives undertaken during the last decade that focus on issues of nursing worklife. The authors present a model that unifies the many dimensions that must be examined in studying this important problem. Nurse administrators will find this review valuable as a guide to research and practice initiatives associated with quality of working life.


The economic crisis and nursing.

The economic crisis and nursing. As Federal and Provincial governments wrestle with the economic crisis, Ministries of Health in every province are frantically and systematically introducing actions and major reforms to curb escalating health care expenditures. The reforms that are being introduced with an alarming speed are less of a threat to nurses than they are to doctors. The impending battles over professional turf will ultimately shape the nature and design of the new systems. This crisis constitutes an opportunity for nurses to become engaged in the reform process and thus shape the health care delivery system to their advantage.


Overview of nursing research in health care within the current economic context. This is an overview of nursing research findings in the following areas: forecasting the need for nursing personnel; evaluating the effectiveness of nursing care; and, costing nursing services. The author suggests the models for forecasting the need for nursing person power require further development and should incorporate more of the multitude of intricate factors that impact on nursing and the demands for care. Research in nursing case costing, workload measurement systems and the cost effectiveness of nursing care are also addressed in leading to the conclusion that there is an urgent and timely need for more nurse researchers to examine all of these complex nursing issues in relation to the whole health care system and thus be ready and in position to influence health policy and costs.


Utilization review and management: a primer. URM, HIS, HMRI, DRG's, CMG'S, RIW's, etc. At the fall 1990 National Congress on Utilization Review and Management in Edmonton, Dennis Psutka referred to these as "alphabet soup". It is probable that many front line managers find many of these terms and abbreviations confusing, if not overwhelming. Intended as a primer, this manuscript will: define the key terms and concepts in utilization review and management; explain their interrelationships; and discuss why it is important for nurse managers to understand and use them, as the entire health care system struggles to achieve more with fewer resources.


Mechanical circulatory support and heart transplantation. Mechanical circulatory support systems are currently in clinical use to keep patients alive with the aim of either cardiac recovery after open heart surgery, myocardial infarction and after heart transplantation with acute graft failure, or as a bridge to transplantation in heart transplant candidates. At the German Heart Institute the "Berlin Heart" mechanical circulatory support system has been used invariably since 1987. Up to 1991 there were 22 patients in the "recovery" group. Four patients could be weaned from the system, but only one patient was discharged from the hospital. In 65 patients mechanical circulatory support systems were implanted as a bridge to transplantation, 39 patients had transplants, and 22 patients left the hospital. Risk factor analysis in the bridging group revealed that previous heart surgery, infective pneumonia, shock-related coagulation disorders, and an age greater than 50 years had an unfavorable influence on patient survival. It is concluded that patients may be kept alive for weeks and months after any kind of cardiogenic shock. Complete cardiac recovery may be achieved in the case of early posttransplant graft failure. Reliable prediction of outcome in the bridge to transplantation group requires further experience.