Differential production of gamma delta T cells in the urine of bladder cancer patients receiving Bacillus Calmette Guerin immunotherapy

Bacillus Calmette Guerin (BCG) intravesical therapy of bladder cancer is arguably the most effective immunotherapy for any human solid tumour. It combines a high incidence of remission induction with a low level of side effects and a low rate of recurrence. Its mechanism, however, remains poorly understood. In this study we have investigated whether gamma delta T lymphocytes, which are known to be activated by mycobacteria, are preferentially induced in patients urine following therapy. This has necessitated the development of a procedure which facilitates the preservation, enrichment and detection of small number of lymphocytes [especially of those bearing gamma delta T cell receptor (TCR)I which appear in patients urine. Here we describe in detail a method for phenotyping of a minor subpopulation of lymphocytes in patients' urine, namely, gamma delta T lymphocytes which comprised less than 0.1% of all urinary sells. Using this technique we have found gamma delta T cells in the urine of all patients. Furthermore, the patients could be separated into 2 distinct groups, with low and high numbers of gamma delta cells (0.5-5% and 5-20% respectively of the CD3 positive cells). The elevation of gamma delta T cells was observed locally but not in peripheral blood and the detected gamma delta T were almost entirely of the V delta 2 gamma 9 subset.     

Isolation of the ERG2 gene,encoding sterol Δ8Δ→7 isomerase,from the rice blast fungus Magnaporthe grisea and its expression in the maize smut pathogen Ustilago maydis

The Magnaporthe grisea ERG2 gene, encoding ⁸⁷ sterol isomerase, was isolated from a genomic library by heterologous hybridization to a fragment of the Ustilago maydis ERG2 gene. The isolated gene contained a reading frame of 745 bp which encoded a protein of 221 amino acids. The coding region was interrupted by a single putative 79-bp-long intron. The deduced amino-acid sequence exhibited similarity to the ERG2 gene products of U. maydis and of Saccharomyces cerevisiae, particularly in the central region of the proteins. The NH₂-terminal of all three proteins contained a long stretch of amino acids that were strongly hydrophobic, suggesting that they may function by anchoring the protein to a membrane surface. The M. grisea ERG2 gene complemented a U. maydis deletion mutant in which the ERG2 gene had been removed using a one-step gene replacement procedure. The ⁸⁷ sterol isomerase produced by the M. grisea ERG2 gene exhibited a level of sensitivity to the sterol biosynthesis inhibitor, tridemorph, similar to that of the enzyme derived from the U. maydis ERG2 gene.     

Use of psychoactive substances in three medical specialties: anaesthesia,medicine and surgery

In order to determine the prevalence of psychoactive substance use in three specialty groupings, 1,624 questionnaires were sent to physicians in medicine, surgery and anaesthesia; all had trained at the same academic institution. A response rate of 57.8% was achieved. Comparison of prevalence of impairment rates showed no differences between Surgery (14.4%), Medicine (19.9%) and Anaesthesia (16.8%). Substance abuse was clearly associated with a family history of abuse; 32.1% of the abusers had a family history of such abuse compared with 11.7% of the non-abusers. Increased stress at various career stages did not appear to increase substance abuse; problem areas during medical life times were similar for each specialty. Substances most frequently used were marijuana (54.7%), amphetamines (32.9%); and benzodiazepines (25.1%). Seventy-three used psychoactive drugs which were non-prescribed. Drug counselling programmes were judged inadequate by most. Use of alcohol and drugs by faculty members was reported by a number of respondents.     

Spinal anaesthesia but not general anaesthesia enhances neutrophil biocidal activity in hip arthroplasty patients

The purpose of this study was to compare neutrophil cidal activity during general or spinal anaesthesia. Assays were performed on neutrophils extracted from the blood of patients after surgery had been under way for one hour. First, the ability of the neutrophils to kill a standard laboratory strain of S. aureus was examined. Neutrophils extracted from the blood during surgery in the spinal anaesthetic group and incubated with the staphylococci for one hour killed twice as many bacteria than those from two groups of patients that received halothane or isoflurane general anaesthesia (P < 0.05). This effect persisted, to a lesser extent, in the spinal group neutrophils after two hours of incubation with the bacteria. Second, neutrophils from patients under the same conditions of surgery and anaesthesia were tested to examine the effect of the different anaesthetic techniques on neutrophil biocidal mechanisms. Neutrophils extracted during surgery in the spinal group released more superoxide in response to phorbol-12-myristate-13-acetate (PMA) than those from both groups of patients that received general anaesthesia (P < 0.05). It is concluded that there is an increased state of reactivity of the neutrophil cell membrane NADPH oxidase system in patients receiving spinal anaesthesia than in patients receiving general anaesthesia.     

Anaesthesia for Caesarean section in a patient with Watson’s syndrome

Watson’s syndrome is an uncommon genetic disorder whose features include mental retardation and pulmonary valvular stenosis. The purpose of this report is to describe one management strategy used successfully to anaesthetize a woman with this disorder who presented for Caesarean section. Epidural anaesthesia using 0.5% bupivacaine without epinephrine in 2–3 ml boluses to a total dose of 15 ml was administered over 30 min. Invasive haemodynamic monitoring in the form of arterial and central venous catheters were used to guide therapy and help ensure maternal and fetal well-being. Intravenous ketamine in doses of 10–20 mg every five minutes to a total dose of 245 mg (4.5 mg · kg^?1) was used to overcome the patient’s uncooperative nature and facilitate invasive procedures. Postoperative analgesia was provided using 3 mg epidural morphine. The patient was observed in the intensive care unit for the first postoperative day and experienced an uncomplicated intra- and postoperative course. We conclude that this technique represents a safe and effective method for anaesthetizing patients with this complicated problem for Caesarean section.     

Rest and treadmill exercise first-pass radionuclide ventriculography: Validation of left ventricular ejection fraction measurements

Background

To assess the accuracy of rest and treadmill exercise first-pass radionuclide ventriculographic measurements of left ventricular ejection fraction (LVEF), 40 patients underwent treadmill exercise first-pass and bicycle exercise equilibrium radionuclide ventriculography. To determine the frequency of technically adequate treadmill exercise first-pass studies, an additional 128 consecutive patients undergoing treadmill exercise first-pass procedures during stress^99mTc-labeled sestamibi myocardial perfusion studies were assessed.

Methods and Results

The treadmill exercise first-pass procedure used a multicrystal camera and an²⁴¹Am point source to allow for correction of patient motion. Excellent correlations were observed between resting first-pass and resting equilibrium LVEF (r=0.91; standard error of the estimate=5.6). A high correlation was also observed between treadmill exercise first-pass and bicycle equilibrium exercise LVEF measurements (r=0.85, standard error of the estimate=7.6). Treadmill first-pass LVEF systematically underestimated the bicycle equilibrium LVEF. Intraobserver agreement for rest and exercise first-pass LVEF was high (r values of 0.98 and 0.94, respectively). Of the 168 consecutive treadmill exercise first-pass studies evaluated for technical adequacy, 21 (12.5%) were deemed technically inadequate, with most of the sources of error being avoidable. The frequency of technically adequate studies was as high (87%) in high levels of exercise (Bruce stages 3 and 4) as in lower levels (88%). The findings of this study validate the first-pass treadmill exercise LVEF measurement.

Conclusion

This procedure now provides the option for combining the information of peak treadmill exercise LVEF with measurements of exercise myocardial perfusion from the same injection of radioactivity.     

Prophylactic treatment of patients with esophageal varices: Is it ever indicated?

The prognosis of patients who bleed from esophageal varices is dismal. Prophylactic treatment of the varix or the elevated portal venous pressure offers a possibility of improving the outlook for these patients. However, as only approximately one-third of patients with varices bleed during their lifetime, correct identification of high-risk patients is vital before embarking on prophylaxis. At present, neither European or Japanese selection criteria are perfect in this respect. The documented incidence of initial variceal bleeding varies between 27% and 48%, and most bleeding episodes occur within the first year after varices are diagnosed. Data from six randomized controlled trials comparing prophylactic -blockers with placebo demonstrated a decreased incidence of bleeding in propranolol-treated patients, which in large measure may depend on patient compliance and did not significantly affect survival in all but one study. Early randomized studies of prophylactic sclerotherapy have shown significant reductions in both the incidence of bleeding and mortality, but this promise has not been sustained by subsequent trials, and indeed sclerotherapy was detrimental in two studies. The impressive results in highly selected patients treated in Japan by prophylactic surgery are unlikely to be repeated in a Western setting, involving patient populations that consist predominantly of alcoholic cirrhotics. At present prophylaxis with -blockade seems to offer the best therapeutic option, but the future may lie in the development of new interventional techniques such as tranjugular intrahepatic portosystemic stent shunting (TIPS) or variceal banding, and ultimately with hepatic transplantation.

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Resumen El pronóstico de los pacientes que sangran como consecuencia de várices esofágicas es sombró. El tratamiento profiláctico de las várices o de la elevada presión portal ofrece una posibilidad de mejorar el futuro de estos pacientes.Sin embargo, como apenas aproximadamente un tercio de los pacientes con várices sangran en el curso de su vida, la correcta identificación de los casos de alto riesgo es de vital importancia antes de embarcarse en tratamiento profiláctico.En la actualidad ni los criterios de selección europeos ni los japoneses pueden considerarse como perfectos a este respecto. La frecuencia del sangrado varicoso inicial oscila entre 27% y 48%, y la mayoría de los episodios hemorrágicos ocurren dentro del primer año después de establecido el diagnóstico de las várices. Los resultados de seis (6) ensayos clinicos randomizados en que compararon los beta-bloqueadores con placebeo demuestran una disminución en la incidencia de sangrado en los pacientes tratados con propranolol, lo cual en gran parte depende de la obediencia del paciente, pero afectó en forma significativa la sobrevida, excepto en uno de los estudios.Anteriores estudios randomizados sobre escleroterapia profiláctica han demostrado reducciones significativas tanto en la incidencia de sangrado como en la mortalidad, pero ésto no ha sido reproducido en ensayos clínicos subsiguientes, y en realidad la escleroterapia pareció ser nociva en dos estudios. Los impresionantes resultados en pacientes altamente seleccionados logrados en el Japón con la cirugía profiláctica muy probablemente no lograrán ser reproducidos en Occidente, donde las poblaciones de pacientes están conformadas predominantemente por cirróticos alcohólicos. En el momento actual la profilaxis con beta-bloqueadores parece ser la mejor opción terapéutica, pero el futuro puede bien ser el desarrollo de nuevas técnicas intervencionistas tales como shunts transyugulares intrahepáticos (TIPS) o la ligadura endoscópica de las várices y, por último, el trasplante de hígado.

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Résumé Le pronostic des patients ayant saigné de varices oesophagiennes est médiocre. Le traitement prophylactique des varices ou d'une hypertension portale permet une amélioration potentielle du pronostic de ces patients. Cependant, comme seulement un tiers des patients avec des varices saignent pendant leur vie, l'identification correcte des patients à risque élevé est capitale avant d'envisager une politique prophylactique généralisée. Actuellement, ni les critères européens ni les critères japonais ne sont suffisants pour déterminer cette population à risque. L'incidence d'hémorragie par rupture des varices initiale va de 27% à 48% dans la littérature et la plupart des hémorragies se produisent pendant la première année après le diagnostic de varices oesophagiennes. Les résultats provenant de six études comparant les béta bloqueurs à un placebo ont démontré une baisse de l'incidence de l'hémorragie chez les patients traités par le propranol. Ce résultat peut certes être attribué à une différence de coopération parmi les patients: la survie n'est pas différente d'une étude à l'autre sauf une. Les études randomisées de sclérothérapie prophylactique ont démontré une réduction significative dans l'incidence d'hémorragie et de la mortalité, mais cet espoir n'a pas été retrouvé par les essais suivants et la sclérothérapie a été néfaste dans deux de ces essais. Il est peu probable que les résultats impressionnants recueillis au Japon puissent être reproduits en Occident où la population est composée en grand majorité par des cirrhotiques d'origine alcoolique. Actuellement, la prophylaxie par béta-bloqueurs semble être le meilleur des traitements mais à l'avenir, la meilleure option thérapeutique pourrait être le shunt intrahépatique transjugulaire ou le wrapping périoesophagien et ultérieurement la transplantation hépatique.

     

To Stay or Not to Stay: Issues in Rural Primary Care Physician Retention in Eastern Kentucky

An important aspect of primary care physician availability is the retention of physicians once they have located. While retention has been under-researched compared to recruitment, it is especially important in rural areas where physician shortages already exist. This study reports the results of a retention survey completed by 132 primary care physicians in rural eastern Kentucky. The survey sets up an objective, hypothetical retention scenario and asks physicians to respond to structured questions and to an open-ended question about factors not appearing in the survey. In response to the structured portion of the survey, physicians indicate that relief coverage is the most important factor in rural physician retention. A content analysis of 75 open-ended responses reveals that besides the other factors in the survey, "sociocultural integration" is the pre-eminent retention issue for rural practitioners. This article concludes that the role of the local rural community may be more important in retention than in recruitment. Finally, it is suggested that additional in-depth qualitative research be conducted within the local contexts to enhance the understanding of rural physician retention processes.     

The Influence of Obesity on the Self-Reported Health Status of Chamorros and other Residents of Guam

PURPOSE OF THE PAPER. We report on an analysis of the relationship of obesity to self-assessments of physical health for a probability sample of Guam's indigenous (Chamorro) and resident populations. Further, we examine whether Guam's populations fit a Western model, in terms of viewing obesity as an unhealthy condition. As background for our analysis, we review the literature on (1) the relationship between obesity and chronic noninfectious diseases; (2) social and behavioral associations of obesity; and (3) the reliability of self-assessed physical health and measures of obesity. METHODS. The data analyzed were taken from a Behavioral Risk Factor Survery (BRFS) conducted on Guam in 1991. We employed various standard univariate (chi-square analysis, ANOVA) and multivariate (OLS regression and logisitic regression analusis) statistical procedures in exploring our data and testing hypotheses on the correlates and associations of self-reported health and obesity. PRINCIPAL FINDINGS. Controlling for ethnicity, age, gender, marital and socioeconomic status, we found that obesity and being Chamorro was associated significantly with low assessments of physical health and that income was a signifcant predictor of higher self-assessments. A small sample of Micronesians, with a slightly greater level of obesity than the Chamorros, did not show the same tendency towards lower self-evaluation of their health. This probably reflects their lesser degree of internalizaition of Western ideas about obesity, appearance and health. When controlling for self-assessments of physical health, obesity was also shown to be related significantly with dieting by Chamorro women but was not a significant predictor of their increased participation in physical exercise. Young males were significantly more likely to report participation in physical exercise regardless of their weight or ethnicity. CONCLUSIONS. We hypothesize that historical (acculturative) changes to the diet and life ways of Chamorros, together with a likely genetic predisposition to store fat, has led to the relatively high levels of obesity seen on Guam today. Because of internalization of Western ideals about obesity and appearance, and increased community awareness of the health perils of obesity, Chamorros are at a public health crossroads. Effective health interventions must reckon with powerful genetic and cultural cross-currents. RELEVANCE TO ASIAN PACIFIC ISLANDER AMERICAN POPULATIONS. Colleagues are encouraged to examine the effects of ethnicity and acculturation on the health attitudes, behaviors, and status of other Pacific Islander and Asian populations. The creation of such a comparative data base will service APIA health interventions. KEY WORDS. Guam, Chamorros, Asian Pacific Islander Americans, survey, obesity, self-evaluated health status, socioeconomic status, cross-cultural comparisons.     

Effects of two stressors on behaviour in the elevated X-maze: preliminary investigation of their interaction with 8-OH-DPAT

Effects of water deprivation and restraint were compared in the rat elevated X-maze. Water deprivation for 12–48 h increased corticosterone and had a duration-dependent anxiolytic effect in the elevated X-maze, increasing the ratio of open/total arm entries (OTR) and the proportion of time spent on the open arms (% time) without affecting total entries. Brain 5HIAA/5HT was increased only after 24 or 48 h deprivation. Restraint for 15 min also increased plasma corticosterone and brain 5HIAA/5HT but had no effect on behaviour in the elevated X-maze when rats were tested immediately afterwards. However, 1 h restraint was anxiogenic in the elevated X-maze immediately after release, reducing OTR and % time, but with a less consistent reduction in total entries; reductions in OTR and % time were still present 24 h later. The 5HT_1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.1–0.2 mg/kg), administered 10 min before testing in the elevated X-maze, had anxiogenic actions in non-stressed rats. The effect of 0.1 mg/kg 8-OH-DPAT was not significantly altered by 24 or 48 h water deprivation but was abolished by restraint for 1 h immediately beforehand, despite the anxiogenic effect of restraint alone. Similar mutual antagonism of 8-OH-DPAT and restraint occurred when the dose of 8-OH-DPAT was increased to 0.2 mg/kg. Twenty-four hours after restraint, restrained rats which had received 8-OH-DPAT (0.1–0.2 mg/kg) still did not show any significant anxiogenic effect compared with non-restrained vehicle treated controls. Restraint-induced deficits in elevated X-maze exploration may prove a useful model with which to study the pharmacology of depression-related anxiety. However, the effects of the stressors examined, and their interaction with 8-OH-DPAT in the elevated X-maze, appear to depend on the nature of the stressor.