The challenge of follow-up for clinical trials of somatic gene therapy.

Although extensive efforts have been made to optimize the safety of vectors for somatic gene transfer and somatic gene therapy, the safety of these agents must ultimately be assessed in clinical trials. A statistically significant assessment of safety will be complicated by the relatively small number of patients who will be enrolled in initial clinical trials, the need for long-term longitudinal follow-up of patients and perhaps their progeny, and the traditionally poor participation in long-term follow-up by many patients. This article reviews the potential risks of retroviral-mediated gene transfer, the statistical power required to assess the true incidence of potential complications, the number of patients who may participate in clinical trials involving retroviral vectors, and the factors that make thorough follow-up and uniform data ascertainment difficult. The role of the FDA in assessing the safety of retroviral vectors and the potential role of registries for patient tracking and data ascertainment are discussed.


Diarrhoea in Australian Aborigines.

Infectious diarrhoea has been recognised as a serious public health problem for Aboriginal Australians, particularly infants and young children, for more than two decades. These diseases are caused by bacterial, viral and parasitic infections which are spread mainly by the faecal-oral route and which must be interrupted if prevention is to be effective. This paper reviews published reports on this subject and interventions which have been used elsewhere to reduce the incidence of infectious diarrhoea. These reports have important implications for Aboriginal health but interventions and strategies to overcome this problem must recognise the unique circumstances of Aboriginal people in Australia.


The cost of cervical cancer screening provided by a women's health nurse.

This study examines the cost of cervical cancer screening provided by a women's health nurse. Methods used to estimate the cost of taking a Pap smear were based on the economic principle of opportunity cost. Techniques for estimating the magnitude of some costs were developed specifically for this study because the cost of taking a Pap smear had to be isolated from the costs of other services provided by the women's health nurse. The cost of taking a Pap smear in 1989 was estimated to be between $17.68 and $17.95. A sensitivity analysis was carried out so that the results of this study could be adapted for practices which differ from the women's health nurse's practice in the Mount Druitt and Hawkesbury area of New South Wales. As a result of this analysis, the cost of taking a Pap smear ranged from $14.16 to $38.88, depending on whether the women's health nurse was a Clinical Nurse Consultant or Clinical Nurse Specialist, the number of Pap smears taken, the proportion of clients who come for postnatal examinations, length of consultations and the distance travelled. It should be noted that the cost of taking a Pap smear would rise considerably above $38.88 for women's health nurses working in remote areas.


Estimates of the number of injecting drug users in a defined area.

Three estimates of the number of injecting drug users residing within the Eastern Sydney Area Health Service (ESAHS) were obtained by applying the capture-recapture technique to data from three reliable sources, specifically, Methadone Services, the Bourke Street Drug Advisory Service and the Albion Street Clinic. The obtained estimates were 3449, 3046 and 1103 respectively. Statewide methadone statistics were also used to obtain an estimate of 15,082 injecting drug users in New South Wales. This estimate was close to the linearly projected estimates (14,274 and 14,416) from two previous studies. Estimates based upon the methadone statistics indicate that approximately 23% of injecting drug users in New South Wales reside within the ESAHS. A sensitivity analysis was performed to assess the effects on the estimates of the likely violation of the closed population assumption.


Teenage pregnancy and fertility in New South Wales: an examination of fertility trends, abortion and birth outcomes.

This paper reviews the data available in New South Wales on teenage fertility rates and pregnancy outcomes. Teenage births comprise six per cent of all births in New South Wales, but they constitute a significant public health problem because they are associated with elevated rates of adverse pregnancy outcomes, which include low birthweight, perinatal death and pre-eclampsia. Risk is concentrated in females under 18 years of age. Pregnancy outcomes for females aged 18 to 19 years are similar to those of women aged 20 to 24 years. Teenage fertility rates have remained stable since the mid-1980s, following a decline which began in the early 1970s. There are large geographic variations in teenage fertility within the state, with the highest rates in the far west of New South Wales and in western Sydney. Teenage pregnancy in New South Wales (as distinct from fertility which reflects births) cannot be assessed accurately because of the lack of information on terminations of pregnancy. However, available data suggest that teenage pregnancy rates have not increased during the 1980s.


Indoor nitrogen dioxide and childhood respiratory illness.

Nitrogen dioxide is produced from the combustion of fossil fuels and as an emission from gas-fired appliances, and is also a component of tobacco smoke. Nitrogen dioxide has been shown in experimental animals to be toxic to the respiratory tract. A n number of recent studies have suggested that children exposed to significant levels of nitrogen dioxide in the home may be more susceptible to respiratory illness than children exposed to normal ambient levels. Respiratory illness is a major cause of morbidity in children everywhere. Here, we review the available evidence of this association and explore methodological issues in measurement of nitrogen dioxide exposure--misclassification of subjects, symptom bias and confounding. It has recently been shown that some New South Wales school rooms, where unflued gas heaters are often used as a source of warmth, have nitrogen dioxide levels which are above recommended ambient levels for outside air. This has underlined the need for setting standards for indoor levels of various pollutants, and cohort studies are suggested, to include personal monitoring and prospective data collection techniques.


Mortality from respiratory system cancer in New South Wales and Sydney.

Differential and spatial analyses of respiratory system cancer were undertaken for New South Wales and Sydney for the period 1980-1986. The source of data was death certificate information on the unit list mortality file tapes provided by the Australian Bureau of Statistics. Characteristics of persons dying included age, sex, birthplace, occupational status and cause of death (ICD9 classification). The aim was to identify populations at risk from respiratory system cancer, and where they were located. Deaths were disaggregated for the abovementioned categories by cross-tabulation at the state level and for geographical areas having populations with higher levels of respiratory cancer mortality. Never-married males of lower occupational status had higher rates of respiratory cancer, mainly lung cancer. Divorced men also had higher mortality as did widowers who were in lower occupational status work, while married men in managerial work also had significantly high mortality. The marital status variation was mostly not found with females, although significantly high female mortality was found in several low socioeconomic status areas of Sydney. Mortality of both sexes was significantly higher in metropolitan Sydney than in the rest of New South Wales and associations between older age mortality and some industrial areas were found in Sydney.


Carbon monoxide exposure in blast furnace workers.

This study investigated the occupational exposure to carbon monoxide (CO) of a group of blast furnace workers from an integrated steelworks, compared to a control group having no significant occupational CO exposure from other areas in the same works. The study was undertaken in 1984 at Port Kembla, New South Wales. Carboxyhaemoglobin (COHb) levels before and after an eight-hour work shift were measured in 98 male steelworkers: 52 from two CO-exposed iron blast furnaces and 46 controls from production areas in the same steelworks. The sample was stratified by smoking habits. Environmental air CO levels had been found to be consistently higher on one furnace than on the other. Absorption of CO from the working environment occurred in workers on the blast furnace with higher CO levels, regardless of smoking habits. On this blast furnace, some readings of COHb levels after a workshift in nonsmokers approached the proposed Australian occupational limit of 5 per cent COHb saturation. Overall, workers with the highest occupational exposure who smoked most heavily had the highest absorption of CO over a work shift. Biological monitoring gives an accurate measure of individual worker 'dose' of CO from all sources. Both environmental monitoring and biological monitoring need to be included as part of a program for controlling occupational CO exposure.


Human factors in rural road crashes.

An in-depth study of 79 vehicle crashes on rural roads in an area of about 100 km radius around Adelaide examined sociodemographic and psychophysiological characteristics of the drivers and riders involved. In many respects this sample of crashes was similar to a much larger number of police-reported crashes in the same area but included: relatively more crashes with severe or fatal injuries; more crashes on divided roads, on sealed roads and on curves; and more crashes involving trucks. Alcohol and lack of seat belt use were shown to be major problems in these rural crashes. The drivers and riders most strongly associated with these particular problems were males, in blue collar occupations and with limited education; they tended to be aged 30 years or more in the case of alcohol abuse, and were likely to be under 30 years in the case of restraint misuse. The attitudes of these drivers and riders, and other characteristics likely to have contributed to their involvement in a crash, are discussed. There is a need to develop specific and effective countermeasures to reduce drink-driving and increase seat belt wearing in rural areas.


Compliance with dietary goals in a Queensland community.

Dietary goals designed to improve nutritional health and lower the risk of chronic disease have been drawn up in Australia. Compliance with quantified goals was assessed in a random sample of 91 residents of Nambour, a typical community in southeast Queensland. Compliance was highest for alcohol and cholesterol goals. About three-quarters of the sample complied with the goal of limiting alcohol intake to five per cent of energy intake, and over half complied with the goal to limit daily cholesterol intake to less than 300mg. Compliance was lower for total fat and fibre goals. About 40% of the sample complied with the goal of consuming less than 33% of energy as fat or the goal of consuming 30g or more fibre per day. Compliance was slightly better for women than for men. Only a small proportion of the sample complied with goals to increase total carbohydrate intake to 55% or more of energy, or to limit saturated fatty acid intake to 10% of energy. For each of the goals, some were far from complying. In general, compliance with goals was lowest for males under 40 and was also low for women under 40.


Hearing loss--an underestimated public health problem.

Estimates of hearing loss in Australia, collected over the last decade and a half, have reported a prevalence rate ranging from 0.1 to 7 per cent. This survey of a random sample of South Australians provides, depending upon definition, two estimates of 15 and 19 per cent. These data suggest that hearing loss has been underestimated as a public health problem. The need for an epidemiological study which measures actual hearing impairment, which can be used to develop an appropriate public health response, is discussed.


Arthritis outpatients: disability, pain and alcohol use.

There is a small body of literature describing investigations into the relationships between pain and disabling conditions and alcohol consumption. Of these few studies, most have concluded that pain and disability are positively associated with alcohol consumption, though these particular studies have not been methodologically rigorous. Arthritis is the most prevalent of the disabling conditions, and one of the major symptoms of arthritis is pain. Several factors associated with the disease are thought to make arthritis sufferers particularly vulnerable to the use of alcohol for its mind-altering and analgesic properties. In the present study, conducted in 1987, a sample of 154 Perth arthritic outpatients were interviewed to investigate the relationship between pain, disability and alcohol consumption. Results showed that pain and disability scores were very weak predictors of volume of weekly alcohol consumption for males, but the relationship was in a negative direction. Results from a previous study were confirmed in the finding that being an ex-drinker was a predictor of a higher disability score for females. Fewer patients were drinkers than in the population at large and fewer drank at the level of the highest consumption category. However, the proportions of male and female patients drinking above NHMRC low risk levels were the same as the general population (age-standardised comparison). Most who considered themselves current drinkers said that alcohol did not help their pain, stiffness or weakness. Various possible explanations are offered for these results and recommendations for future research are presented.


Paying for efficiency: what price the quality of hospital care?

Economic recession prompts governments and health service ministers to seek increased efficiency in the production of hospital services in order to reconcile increasing demands with scarce resources. As one approach to the problem, the National Health Strategy is recommending pilot schemes, similar to those which have been introduced in both the United Kingdom and the Netherlands, which involve the separation of purchaser from the provider of hospital services. It is argued that such separation, with the introduction of competition between providers of hospital services for contracts placed by publicly funded Area Health Boards, will increase efficiency and accountability in the use of resources. However, this argument ignores the hospital management's ability to keep costs down by altering the quality of hospital care in ways which are difficult to monitor by purchasing agencies. The article considers the effects the introduction of managed competition is likely to have on the quality of hospital services. The outcome is uncertain and competition may improve some dimensions of quality while jeopardizing others. If managed competition is tried in Australia, the opportunity should also be taken to examine its impact on the quality and outcomes of hospital care.


An outbreak of measles in the Hunter area of New South Wales.

An outbreak of measles occurred in 1990 in the Port Stephens Shire of New South Wales. The incidence of confirmed cases of measles and associated histories of immunisation are detailed by age for the period 24 June 1990 to 31 December 1990. Data were obtained from health and education professionals and from interviews with parents. Among the 158 cases were 116 school pupils, 82 of whom attended two large primary schools which had attack rates of 9.4 per cent and 4.1 per cent. The cases also included 29 persons who had been appropriately immunised. Inadequate immunisation coverage was seen as the principal cause of the outbreak in the Port Stephens Shire. Observance of institutional protocol was regarded as a principal impediment to disease counter-measures in a neighbouring measles-affected area. Regulated immunisation of young children and cooperative interaction among service providers could ultimately lead to the control of this serious disease in New South Wales.


Socioeconomic correlates of mortality and hospital morbidity differentials by Local Government Area in Sydney 1985-1988.

To determine the magnitude of differentials in mortality and hospital morbidity by Local Government Area (LGA) in Sydney (1985-1988), and to correlate these with LGA indicators of socioeconomic status. Cross-sectional group-based comparative study of mortality and hospital separations, and a group-based correlations analysis in relation to socioeconomic indicators. Mortality--life expectancy at birth, infant mortality, 0- to 4-year mortality, age-standardised 15- to 64-year mortality (all-cause and various causes), sex-specific (except infant and 0- to 4-year mortality). Hospital morbidity rates--0- to 4-year hospital separations, age-standardised 15- to 64-year hospital separations (all-cause and various causes), sex-specific. Census-derived LGA proportions of immigrants, Aborigines, professionals, unskilled workers, unemployed persons, those with a university degree and those having no qualifications, and the composite Ross Indicator. Considerable differences in mortality and hospital morbidity by LGA in Sydney were found. Males had higher mortality and lower rates of hospital separation than females. LGA differentials were most obvious for adults, with little variation noted for infants or children. Most socioeconomic indicators were highly correlated with adult mortality and hospital morbidity in the expected direction, particularly indicators of low socioeconomic status. The unemployment rate, proportion Aboriginal, proportion unskilled, proportion unqualified, and the Ross Indicator were the most highly correlated variables. There are persistent differentials by LGA in mortality and hospital morbidity in Sydney which are strongly associated with socioeconomic status. The Ross Indicator was found to be a useful composite indicator. The high correlations of mortality and hospital morbidity with the unemployment rate raise the question of to what extent this is due to illness and premature mortality in the unemployed. Monitoring of health status differentials needs to continue if progress towards Health For All targets is to be evaluated.


Socioeconomic status and mortality revisited: an extension of the Brisbane area analysis.

Using the methodology of an earlier study of socioeconomic mortality gradients, we partitioned Brisbane City into five strata of equal size on the basis of suburb scores derived from aggregate socioeconomic census data. Numbers of deaths by stratum, age, sex and cause were obtained from mortality files. For almost all causes, mortality gradients had not changed between 1976-1979 and 1980-1987. A new category, medically-preventable death under age 65, had lower rates in higher-ranking suburbs. Potential years of life lost (PYLL) per unit of population, age-standardised, were also computed by stratum and cause. External causes of death were the main contributors to PYLL among men, with a strong socioeconomic gradient, while neoplasms were most important among women, with little evidence of a social class effect. It is estimated that, in urban Australia, the annual number of additional deaths under age 65 due to socioeconomic circumstances is over 2000 for males and over 1000 for females. This study provides a baseline against which the programs of health advancement initiated in the mid-1980s may be evaluated, or conversely, the effects of societal changes assessed.


A note on sex-specific mortality and social class in Sydney, 1979 to 1983.

Simple indicators such as education, income, occupation, and employment status are often used to adjust for social class in studies of morbidity or mortality. The effect of social class on such outcomes can be different for men and women. In population-based studies, residential area may be the only means of assessing social class. This study investigated sex differences in the association between mortality between 1979 and 1983 and several area indices of social class--percentage with a degree, percentage professional, percentage blue collar, percentage unemployed, percentage with annual income greater than $40,000, and the composite indicator constructed by the Australian Bureau of Statistics. Thirty-seven Sydney statistical local areas were ranked for men and women separately according to the indicators and standardised mortality ratios. Correlations between the indicators and mortality were all negative and stronger for men than for women. The composite indicator and percentage unemployed correlated most strongly with mortality. There was a moderate correlation between the remaining indicators and mortality for men, but only a weak correlation for women. The results suggest that the use of simple area indicators may be inadequate to classify the social class of women, and that the unemployment rate in those over 35 years of age may be a reasonable alternative to the composite indicator for the purpose of social class adjustment in mortality studies.


Media sources of HIV/AIDS information in injecting drug users.

We report on media habits of 797 members of a sample of 1245 injecting drug users interviewed in Sydney, Australia. While preferred hours of television viewing and radio listening were similar to those of the general population, the preferred channels and stations were different. These findings could assist in targeting injecting drug users with information about HIV/AIDS prevention. However as the self-regulatory advertising process has constrained broadcast and publication of overt messages directed at homosexual and bisexual men, similar restrictions may prevent optimal mass media approaches to educating this other important group at risk of HIV infection.


[Effect of anesthesia and operation on essential immune functions].

Study of the references listed leaves no doubt that essential specific and unspecific immune functions are more or less strongly influenced by a wide variety of anaesthetics. In clinically employed concentrations these negative effects are rapidly and completely reversible. No clinically relevant adverse actions on the immune system have ever been identified in short-term anaesthesia with any substance, not even with the thiobarbiturates although these are known to be highly inhibitory. However, matters are entirely different in respect of highly dosed long-term sedation. In such cases, it may occur with e.g. thiobarbiturates or diazepam that in the course of days or weeks concentrations are attained in the tissue which may lead us to expect in vivo quite considerable suppression of both unspecific and antigen-specific cellular immune mechanisms. This expectation, which is first of all based on in-vitro results, has been indirectly supported by a clinical study in patients suffering from craniocerebral trauma who received artificial respiration and in whom an association was seen between thiopental administration and the incidence of bacterial pneumonias. Over and above this, however, the preoperative condition of the patient and of course mainly the operation as such with its associated stress reaction will cause direct and indirect changes in the immune system (Fig. 4). Trauma and anaesthesia exert not only a direct action, but act as inhibitors or stimulators of important immune functions chiefly by modulating the stress response. We are still unaware as to whether and to what extent the prognosis of the individual patient is actually adversely affected by the combined action of these factors. Many findings, however, seem to point to an essential role played by both the surgical trauma and the stress response it induces, as well as by the pre-operative immune status of the patient, in the occurrence of subsequent infectious complications (Fig. 4).


[Spinal anesthesia for surgery of inguinal hernia in infants at risk for respiratory complications. Initial experiences with 12 patients].

11 former premature babies born at a mean gestational age of 32 weeks (range 27-34 weeks) and one baby born at term with congenital diaphragmatic hernia scheduled for inguinal hernia repair were selected to receive a spinal anaesthesia after informed written consent was obtained from one of the parents. At birth, 10 infants were intubated and received assisted ventilation; the remaining two were on nasal CPAP for 24 hours after birth. The mean post-conceptual age of the former premature infants on the day of surgery was 39 weeks (range 36-43 weeks), the mean weight was 2.2 kg (range 1.8 to 3.6 kg). One boy with congenital diaphragmatic hernia who was intubated for 19 days after birth aged 4 months on the day of operation and weighed 5.3 kg. None of the children was oxygen-dependent on the day of surgery. Spinal anaesthesia was performed in 3 children in the lateral decubitus and in 9 children in the sitting position. In each group, there was one case when spinal anaesthesia could not be performed due to a bloody spinal tap. These children received general anaesthesia, one of them in combination with a caudal block. The 9 former premature received 0.6 ml isobaric bupivacaine 0.5%, and the child born on term with diaphragmatic hernia 0.8 ml isobaric bupivacaine 0.5%. The onset of the motor blockade in the former preterm infants was within 60-90 seconds, while in the older child the onset was 10 minutes. With the given dose, the operation could be performed without any problems.(ABSTRACT TRUNCATED AT 250 WORDS)


[Effect of the volatile anesthetics halothane, enflurane and isoflurane on liver circulation in the human].

In 40 patients with normal liver function total hepatic blood flow (HBF) was determined by the indocyanine-green clearance method simultaneously with haemodynamic parameters, including cardiac output by means of the noninvasive thoracic electrical bioimpedance method. Furthermore, the influence of halothane, enflurane or isoflurane on HBF and the interaction with haemodynamic parameters was studied. HBF and the cardiocirculatory parameters were determined under normal conditions (waking state) and the 40 patients were then divided into 4 groups (each n = 10). After standardised induction of anaesthesia (0.3 mg/kg etomidate and 2 micrograms/kg fentanyl) and tracheal intubation (1.5 mg/kg suxamethonium chloride) an inhalation anaesthesia in O2/air under control of normal end tidal carbon dioxide concentration was performed by intermittent positive pressure ventilation. Anaesthesia was maintained in the 4 groups either with 1 MAC halothane, 1 MAC enflurane, 1 MAC isoflurane or 1.3 MAC isoflurane. The measurements were repeated at a steady of the desired end expiratory concentration of the respective volatile anaesthetic. All three anaesthetics produced a significant and comparable decrease of cardiac output and arterial blood pressure. Differences between halothane, enflurane and isoflurane in respect of haemodynamic parameters were only minimal. Contrariwise, marked differences could be seen in the effects of the anaesthetics on HBF. In the presence of halothane and enflurane HBF dropped to 58% and 56% resp. of the control value, whereas during isoflurane anaesthesia HBF remained unchanged. Furthermore, only during halothane anaesthesia a significant correlation between arterial blood pressure and HBF could be observed indicating a loss of autoregulation of the hepatic blood flow.


[Changes in cerebral metabolism and cerebral blood flow caused by halothane and isoflurane in increasing concentrations].

The results of two studies on the effects of halothane and isoflurane in increasing end-tidal concentrations (0.25; 0.5; 1.0vol%) on the cerebral metabolic rate for oxygen and the cerebral blood flow are compared. Both studies were performed on baboons using the same experimental model. Cerebral blood flow was determined from a washout curve after the intracarotid injection of 133xenon. Halothane and isoflurane led to a dose-dependent decrease of the cerebral metabolic rate for oxygen. Increasing concentrations of halothane caused a decrease of cerebral oxygen consumption from 3.4 +/- 0.8 (baseline) to 2.9 +/- 0.8 (0.25vol%), 2.7 +/- 0.7 (0.5vol%) and 2.4 +/- 0.4 mlO2 100 g-1min-1 at 1.0vol%. The administration of isoflurane reduced the cerebral oxygen consumption significantly from baseline 3.7 +/- 1.0 to 2.9 +/- 0.9 at 0.25vol%, 2.6 +/- 0.6 at 0.5vol% and 1.8 +/- 0.8 mlO2 100 g-1min-1 with 1.0vol%. A significant, dose-independent reduction of the cerebral blood flow from 55.8 +/- 8.0 to 46.3 +/- 10.2 (0.25%) to 44.6 +/- 9.5 (0.5vol%) and 44.5 +/- 10.2 ml 100 g-1min-1 (1.0vol%) was observed with halothane. However, a dose-dependent decrease in calculated cerebrovascular resistance was seen at 1.0vol% of halothane. If mean arterial pressure was kept within the normal limits of cerebrovascular autoregulation by the administration of angiotensin-II-amid during 1.0vol% of halothane a marked increase in cerebral blood flow above the baseline value was observed. The lacking increase in cerebral blood flow observed at 1.0vol% of halothane without blood pressure support appeared to be caused by the low cerebral perfusion pressure rather than by vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)


[Massive natriuresis and polyuria after triple craniocervical subarachnoid hemorrhage: cerebral salt wasting syndrome?].

A thirty-year-old male patient suffered subarachnoidal haemorrhage from an angioma positioned in the cranio-cervical transition. After rebleeding twice the patient developed a hydrocephalus internus malresorptivus and excessive natriuresis and polyuria, accompanied by depressed renin activity and extremely low aldosterone plasma levels. Neither fluid restriction and sodium substitution, nor administration of hydro-chlorothiazide/indomethacin affected natriuresis and polyuria. It was only after treatment with fludrocortisone-acetate/hydrocortisone that hyponatraemia and polyuria were resolved. At the same time a ventriculo-peritoneal shunt was applied. Differential diagnosis excluded the syndromes of inadequate antidiuretic hormone secretion, renal and cerebral diabetes insipidus, osmotic receptor hypofunction, chronic renal dysfunction and tubular necrosis. Natriuresis and polyuria developed under dexamethasone therapy. Since patient history, physical examination and laboratory criteria could not explain the electrolyte and fluid imbalance, this might be attributed to the hydrocephalus. Similar disturbances have been reported from other patients with intracranial disorders. Mechanical pressure exercised on the hypothalamus might cause the disturbance of fluid and sodium balance. Assuming a cerebral salt wasting syndrome, a putative natriuretic factor coming from the brain or an imbalance in the cerebral renin-angiotensin-system, as described in rats and dogs, must be discussed.


Is continuous ambulatory peritoneal dialysis adequate long-term therapy for end-stage renal disease? A critical assessment.

The significant growth in the continuous ambulatory peritoneal dialysis (CAPD) population and the recent interest in the quantitation of dialysis delivered have stimulated much work in the field of kinetic modeling, correlation between model parameters and clinical outcome, and comparison between the long-term benefits of hemodialysis and peritoneal dialysis. A critical assessment of the long-term results of CAPD therapy is made on the basis of clinical results and recent experience with kinetic models including urea and creatinine. The significant differences between the hemodialysis and CAPD techniques have generated hypotheses to allow comparison between the two groups using similar kinetic models. Although CAPD has proven beneficial in the initial treatment of large numbers of patients with ESRD, there is concern about the adequacy of CAPD as long-term therapy for many patients. Prospective, long-term studies applying solute kinetic modeling are necessary to establish the adequacy of CAPD.


Insulin resistance, hyperinsulinemia, and obesity-associated hypertension.

Recent work to elucidate the cause of obesity-associated hypertension has focused on insulin resistance and hyperinsulinemia. A significant amount of epidemiologic and correlational evidence suggests a link between these factors and obesity-associated hypertension, and acute insulin infusion studies have revealed renal, neural, and cardiovascular effects of this hormone that, if maintained chronically, could cause hypertension. However, correlations and acute effects may not reliably predict a chronic cause-and-effect relationship, and the fundamental question of whether chronic increases in plasma insulin concentration per se can produce a sustained increase in arterial pressure has not been completely resolved. Recent studies designed to address this question directly have found no evidence of a hypertensive effect of insulin in normal dogs, or in dogs with a 70% reduction in kidney mass and given a high sodium intake. Chronic hyperinsulinemia also did not potentiate the pressor effects of angiotensin II or norepinephrine. In fact, hyperinsulinemia caused significant reductions in total peripheral vascular resistance in dogs and a decrease in arterial pressure. Furthermore, induction of insulin resistance in dogs made obese by being fed a high-fat diet eliminated the decrease in peripheral vascular resistance during chronic insulin infusion but did not uncover a pressor effect of hyperinsulinemia. In contrast, insulin infusion for up to 7 days produced a sustained increase in arterial pressure in rats. Although the mechanism for this pressor response is unknown, these data indicate either that there are major species differences in the chronic blood pressure response to insulin or that specific, presently unknown, conditions must exist in order for insulin to raise blood pressure. Also, it is not clear whether humans respond more like rats or dogs with respect to blood pressure changes during chronic hyperinsulinemia. However, it is apparent that obesity hypertension is probably much too complex to be ascribed to insulin resistance and hyperinsulinemia alone.


Effects of hyperglycemia on glucose transporters of the muscle: use of the renal glucose reabsorption inhibitor phlorizin to control glycemia.

Individuals with non-insulin dependent or insulin-dependent diabetes mellitus present insulin resistance in peripheral tissues. This is reflected in a subnormal whole body insulin-dependent glucose utilization, largely dependent on skeletal muscle. Glucose transport across the cell membrane of this tissue is rate limiting in the utilization of the hexose. Therefore, it is possible that a defect exists in insulin-dependent glucose transport in skeletal muscle in diabetic states. This review focuses on two questions: is there a defect at the level of glucose transporters in skeletal muscle of diabetic animal models, and is this a consequence of abnormal insulin or glucose levels? The latter question arises from the fact that these parameters usually vary inversely to each other. Glucose transport into skeletal muscle occurs by two membrane proteins, the GLUT1 and GLUT4 gene products. By subcellular fractionation and Western blotting with isoform-specific antibodies, it was determined that isolated plasma membranes (PM) contain GLUT4 and GLUT1 proteins at a molar ratio of 3.5:1 and that an intracellular fraction (internal membranes; IM) different from sarcoplasmic reticulum contains only GLUT4 transporters. The IM furnishes transporters to the PM in response to insulin. Both transporter isoforms bind cytochalasin B in a D-glucose-protectable fashion. In streptozocin-induced diabetes of the rat with normal fasting insulin levels and marked hyperglycemia, the number of cytochalasin B-binding sites and of GLUT4 proteins diminishes in the PM whereas the GLUT1 proteins increase to a new ratio of about 1.5:1 GLUT4:GLUT1. In the IM, the levels of GLUT4 protein drop, as does the cellular GLUT4 mRNA. To investigate if these changes are associated with hyperglycemia, glucose levels were corrected back to normal values for a 24-h period with sc injections of phlorizin to block proximal tubule glucose reabsorption. This treatment restored cytochalasin B binding, restored GLUT4 and GLUT1 values back to normal levels in the PM, and partly restored cytochalasin B binding but not GLUT4 levels in the IM, consistent with only a partial recovery of GLUT4 mRNA. It is concluded that GLUT4 protein in the PM correlates inversely whereas GLUT1 protein correlates directly with glycemia. It is proposed that the decrease in GLUT4 levels is a protective mechanism, sparing skeletal muscle from gaining glucose and experiencing diabetic complications, albeit at the expense of becoming insulin resistant.(ABSTRACT TRUNCATED AT 400 WORDS)


Unusual causes of peritonitis in patients undergoing continuous peritoneal dialysis with emphasis on Listeria monocytogenes.

Peritonitis remains a significant cause of morbidity in ESRD patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Staphylococcus species, Streptococcus species, and less commonly, gram-negative rods comprise the majority of isolated organisms. Other organisms, including unusual bacteria, fungi, and mycobacteria, comprise 5% or less of cases. Many of the uncommon causes of CAPD peritonitis have been reviewed, with special emphasis on antimicrobial therapy and whether catheter removal was required. The presumed third case of CAPD-associated peritonitis caused by Listeria monocytogenes is also described. In contrast to two other reported cases, our patient was not overtly immunosuppressed. L. monocytogenes infection should therefore be considered in CAPD patients with gram-positive rod peritonitis, even if immunocompetence is presumed.


Extrarenal clearance of oxalate increases with progression of renal failure in the rat.

Oxalic acid is an end product of metabolism, and no significant degradation of oxalate occurs in mammals. The sole route of oxalate excretion is believed to be via the kidney. The extrarenal clearance of oxalate in control rats (N = 16) and in 5/6 nephrectomized rats (N = 25) with renal insufficiency was investigated. [14C]oxalic acid, approximately 2 microCi/day, was infused sc by a mini osmotic pump over 4 days. Excretion of 14C was measured in urine, in feces, and in expired CO2. The 14C content of kidney, heart, liver, muscle and bone was also determined at the time the animals were killed. Plasma oxalate was determined by an enzymatic method and by an isotopic dilution procedure. Creatinine clearance in the controls was 1.82 +/- 0.1 mL/min (mean +/- SE) compared with 0.31 +/- 0.04 mL/min (P < 0.0005) in the nephrectomized rats. Plasma oxalate was 5.6 +/- 0.6 mumol/L in controls and 27.0 +/- 3.9 (mean +/- SE; N = 24) in nephrectomized animals (P < 0.0005). The total 14C recovered in urine, feces, and CO2 combined was similar in both groups. The 14C excreted in the feces over the 4-day period was 27.8 +/- 1.5% (of the 14C recovered) in rats with renal failure and 6.5 +/- 0.5% in controls (P < 0.0005). Percent fecal 14C excretion in nephrectomized rats was inversely correlated with creatinine clearance (r = 0.80; P < 0.0001) and directly correlated with plasma oxalate (r = 0.66; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of epidermal growth factor in the rat 5/6 renal ablation model.

Acute administration of epidermal growth factor (EGF) has been shown to promote recovery from ischemic and nephrotoxic acute renal failure in vivo. The question of whether chronic subcutaneous administration of EGF (19.1 micrograms/day for 3 or 6 wk) could alter the course of chronic renal failure in rats subjected to 5/6 nephrectomy was studied. By week 6, there was no difference in renal function, as assessed by animal survival, BUN, urea and inulin clearances, proteinuria, renal morphometry, or renal size, between EGF- and vehicle-treated rats. This suggests that chronic renal insufficiency differs from acute tubular injury in its sensitivity to exogenous EGF. Unexpectedly, EGF significantly attenuated the rise in systolic blood pressure that occurred by the fourth week after 5/6 nephrectomy. The antihypertensive effect of EGF was still evident at week 5. Urinary flow rate, free water clearance, and excretion of total solutes, Na+, and K+, however, were not significantly altered by EGF at weeks 2, 4, 5, or 6, suggesting a mechanism other than increased natriuresis or diuresis for this antihypertensive effect.


The effect of uninephrectomy on progression of renal failure in autosomal dominant polycystic kidney disease.

The evolution of renal failure was compared in 47 patients (21 male, 26 female) with autosomal dominant polycystic kidney disease (ADPKD) in Germany, France, Spain, and Portugal who had undergone uninephrectomy (UNX) (median age at uninephrectomy, 41 yr; range, 22 to 54) and 47 non-UNX matched controls. UNX was usually performed because of uncontrolled urinary tract infection (N = 30), stones (N = 8), trauma (N = 2), or hemorrhage (N = 7). Median serum creatinine at UNX was 2.1 mg/dL (0.9 to 4.3). Twenty-eight of the 47 uninephrectomized patients progressed to end-stage renal failure. When the age at renal death was evaluated by survival analysis, only minor and nonsignificant acceleration was seen in the uninephrectomized patients (median, 50 yr; p25 = 43.6 yr; p75 = 58.3 yr, where p is the percentile) compared with non-UNX patients matched for age, sex, and serum creatinine at the time of UNX in the propositus (51.2 yr; p25 = 48.6 yr; p75 = 56.1 yr). In addition, the median interval for serum creatinine to rise from 4 to 8 mg/dL was similar in UNX (21.3 months) versus nonuninephrectomized ADPKD patients (21.9 months). Renal survival differed in the two genders. In females, no significant difference of age at renal death was found between UNX (median age, 51.6 yr) and non-UNX ADPKD patients (53.7 yr). In male UNX patients, age at renal death was slightly (but not significantly) less than in non-UNX patients (median age, 47.3 versus 52.7 yr). All male patients reaching end-stage renal failure before age 44 were severely hypertensive.


Comparison of continuous ambulatory peritoneal dialysis and hemodialysis patient survival with evaluation of trends during the 1980s.

To evaluate the mortality of continuous ambulatory peritoneal dialysis (CAPD) patients relative to hemodialysis (HD) patients, all Michigan residents 20 to 59 yr of age who initiated therapy for ESRD during the 1980s (N = 4,288) were studied. The study population was stratified by primary renal diagnosis (glomerulonephritis, hypertension, diabetes, other), and analyses were conducted within each group by Cox proportional hazards methods controlling for age, race, sex, and year in which chronic dialysis was initiated. Intent-to-treat (ITT) and treatment history (RxHx) censoring criteria were used. For patients with hypertension or other reported causes of ESRD, there was no significant difference in CAPD and HD patient mortality (relative risk (RR) = 0.99 and 1.05, respectively). In the ITT analysis, both glomerulonephritic (RR = 0.73; P = 0.10) and diabetic patients using CAPD experienced mortality rates lower than their HD counterparts. Among diabetics, this difference ranged from a RR of 0.40 to 0.70, being lowest for younger diabetics and statistically significant (P < or = 0.05) for ages 20 to 52 yr. Evaluation of mortality trends showed a significant (P < 0.01) decrease in diabetic CAPD mortality rates during the decade, whereas diabetic HD mortality rates increased (P = 0.06). Among diabetics, men had higher mortality rates than women (ITT--RxHx; RR = 1.22 to 1.27; P < 0.001) and white patients had higher mortality rates than black patients (ITT--RxHx, RR = 1.34 to 1.44; P < 0.001). Differences in mortality by sex and race were not found among nondiabetics, but mortality did increase significantly with age in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Increased lipoprotein(a) concentrations in chronic renal failure.

Subjects with chronic renal failure have a greatly increased risk of coronary heart disease and dyslipidemia. Relatively few studies have examined the relationship of chronic renal failure to lipoprotein (Lp)(a) concentrations, an important risk factor for coronary heart disease. Diabetic subjects have been reported to have both increased Lp(a) concentrations and an increased risk of renal failure, thereby possibly confounding the Lp(a)-renal failure association. The association between Lp(a) and chronic renal failure in 359 control subjects and 111 subjects with renal failure was examined. Lp(a) (in milligrams per deciliter) was elevated in subjects with chronic renal failure, regardless of ethnicity (Mexican Americans, 19.8 +/- 2.7 versus 14.1 +/- 1.3; P = 0.03; non-Hispanic white patients, 24.9 +/- 3.0 versus 16.3 +/- 1.2; P = 0.006;). These differences persisted after adjustment for diabetes and ethnicity (P < 0.001). The type of treatment for chronic renal failure (diet, hemodialysis, or peritoneal dialysis) did not have an effect on Lp(a) concentrations. Lp(a) levels were not correlated with the level of creatinine in subjects with chronic renal failure. Thus, the elevation of Lp(a) levels in renal failure must occur early in renal failure, or alternatively, elevated Lp(a) levels may promote progression to chronic renal failure. These results indicate that Lp(a) concentrations are increased in chronic renal failure and may increase the risk for coronary heart disease in these subjects.


Clusterin production in the obstructed rabbit kidney: correlations with loss of renal function.

Clusterin, a protein associated with cell death, has been suggested as a marker of renal injury. Correlation of clusterin gene expression with changes in renal function and quantitative measurement of clusterin protein levels after ureteral obstruction have not been previously reported. With unilateral ureteral obstruction in rabbits as the experimental model, the time course of alterations in renal function, clusterin mRNA accumulation, and concentrations of clusterin protein in serum, urine, and renal tissue were investigated. RBF, GFR, and renal concentrating ability (percent sodium reabsorption and urine osmolarity) all decreased (P < 0.05) in the obstructed kidney from control values within 1 day of ureteral obstruction. Clusterin mRNA levels started to rise in the ipsilateral kidney within 12 h of ureteral obstruction and increased up to 10-fold above control levels after 3 days of obstruction. Hybridization histochemistry showed that clusterin mRNA was initially detectable in collecting ducts and distal tubules within 12 h of ureteral obstruction. After 7 days of obstruction, increased accumulation of clusterin mRNA was also detectable in proximal tubular epithelial cells. Clusterin gene expression remained elevated in collecting ducts after 60 days of obstruction. Clusterin expression in the contralateral kidney was increased twofold over control values after 12 h of obstruction. No increase in clusterin mRNA accumulation was detectable after 24 h in the contralateral kidney. Total clusterin protein in the obstructed kidney increased from 0.59 +/- 0.66 (mean +/- 1 SD) to 2.5 +/- 1.3 micrograms after 7 days of ureteral obstruction (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Interaction of complement and clusterin in renal injury.

Clusterin is a heterodimeric glycoprotein that has been associated with such diverse biologic functions as reproduction, cell regression, cell aggregation, and regulation of the cytolytic activity of the membrane attack complex of complement. Clusterin is a component of glomerular immune deposits in the kidney, and increased clusterin expression occurs in a number of renal injury states. To further explore the interaction between clusterin and complement, the requirement for an intact complement system for renal clusterin induction in an acute (folic acid nephropathy) and a chronic (subtotal renal ablation) model of renal injury was examined. After it was first demonstrated that folic acid increased renal clusterin mRNA in the rat, a species in which renal clusterin was highly inducible by other stimuli, the effects of folic acid (250 mg/kg ip) on clusterin mRNA and immunoreactivity were examined in mice sufficient and deficient for the fifth component of complement. Similar increases in clusterin mRNA and immunoreactivity were seen in both the C5-sufficient and C5-deficient mice compared with their respective vehicle-injected control groups. Renal clusterin mRNA was also increased to a similar extent in the remaining kidney of both C5-sufficient and C5-deficient mice 10 days after subtotal nephrectomy. In conclusion, the induction of clusterin after folic acid administration or subtotal nephrectomy was independent of the presence of an intact complement system, because similar increases in clusterin expression were observed in C5-sufficient and C5-deficient mice.


Spatial learning impairments in rats with selective immunolesion of the forebrain cholinergic system.

A monoclonal antibody to the low-affinity NGF receptor, 192 IgG, coupled to a cytotoxin, saporin, was recently introduced as an efficient selective neurotoxin for the NGFr-bearing cholinergic neurones in the rat basal forebrain. In the present study we report that an intracerebroventricular injection of this 192 IgG-saporin conjugate induces a severe, long-lasting spatial learning impairment, as assessed in the Morris water-maze task. This behavioural impairment was associated with 65-90% depletion of choline acetyltransferase activity (ChAT) in the hippocampus and cortex. ChAT activity associated with other cholinergic neurone systems in the brain (striatum, mesencephalon, spinal cord), was left virtually unaffected. This new immunotoxin holds great promise as a tool for selective and efficient lesions of the forebrain cholinergic system in functional and behavioural studies.


Effects of paroxetine on 5-HT-induced head twitches and phosphatidylinositol hydrolysis in mice.

Head-twitch response and phosphatidylinositol (PIP) hydrolysis in cortex and spinal cord were measured after single or chronic (21 days) administration of paroxetine to normal mice or to mice neonatally treated with 5,7-dihydroxytryptamine, a serotonergic neurotoxin. In normal animals, a down-regulation of 5-HT-receptor numbers after chronic paroxetine was suggested by the attenuation of head-twitch responses compared with a single dose. There was a concomitant decrease in PIP hydrolysis. In DHT-treated animals, although changes in behavioural responses were comparable to those in normals, PIP hydrolysis in cortex and spinal cord after chronic paroxetine increased significantly. These results demonstrate that head-twitch responses and PIP hydrolysis may not be mediated by the same receptor and that the effects of chronic administration of paroxetine depend on the functional state of the serotonergic pathways.


Effects of TRH-T on spinal motoneurones in man.

The effect of thyrotropin-releasing hormone tartrate (TRH-T) on the decrease in H Max/M Max ratio, an index of the spinal motoneurone pool, induced by haloperidol, was studied in 15 healthy volunteers. In all subjects, the H response was examined by an electromyographic apparatus. The values were expressed as H Max/M Max ratio, that gives an index of excitability of the spinal motoneurone pool. It was found that the mean H Max/M Max ratio value significantly decreased after haloperidol administration, but this effect was completely reversed by the injection of TRH-T. This finding suggests that the peptide may modulate motoneurone functions.


Effects of the 5-HT1A agonist 8-OH-DPAT on food intake in food-deprived rats.

The effects of 8-OH-DPAT were investigated on food intake in food-deprived rats in both non-operant and operant feeding paradigms. 8-OH-DPAT produced dose-related reductions in food intake in both paradigms. While the higher doses of 8-OH-DPAT used in this study (i.e. 125-500 micrograms kg-1) produced a number of stereotyped behaviours which may have interfered with normal feeding, these behaviours were not apparent with the lower doses (i.e. 15.625-62.5 micrograms kg-1) which also depressed food-intake. The results of this study thus suggest that the inhibitory effect of 8-OH-DPAT on feeding in food-deprived rats is not secondary to the induction of stereotypy.


Blockade of natural and neuropeptide Y-induced carbohydrate feeding by a receptor antagonist PYX-2.

Neuropeptide Y (NPY injected into the paraventricular nucleus (PVN) of rats has a potent stimulatory effect specifically on carbohydrate intake. This study examined the behavioral effects of a newly synthesized NPY antagonist, PYX-2. After PVN injection of PYX-2 (50-900 pmoles) alone, a strong dose-dependent reduction in spontaneous carbohydrate intake at the onset of the dark cycle was observed in freely-feeding rats. Moreover, at even lower doses (12.5 and 25.0 pmoles), PYX-2 also blocked the stimulatory action of PVN NPY (100 pmoles) on carbohydrate ingestion. These results provide the first evidence for the existence of endogenous NPY receptors in mediating the action of exogenous NPY in the hypothalamus. They also constitute a crucial step in demonstrating a physiological function of these PVN NPY receptors specifically in controlling carbohydrate ingestion at the onset of the natural feeding cycle.


Neuromedin N decreases self-stimulation of the medial prefrontal cortex.

Intracerebral microinjections of neurotensin (NT) decrease intracranial self-stimulation (ICSS) of the medial prefrontal cortex (MPC) in the rat. This effect could be due to the ability of NT to bind dopamine. To test this hypothesis we studied the effects of intracerebral microinjections of neuromedin N, a natural NT analogue that does not bind dopamine, on ICSS of the rat MPC. Unilateral microinjections of neuromedin N into the MPC at doses of 2.5, 5, 10, 20 and 40 nmol produced a dose-related decrease in ICSS of the ipsilateral MPC. ICSS of the contralateral MPC, used as a control, was not affected by the microinjections. These results suggest that the inhibitory effect of NT on ICSS is independent of NT-dopamine binding. Because neuromedin N is also present in the MPC, these results also suggest a possible neuromodulatory role of this neuropeptide on ICSS of the prefrontal cortex.


Activated astrocytes of the mouse hippocampus contain high levels of NADPH-diaphorase.

NADPH-Diaphorase has recently been shown to be identical to nitric oxide synthase in brain neurones. In the intact brain, NADPH-diaphorase is only present in selected populations of neurones and is not detectable in glia. However following a lesion in the mouse retrosplenial cortex, activated astrocytes display intense NADPH-diaphorase activity throughout their cytoplasm. After a control saline injection, NADPH-diaphorase-positive activated glia are only observed in damaged tissue immediately surrounding the injection site, but when kainic acid is injected unilaterally, activated astrocytes occur in the hippocampal formation bilaterally. This indicates that astrocytes activated by intense neuronal activity, as well as by direct mechanical damage, express high levels of NADPH-diaphorase.


Increased mortality in female rats after brain trauma is associated with lower free Mg2+.

Male and female Sprague-Dawley rat siblings (200-350 g) were monitored by phosphorus magnetic resonance spectroscopy for 4 h after moderate (2.8 atmospheres) fluid-percussion-induced traumatic brain injury. Following injury, two of nine male animals died whereas 100% of all female rats (n = 16) died (p < 0.01). Prior to injury, brain free magnesium concentration in males was 0.58 +/- 0.05 mM and in females 0.41 +/- 0.09. After injury, mean brain free magnesium concentration in males declined to 0.32 +/- 0.06 whereas mean brain free magnesium concentration in ventilated females (n = 6) after injury declined to 0.17 +/- 0.03 (p < 0.05). There were no significant differences between groups with respect to any other measured variables. We conclude that female rats are more susceptible to irreversible injury after brain trauma, and that this increased susceptibility to injury may be related to brain free magnesium levels.


Metal uptake in neurone cultures: a systematic study.

We present the first comparative study of the uptake of metal ions by neurons, performed for Zn, Cr, Co, Mo, Al, Ni, Mn and Cd. The study reveals substantial differences in the uptake of different metals, under similar exposure procedures. In particular, we found very large uptakes for aluminium and molybdenum. We also found significant effects of excitatory substances, in particular kainate, as stimulants of uptake of some of the metals.


Dopamine transporter imaging with novel, selective cocaine analogs.

RTI-121 and RTI-122 are 3 beta-substituted phenyltropane analogs of cocaine that have high, selective binding affinity for dopamine transporters. [123I]RTI-121 and [123I]RTI-122 bind to dopamine transporters in vivo after intravenous administration and permit imaging of the transporters.


Regulation of an acetylcholine receptor LacZ transgene by muscle innervation.

The role of motor innervation in the expression of beta-galactosidase targeted to the nucleus (nls beta gal) under the control of a chicken muscle acetylcholine receptor alpha-subunit promoter of 850 bp was investigated using two lines of transgenic mice. After birth, nls beta gal was transiently expressed in the endplate areas of extensor digitorum longus, tibialis anterior and diaphragm muscles. In the adult, denervation of several fast twitch muscles caused a burst of transgene expression which started at endplates and displayed defined though transient spatio-temporal patterns; in the slow soleus muscle, no regular patterns were observed. Thus, in vivo, the 850 bp promoter confers preferential expression of nls LacZ in the motor endplates of newborn mice and, in addition, directs expression of nls LacZ in denervated adult muscles.


Elevated NMDA receptors in parkinsonian striatum.

Dopamine-glutamate interactions contribute to normal striatal function and have been implicated in neurotoxicity at nigrostriatal dopamine (DA) terminals. The present study examined the striata of idiopathic Parkinson's disease (PD) patients and age-matched controls for regional differences in the DA transporter and binding to N-methyl-D-aspartate (NMDA) receptors. [3H]Mazindol labeling of the DA transporter was reduced by 70-80% in the caudate and putamen of PD patients, with reductions being more extensive dorsally than ventrally. In contrast, L-[3H]glutamate binding to NDMA-sensitive receptors was 20-40% higher in PD cases than in controls. These findings raise the possibility that modifications occur within corticostriatal glutamate synapses of PD patients, possibly as a consequence of reduced nigrostriatal DA activity.


Selective dopamine transporter inhibition by cocaine analogs.

Several isopropyl and phenyl esters of 3 beta-(4-substituted phenyl) tropan-2 beta-carboxylic acid analogs of cocaine are relatively more potent and selective than cocaine and some other compounds in inhibiting dopamine uptake. These analogs can be used as binding ligands and as tools for elucidating the mechanisms of action of cocaine.


The influence of haematocrit and blood glucose on cerebral blood flow in normal and in diabetic rats.

Cerebral blood flow (CBF) was measured at varying haematocrit values in 8 streptozotocin-diabetic and in 7 control rats using the intracarotid 133Xe technique. A hyperbolic relationship between CBF and haematocrit was established for the individual rats in both groups. Diabetic animals showed a preserved CBF response to changes to haematocrit. In 10 normal rats, CBF was measured during acute hyperglycaemia induced by intraperitoneal glucose injection. A significant, inverse correlation was found between CBF and blood glucose. We conclude that the CBF response to changes in haematocrit and thereby in pO2 is preserved in experimental diabetes. Secondly, in acute hyperglycaemia CBF varies inversely with blood glucose, by mechanisms not fully understood.


Guanosine enhances NGF-stimulated neurite outgrowth in PC12 cells.

Guanosine at 30 and 300 microM elicited the de novo extension of neurites from PC12 cells. With saturating concentrations of NGF, guanosine acted in a synergistic manner to enhance neuritogenesis. Adenosine alone also stimulated neurite outgrowth, but did not enhance NGF-induced neuritogenesis. 5'-N-ethylcarboxamidoadenosine (NECA), an adenosine analog and A1/A2 receptor agonist, also alone had neuritogenic effects. It enhanced NGF-induced neuritic outgrowth but not to the same extent as guanosine. However, when NECA was added together with guanosine in the presence of NGF, these compounds elicited a greatly enhanced neuritogenic response. This suggested that the mechanisms through which NECA modulates the neuritogenic effects may be different from those of guanosine and NGF.


Practical guidelines for body substance precautions in long term care.

In recent years acute care hospitals have recognized increasing risks to caregivers for acquiring infections in the workplace. As a result, many acute care hospitals are instituting body substance precautions as their infection control policy. However, little attention has been given to similar precautions in long term care facilities even though there is substantial potential for infection in elderly populations. Increased infection rates in the elderly are related to an age-associated decline in immunological functioning and underlying diseases. Infection control guidelines which currently exist for long term care facilities are general and lack the required specificity for task-centred caregivers. Before implementing body substance precautions, management and caregivers will have to consider issues such as the inappropriate use of barrier precautions and the attendant financial implications. Once a commitment to the infection control policy has been made, a task-specific guideline designed for long term care activities will facilitate implementation of body substance precautions. With multidisciplinary planning and education, body substance precautions can effectively be introduced into long term care facilities with benefits resulting to staff and residents.


The long term ventilator-dependent client: 35 years' experience.

The George Pearson Centre is a part of the British Columbia Rehabilitation Society. Twelve per cent of its 200 beds are long term ventilator-dependent clients. The range of years ventilated is one to 35. This paper addresses experience with the long term ventilator-dependent client. The care for these clients is based on appropriate sections of the Laboratory Centre for Disease Control Guidelines, relevant research and literature, and on the clinical experience of the Pearson team--infection control, medicine, nursing and respiratory therapy. The long term ventilator-dependent client differs greatly from the acute care intensive care unit ventilator-dependent patient. These aspects and related considerations are discussed. Finally, key components of the standards are presented.


Reported seroconversions to human immunodeficiency virus among workers worldwide--a review.

The authors undertook a review of published articles on reported worldwide seroconversions to the human immunodeficiency virus (HIV) among workers who sustained occupational exposure to HIV. Documented seroconversions are occupational exposures for which the worker is tested and found negative for HIV antibody shortly after the exposure (usually within 30 days). The worker may develop symptoms of a retroviral illness, and seroconversion occurs usually within six months. In all cases the worker is interviewed to determine that there were no other risk factors for infection. Review of the literature identified 16 parenteral exposures (needlesticks or cuts with a sharp object), two mucous membrane exposures, two nonintact skin exposures and one cutaneous exposure to infected blood or body fluids.


Education to increase ophthalmologic care in older onset diabetes patients: indications from the Wisconsin Epidemiologic Study of Diabetic Retinopathy.

Both physicians and diabetic persons must be educated about the need for regular ophthalmologic examinations to prevent blindness. A large population-based study of diabetic persons living in Southern Wisconsin (Wisconsin Epidemiologic Study of Diabetic Retinopathy), designed to evaluate the incidence and associated risk factors for diabetic retinopathy, provided the opportunity to evaluate an intervention to increase ophthalmologic care. As part of this study, a sample of persons less than 80 years of age with older onset diabetes of less than 15 years duration was identified and examined in both 1980-1982 and 1984-1986 (n = 619) using standardized protocols. Study subjects received educational material on diabetic eye disease, and examination findings were conveyed to each participant and their primary physician. To evaluate the effect of this intervention, a random representative sample of diabetic persons who were not selected for examination (a nonintervention control group) was identified and interviews were completed with 241 (80%) of the surviving subjects. The two study groups were similar with respect to demographic factors, employment status, medical history, and frequency of physician visits and hospitalizations, but not for income. Self-assessments of general health were also identical between the selected and nonintervention groups. Overall, both groups reported very similar patterns of ophthalmologic care, visual impairment, and knowledge of retinopathy. These results suggest that a more intensive intervention is needed to improve the ophthalmologic care patterns of the diabetic population at risk of eye disease.


Does adequate control of diabetes in the preinfarction period improve the short-term postinfarction course?

It is uncertain whether adequate preinfarction diabetes control would alter the clinical outcome in diabetic patients once myocardial infarction has occurred. This study attempts an evaluation. Diabetic patients admitted successively to the cardiac intensive care unit with their first acute myocardial infarction were enrolled and followed throughout hospitalization. Every fourth consecutive patient with infarction, but not diabetic, was assigned to a control group. All patients were kept in the cardiac care unit for at least 48 h and vital signs and cardiac arrhythmias were continuously monitored. Radionuclide ventriculography was done within 24 h of admission and again upon discharge. When feasible, patients with postinfarction angina underwent coronary balloon angioplasty. During a 1-year period, 49 diabetic patients were studied, while 18 comparable nondiabetic patients served as controls. Diabetes was considered adequately controlled in 16 patients with glycosylated hemoglobin (HbA1c) of 8.8 +/- 0.7%, whereas in 33 patients diabetes was uncontrolled (HbA1c 14 +/- 3%), p < 0.001. No difference was found in the extent of infarct size, occurrence of heart failure, arrhythmias, and mortality when comparing the adequately with the inadequately controlled diabetics during a hospitalization period of 11 days. In diabetics, no differences were found in the short-term clinical course after acute myocardial infarction, whether the diabetes was adequately controlled or not in the preinfarction period.


Astemizole reduces blood-retinal barrier leakage in experimental diabetes.

We examined the potential of astemizole, a histamine H1-receptor antagonist that does not cross the blood-brain barrier, to reverse blood-retinal barrier leakage to albumin in streptozotocin diabetic rats. Four groups of nondiabetic and four groups of diabetic rats received vehicle or astemizole at dosages of 5, 10, or 20 mg/kg body weight for days 22-28 of a 28-day holding period. There were no significant differences in nondiabetic plasma-vitreous albumin ratios between animals receiving vehicle or any of the three astemizole dosages. Only diabetic rats receiving vehicle showed a significant (p < 0.05) 100% increase in the plasma-vitreous albumin ratio over their nondiabetic counterparts. Diabetic rats receiving either 5, 10, or 20 mg/kg astemizole exhibited total normalization of vitreous albumin accumulation, despite persistence of diabetes. These data indicate that astemizole, an H1-receptor antagonist that does not cross the blood-retinal barrier, is effective in reversing blood-retinal barrier leakage of albumin in experimental diabetes.


Thin-layer chromatographic separation of the ferrochelatase-inhibitory ring A and ring B regioisomers of N-ethylprotoporphyrin from a mixture of the four regioisomers.

When N-alkylprotoporphyrins are prepared synthetically or biologically, a mixture of four regioisomers is obtained. For our studies, separation of the potent ferrochelatase-inhibitory ring A (NA) and ring B (NB) regioisomers from the ring C (NC) and ring D (ND) regioisomers of low potency is required. Previously this separation required two successive high-performance liquid chromatography procedures. We now report that the separation of the zinc complexes of the NA and NB regioisomers from the NC and ND regioisomers can be achieved by a rapid and inexpensive thin-layer chromatography procedure.


Placental perfusion. An overview of the literature.

Placental perfusion techniques are currently used to study not only the organ functions but also the transfer profile and metabolic pathway of different compounds. In view of the interest in the mechanism of transfer and potential adverse effects of compounds there are numerous publications on the topic, but no systematic picture is yet available. Thus an overview has been made of all studies published from 1966 to 1990 that use this experimental approach. Out of 359 computer-retrieved articles, 266 (74%) actually dealt with the target topic; 68 articles were added after a systematic hand search, so a total of 334 articles were analyzed. The distribution of papers per year was constant until 1980, and rose significantly thereafter. Animal studies using placental perfusion were performed either in situ or in vitro, whereas human investigations were mostly examined by in vitro perfusion techniques. Animal experiments were done on seven species, the guinea pig being the most widely used. The aims of all studies could be divided into five main categories: 132 studies researched the kinetics of compounds in the placenta; 100 studies investigated placental metabolism; methodology of perfusion was reported in 22 articles; and 49 studies examined physiological changes of placental variables. A clear increase in pharmacological studies was noted starting from 1986 (there were 31 such studies). Compounds studied were either endogenous or exogenous. Almost all endogenous compounds were investigated, some of them quite extensively (mainly hormones, angiotensin, glucose, and lactate). There seemed to be no preferential field for exogenous compounds (62 compounds could be assigned to 20 classes).(ABSTRACT TRUNCATED AT 250 WORDS)


The influence of outpatient insurance coverage on the microvascular complications of non-insulin-dependent diabetes in Mexican Americans.

Does poor health insurance coverage contribute to increased microvascular complications (nephropathy and retinopathy) in Mexican Americans with non-insulin-dependent diabetes? Mexican-American subjects with diabetes were identified in a population-based cardiovascular risk factor survey, the San Antonio Heart Study. Retinopathy, nephropathy, source of health care, and type and extent of health insurance coverage were assessed in a special diabetes complications exam. Among Mexican-American subjects with non-insulin-dependent diabetes diagnosed prior to their participation in the survey (n = 255), 26% (n = 67) lacked any type of health insurance, and 28% relied on county- or federal-funded clinics rather than private doctors as their primary source of care. Among those with health insurance (188 of 255), only 68% (127 of 188) or 24% of the total sample had private health insurance, and, of those with private insurance, 48% (35 of 73) received reimbursement for outpatient doctor visits and 57% for outpatient medications. Microvascular complications were more common among those who received their health care from a clinic versus a private doctor, and among those who lacked health insurance coverage for outpatient doctor visits and medications. Thus, poor health insurance coverage in the outpatient setting correlates with higher rates of microvascular complications among Mexican Americans with non-insulin-dependent diabetes mellitus.


Assessment of right ventricle dimensions with microsonometry in anesthetized rabbits.

Dimension measurements of the right ventricle are difficult to obtain because of its complex geometry, thus we evaluated a method of right ventricular dimension measurements. Crystals were placed on the ventral and dorsal side of the right ventricular free wall, approximately one-fourth of the right ventricular semicircle away from the septum, in the middle of a cranio-caudal axis of the ventricles. The effects of an increased (infusion of 20 mL/kg of 5% glucose for 3 min into seven rabbits), as well as decreased preload (nitroglycerin, 5 micrograms/kg/min i.v. n = 6) were measured and compared with changes during a placebo infusion (n = 6). The change in shortening of the right ventricle wall segment correlated with changes in both atrial natriuretic factor (ANF) plasma concentration (r = 0.89, p < 0.05) and central venous pressure (CVP) (r = 0.94, p < 0.05), respectively. Both these variables are influenced by right ventricular function and dimensions in healthy animals. Dimension measurements obtained across the free wall of the right ventricle appear to reflect right ventricular function well and should be useful in assessing the effects of drugs intended for the treatment of angina pectoris or heart failure.


Nonmydriatic fundus photography in screening for treatable diabetic retinopathy.

Diabetic retinopathy is a complication of both insulin-dependent (type I) and non-insulin-dependent (type II) diabetes. The American Diabetes Association and others recommend screening for retinopathy, beginning 5 years after onset of symptoms for patients with type I diabetes and at the time of diagnosis for patients with type II diabetes. Ideally, diabetic patients are evaluated at recommended intervals by an ophthalmologist. Realistically, however, this is often not feasible, for reasons both of cost and availability. There is evidence that many diabetic patients are being referred too late for intervention, perhaps in part due to lax screening and detection, often the responsibility of internists and other primary care physicians. Data supports the need for a cheap, widely available, easy-to-use, effective screening tool for detecting treatable diabetic retinopathy. To this end, several studies have evaluated nonmydriatic fundus photography, and compared it with more-established methods of detecting diabetic retinal disease. The real question to be considered is whether nonmydriatic fundus photography will help to detect early treatable retinopathy better than the average physician using ophthalmoscopy. Several studies support its usefulness in this regard, and are discussed in this review. Questions remain, however, and further study is warranted in evaluating its potential role.


A tail-artery cannulation method for the study of blood parameters in freely moving rats.

The aim of this study was to improve the chronic tail-artery cannulation technique for repeated substance administration and blood sampling under stress-free conditions in freely moving rats. For that purpose, a special metal capsula and spring-tube system were developed, which not only protects the inserted cannula but also provides a less injurious insertion procedure and improves the animals' welfare as illustrated by normal cleaning and feeding behavior. Intraarterial application of test substances and repeated blood sampling can be done under minimal stress conditions as shown by unaltered plasma levels of highly stress-sensitive prolactin and the catecholamines (CA), epinephrine (E), norepinephrine (NE), and dopamine (DA), after infusion of 300 microL saline.


Infections in the diabetic patient: the role of immune dysfunction and pathogen virulence factors.

It is a common belief that certain infections occur more frequently in patients with diabetes mellitus than in nondiabetics. In some infections, poor diabetic control is strongly linked. Diabetics comprise 50%-70% of all patients who undergo nontraumatic foot or leg amputations, the overwhelming majority of which are necessitated by infection and necrosis of soft tissue and/or bone. Imputed host defense abnormalities include defective immune responses (e.g., white blood cell function, granuloma formation), peripheral neuropathies, impaired distal arterial supply, and problems in "control" of the diabetic state eventuating in catabolic metabolism. Increased bacterial translocation as a source of the causative bacteria is another potential entry site. Possible virulence factors of the invading organisms include polymicrobial synergism, glycocalyx formation, and inoculum size. Attention to the principles of preventive education, vascular evaluation, diabetes management, and adequate debridement maximize healing potential.


Correlation between erythrocyte aldose reductase activity and the width of skeletal-muscle capillary basement membrane in insulin-dependent diabetes mellitus.

Thickening of capillary basement membrane has been demonstrated in diabetic subjects, and it is considered to be the characteristic pathological lesion of diabetic microvascular disease. There are studies reporting the effects of inhibitors of aldose reductase, the first enzyme of the polyol pathway, on the thickening of the capillary basement membrane. These observations indicate a significant role of the polyol pathway in the development of microvascular disease. However, it is unknown whether or not there is any correlation between the thickness of the capillary basement membrane and the activity of aldose reductase in diabetic patients. To clarify this issue, we measured the width of skeletal-muscle basement membrane and erythrocyte aldose reductase activity in 27 insulin-dependent diabetic and 8 nondiabetic individuals. The results showed that both the aldose reductase activity and the width of capillary basement membrane were increased in diabetic patients as compared to nondiabetic individuals (6.89 +/- 0.38 versus 5.15 +/- 0.60 mL/mU erythrocytes, p < 0.05 and 2257 +/- 166 versus 1136 +/- 69 A, p < 0.0001, respectively) (mean +/- SE), but marked variability was observed in both the enzyme activity and the basement membrane thickness among the diabetic patients. There was a significant correlation between the capillary basement membrane thickness and the activity of erythrocyte aldose reductase (r = 0.51, p < 0.01) in diabetic patients. Our data suggest that the polyol pathway plays an important role in thickening of capillary basement membrane in diabetic individuals, and the variability in aldose reductase activity seen among diabetic patients may result in the varying susceptibility to the development of diabetic microvascular disease.


Association of sexual activity and bacteriuria in women with non-insulin-dependent diabetes mellitus.

A group of 215 patients with non-insulin-dependent diabetes mellitus (NIDDM) (147 women and 68 men) were selected by home interview, and accepted to undergo clinical examination including urine culture, in order to determine the frequency of bacteriuria and its possible associations with clinical and laboratory findings. Bacteriuria was found in 17.7% of women and 1.5% of men. Univariate and multivariate analysis performed for the group of women revealed sexual intercourse and pyuria as the only factors associated with the frequency of bacteriuria. It was concluded that asymptomatic bacteriuria may be associated with sexual activity in women with NIDDM.


The rat external urethral sphincter an in vitro model to evaluate the activity of drugs on the smooth and striated components of the urinary bladder outlet.

Electrical field stimulation (EFS, 2.5 Hz, 60 V, 1 ms, trains of 5 sec every 5 min) of the rat external urethral sphincter (EUS) produced contractile responses characterized by a "slow" tonic contraction on which was superimposed a series of phasic "twitch-like" contractions. Both responses were abolished by tetrodotoxin (0.6 microM), and their amplitude was significantly lower in samples taken from denervated (15 days before) sphincters. The tonic contraction showed duration, voltage, and frequency dependency, whereas the twitches were markedly duration dependent. No correlation was found between the amplitude of the tonic and that of the twitch-like contractions. Phentolamine (3 microM) reduced by 95% the amplitude of the tonic contraction produced by maximal parameters, whereas it did not affect the twitches. On the other hand, hexamethonium (10 microM) was ineffective on both components. Dantrolene (10 microM) inhibited the twitch response, whereas it did not influence the tonic component. Preincubation with d-tubocurarine (0.2 mM) or succinylcholine (2 mM) significantly inhibited the amplitude of twitches produced by EFS (0.1 Hz, 60 V) up to a duration of 50 microseconds. Stimulus width higher than 50 microseconds, resulted in twitches that were resistant to neuromuscular blocking agents but sensitive to dantrolene (10 microM). Our results indicate that the rat external urethral sphincter is a reliable and easy "in vitro" model for studying the activity of drugs capable of interfering with the nerve-mediated activity of the striated and smooth muscle portion of the urinary bladder outlet.


A radiotelemetry system for chronic measurement of blood pressure and heart rate in the unrestrained rat validation of the method.

Chronic measurements of systemic arterial blood pressure and heart rate via a chronically implanted telemetric transmitter in unrestrained rats, was validated in a three-phase study. In the first part, week-to-week variability of systolic, diastolic, and mean arterial pressures, and heart rate was found to be minimal over the course of nine weeks. In the second part, the reproducibility of cardiovascular response to three successive administration of sotalol, an antihypertensive agent, was studied. In the last part, cardiovascular parameters determined by telemetry were compared to those obtained by direct arterial catheterization and showed a good linear correlation between those two methods.


Prohibiting lawyer-client sex.

Psychotherapists' and physicians' sexual contact with their patients has been long held as unethical conduct. However, lawyers' sexual contact with clients has been largely ignored in the professional literature. This article uniquely anatomizes the similarities in the vulnerabilities and power imbalances that exist between psychotherapists' and lawyers' relationships with patients/clients. These characteristics enable the professional to exert undue influence over the less-powerful party, and for these reasons lawyers should be held to fiduciary standards in their personal dealings with clients. The authors propose a rebuttable presumption that sexual contact between an attorney and client was obtained through the attorney's exercise of undue influence and was therefore a breach of the attorney's fiduciary duties to the client.


Asbestos exposure and psychic injury--a review of 48 claims.

Asbestos exposure has been a common occupational risk resulting in much litigation. Where pulmonary dysfunction has been minimal or even absent, psychic injury has been made an element in claimed damages. Analysis of psychiatric and psychologic claims in 48 cases reveals that diagnoses often do not conform to professional standards, are based on insufficient data sampling, lack adequate overall history as well as medical history, and do not comport with the standard of probability usually required for litigation. The group studied was elderly (mean age--62.6), mostly retired (71%), with some significant medical illnesses (18% on medical retirement). None were retired for pulmonary reasons. As expected, conflict in opinion between the opposing professional medical participants was frequent. Commonly the patients did not substantiate the complaints reported in the medico-legal reports; some ridiculed statements made on their behalf. Many psychological reports reflected simplistic or erroneous concepts of medicine or ignored relevant medical data. This study indicates that in this group claims of psychic injury due to asbestos exposure have little justification and supports the view that the current system of utilization of expert opinions is not reliable or in conformity with reasonable professional standards. Correspondingly, these claims did not result in augmented awards.


Grievances and law suits against public mental health professionals: cost of doing business?

Although there has been an increase in risk of malpractice for all physicians, general psychiatrists continue to have a relatively low risk of being sued. With the change in the nature of involuntary patient populations as a result of dangerousness criteria for commitment, and the advent of an activist mental health bar, however, psychiatrists who work in the public sector are significantly more likely than private psychiatrists to face grievances and law suits. While specific data providing direct comparisons of numbers of lawsuits between private and public psychiatrists are not available, a review of the existing literature supports this hypothesis, particularly with respect to grievances. The author suggests reasons for the increased risk of legal challenges faced by psychiatrists working with committed patients, and discusses various strategies for preparing ward staff as well as professional staff to reduce the risk of being challenged as well as the chance of losing grievances and law suits. While the article focuses on psychiatrists, most of its arguments are equally applicable to other mental health professionals, whose risk of being legally challenged is escalating rapidly.


Sexual harassment: issues for forensic psychiatrists.

The number of civil lawsuits related to sexual harassment is increasing. The author bases this paper on her experience as an expert witness in 28 sexual harassment cases over the last 10 years. She delineates the psychological and legal issues about which forensic psychiatrists may be consulted. These include issues related to helping a jury determine the veracity of the complaints of harassment, the psychological effects of the harassment, the prognosis, and the treatment for women who have been harassed. The author gives examples of cases where psychiatric testimony was given to help in the decision making about damages related to the psychological effects of sexual harassment.


On the duty to protect: an evolutionary perspective.

Psychotherapists' duty to protect potential victims from their patients' violence has evolved in recent years toward a narrower set of obligations. This reformulation of the duty appears to us to be consistent with a sociobiological analysis of the reasonableness of compelled altruism. Altruistic behavior (e.g., rescuing a potential victim) takes place rarely in the animal world, and even among humans usually occurs only in situations in which reciprocity is likely. The Tarasoff-like duty to protect violates this sociobiological rule by requiring therapists to place the interests of an unknown victim over a known patient, and even to subordinate their own interests to the victim's. This has never been a socially tenable position. Psychotherapists appear to have escaped from this situation by avoiding potentially dangerous patients. The changes in the duty to protect have mitigated this dilemma, by moving the duty in a direction consistent with the evolutionary theory of altruism.


Tarasoff and the dangerous driver: a look at the driving cases.

In three recent cases, hereinafter referred to as the driving cases, the courts have taken up the issue of whether a psychotherapist should be held liable for negligent diagnosis and treatment and failure to warn third parties of a patient's potential danger to others in the operation of an automobile. These cases will be discussed as (1) an extension of the Tarasoff decision, which established psychotherapists' duty to protect third parties from patients' violent acts, and (2) what some commentators regard as a move toward holding the mental health professions to a standard of strict liability. How far have the courts in these cases extended the Tarasoff duty to protect and is the specter of strict liability real or imagined? This review finds the court adhering to a professional negligence standard as altered by the Tarasoff case in which the court applied the Restatement of Torts (Second) section 315 and held that the psychotherapist-patient relationship is a special relationship requiring a duty to protect or warn. And while a negligence standard ostensibly applies, the conclusions reached in these cases reveal an undeniable trend toward results one might expect to accrue under a strict liability standard.


Child sexual abuse and forensic psychiatry: evolving and controversial issues.

Child sexual abuse has received growing attention in recent years, and the topic continues to spark controversy among mental health and legal professionals as well as in the popular media. This paper will review the concept of child sexual abuse, cover relevant definitions, address the clinician's role, and then will address the principal evolving and controversial areas. These areas include psychic damages, false allegations, improper investigatory techniques, use of anatomical dolls, admissibility of expert testimony, hearsay testimony, and the competency of minors to testify.


Legal aspects of clinical care for severely mentally ill, homeless persons.

The problem of widespread homelessness among mentally ill persons is often attributed to changes in mental health law. In consequence, suggestions for addressing homelessness frequently involve legal interventions, including loosening of commitment standards. A review of the limited data on the relation of legal standards to homelessness suggests that the problem is not primarily a result of statutory changes or court decisions, but stems from broader social problems, including the diminution of public psychiatric services. Simple legal remedies are, therefore, unlikely to be found. Nonetheless, there may be ways in which legal initiatives can be useful in mitigating homelessness, ranging from implementation of outpatient commitment to modification of rules concerning confidentiality, to efforts to establish entitlements to psychiatric and social services.


The treatment of mentally disordered offenders: a national survey of psychiatrists.

A nationwide (U.S.) survey of major public mental hospitals treating patients who are incompetent for trial, not guilty by reason of insanity, mentally disordered sex offenders, or mentally ill inmates was conducted. Responses were received from 71 percent of the 115 facilities surveyed. Respondents were the directors of psychiatry from the respective facilities. The pattern of treatments delivered generally appeared clinically appropriate. However, behavioral and cognitive-behavioral treatments were reported infrequently, even in areas in which they would be particularly useful.


Outcomes of cefazolin versus ceftriaxone therapy in treating lower respiratory tract infections in adults.

To determine whether choice of a first- versus third-generation cephalosporin as initial therapy for lower respiratory tract infections in hospitalized adults affects the course and duration of care, both of which may influence antimicrobial treatment cost. Retrospective analysis of discharge abstracts and hospital pharmacy records. Forty-eight US acute-care hospitals. One thousand ninety-two hospitalized adults (aged > 17 y) with principal diagnoses of lower respiratory tract infections (DRGs 79-80, 89-90). Cefazolin or ceftriaxone, given as sole antimicrobial therapy for at least one day. (1) The number of patients who received another parenteral antibiotic anytime prior to hospital discharge; (2) the number of days during which patients received any parenteral antibiotic while in the hospital; and (3) the number of days patients remained hospitalized following the start of antibiotic therapy. Patients treated with cefazolin (n = 763) were more likely to receive another parenteral antibiotic while in the hospital (30.3 vs. 20.7 percent; p < 0.001) and received more total days of therapy (7.2 vs. 6.7 d; p < 0.05) than those treated with ceftriaxone (n = 329). Although the time to hospital discharge did not differ in the full sample (9.2 d for both groups), it was greater among those receiving cefazolin (8.6 vs. 8.0 d; p < 0.05) when patients with lengths of stay exceeding 24 days were excluded from both groups. In addition to acquisition cost, differences in course and duration of care should be considered when determining the most cost-effective choice for antimicrobial therapy.


Incidence and cost of hospital admissions secondary to drug interactions involving theophylline.

To determine the incidence and cost of hospital admissions for theophylline toxicity, which occurred as a result of the concurrent use of one of the following medications: cimetidine, erythromycin, or ciprofloxacin. Retrospective chart review (18 months, between June 1989 and November 1990). A Department of Veterans Affairs Medical Center. All patients who were receiving theophylline chronically (913 patients) and also had a prescription for cimetidine (124 patients with 140 treatment courses), erythromycin (66 patients with 93 treatment courses), or ciprofloxacin (39 patients with 59 treatment courses) dispensed. Each patient's medical record was reviewed to identify hospital admissions within 30 days following the dispensing of the interacting drug. Admissions were considered to be related to theophylline toxicity if appropriate signs and symptoms were present and the theophylline concentration was above 20 micrograms/mL or had increased significantly from the concentration obtained prior to introduction of the interacting drug. One patient who received cimetidine and one who received ciprofloxacin were admitted for theophylline toxicity (2 of 292 potential interactions, 0.81 percent). Admissions were for 16 and 13 days, respectively, and total costs for the two admissions were $12,864.22 or $44.00, respectively, per potential interaction. The entire admission was not for theophylline toxicity; it appeared that iatrogenic factors contributed to the duration. The incidence of hospital admissions secondary to theophylline drug interactions with cimetidine, ciprofloxacin, or erythromycin is low, but the admissions represent considerable expense, even when distributed among all patients at risk for the interactions.


Assessment of the drug interaction between intravenous nitroglycerin and heparin.

To assess whether a clinically significant interaction occurs between heparin and nitroglycerin (NTG). Activated partial thromboplastin time (APTT) was measured in patients with unstable angina who were stabilized on intravenous NTG and heparin just prior to weaning the NTG infusion, and one and four hours after stopping the NTG. In 22 heparin-treated patients (20 men, 2 women; aged 56.7 +/- 10 years; weight 79.5 +/- 15 kg), the APTT ratio was inversely related to the dose of NTG (slope = -0.003; p < 0.05). However, there were no significant differences between the APTT values measured before and after discontinuation of NTG (p = 0.8511). Our study demonstrates a clinically insignificant interaction between NTG and heparin at NTG doses commonly used in patients.


Seizures associated with high-dose intravenous morphine containing sodium bisulfite preservative.

To report a case of seizures occurring during administration of high-dose intravenous morphine containing sodium bisulfite as a preservative. A 56-year-old woman hospitalized with multiple myeloma developed myoclonic and tonic-clonic seizures following administration of intravenous morphine with sodium bisulfite preservative at doses exceeding 400 mg/h. These seizures resolved when the morphine was discontinued, anticonvulsants were administered, and the drug therapy was changed to intravenous fentanyl without preservative. The factors potentially associated with this adverse reaction are discussed and the literature concerning the adverse central nervous system effects of opiates and sulfites is reviewed. High doses of intravenous morphine with sulfite preservative may be associated with seizure development. If patients require high doses of intravenous morphine, a preservative-free formulation should be used to avoid possible additive or synergistic toxicities.


Abnormal platelet aggregation associated with fluoxetine therapy.

To document the development of abnormal hemostasis in a patient treated with fluoxetine. A 49-year-old man developed a release-type defect in platelet aggregation during treatment with fluoxetine. Abnormal platelet aggregation was observed during platelet viability testing, in which adenosine diphosphate, epinephrine, ristocetin, arachidonic acid, and collagen were used as agonists. Two days after the withdrawal of fluoxetine, platelet function returned to normal. Fluoxetine is an antidepressant that is thought to act through inhibition of serotonin reuptake in the central nervous system. Fluoxetine also inhibits the reuptake of serotonin in platelets, significantly decreasing granular storage and potentially influencing platelet aggregation characteristics. Clinical manifestations of abnormal platelet function have been reported in association with fluoxetine therapy. The rapid normalization of platelet aggregation after the withdrawal of fluoxetine in this patient does not conform to the known clinical pharmacokinetics of norfluoxetine. The half-life of fluoxetine is shorter, suggesting that the parent drug (rather than norfluoxetine) was the causative agent. Serum fluoxetine and norfluoxetine concentrations were not measured in this patient.