Parents and AIDS education.

The objective of this research was to study parents' attitudes toward AIDS education in schools. Questionnaires were mailed to employees in an industrial plant and a hospital in a city of 150,000 in Ontario, Canada. Two hundred and sixteen questionnaires from parents with children in schools were analyzed. Two thirds of the parents agreed that AIDS education should discourage premarital sex; whereas, 88% believed that AIDS education should teach about condoms. Pearson correlations and multiple regression were used to analyze hypotheses that tested attitudes toward AIDS education in the schools. Two predictor variables--attitude toward premarital intercourse and fear of casual contact of AIDS--were significantly correlated with all three measures of attitudes toward AIDS education in the schools. Church attendance and knowledge of AIDS were related to both attitudes toward discouraging premarital sex and teaching about condoms. Three multiple regression models were constructed to predict attitudes toward AIDS education in the schools. The final models accounted for between 11% and 33% of the variance.


The impact of HIV antibody status on gay men's partner preferences: a community perspective.

As more gay men are tested for antibodies to human immunodeficiency virus (HIV), serostatus may influence the formation of primary partner bonds in this community. We compared seropositive (n = 157), seronegative men (n = 205), and those who had not been tested (n = 158) from our ongoing AIDS Behavioral Research Project (total response in 1988 = 540). Subjects responded to mailed surveys regarding sexual behavior, relationship status, HIV antibody testing and serostatus preference when forming relationships for romance and friendship. Sixty-eight percent of seropositive gay male respondents reported no serostatus preference in partners for romance, while 83% of seronegative respondents and 74% of untested respondents preferred seronegative partners for romance. In addition, 15% of seronegative respondents and 12% of untested respondents preferred seronegative individuals for friendship. Seropositive individuals were much less likely to be desired for romance or friendship by seronegatives and those who have not been tested--at a time when emotional support and companionship are obviously needed.


Joining the front line against HIV: an education program for adult probationers.

This article describes the implementation and evaluation of a human immunodeficiency virus (HIV) education program for adult offenders. Samples of Cook County (Chicago) probationers were educated about either HIV or heart disease in small group and in one-on-one sessions. The evaluation employed a 2 x 2 factorial design. Data were collected at 3 points in time: during a pretest, posttest, and follow-up. Results showed that offenders' knowledge of HIV was increased significantly at posttest and follow-up. Although the HIV presentation increased knowledge significantly, it had little impact on HIV-related behavioral intentions at posttest or on actual prevention behaviors at follow-up. The implications of these findings are discussed with respect to HIV education programs in criminal justice settings.


The link between sexually transmitted disease clinics and HIV counseling and testing centers: who is not getting referred?

A total of 236 clients attending human immunodeficiency virus (HIV) counseling and testing (C&T) centers and sexually transmitted disease (STD) clinics were interviewed to evaluate who is being reached by C&T services and if STD clients are being referred to HIV C&T centers. Respondents receiving HIV C&T reported significantly more sexual risk based on characteristics of their partners, whereas STD clinics respondents more frequently reported previous STD diagnoses and sex with prostitutes. Over 50% of the high-risk individuals attending STD clinics were not referred to HIV C&T centers. The differences in perceived risk of current and future infection between STD and HIV C&T centers and the low referral rates of high-risk individuals for HIV C&T indicate a need for increased education efforts, more effective risk-assessment policies in STD clinics, and a tightening of the link between STD clinics and HIV C&T centers.


Young children's awareness, knowledge, and beliefs about AIDS: observations from a pretest.

Starting from the assumption that AIDS education can be most effective when initiated prior to the age when AIDS risk behaviors emerge, a number of researchers and public health officials have advocated AIDS education for preadolescents. Yet there have been few published reports assessing children's awareness, knowledge, and attitudes about AIDS and persons with AIDS. In this paper, basic data are presented for each of these dimensions broken down by race, gender, and grade. The data suggest that, although many students are aware of AIDS by the first grade, it is not until the fifth grade that nearly all students are aware of the existence of the disease. Over all, nearly 44% of the students who know about the disease believe that they or someone they know will get it. Students in the fifth grade have a higher level of AIDS knowledge than those in the first grade, but even the former are relatively uniformed and have a number of misconceptions about the disease and persons with it. Children's attitudes reflect confusion and some anxiety over AIDS and the treatment of persons with it. Some significant race and gender differentials are noted.


Preliminary findings from the survey about AIDS for seventh and eighth graders (SASEG).

Four hundred and twelve seventh- and eighth grade students from a predominantly white, suburban, middle-class school were surveyed regarding their knowledge and attitudes about AIDS. The Survey about AIDS for Seventh and Eighth Graders (SASEG) utilized for the study is a 56-item, self-administered questionnaire that includes 26 multiple-choice knowledge items, 20 Likert-type attitude items, and 10 demographic/experiential items. Overall, students were judged to possess reasonably high knowledge levels and generally favorable attitudes regarding AIDS. However, there were several areas of misinformation and unfavorable attitudinal responses. A low positive relationship was found between knowledge and attitudes. Higher levels of knowledge and more favorable attitudes were associated with being female, being older, and having discussed AIDS with one's parents. Higher levels of knowledge were also associated with having had previous AIDS instruction and with not knowing someone with AIDS. These findings support the need for AIDS education in the pre-high school setting.


AIDS knowledge in three sites in Bas-Zaire.

This study surveyed 5,494 women in one urban and two rural sites of Bas-Zaire on their knowledge, attitudes, and practices regarding AIDS. The AIDS Risk Reduction Model (ARRM) was used to analyze the results to better understand factors that may be related to motivation for behavior change. The results show that there are considerable barriers to achieving the first stage of the 3-stage model. Most notably, only a third of the women believed they were at risk of getting AIDS. Those aged 25-29, educated, and married felt themselves to be most at risk. Results are compared to other knowledge, attitudes, and practices studies conducted in Zaire. Policy implications of these results are discussed.


HIV/AIDS education and prevention among African-Americans: a focus on culture.

African-Americans have emerged as the "second wave" of the AIDS epidemic. Epidemiologic evidence indicates that African-Americans adults as well as adolescents have a disproportionately higher risk of AIDS and human immunodeficiency virus (HIV) infection. While programs designed to increase self-protective behaviors are urgently needed to avert a further increase in HIV infection among this population, there is little understanding of African-American sociocultural factors that may influence the acceptance of HIV information and the adoption of HIV-preventive behaviors. This paper describes African-American cultural values and mores which may be related to risk-taking behavior. Barriers to the effective dissemination of HIV prevention education are identified and strategies that may be effective in surmounting these barriers and implementing culturally-appropriate HIV behavioral modification programs are described.


3D acquisition and reconstruction in positron emission tomography.

3D positron emission tomography (PET) refers to an acquisition geometry and reconstruction procedure that allows all coincidence events within the solid angle of the tomograph to be recorded and subsequently reconstructed. The reconstruction algorithm must consider the angle of each coincidence event relative to the central axis of the scanner. The aim of the technique is to maximise the sensitivity of the system by utilising all events that it is possible to record from the object. Conventional cylindrical 2D PET systems typically detect approximately 0.4%-0.5% of decaying nuclei within the field of view; with a 3D system this can increase to over 3%. Reconstruction in 3D using filtered-backprojection techniques has been developed and provides results that show little degradation of physical characteristics compared with 2D systems, apart from an increased scatter event rate. 3D techniques may be used to (i) improve data quality using currently acceptable doses of radioactivity and scanning times; (ii) extend the scanning period for short-lived tracers, especially 11C-labeled ligands; or, conversely (iii) decrease injected doses of radiotracer or reduce scanning times to achieve similar results as those using current methods in 2D.


The role of nuclear medicine in oncology.

Nuclear Medicine offers screening methods for oncology such as bone and bone marrow scintigraphy. During the last two decades, special procedures have gained widespread application. This paper is centered around the "tumor-specific" radiopharmaceuticals. In patients with thyroid cancer, I-131 still plays a significant role. Ga-67 still has its indications in lymphoma, while in other diseases Tl-201 chloride is now the agent of choice. Especially in thyroid cancer, Tl-201 has proved to be a reliable tumor imaging radiopharmaceutical. More recently, Tc-99m MIBI was introduced for tumor imaging. Tc-99m HMPAO may also be used for tumor scintigraphy, especially in brain lesions. In addition, I-123 IMP has successfully been used for imaging malignant melanoma. Another promising field of tumor diagnosis is receptor imaging. In neuroblastoma and malignant pheochromocytoma, I-131/123 mIBG is the radiopharmaceutical of choice and may be considered as a receptor imaging agent also. First clinical results with In-111 octreotide show potentials as somatostatin-receptor radiopharmaceutical in insulinoma, islet cell carcinoma, medullary and lung cancer, while I-123 estradiol needs some improvement until it may be recommended as diagnostic tool in breast cancer. Since 1978, radiolabeled poly- or monoclonal tumor antibodies and their fragments have gained widespread application. Especially the Tc-99m 225.28S melanoma antibody, I-131 or Tc-99m CEA and In-111/I-131 labeled OC-125 antibodies have proven to be of clinical significance in melanoma, colorectal and ovarian cancer.


Re-appraisal of clinical usefulness of 67Ga-citrate scintigraphy for primary colorectal carcinoma: with evaluation of scintigram obtained from resected specimens.

Clinical usefulness of 67Ga-citrate scintigraphy for the diagnosis of colorectal carcinoma was reappraised at the standpoint of clinicopathological diagnosis. Fifty-eight patients with colonic carcinoma were subjected to this study. They underwent 67Ga scintigraphy before surgery. Colorectal carcinomas were detected in 38 patients, 65.5% by this procedure. Surgical specimens from thirty-seven patients underwent postoperative scanning. The scanning of the surgical specimen revealed accumulation of 67Ga-citrate in all 37 patients, suggesting that 67Ga-citrate accumulated in the carcinoma of the colon. The results suggested that detectability of carcinoma of the colon by 67Ga scintigraphy in this series was better than generally considered. 67Ga scintigraphy was considered to provide useful information in cases of severe stenosis and dolichocolon which were difficult to diagnose with a Barium enema and fiberscope. The problem is that abnormal accumulation is sometimes hard to distinguish from physiological excretion in the stools. However we believe that images should be carefully evaluated, keeping in mind the fact that 67Ga-citrate could accumulate in a colorectal carcinoma, and also believe that we radiologists should actively promote Ba-enema examination in positive cases rather than to devote time to the differentiation between physiological excretion of 67Ga in the stools and accumulation in a colorectal carcinoma.


Prolonged lung retention of 123I-IMP in pulmonary fibrosis.

We compared radiographic findings and the retention of N-isopropyl- p[123I]-iodoamphetamine (123I-IMP) in 23 patients with pulmonary fibrosis. During the 30 minutes following a rapid injection of 55.5 MBq of 123I-IMP into the antecubital vein, the image of regional activity was stored. After this, 185 MBq of 99mTc-MAA was injected and its image was stored to determine the region of interest. The half time (T1/2) of 123I-IMP release from the lung was calculated in each pixel between 10 and 25 minutes after the injection. Chest roentgenograms were taken, and the lung field was divided into 6 portions (right upper, middle and lower, and left upper, middle and lower). A quantitative score was assigned to the radiographic finding (X-ray score). The T1/2 values in the above patients were longer than the T1/2 values in normal subjects. Prolonged T1/2 values were observed in the lung fields which had high X-ray scores. The X-ray scores and the T1/2 values in corresponding areas had a positive relation.


Correction of scattered photons in Tc-99m imaging by means of a photopeak dual-energy window acquisition.

We are proposing a new method for correcting of scattered photons in technetium-99m (99mTc) imaging by means of photopeak dual-energy window acquisition. This method consists of the simultaneous acquisition of two images and estimation of a scatter image included in the symmetric energy window (SW) image by the difference between these images. The scatter corrected image is obtained by subtracting the scatter image from the SW image. In order to evaluate this method, we imaged a planar and a SPECT phantom with cold lesions and calculated the contrast value with and without the scatter correction. In addition, we performed asymmetric energy window (ASW) imaging to compare with this scatter correction method for planar images. In the planar image with the tissue-equivalent material of 10 cm, the scatter correction method removed 32% of the counting rate of the SW image and improved from 0.81 to 0.94 of the contrast value for a 4 cm-diameter cold lesion, while the contrast value with the ASW was 0.87 for such a cold lesion. The scatter corrected SPECT image had a reduction of 18% of the counting rate of the SW SPECT image and improvement of approximately 11% in contrast for cold spot sizes larger than a 3 cm-diameter, compared with the SW SPECT image. In addition, a perfusion defect could be well visualized by this scatter correction method on 99mTc-HMPAO regional cerebral blood flow SPECT of a patient. Our proposed scatter correction method can improve both planar and SPECT images qualitatively and quantitatively.


In vitro and in vivo characterizations of established human follicular carcinoma cell line derived from thyroid cancer: a novel model for well-differentiated thyroid malignant tumor.

A continuous cell line, named SMC R86 F1, was established from a surgically resected primary thyroid lesion. The cell grew as an adhering monolayer with a doubling time of about 25 hours in modified Eagle's medium supplemented with fetal bovine serum. When the cells were transplanted into athymic nude mice, tumors developed at the site of inoculation. The cells not only showed epithelial origin upon light and electron microscopic examination but also possessed a biosynthetic marker human thyroglobulin (hTg). In order to examine the iodide trapping ability of the xenografts, radioiodine at doses of 3.7 MBq was injected into the peritoneum of 131I treated nude mice bearing xenografts at about 4 weeks after the cell inoculation. Judging from the results of scintigraphic, autoradiographic and biodistribution studies, viable tissue of the xenografts in the treated mice had the ability to trap radioiodine. Histological sections of the xenografts resected from the treated mice consisted of follicle-like and trabecular growing structures, and immunohistochemically the cytoplasm of the tissues was hTg positive. The cells possessed the ability to trap radioactive iodine in vitro under the control of TSH. In addition, the expression of iodinated 19S Tg in the cell cytoplasms in the monolayer cultures was revealed by immunoblotting and autoradiographic assays. These observations provide strong evidence that the SMC R86 F1 cell line possesses well-differentiated properties of the malignant thyroid follicular epithelial cells.


An artificial amino acid radiopharmaceutical for single photon emission computed tomographic study of pancreatic amino acid transports 123I-3-iodo-alpha-methyl-L-tyrosine.

123I-3-iodo-alpha-methyl-L-tyrosine (123I-L-AMT) was selected and its characteristics on pancreas accumulation, metabolic selectivity and metabolic stability of 125I-L-AMT were studied. The studies on rat tissue slice as well as mouse biodistribution proved very high accumulation of 125I-labeled L-AMT in the pancreas, which was remarkably inhibited by the active transport inhibitor, ouabain. 125I-L-AMT does not enter into protein synthesis and general amino acid catabolism. Moreover, 125I-L-AMT was very stable against enzymatic deiodination. Thus, the above studies indicated that the 123I-labeled L-AMT was an "artificial amino acid" radiopharmaceutical to be used for the selective measurement of the membrane amino acid transport rate in the pancreas.


In vivo distribution of Tc-99m labeled recombinant tissue-type plasminogen activator in control and thrombus-bearing rats.

In vivo distribution of Tc-99m labeled recombinant tissue-type plasminogen activator (Tc-99m-rt-PA) was studied in control rats and thrombus-bearing rats. To compare fibrin binding in vivo with that in vitro, Tc-99m-rt-PA binding to fibrin gel in vitro was also imaged. Rapid blood clearance and accumulation into the liver and kidneys were observed in both control and thrombus-bearing rats. Accumulation in the stomach, which indicates instability of labeled rt-PA in vivo, was very low until two hours after injection. Tc-99m-rt-PA accumulation in the clots was higher than that in skeletal and heart muscles, although it was lower than in blood, liver, and kidneys. Administration of aprotinin, an antifibrinolytic agent, significantly prolonged clot accumulation of Tc-99m-rt-PA at 30 minutes after injection. These results suggest that fibrinolysis is responsible for the low rt-PA concentration in the clots. A scintigram of a thrombus-bearing rat demonstrated increased radioactivity at the clot forming site. On the other hand, Tc-99m-labeled human albumin, which was used as a control, was not accumulated in the clot. Tc-99m-rt-PA binding to fibrin gel in vitro was clearly imaged. By comparison, in vivo fibrin binding of Tc-99m-rt-PA was much lower than in vitro. The reasons for low thrombus uptake in vivo may be: 1. biochemical inactivation of extrinsically administered rt-PA by t-PA inhibitor. 2. fibrinolysis by rt-PA activated plasminogen. Overcoming these limitations will enable Tc-99m-rt-PA to reach the stage of clinical trials.


Localization of hyperfunctioning parathyroid glands by means of thallium-201 and iodine-131 subtraction scintigraphy in patients with primary and secondary hyperparathyroidism.

The accuracy of the preoperative localization of hyperfunctioning parathyroid glands by subtraction scintigraphy with 201Tl and 131I was evaluated by comparison with the operative findings. The subjects were 67 consecutive patients with hyperparathyroidism (HPT), including 24 with primary and 43 with secondary HPT. In primary HPT, surgery revealed 26 adenomas weighing 0.26-15.80 g (mean +/- SD; 3.01 +/- 3.04 g). Two patients had double adenomas. Scintigraphy correctly localized 25/26 adenomas (96.2%) in primary HPT for a sensitivity, specificity, and accuracy of 96.2%, 98.5%, and 97.9%, respectively. In secondary HPT, 163 hyperplastic glands weighing 0.03-5.08 g (0.85 +/- 0.93 g) were found. Scintigraphy correctly localized 79 glands (48.5%) weighing 0.03-5.08 g (1.19 +/- 1.10 g), but 84 glands (51.5%) weighing 0.04-2.70 g (0.51 +/- 0.50 g) were not detected. Thus, the sensitivity, specificity, and accuracy of scintigraphy were respectively 48.5%, 100%, and 51.2%, in secondary HPT. These results show that scintigraphy with 201Tl and 131I can be used to locate abnormal parathyroid glands with an efficacy equal to or better than that of the conventional methods with 201Tl and 99mTc or 201Tl and 123I.


Visualization of bladder diverticulum during Tc-99m DTPA renal scintigraphy.

An eight-year-old boy with recurrent urinary infection underwent Tc-99m DTPA renal scintigraphy for the evaluation of renal function. Stasis of the tracer was observed in the pelvocalyceal systems of both kidneys. Intravenous diuretic was administered to evaluate a possible mechanical obstruction. During the course of the study, a well-defined, round area of activity extended from the bladder which was subsequently confirmed to be a diverticulum on voiding cystourethrogram and at surgery.


The value of 99mTc-DTPA renal scintigraphy in the evaluation of post-traumatic abdominal fluid collection.

A patient with a post-traumatic retroperitoneal urinoma is presented. On admission, there was a clinical suspicion of retroperitoneal hematoma and ultrasonography (US) was performed which showed a hypoechoic fluid collection suggesting retroperitoneal hematoma. In order to determine the nature of the fluid, radionuclide angiography and renal scan were performed successively with 99mTc-DTPA. Demonstration of urinary leakage into the mass in the delayed renal scintigraphic images suggested a urinoma. At laparotomy, total transection of the left ureter in the uretero-pelvic region was found and the diagnosis of urinoma was confirmed.


Demonstration of inguinal hernia by means of peritoneal 99mTc-MAA scintigraphy with a load produced by standing in a patient treated by continuous ambulatory peritoneal dialysis.

A 45-year-old man receiving continuous ambulatory peritoneal dialysis developed scrotal swelling and edema which was aggravated in the standing position. Physical examination failed to find inguinal hernia and although ultrasonography revealed the patent had processus vaginalias, it failed to prove its continuity to the peritesticular space of the tunica vaginalis. Peritoneal scintigraphy with intraperitoneal instillation of 99mTc-Macroaggregated albumin followed by standing clearly demonstrated the connection. The use of the standing load makes possible faster visualization of a positive finding and more accurate diagnosis than examination in the supine position.


Functional and morphologic characterization of human T lymphocytes expressing the TCR gamma/delta.

A minor subset of T lymphocytes express a TCR composed of gamma and delta chains. This subset differs from conventional T cells for a number of phenotypic and functional characteristics. TCR gamma/delta+ cells simultaneously lack both CD4 and CD8 antigens. Cloning of CD4-8- peripheral blood lymphocytes, under limiting dilution conditions, revealed that they are homogeneously composed of cytolytic cells which efficiently lyse tumor target cells. Formal proofs have been provided that TCR gamma/delta+ cells are able to recognize antigens. For example, they proliferated in response to allogeneic mixed lymphocyte culture (MLC); in addition, MLC-derived TCR gamma/delta+ cells specifically lysed PHA-induced blast cells bearing the stimulating alloantigens. The selection of monoclonal antibodies specific for TCR gamma/delta molecules allowed to identify two distinct subsets of TCR gamma/delta+ cells. Both of these mABs, termed BB3 and delta TCS-1 respectively, induced specific activation of cloned cells expressing the corresponding antigenic determinants (as assessed by measurements of intracellular Ca++ and/or lymphokine production or cytolytic activity). Analysis of the distribution of subsets expressing different forms of TCR gamma/delta, showed that the BB3-reactive form is prevalent in the peripheral blood. In contrast, delta-TCS-1-reactive cells are relatively infrequent in peripheral blood but represent the majority of TCR gamma/delta+ cells in tissues.


Studies on NK cell purification by negative selection in human peripheral blood.

We have attempted to improve negative selection procedures for the large scale purification of human CD-3 CD56+ NK cells. In a series of experiments, purifications of NK cells from 10(8) PBMC were performed by T cell depletion using either direct or indirect anti-CD3 labeling and the Magnetic Activated Cell Separation (MACS) procedure. Contaminating CD3+ cells were still present using either one of these two different T cell depletion protocols as shown by phenotyping IL-2 supplemented cell cultures on day 12. A second cycle of purification was therefore added. When MACS and Dynabeads were compared as complementary procedures to the first MACS cycle starting with 10(8) cells, the Dynabeads method was found to be superior to the MACS with regard to the elimination of residual T cells. Starting from 10(9) PBMC, we showed that this MACS+Dynabeads procedure gave similar satisfactory results when compared to the scaling-up of a previously established two steps procedure using Dynabeads. These two approaches (MACS+Dynabeads and 2 cycles of Dynabeads) have been also tested in a clinical setting to purify NK cells from cancer patients prior to in vitro expansion. The results indicate that the two methods are equivalent with respect to purity and recovery rate; a slight advantage in terms of feasibility was found in favor of 2 cycles of Dynabeads.


Therapeutic and life-prolonging effect of intrapleural injection with a streptococcal preparation, OK-432, and IL2-cultured effusion lymphocytes to breast cancer patients with malignant pleural effusion.

We developed a local AIT using PEL cultured with TCGF combined with preadministration of OK-432. Twenty-six patients of breast cancer with pleural effusion have been treated with this therapy since 1983. PEL expanded and tumor cells collapsed by day 9 in culture with TCGF. Cultured PEL possessed significantly higher cytotoxic activity against autologous tumor cells than PBL cultured in the same condition (p less than 0.05), but there was no difference between their cytotoxic activities against K562. The proliferation rate of PEL obtained after intrapleural administration of OK-432 was higher than that obtained before OK-432 (p less than 0.01). Moreover, the cytotoxic activities against both autologous tumor and K562 of cultured PEL obtained after OK-432 administration was significantly (p less than 0.05) higher than those cultured PEL obtained before. Cultured PEL (1 x 10(8)-6 x 10(9)) were transferred into the pleural cavity after the intrapleural administration of OK-432 (1-5 KE). The volume of pleural effusion increased temporarily after the administration of OK-432 but significantly (p less than 0.01) decreased after AIT. Tumor cells disappeared cytologically in 22 patients at the last puncture of pleural effusion. Pleural effusion disappeared completely in 19 of 26 patients and decreased by more than 50% in volume in 6 patients. Performance status improved in 22 patients. The response rate for OK-432-combined AIT in the present study was 96%. The survival period of the patients treated by OK-432-combined AIT in this trial was significantly (p less than 0.002) prolonged compared to that of the patients receiving chemotherapy alone.(ABSTRACT TRUNCATED AT 250 WORDS)


Implications of HIV-specific cytotoxic T lymphocytes in AIDS.

The immune response to HIV in infected humans leads to the production of HIV-specific cytotoxic T lymphocytes (CTL) which circulate in high frequencies. The presence of these CTL and their eventual protective activities have been studied by various laboratories, and correlations have been made with certain immunopathological manifestations of HIV infections. It seems probable that HIV-immune CTL participate in the induction of certain disorders by initiating inflammatory reactions in the lungs, central nervous system, and lymph nodes. Various virus antigens recognized by HIV-immune CTL on the surface of the infected cell have been identified, and the molecular definition of the epitopes recognized is well under way. Likewise, numerous HLA transplantation antigens that regulate HIV antigen recognition by CTL have been identified. These data are discussed in view of the development of an eventual vaccine and of functional immunotherapies. They are compared with results obtained in animal experimental systems.


Effective in vivo induction of lymphokine-activated killer (LAK) cells by pretreatment with a streptococcal preparation, OK-432.

Effects of a streptococcal preparation, OK-432, on precursors of lymphokine-activated killer (LAK) cells were observed in vivo. Total number of splenocytes and the ratio of asGM1+ cells increased gradually after i.v. administration of OK-432, reaching their peaks at 3 to 4 days. It was found that asGM1+ cells were nonadherent and large in size. There were little differences in the ratios of Thy-1+, Lyt-2+, and L3T4+ cells before and after OK-432 treatment. Mice were injected i.p. with recombinant interleukin 2 (rIL-2) at a dose of 5 x 10(4) U per mouse 4 days after OK-432 administration and LAK activity in their splenocytes was examined using natural killer (NK) resistant EL-4 target cells. Splenocytes in mice treated with both OK-432 and rIL-2 showed higher LAK activity than those in mice treated with rIL-2 alone. In vivo treatment with anti asGM1 antibody prior to rIL-2 injection abolished completely such augmentation of LAK activity in OK-432 treated mice. These results demonstrated that asGM1+ LAK precursor cells induced by OK-432 were effectively differentiated into LAK cells by rIL-2.


Cytolytic T lymphocytes: an overview of their characteristics.

Cloned T cells have been useful for assessing the lytic potential of distinct T cell subsets and for determining the relative contribution of different effector mechanism involved in the lytic process. Alloreactive CD8+ murine T cell clones and cloned murine CD4+ TH1 and TH2 T cells reactive with nominal antigen (ovalbumin) lysed nucleated target cells bearing antigen or coated with anti-CD3 monoclonal antibody in a short term 51Cr-release assay. These clones were also evaluated for their ability to lyse efficiently sheep erythrocyte (SRBC) target cells coated with anti-CD3 mAb by a mechanism (presumably involving membrane damage) that does not involve nuclear degradation. Three patterns of lysis were observed: CD8+ and some CD4+ TH2 effector cells lysed efficiently nucleated target cells and anucleated SRBC coated with anti-CD3 mAb. However, CD4+ TH1 (and a few TH2) T cells which lysed nucleated target cells bearing antigen or coated with anti-CD3 mAb did not lyse efficiently the SRBC coated with anti-CD3 mAb. One CD4 bearing TH2 cell failed to lyse efficiently either nucleated target cells or anucleated SRBC coated with anti-CD3 mAb. These results indicate that both TH1 and TH2 clones have lytic capabilities. Furthermore, they suggest that some but not all TH2 murine T cell clones have lytic characteristics similar to those of conventional CD8+ CTL. However, it is not certain how these patterns of lysis of target cells in vitro relates to the capacity of CTL to lyse such target cells in vivo.


Enhancement of tumor cell susceptibility to lymphokine-activated killer cells by treatment with the streptococcal preparation OK432.

We investigated whether tumor cell lysis by LAK cells was augmented by treatment with OK432 in vitro. NK and LAK activity against K562 cells was not enhanced by their treatment with OK432. In contrast, the susceptibility of OK432-treated Daudi and KATO-III cells to lysis by LAK cells was enhanced. Succinate dehydrogenase activity and RNA synthesis were impaired in Daudi and KATO-III cells by treatment with OK432, and moreover the expression of HLA Class I antigen and beta 2-microglobulin was inhibited in OK432-treated KATO-III cells. Thus, it is suggested that the enhancement of the susceptibility of OK432-treated tumor cells with regard to succinate dehydrogenase activity, RNA synthesis, and HLA Class I antigen expression.


Malignant melanoma.

The incidence of malignant melanoma in some parts of the world continues to increase at a surprising rate. The medical profession is increasingly aware of the prognostic implications of tumour thickness, site and the potential value of early detection. Surgery for thin lesions remains overwhelmingly the most valuable therapy, and despite the very considerable endeavours of research groups around the world there is little sight of significant progress in increasing the survival of patients with more advanced disease. The reports summarised in this and previous annuals confirm the very disappointing results of cytotoxic drugs. The results referred to in this review establish that modern immunology is capable of devising much more specific immunotherapy than was tried in the early days of BCG and C. parvum; notwithstanding the considerable morbidity of some biological response modifications, it remains to be shown that the response rates achieved can provide useful extension of survival.


Pharmacodynamics of venlafaxine evaluated by EEG brain mapping, psychometry and psychophysiology.

1. In a double-blind, placebo-controlled study the effects of venlafaxine--a novel nontricyclic compound inhibiting neuronal uptake of serotonin, noradrenaline and to a lesser extent dopamine--were investigated utilizing EEG brain mapping, psychometric and psychophysiological measures. 2. Sixteen healthy volunteers (eight males, eight females) aged 21-36 years received randomized and at weekly intervals single oral doses of placebo, 12.5 mg, 25 mg and 50 mg venlafaxine. EEG recordings, psychometric and psychophysiological tests, and evaluation of pulse, blood pressure and side-effects were carried out at 0, 2, 4, 6, and 8 h. 3. EEG brain mapping demonstrated that venlafaxine exerted a significant action on human brain function as compared with placebo at all three doses, characterized mostly by attenuation of absolute power, increase of relative delta/theta and beta, and decrease of alpha power, as well as by an acceleration of the total centroid fronto-temporally and by its slowing centrally and parietally. These findings are similar to antidepressants such as imipramine. Topographically, drug-induced alterations were most pronounced over both fronto-temporal and the right temporal to temporo-occipital regions. 4. Psychometric and psychophysiological investigations demonstrated significant dose-dependent psychotropic properties of the drug. Multivariate statistics exhibited an improvement of both the noopsyche (e.g. attention, concentration, attention variability, memory, fine motor activity, reaction time performance) and thymopsyche (e.g. drive, wakefulness)) but also significant psychophysiological activation (e.g. in c.f.f., pupillary and skin conductance measures). 5. Time-efficiency calculations showed significant central effects from the 2nd hour onwards, with increasing differences between placebo and treatment up to the 8th hour. Nausea was the most frequent complaint and appeared dose dependent.


Scintigraphic studies on the corneal residence of a New Ophthalmic Delivery System (NODS): rate of clearance of a soluble marker in relation to duration of pharmacological action of pilocarpine.

1. A gamma scintigraphic study has been carried out on the precorneal residence and pharmacodynamic action of a radiolabelled New Ophthalmic Delivery System (NODS) containing pilocarpine nitrate in 12 healthy volunteers. 2. The NODS was radiolabelled with the soluble marker technetium-99m labelled diethylenetriaminepentaacetic acid, to mark the release characteristics of soluble drugs contained within the matrix. 3. The relationship between the precorneal residence time of the marker and the duration of drug effect on intraocular pressure and pupil diameter was monitored. Results obtained following administration of the NODS were compared with those obtained after administration of a 25 microliters drop of a 2% w/v pilocarpine nitrate solution. Each formulation was administered to one eye only, the other eye acting as a control. 4. Dissolution of the radiolabel from the NODS in vivo showed considerable intersubject variation with half-times of dissolution ranging from 46 s to 833 s (mean +/- s.d. -280 +/- 217 s), the mean (+/- s.d.) half-time of clearance of the radiolabel from the NODS and corneal region of interest was 406 +/- 214 s whereas the radiolabelled solution had a mean (+/- s.d.) ocular surface residence time of 2.9 +/- 1.5 s. 5. Pupil diameter and intraocular pressure were measured for 5 h post-administration of the NODS and the solution. After both treatments pupil diameter was significantly constricted in the test eye when compared with the control eye (P less than 0.001; Student's paired t-test). Pupil diameter was constricted by 52% after administration of the NODS and by 35% after administration of the solution.(ABSTRACT TRUNCATED AT 250 WORDS)


Autoinduction and steady-state pharmacokinetics of carbamazepine and its major metabolites.

1. The effect of carbamazepine (CBZ) dose change on mean plasma concentrations of CBZ, its two metabolites and apparent steady-state clearance was studied in 77 affectively ill patients receiving CBZ at doses of 100-1200 mg day-1. 2. Autoinduction of CBZ metabolism appeared to be complete within 1 week of starting CBZ therapy or dose change, and its degree was linearly related to CBZ daily dose. 3. Curvilinear plots were obtained for steady-state concentrations of CBZ and its -10,11-epoxide metabolite, and for the ratio of CBZ-10,11-epoxide to CBZ level, versus daily dose of CBZ. 4. On the contrary, steady-state concentration of CBZ-10,11-diol increased proportionately with the dose. This indicates that there is no dose dependency in absorption of CBZ, and that dose-dependent autoinduction of CBZ metabolism is the main cause of the curvilinear relationship between dose and steady-state concentration of CBZ and its intermediary metabolite, CBZ-10,11-epoxide.


The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects.

1. The pharmacokinetics and metabolism of oxycodone were studied in nine healthy young volunteers in a cross-over study. Each subject received oxycodone chloride once intramuscularly (0.14 mg kg-1) and twice orally (0.28 mg kg-1) at intervals of 2 weeks. A double-blind randomized pretreatment with amitriptyline (10-50 mg a day) or placebo was given prior to oral oxycodone. 2. The concentrations of oxycodone, noroxycodone and oxymorphone in plasma and the 24 h urine recoveries of their conjugated and unconjugated forms were measured by gas chromatography. 3. No differences were found between treatments in mean Cmax and AUC values of oxycodone which varied from 34 to 38 ng ml-1 and from 208 to 245 ng ml-1 h, respectively. The median tmax of oxycodone was 1 h in all groups. The bioavailability of oral relative to i.m. oxycodone was 60%. The mean renal clearance of oxycodone was 0.07-0.08 l min-1. The kinetics of oxycodone were unaffected by amitriptyline. 4. The mean ratio of the AUC(0.24 h) values of unconjugated noroxycodone to oxycodone was 0.45 after i.m. oxycodone and 0.6-0.8 after oral oxycodone. Plasma oxymorphone concentrations were below the limit of the assay. Eight to 14% of the dose of oxycodone was excreted in the urine as unconjugated and conjugated oxycodone over 24 h. Oxymorphone was excreted mainly as a conjugate whereas noroxycodone was recovered mostly in an unconjugated form.


Pharmacokinetics and pharmacodynamics of verapamil following sublingual and oral administration to healthy volunteers.

1. The pharmacokinetics and pharmacodynamics of verapamil administered via the oral and sublingual routes were compared in a randomised, two-way cross-over study involving six healthy male volunteers. 2. Administered sublingually, a verapamil 40 mg (Securon) crushed tablet produced a significantly higher peak plasma concentration (P less than 0.05), a greater rate of absorption (P less than 0.05), and greater bioavailability (P less than 0.05) when compared with orally administered verapamil 40 mg (Securon). 3. In comparison with oral dosing, PR intervals were significantly (P less than 0.05) prolonged between 30 and 90 min after sublingual verapamil dosing. 4. Correlations between log plasma verapamil concentration and percentage increase in PR interval were greater after sublingual compared with oral dosing in all volunteers.


The pharmacokinetics of mecillinam and pivmecillinam in pregnant and non-pregnant women.

1. The pharmacokinetics of parenteral mecillinam (n = 27) and oral pivmecillinam (n = 12) were studied in pregnant (n = 27) and non-pregnant (n = 12) subjects. 2. In early pregnancy (9-14 weeks of gestation) the mean peak plasma drug concentration (Cmax = 19 +/- 9 micrograms ml-1) after an intravenous injection of 200 mg mecillinam was significantly lower (P less than 0.05) and the volume of distribution (V = 49 +/- 20.1) significantly larger (P less than 0.05) than in non-pregnant subjects (Cmax = 35 +/- 18 micrograms ml-1, V = 29 +/- 12.1). In late pregnancy (39-40 weeks of gestation) the plasma mean peak concentration (Cmax = (29 +/- 14 micrograms ml-1) after parenteral administration of 200 mg mecillinam was slightly lower and the volume of distribution (V = 65 +/- 29.1, V = 0.9 +/- 0.4 l kg-1) significantly larger than that in non-pregnant subjects (V = 0.4 +/- 0.3 l kg-1). Also after oral administration of 200 mg pivmecillinam, equimolar to 136.5 mg mecillinam, the mean peak plasma concentration in pregnant subjects (Cmax = 1.8 +/- 1.2 micrograms ml-1) was slightly lower than that in non-pregnant subjects (Cmax = 1.7 +/- 1.2 micrograms ml-1). 3. The mean half-life of elimination after parenteral administration of mecillinam was significantly longer during both early (t1/2,Z = 133 +/- 38 min, P less than 0.05) and late pregnancy (t1/2,Z = 107 +/- 41 min, P less than 0.05) as compared with the non-pregnant state (t1/2,Z = 75 +/- 21 min).(ABSTRACT TRUNCATED AT 250 WORDS)


The excretion of dothiepin and its primary metabolites in breast milk.

1. The excretion of dothiepin, nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide into breast milk was studied in eight women. Exposure to drug was measured in five of their infants, and possible drug-related effects were assessed in all eight infants. 2. Using pre-feed milk samples mean (+/- s.e. mean) milk:plasma (M:P) ratios were 0.78 +/- 0.12, 0.85 +/- 0.16, 1.18 +/- 0.29 and 1.86 +/- 0.29 for dothiepin, nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide, respectively. In post-feed milk samples, the mean M:P ratio for dothiepin (1.59 +/- 0.32) was significantly greater (P less than 0.05) but M:P ratios for the metabolites were similar. 3. Mean total calculated infant daily doses, (in dothiepin equivalents and as a percent of the maternal dose) were 0.58% for dothiepin, 0.23% for nordothiepin, 2.47% for dothiepin-S-oxide, and 1.17% for nordothiepin-S-oxide. 4. Plasma samples were obtained from five infants. In one, both dothiepin and nordothiepin were below their minimum quantifiable levels (2 micrograms l-1) while in four others both dothiepin-S-oxide and nordothiepin-S-oxide were below their minimum quantifiable levels (10 micrograms l-1). No adverse effects were found in any of the eight infants. 5. Use of dothiepin by depressed mothers is unlikely to be a significant hazard to their breast-feeding infants.


The influence of particle size on the bioavailability of inhaled temazepam.

1. Temazepam was administered by aerosol using a standard protocol to healthy volunteers. Two studies are reported in which different dosage formulations were used: a) 30 mg of the 5 mu diameter particle (n = 6); b) 10 mg of the 2 mu diameter particle (n = 6). 2. An open crossover design was followed in each study. On one occasion in both studies subjects used a gargling procedure to remove drug which had been deposited in the mouth and oropharynx. 3. Serial venous blood samples were drawn for a period of 24 h. The mean total AUC of the 5 mu preparation was significantly reduced by gargling (3153 ng ml-1 h to 1066 ng ml-1 h) (F = 0.32). Gargling also had a significant effect on the mean AUC(0-1 h). 4. In contrast gargling had no significant effect on the mean AUC associated with the smaller diameter particle preparation (630 ng ml-1 h) vs 397 ng ml-1 h (F = 0.74). 5. These findings also indicate that temazepam deposition in the pulmonary tree is enhanced by the use of a 2 mu rather than a 5 mu diameter particle. However, the plasma drug concentrations achieved are unlikely to produce a sufficiently marked sedative effect for endoscopic investigations such as gastroscopy.


Variability of the serum protein binding of theophylline in patients with asthma and cystic fibrosis.

1. The serum protein binding of theophylline was studied in 28 asthmatics and 11 patients with cystic fibrosis (CF) who were receiving the drug regularly. Peak theophylline samples were collected at 2 week intervals on four occasions in each asthmatic and on three occasions in each CF patient. The binding was measured using ultrafiltration at 37 degrees C and pH 7.4. The total and free (unbound) theophylline concentrations were measured using high-performance liquid chromatography. 2. The mean free-fractions (+/- s.d.) in asthmatics (0.50 +/- 0.03) and in CF patients (0.51 +/- 0.04) were not significantly different. The intra- and inter-subject variability in the free-fraction (fu) was relatively small in both patient groups. The binding was found to be concentration-independent at serum theophylline concentrations up to 30.9 micrograms ml-1. The effects of age, gender, serum albumin and total serum protein on the free fraction were evaluated. 3. The results indicate that the binding of theophylline is similar in the two disease states. The low degree of variability in serum theophylline binding indicates that measurements of total serum theophylline concentrations will reflect unbound serum concentrations with acceptable accuracy in both patient groups studied.


The effect of a protein meal on zidovudine pharmacokinetics in HIV-infected patients.

Eleven HIV-infected men participated in a randomized, two-treatment, two-period crossover study to determine the effect of a 25 g protein meal on zidovudine pharmacokinetics. On two separate occasions, 1 week apart, each patient received 200 mg zidovudine in a fasting state or immediately following the protein meal. A protein meal significantly decreased Cmax [532 (228 s.d.) vs 802 (452 s.d.) ng ml-1, P = 0.004] and increased mean residence time (138 (26 s.d.) vs 114 (26 s.d.) min, corrected for lag times, P = 0.001). However, AUC, tmax, terminal half-life and renal clearance were not significantly altered (P greater than 0.05). The power to detect a 20% change in AUC was 98% at the 5% significance level. In contrast to fat-containing foods, protein-based meals may not alter the extent of zidovudine absorption.


Cyclosporin metabolism by human gastrointestinal mucosal microsomes.

The in vitro metabolism of the immunosuppressant cyclosporin (CsA) by human gastrointestinal mucosal microsomes has been studied. Macroscopically normal intestinal (n = 4) and liver (n = 2) tissue was obtained from kidney transplant donors, and microsomes prepared. Intestinal metabolism was most extensive with duodenal protein (15% conversion to metabolites M1/M17 after 2 h incubation at 37 degrees C; metabolite measurement by h.p.l.c). Western blotting confirmed the presence of P-4503A (enzyme subfamily responsible for CsA metabolism) in duodenum and ileum tissue, but not in colon tissue. The results of this study indicate that the gut wall may play a role in the first-pass metabolism of CsA, and could therefore be a contributory factor to the highly variable oral bioavailability of CsA.


Flosequinan does not affect systemic and regional vascular responses to simulated orthostatic stress in healthy volunteers.

1. The effects of a single oral dose (100 mg) of flosequinan on systemic and regional (forearm, splanchnic and renal) vascular responses to simulated orthostatic stress (lower body negative pressure, LBNP) were investigated in nine healthy male volunteers, in a double-blind, placebo-controlled crossover study. 2. Forty-five minutes after its administration and before LBNP, flosequinan induced a significant decrease in total peripheral and in forearm vascular resistances without any concomitant change in arterial pressure, in heart rate and in the investigated biological parameters (plasma catecholamines, arginine vasopressin and renin activity). 3. After flosequinan and placebo, LBNP induced similar decreases in central venous pressure at all levels of LBNP (-10, -20 and -40 mm Hg) and in pulse pressure at LBNP -40 mm Hg. LBNP-induced increase in forearm vascular resistance was significantly more marked after flosequinan than after placebo at all levels of LBNP, and this was also true for splanchnic vascular resistance but at LBNP -40 mm Hg only. However, inasmuch as the basal values of these two parameters before LBNP were lower after flosequinan than after placebo, their final values after LBNP -40 mm Hg were similar. Finally, LBNP-induced changes in renal vascular resistance, glomerular filtration rate and filtration fraction as well as in plasma catecholamines, arginine vasopressin and renin activity were similar after flosequinan and placebo at all levels of LBNP. 4. Flosequinan affected neither reflex control of heart rate (phenylephrine test) nor non-specific vasoconstrictor responses (cold pressor test). (ABSTRACT TRUNCATED AT 250 WORDS)


Postmarketing surveillance of captopril for hypertension.

1. A scheme for augmented spontaneous reporting of adverse drug events using advanced view data systems was developed and applied to study 67,698 consecutive patients prescribed captopril in general practice for the treatment of hypertension. 2. Captopril was an effective hypotensive agent in this population, as only 1.9% of patients were withdrawn because of apparent inefficacy. 3. Adverse effects of captopril resulted in withdrawal of treatment in 8.9% of recipients, and such effects were more frequent in elderly and female recipients. 4. Skin reactions--usually maculopapular rashes--tended to occur early during therapy whereas cough occurred much later and was reported more frequently in non-smokers. 5. Some 1.1% of recipients died during follow-up. There was no evidence of any unusual or unexpected causes of death which might be partially or totally captopril-related in the study cohort. 6. The study confirms the feasibility of large scale postmarketing surveillance studied in general practice and allowed risk benefit assessments to be made on the use of captopril for treating hypertension.


Pharmacokinetics of gamma-hydroxybutyric acid in alcohol dependent patients after single and repeated oral doses.

1. The pharmacokinetics of gamma-hydroxybutyric acid (GHB) were studied in 10 alcohol dependent subjects after single and repeated therapeutic oral doses (25 mg kg-1 every 12 h for 7 days). 2. GHB was readily absorbed and rapidly eliminated (tmax = 20-45 min; mean t1/2z 27 +/- 5 s.d. min). Urinary recovery of unchanged GHB was negligible (less than 1% of the dose). gamma-butyrolactone was not detected in either plasma or urine, indicating that lactonization of GHB does not occur in vivo. 3. The multiple-dose regimen resulted neither in accumulation of GHB nor in time-dependent modification of its pharmacokinetics. 4. In five subjects, the data were consistent with nonlinear elimination kinetics of GHB. Administration of a 50 mg kg-1 dose to these subjects resulted in significant increases in dose-normalized AUC, t1/2z and mean residence time. 5. Doubling of the dose also resulted in a significant increase in tmax with little change in Cmax. 6. At the administered doses, GHB did not accumulate in the plasma and caused no serious side effects.


The use of cimetidine to reduce dapsone-dependent methaemoglobinaemia in dermatitis herpetiformis patients.

1. We have attempted to reduce dapsone-dependent methaemoglobinaemia formation in six dermatitis herpetiformis patients stabilised on dapsone by the co-administration of cimetidine. 2. In comparison with control, i.e. dapsone alone, methaemoglobinaemia due to dapsone fell by 27.3 +/- 6.7% and 26.6 +/- 5.6% the first and second weeks after commencement of cimetidine administration. The normally cyanotic appearance of the patient on the highest dose of dapsone (350 mg day-1), underwent marked improvement. 3. There was a significant increase in the trough plasma concentration of dapsone (2.8 +/- 0.8 x 10(-5)% dose ml-1) at day 21 in the presence of cimetidine compared with control (day 7, 1.9 +/- 0.6 x 10(-5)% dose ml-1, P less than 0.01). During the period of the study, dapsone-mediated control of the dermatitis herpetiformis in all six patients was unchanged. 4. Trough plasma concentrations of monoacetyl dapsone were significantly increased (P less than 0.05) at day 21 (1.9 +/- 1.0 x 10(-5)% dose ml-1) compared with day 7 (1.6 +/- 0.9 x 10(-5)% dose ml-1:control). 5. Over a 12 h period, 20.6 +/- 8.9% (day 0) of a dose of dapsone was detectable in urine as dapsone hydroxylamine. Significantly less dapsone hydroxylamine was recovered from urine at day 14 (15.0 +/- 8.4) in the presence of cimetidine, compared with day 0 (control: P less than 0.05). 6. The co-administration of cimetidine may be of value in increasing patient tolerance to dapsone, a widely used, effective, but comparatively toxic drug.


N-demethylation of ethylmorphine in pregnant and non-pregnant women and in men: an evaluation of the effects of sex steroids.

1. The effects of oestrogens, testosterone, progesterone and medroxyprogesterone acetate (MPA) on the rate of N-demethylation of ethylmorphine (EM) to norethylmorphine (NEM) were studied in human adult liver microsomes. 2. N-Demethylase activity was found to be inhibited by progesterone and MPA to a similar extent while oestrogens and testosterone had no or negligible effects. 3. These findings prompted us to measure the N-demethylation of EM in relation to serum progesterone concentration in vivo in three groups of volunteers with large physiological differences in their endogenous levels of progesterone, i.e. i) pregnant women, ii) non-pregnant ovulating women and iii) men. 4. The metabolic ratio (MRP) of EM to NEM in plasma 60 min after dosage and the corresponding ratio in urine sampled for 6 h (MRU,1), measured on two occasions 14 days apart were used to reflect intraindividual variation in the rate of N-demethylation. 5. The average difference in MRP and MRU,1 between the two occasions was similar in all groups. However, the variability in MRP between individuals within a group was significantly higher in ovulating women than in men, but this had no relation to the serum concentrations of progesterone or oestradiol. 6. The cumulative 12 h urinary excretion of EM, NEM and morphine (MO) after hydrolysis with beta-glucuronidase was about 46%. There was no difference in the metabolic ratio of EM to NEM and its conjugate(s) in the urine between the luteal and the follicular phases. Our findings suggest that the menstrual cycle does not influence the rate of N-demethylation of EM.


Inhibitors of imipramine metabolism by human liver microsomes.

1. The aromatic 2-hydroxylation of imipramine was studied in microsomes from three human livers. The kinetics were best described by a biphasic enzyme model. The estimated values of Vmax and Km for the high affinity site ranged from 3.2 to 5.7 nmol mg-1 h-1 and from 25 to 31 microM, respectively. 2. Quinidine was a potent inhibitor of the high affinity site for the 2-hydroxylation of imipramine in microsomes from all three human livers, with apparent Ki-values ranging from 9 to 92 nM. This finding strongly suggests that the high affinity enzyme is CYP2D6, the source of the sparteine/debrisoquine oxidation polymorphism. 3. The selective serotonin reuptake inhibitors (SSRI), paroxetine, fluoxetine and norfluoxetine were potent inhibitors of the high affinity site having apparent Ki-values of 0.36, 0.92 and 0.33 microM, respectively. Three other SSRIs, citalopram, desmethylcitalopram and fluvoxamine, were less potent inhibitors of CYP2D6, with apparent Ki-values of 19, 1.3 and 3.9 microM, respectively. 4. Among 20 drugs screened, fluvoxamine was the only potent inhibitor of the N-demethylation of imipramine, with a Ki-value of 0.14 microM. 5. Neither mephenytoin, citalopram, diazepam, omeprazole or proguanil showed any inhibition of the N-demethylation of imipramine and the role of the S-mephenytoin hydroxylase for this oxidative pathway could not be confirmed.


The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes.

Inhibition of human cytochrome P4502D6 (CYP2D6)-catalysed metabolism can lead to clinically significant alterations in pharmacokinetics. Since there is evidence that the selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs might inhibit CYP2D6, the effects of five SSRIs on human liver microsomal CYP2D6 activity were compared with each other and with three tricyclic antidepressant drugs. On a molar basis, paroxetine was the most potent of the SSRIs at inhibiting the CYP2D6-catalysed oxidation of sparteine (Ki = 0.15 microM), although fluoxetine (0.60 microM) and sertaline (0.70 microM) had Ki values in the same range. Fluvoxamine (8.2 microM) and citalopram (5.1 microM) also inhibited CYP2D6 activity. The major circulating metabolites of paroxetine in man produced negligible inhibition. In contrast, norfluoxetine the active metabolite of fluoxetine, was a potent CYP2D6 inhibitor (0.43 microM). CYP2D6 activity was also diminished by the tricyclic antidepressant drugs clomipramine (2.2 microM), desipramine (2.3 microM) and amitriptyline (4.0 microM). These findings suggest that compounds with SSRI activity are likely to interact with human CYP2D6 in vivo with the potential of causing drug interactions.


Ipratropium bromide delivered orally by metered dose inhaler does not decrease salivary flow in normal subjects.

A randomised placebo-controlled cross-over group study was conducted to ascertain the occurrence and duration of xerostomia induced by 240 micrograms (high dose) and 120 micrograms (low dose) of ipratropium bromide (IPB) delivered by metered dose inhaler (MDI) into the mouth in normal subjects. Salivary output was higher with both doses of IPB than with placebo though the differences were not statistically significant. IPB was less palatable than placebo as indicated on visual analogue scale (VAS) and the taste of the drug may have caused a reflex increase in salivary output from the major salivary glands which would have masked any possible local effect of the drug on the smaller submucosal glands of the mouth. IPB delivered into the oral cavity by MDI is therefore not a suitable treatment for hypersalivation.


Ocular hypotensive effects of medifoxamine.

Medifoxamine is a novel monoamine re-uptake inhibiting antidepressive drug which preferentially inhibits dopamine reuptake. In human volunteer studies it has been found to reduce significantly intraocular pressure after single oral doses of 300-1000 mg, and to produce a small but statistically significant miosis. Its maximal ocular hypotensive action was less than that of oral timolol 20 mg.


Diffusion of cloxacillin into synovial tissue.

After a 30 min i.v. infusion of 1 g cloxacillin, the concentrations of this antibiotic were measured in plasma and synovial tissue samples from 11 patients undergoing total hip replacement. Assuming passive distribution between plasma and tissue the rate constants of distribution were estimated. The mean half-life of distribution was 22 min. The concentration of free drug in synovial tissue was estimated to be 77% of the total tissue concentration. The maximum tissue drug concentration after an i.v. bolus dose is predicted to occur at about 37 min.


A comparison of gastric emptying rate after cimetidine and ranitidine measured by applied potential tomography.

Gastric emptying was measured using applied potential tomography (APT) after crossover administration of 800 mg cimetidine and 300 mg ranitidine orally. Ten volunteers were studied, each on two occasions. Two hours after taking ranitidine or cimetidine, the volunteer was given a liquid and gastric emptying was measured over 60 min. There was a small but statistically significant delay in gastric emptying following ranitidine compared with cimetidine (P less than 0.04). The median (range) time to 50% emptying (t50) was 24 (15-60) min after ranitidine compared with 22 (15-46) min after cimetidine.


Therapeutic modulation of brain temperature: relevance to ischemic brain injury.

Hypothermia was first applied therapeutically as a local anesthetic and later was used to achieve organ protection during procedures necessitating circulatory interruption. Profound whole-body hypothermia, typically carried out in conjunction with extracorporeal bypass, has long been employed during cardiac and neurosurgical operative procedures. More recently, studies in small-animal experimental models of cerebral ischemia have provided persuasive evidence that even small decreases in brain temperature confer striking protection against ischemic neuronal injury. By contrast, small elevations of brain temperature during ischemia accelerate and extend pathologic changes in the brain and promote early disruption of the blood-brain barrier. Hypothermia retards the rate of high-energy phosphate depletion during ischemia and promotes postischemic metabolic recovery. More importantly, mild intraischemic hypothermia markedly attenuates the release of glutamate into the brain's extracellular space and significantly diminishes the release of dopamine. Similarly, the inhibition of calcium-calmodulin-dependent protein kinase II triggered by normothermic ischemia is prevented by hypothermia, as is the ischemia-induced translocation and inhibition of the key regulatory enzyme protein kinase C. Hypothermia also appears to facilitate the resynthesis of ubiquitin following ischemia. Studies of potential clinical importance have shown that moderate hypothermia is capable of attenuating ischemic damage even if instituted early in the postischemic period. In the setting of focal cerebral ischemia, moderate brain hypothermia reduces the infarct size (particularly in the setting of reversible middle cerebral artery occlusion); conversely, hyperthermia markedly increases the infarct volume. These studies underscore the importance of monitoring and regulating the brain temperature during experimental studies of cerebral ischemia to insure a consistent pathologic outcome and to avoid the false attribution of "pharmacoprotection" to drugs that reduce the body temperature. The measurement of brain temperature is now practicable in neurosurgical patients requiring invasive monitoring, and human studies have shown that cortical and cerebroventricular temperatures may exceed systemic temperatures. Mild to moderate decreases in brain temperature are neuroprotective in cerebral ischemia, while mild elevations of brain temperature are markedly deleterious in the setting of ischemia or injury. It is anticipated that controlled clinical trials of therapeutic brain temperature modulation will be undertaken over the next several years.


The blood-brain barrier and cerebral microcirculation in Alzheimer disease.

Current evidence does not preclude the possibility that breach of the blood-brain barrier (BBB) is causally involved in the pathogenesis of Alzheimer disease (AD). There is abundant evidence, however, indicating morphological and biochemical abnormalities in the cerebral microvasculature that implicate breakdown of the BBB in AD. These abnormalities include profound irregularities in the course of vessels and the vascular basement membrane, changes in specific proteins and receptors associated with the cerebral endothelium, and increases in perivascular infiltrates. While noninvasive imaging and permeability studies provide no clear functional evidence to support the prevailing morphological evidence, focal and transient loss of integrity of the BBB in AD is probable. Thus, neuronal populations in circumscribed areas could become vulnerable. Cerebral amyloid angiopathy (CAA) is one of the pathological features highly associated with AD that may exacerbate the degenerative process. CAA may develop as a consequence of vascular changes at predisposed sites and precede at least some of the parenchymal amyloid deposits. It is not unlikely that many of these vascular changes contribute to the development of chronic hypoperfusion (or cerebrovascular insufficiency) that may lead to the progressive decline of cerebral functions in concert with aging.


Capillary circulation in the brain.

A close relationship exists between the local capillary density in different brain structures and their local blood flow and metabolism. Capillary density appears to have developed depending on local functional demands. Investigation of single capillary perfusion has shown that all capillaries are perfused with plasma in the brain at any time point. Theories of capillary cycling and capillary recruitment have been based on experimental artifacts. Indirect evidence exists for a heterogeneity of perfusion under normal conditions, especially with respect to erythrocyte flow. The capillary diffusion capacity depends on, among other things, the available capillary surface area, which would increase with recruitment of capillaries. In the case of capillary perfusion heterogeneity, the capillary diffusion capacity may also be increased by homogenization of the perfusion rate (slowly perfused capillaries becoming faster perfused). This could give a physiological impression of an "apparent" increase in the capillary surface area. It is recommended that the terms "capillary cycling" and "recruitment" should be used in conjunction with more specific explanations, like "recruitment of erythrocytes" and "recruitment of previously nonperfused capillaries".


Structural characteristics of cyclodextrins in the solid state.

A comparison of alpha-, beta-, and gamma-cyclodextrins in the solid state is made. Monomeric features analyzed include orientations of primary hydroxyl groups and pyran ring pucker. Macromolecular features examined include planarity of the oligomer, tilting of pyran rings, and, deviation from Cn symmetry where n = number of monomers. The mean values and standard deviations of these shape descriptors are given for cyclodextrins with and without guests embedded in their interiors. Molecular mechanics calculations using the MM2, AMBER, and CHARMM force fields show that most solid state cyclodextrins are trapped in high-energy conformations relative to the most stable forms found in this study.


Synthesis and pharmacological investigation of stereoisomeric muscarines.

The synthesis of the eight stereoisomers of muscarine has been efficiently accomplished by utilizing the two enantiomers of lactic esters as starting material. The synthetic strategy is based on a SnCl4-catalyzed addition of allyltrimethylsilane to O-protected lactic aldehydes followed by an iodocyclization process. All the final derivatives possess an enantiomeric excess higher than 98%. The four pairs of enantiomers bound to M1, M2, and M3 muscarinic receptor subtypes in membranes from cerebral cortex, heart, and salivary glands, respectively, and recognized heterogeneous states of the receptors. Of the eight isomers, only natural muscarine (+)-1 recognized three affinity states of the M2 receptor. The compound was also the only one to show selectivity in the binding study, demonstrating 37- to 44-fold higher affinity for the M2 than for the M1 or M3 receptors. In addition, the compounds were tested in functional assays on isolated guinea pig atria (M2 receptors) and ileum (mixed population of M2 and M3 receptors) and their muscarinic potencies were determined. Among the eight isomers, again only (+)-1 enantiomer was found to be very active on both tissues. Its potency was more than two orders of magnitude higher than that of its enantiomer (-)-1 as well as the other six isomers. The eudismic ratios (E.R.) deduced from the two functional tests were 324 and 331.


Stereoselective binding of etodolac to human serum albumin.

The protein binding of etodolac enantiomers was studied in vitro by equilibrium dialysis in human serum albumin (HSA) of various concentrations varying from 1 to 40 g/liter, by addition of each enantiomer at increasing concentrations. In the 1 g/liter solution, at the lowest drug levels, the (R)-form is more bound than its antipode, the contrary being observed at the highest drug levels. For higher albumin concentrations, S was bound in a larger extent than R. Using the displacement of specific markers of HSA sites I and II, studied by spectrofluorimetry, it was suggested that R and S are both bound to site I, while only S is strongly bound to site II.


Enzymes in stereoselective pharmacokinetics of endogenous substances.

The use of enzymes to assay individual components of the L-carnitine family in pharmaceuticals, foodstuffs, and biological fluids with various forms of detection is reviewed. The most useful enzyme in the assay of compounds of the L-carnitine family is carnitine acetyl transferase (CAT), which catalyses the reversible interconversion of L-carnitine and its short-chain acyl esters. CAT can be used in one or more coupled reactions combined with U.V., or radiolabelled detection, or combined with HPLC, allowing, enantioselective, structurally specific, and, in the case of radiolabelled tracing, highly sensitive assays to be carried out. When compared with chromatographic separation of enantiomers or diastereoisomers, enantioselective enzyme mediated assays may be cheaper, more sensitive, and simpler, but they do not allow the nonpreferred isomer to be assayed. Consequently, they are appropriate for the specific assay of endogenous enantiomeric substrates of the enzyme concerned, in biological samples. The analysis of the other enantiomer in raw materials or in pharmaceuticals must be more properly approached by enantioselective chromatographic methods.


Stereospecific gas chromatographic method for determination of methadone in serum.

rac-Methadone is used clinically for the chronic maintenance treatment of heroin addiction and for the relief of pain. As the pharmacological activity of methadone is due primarily to the (-)-(R)-enantiomer, stereospecific measurements of methadone serum concentrations in methadone-treated patients are expected to be more relevant for clinical studies than earlier described total drug measurements. This study describes a stereospecific gas chromatographic (GC) method for the determination of methadone in serum. The extracted methadone was derivatizised with (-)-menthyl chloroformate. The diastereometric derivatives were analysed by GC on a capillary column and detected with a nitrogen-phosphorus detector. The resolution factor obtained for the methadone enantiomers was 1.1 with a relatively short time of analysis (30 min). By analysing the pure (-)-(R)-enantiomer, no racemization was seen during the analysis. The lower limit of quantitation was 75 nmol/l for each enantiomer. Measurements of the ratio between (-)-(R)- and (+)-(S)-methadone concentrations in serum from five methadone-treated patients showed interindividual differences (range 0.5-1.1). The patient results correlated well with those from another GC method measuring total methadone.


Resolution of terfenadine enantiomers by beta-cyclodextrin chiral stationary phase high-performance liquid chromatography.

Enantiomers of terfenadine were resolved by high-performance liquid chromatography (HPLC) using a chiral stationary phase (CSP) column packed with beta-cyclodextrin (beta-CD) covalently bound to silica. Separation was achieved in both the reverse phase and normal phase modes. Resolution of enantiomers was confirmed by ultraviolet-visible absorption, circular dichroism, and mass spectral analysis.


[Characteristics of cicatrization of wounds during the fetal period].

Recent clinical experience on open prenatal surgery in human beings, although scarce, suggests that skin wound healing in the fetus differs from that in adult life. This fact is supported by several experimental studies. Three types of skin wounds have been practiced in a group of thirty 23rd-gestational-day rabbit fetuses: sutured incision, non-sutured incision, and electrocautery burn. Seven days later, the resulting scars were assessed by mechanical and hystological studies. The results obtained were compared with those seen in 30 newborn rabbits and 30 adult rabbits in which the same wounds were carried out. In the fetuses, rupture tension of the sutured wound was 20% of that of the normal skin. A similar relationship was found in the group of adult rabbits. The sutured wounds in the fetuses showed a better macroscopic repair than in older rabbits. However, the non-sutured wounds and burns did not heal in the fetuses, on the contrary, their opening increased from the time of the lesion. These results seem to suggest that wound repair in the fetus is more like a remodeling process than in older ages.


[Total parenteral nutrition in rats].

Total parenteral nutrition (TPN) is difficult in rats because of their activity and aggressivity. On the other hand, this animal is an ideal experimental subject because it is easy to handle, resistant to infections, it has a short vital cycle and is very cheap. Long-term TPN can be simulated in rats after only relatively short periods of infusion. We report herein the results on TPN in rats obtained in our laboratory. Male Wistar rats (n = 86) weighing 170-225 g had a central line inserted under general anesthesia and received 330 mL/kg/day of fluids. They were divided into an Experimental Group (n = 70) that had a solution containing carbohydrates, proteins and lipids (310 Kcal/kg/day) and a Control Group (n = 16) receiving only saline and having free access to rat pellets. Total infusion time was 582.9 days. Twenty-five percent of the rats were withdrawn because of technical problems, 7% because of infection, 46% died and only 22% survived until the end of the experimental period. All animals gained weight. Those in the Experimental Group had significantly higher total protein and Chloride whereas those in the Control Group had higher leukocytes, BUN, liver weight, large bowel length and spleen relative weight. This TPN rat model is suitable for metabolic studies in the laboratory and should be further developed.


[Nuclear magnetic resonance of anorectal malformations and persistent postoperative fecal incontinence].

We review our experience with Magnetic Resonance Imaging (MRI) in the evaluation of 6 patients showing anorectal malformation, and 4 more with persistent postoperative fecal incontinence. Preoperative sagittal, axial and coronal planes were studied with special consideration to the pelvic and vertebral structures. The excellent resolution of MRI allowed accurate identification of the pelvic musculature in all patients, including those with bizarre sacral abnormalities. MRI revealed structural anomalies not detected previously, such as teathering cord, intraspinal lipoma, presacral mass and renal malformation. In our institution, MRI has replaced the CT scan in the study of patients suffering of persistent fecal incontinence. In non operated on cases of anorectal malformations, MRI determines with extraordinary accuracy the location of the rectal atretic pouch, the actual pelvic muscular quality, and the detection of previously unsuspected associated anomalies.


[Anorectal manometry in Hirschsprung disease].

To show the absence of inhibitory reflex of the anus (R.I.A.) by ano-rectal manometry is an important sign in the diagnosis of Hirschsprung's disease. Between 1989 and 1991, a series of 199 patients was studied. The patients were divided into two groups: 0-1 month and 1 month to 50 years. Both groups were subdivided into cases with or without clinical and radiological suspicion of aganglionism. In this series, R.I.A. was absent in 88 patients and present in 111. Histologic study and follow-up confirmed the existence of aganglionism in 86 patients, hyperganglionism in 1, anal stenosis in 8, cystic fibrosis in 4 and 1 coeliac disease; the rest were megarecta to a greater or lesser degree. There was 1 false negative, signifying a percentage of error of 0.5%.


[Androgen insensitivity syndrome. Diagnosis and therapy].

Ten patients with complete or incomplete androgens insensitivity syndrome (A.I.S.) is reported. Diagnosis of A.I.S. is presented on the basis: clinical, phenotype, studies of sexual steroids specially androgens, gonadotropins, 5-alpha-reductase activity and possible abnormality of androgen target cells from the genital skin. Histology of the testes is shown. Surgical treatment of these patients is reported, depending of the abnormality of the genitalia.


[Abdominal trauma at a third-level pediatric hospital: study of 150 patients].

All paediatric patients with abdominal trauma admitted in our hospital from 1975 to 1989 were retrospectively studied. We present 150 children with ages ranging from 1 to 14 years, mean age 6 +/- 2.6 years. Sixty-five percent of them were male. Trauma was classified as severe (37%) and mild (63%) and relationated with associated extra-abdominal injuries. The 42% of patients could be attended in other less specialized centres. Since 1982, severe abdominal trauma patient with parenchymal lesions of liver, kidney and spleen were treated according to a non-surgical protocol without secondary complications.


[Localization of the lower esophageal sphincter: a new formula].

The esophageal length in the study of patients with Gastroesophageal Reflux (G.E.R.) has the importance of assuring us of the correct position of the probe/sound of the esophageal ph-metering. We carried out a prospective study which correlated the size with the location of the Lower Esophageal Sphincter (L.E.S.), and we tried an approximation, greater than the one, obtained by other methods, in the measurement of the esophageal length, to obviate the manometric study, when our only aim was to insert correctly the probe/sound of the esophageal ph-metering.


[24-hour simultaneous esophagogastric pH-metry in children].

Twenty-four-hour pH-monitoring of the lower oesophagus is the best test for diagnosis of gastro-oesophageal reflux (GER) because it is the only one allowing its quantification. Unfortunately, it is limited by the fact that acid exposure is not the only mechanism by which GER harms the oesophagus. In the last 12 months we have introduced in our Institution simultaneous oeso-gastric pH-metering using a double-channel recorder and gastric and oesophageal electrodes. This procedure enables us to know when gastric pH turns alkaline because od diet, mucus, hypoacidity or duodeno-gastric reflux (DGR) to the point of making oesophageal pH-metering useless. We report 7 illustrative cases of GER with prolonged episodes of gastric alkalinization leading to oesophageal pH-metering false negatives. In the near future, double pH-metering will very probably modify our current interpretation of conventional tracings.


[Upper obstructive uropathies in newborns and infants. Our experience over the past 11 years].

We review 68 cases of ureterohydronephrosis in the newborn and nursling due to high urinary tract abnormalities, like ureteropelvic junction obstruction, obstructed megaureter, vesicoureteral reflux, renal duplication and simple ureterocele. A diagnostic evaluation is done, referred to his higher precocity, due to prenatal echographic screening. We evaluate also the surgical techniques employed, his complications and his indications. In the last five years, we have found that the definitive surgical correction in the neonatal period ive us good results.


[Urodynamic diagnosis and treatment of neurogenic bladder dysfunction].

A group of 55 patients (28M, 27F) with neurogenic bladder dysfunction was studied. Patient age ranged from 1m. to 20 years (mean age 9.1 years). Most of the patients had neurogenic bladder secondary myelomeningocele (70%). The urodynamic investigations demonstrated detrusor hyperreflexia in 50 (poor compliance in 28p) detrusor areflexia in 3 and normal bladder in 2. Six patients hadn't incontinence and didn't need treatment. The rest (49p), couldn't be dry more than 2 hours. After treatment (anticholinergic, alpha adrenergic agonist, alpha-beta adrenergic agonist, I. C. and bladder augmentation), the continence was improved satisfactorily in 38 patients (77.5%). In conclusion, we think that early treatment from neonatal period, supported with urodynamic studies may prevent long-term renal damage and most patients with neurogenic bladder do not require surgical intervention to improve continence because it can be controlled satisfactorily by other means.


[Anomalous course of a lipomeningocele].

A 9 months old male with a lipomeningocele developed progressive flaccid paraparesis with loss of deep tendon reflexes and sensation to pink prick on the lower extremities. The clinical picture was secondary to a tethered spinal cord syndrome associated to the lipomeningocele. Surgical untethering of the spinal cord was followed by clinical recovery over a 3 months period.


[Gastric duplication associated with heterotopic pancreas].

Gastric duplications are the least frequent location for the alimentary tract duplications, these location is approximately 8%. We present a case of gastric duplication in a neonate, who had a palpable abdominal mass and feeding intolerance. Barium study of upper gastrointestinal tract and ultrasound showed an extrinsic compression of antrum and cyst abdominal mass. The surgical procedure consisted of total excision without violation of the gastric lumen. Gastric mucosal was found by hystological study. Heterotopic pancreatic tissue was also found on the major omentum closely gastric cyst duplication.


[The "abdominal zipper": a surgical surprise].

In our surgical department there are two kinds of mandatory reoperations: the second look and enterostomies. How many times are we thinking to use a zip in a laparotomy, for avoiding abdominal wall damage? The first experience using zip in a newborn with neonatal sepsis and intestinal ischemia is presented. This device allowed to check the bowel every day and to perform the appropriate surgery. Seven days after last surgery we removed the zip and closed the abdominal wall.


[Duodenal atresia and heterotaxia].

We report two cases of duodenal atresia associated with corporal symmetry changes. The one of them presented a "situs inversus total" and the other one a Ivermak syndrome. The association between duodenal atresia and Ivermak syndrome has a very low incidence. We have not found references with respect to the association between duodenal atresia and "situs inversus totalis". The embryo-genetic hypothesis that could relate both anomalies are discussed. Perhaps are not caused by chance.


Health for All. Second evaluation in the Americas, 1991.

In 1991, the fourth stage of surveillance and evaluation was implemented, on progress attained towards reaching the goals of Health for All by the Year 2000 (HFA/2000). A regional report for the Americas was elaborated, to include the 28 national reports received by PAHO and the quantitative information of 11 countries and territories. The regional report was presented to and approved by PAHO Directing Council in September 1991. Following are the main conclusions.


The economic impact of the cholera epidemic, Peru, 1991.

A summary is presented of some of the results of a study designed to determine the economic impact of the cholera epidemic in Peru. The study was carried out by economists Margarita Petrera, principal investigator, and Maibí Montoya, assistant investigator, sponsored by PAHO/WHO upon request of the Peruvian Multisectoral Commission for the Campaign Against Cholera.


[Clinical considerations on spontaneous pneumothorax].

The authors, after confirming the social interest of spontaneous pneumothorax, report the results of their experience taking hint from it for some clinical considerations. They mention different therapies suggested for the treatment of this disease; particularly they dwell upon aspiration techniques considered today the treatment of choice in most cases. They conclude affirming that this technique improves results, diminishes risks and complications, and considerably reduces hospitalization.


[Leiomyosarcoma of the rectum].

Two cases of leiomyosarcoma of the rectum observed between 1980 and 1990 are reported. Both patients underwent abdominoperineal resection: one is still alive at three years from surgery, whereas the other died for neoplastic diffusion after three years. Epidemiological, clinical and therapeutic features of this rare tumor are discussed.


[Acute abdominal pain and appendicitis in childhood].

The diagnosis of acute appendicitis is still difficult to ascertain in children. However, a complete anamnesis, an accurate physical examination as well as a careful evaluation of other medical and surgical possibilities causing abdominal pain allow to arrive to a correct diagnosis in 80% of cases. Laboratory findings may be helpful but usually don't add further information. Each patient suspected to have appendicitis should be admitted to the hospital and kept under observation; if no improvement is registered during the following hours then a surgical exploration is needed. The surgeon, however, must be acquainted with the different medical affections causing abdominal pain in order to decide whether a laparotomy is required. The Authors report their experience in 426 patients submitted to appendectomy and stress the correlation between abdominal pain and intraoperative finding.


[Emergency treatment of caustic lesions of the upper digestive tract].

The role of an early multidisciplinary approach to the management of upper digestive tract caustic lesions in the acute phase is stressed. The accurate evaluation of the lesions through early endoscopy, performed within 24-48 hours of ingestion, is the best means of assessing the degree of injury after caustic ingestion. Massive gastric and/or oesophageal necrosis, tracheoesophageal fistula, massive gastric haemorrhage, gastric and/or duodenal perforation are indications for emergency surgery. Management techniques of acute lesions are controversial because results of the different surgical procedures proposed are not satisfactory. Surgery of complications is mandatory, but up to date morbidity and mortality rates are still high.


Evaluation of the bacteriological quality of seafood.

Bacteria largely determine the quality of fresh and lightly preserved fish products. This paper surveys traditional and rapid methods for estimation of bacterial levels in seafood. The use of traditional agar techniques is discussed with reference to development of substrates and procedures suited for fish and fish products. This includes estimation of the bacteria specifically involved in the spoilage process. During the last decade, several microbiological rapid methods or principles (DEFT, microcolonies, Limulus lysate, ATP, conductance, microcalorimetry, reduction of trimethylamine oxide (TMAO)) have been suggested for estimating the bacteriological quality of seafoods. A brief survey of these methods and the results obtained is given. Preliminary results on development of poly- and monoclonal antibodies against Shewanella putrefaciens are mentioned. Future research may involve the development of DNA-probes against genes coding for specific spoilage reactions.


A comparison of standard cultural methods for the detection of foodborne Salmonella.

The sensitivity of the standard cultural method of the International Organization for Standardization (ISO 6579 and ISO 3565 combined) was compared to that of the Health Protection Branch (HPB) procedure for the detection of foodborne Salmonella. Of 195 foods tested, 84 (43.1%) were found to contain salmonellae by one or more cultural conditions. Of these, 75 (89.3%) and 68 (81.0%) were identified by the ISO and HPB methods, respectively. The apparent lack of agreement between both methods likely stemmed from the low indigenous numbers of salmonellae in several food homogenates, and unequal transfer of the target microorganism into homologous ISO and HPB pre-enrichment broths. The sensitivities of the commercially available Muller-Kauffmann tetrathionate broth (MKTBG43, Oxoid CM343), and a closely-related medium prepared with Oxoid CM29 tetrathionate base varied from 86.9 to 89.3%, and were deemed equivalent to that obtained with the ISO formulation of MKTBG43 (89.3%). Comparatively fewer contaminated samples were identified from selenite cystine (SC35) and selenite brilliant green (SBG35) enrichment cultures (82.1-83.3%). The high selectivity and saccharide-independent response of the bismuth sulfite agar medium warrants its consideration as a mandatory plating medium in ISO methodologies for the effective detection of typical and atypical biotypes of foodborne Salmonella spp.


The contamination of pork with spoilage bacteria during commercial dressing, chilling and cutting of pig carcasses.

Swab samples from the surfaces of carcasses and cuts were obtained at various stages of the dressing, chilling and cutting operations in three pig processing plants. The aerobic microflora obtained from those swabs were enumerated and characterized. The flora on the skins of carcasses exiting the scalding tanks were dominated by Gram-positive organisms, with numbers about 10(3)/cm2. After dehairing, numbers were about 10(4)/cm2 with major fractions of Gram-negative organisms. Flora numbers and compositions were largely unaltered after the singeing operations, but lesser numbers were recovered after the carcasses were polished. Carcass dressing did not change the numbers on the skin. During the chilling of carcasses, the flora at two large plants altered little, but drying of the carcass surfaces at a smaller plant reduced the Gram-negative fraction of the flora. Numbers on serous and fat surfaces exposed during the dressing and cutting of carcasses were initially about 10(2)/cm2. That number was approximately maintained on finished skinned cuts produced at the smaller plant, but further contamination with lactobacilli and Brochothrix thermosphacta occurred during cutting. At the larger plants, the flora on skinned cuts were similar to those on skins, although further contamination with B. thermosphacta occurred at one plant.


[Postoperative infections: the use of thymostimulin (TP1) in patients at risk].

The authors report data related to 212 surgical patients at risk because immunocompromised. Patients were divided in two homogeneous groups, one treated with Thymostimulin and the other as a control group, all affected by severe pathologies. Patients presenting postoperative complications directly related to technical reasons were excluded. Morbidity, postoperative hospitalization and mortality were the parameters considered. Positive results were obtained in the treated group compared to controls. Therefore, it is Authors' opinion that the treatment with Thymostimulin in immunocompromised patients is important in order to avoid or reduce postoperative infection rates.


[Non-palpable lesions of the breast: identification, localization, significance].

The authors report the diagnostic protocol used in the Breast Disease Unit of the 1st Surgical Department - University of Rome "La Sapienza" - (1987-1990) as well as the techniques for identifying and localizing nonpalpable lesions of the breast. Mammographic screening in women over 40 years, ultrasonography in women under 40 years, X-ray and ultrasound-guided fine needle aspiration and stereotactic guide wire placement with excisional biopsy, resulted to be diagnostic in 79 cases of carcinoma of the breast (2.0%) of which 13 (16.4%) were nonpalpable lesions. Moreover, the importance of nonpalpable lesions is discussed, pointing out how "very early" diagnosis of carcinoma of the breast plays a fundamental role with respect to both prognosis and treatment. The very early diagnosis of a "minimal" carcinoma ensures a significant increase in survival as well as more conservative surgical procedures that offer a better quality of life being less psychologically traumatic.


Rapid identification of Saccharomyces cerevisiae, Zygosaccharomyces bailii and Zygosaccharomyces rouxii.

Most strains of Saccharomyces cerevisiae, Zygosaccharomyces bailii and Zygosaccharomyces rouxii have been found to contain plasmid DNA. The sequences of the plasmids from these three yeasts are known to be different. We have used two primers within the plasmid from each yeast species in a multiplex polymerase chain reaction (PCR) to discriminate between these three yeasts. The primers were designed to give easily distinguishable fragment sizes when run on a simple agarose gel. Due to the sensitivity of PCR, crude cells can be used with no need to isolate DNA. The method is rapid when compared with current methods.


[Single lung transplantation: experimental technique and functional results].

Single lung transplantation was performed in 22 pigs. The first 10 experiments were devoted to settle the surgical technique: in these cases we employed small animals (8-12 kg); technical difficulties and the high incidence of perioperative complications induced us to utilize bigger animals (greater than 20 kg) in the subsequent experiments. In the recipient, after left pneumonectomy we prepared the right pulmonary artery and encircled it with an inflatable silicon cuff connected to a reservoir positioned outside the chest cavity of the animal. The inflation of the cuff allows the complete occlusion of the right pulmonary artery and thus the functional evaluation of the isolated transplanted lung. Perioperative functional evaluation has been performed at different times till the third postoperative day, documenting the good status of the transplanted lung. This study confirms the possibility to employ pigs for experimental single lung transplantation to settle the surgical technique with economic and organizing advantages. Furthermore, it confirms the good results achieved in the dog, in which the occlusion of the contralateral pulmonary artery by means of an inflatable silicon cuff allows to evaluate the isolated transplanted lung function.


Occurrence of Yersinia enterocolitica in milk and dairy products in Morocco.

A total of 227 samples of milk and dairy products were examined for the presence of Yersinia enterocolitica. Yersinia spp. were recovered from 11 of 30 raw milks (36.6%), one of 20 pasteurized milks (5%), 15 of 63 traditional fermented milks (23.8%), seven of 94 cheeses and one of 20 cream samples (5%). The overall incidence of Y. enterocolitica in milk and dairy products was 6.6%. The other Yersinia species were Y. intermedia, Y. kristensenii, Y. frederiksenii and Y. pseudotuberculosis. Y. enterocolitica was detected only in raw milk (30% of the samples), in traditional fermented milks (6.3%) and in raw milk-made cheese (4%). The majority of the Y. enterocolitica isolates were of biotype 1 (environmental strains). The Celfulodin-Irgasan-Novobiocin (CIN) Agar was found to be more efficient than the Mac Conkey Agar in the isolation of Yersinia organisms.


Antibiotic and disinfectant susceptibility in Enterobacteriaceae isolated from minced meat.

The resistance of Enterobacteriaceae isolated from minced meat to antibiotics and to an amphoteric surfactant, was examined. Despite the wide range of antibiotic resistance occurring in the strains tested, resistance to the disinfectant was not observed.


Distribution of saposins (sphingolipid activator proteins) in tissues of lysosomal storage disease patients.

Saposins are a group of small glycoproteins derived from a single precursor protein, prosaposin. Each of the four saposins are involved in lysosomal hydrolysis of various sphingolipids. Our recent investigations have shown that saposins accumulate in tissues of several lysosomal storage diseases patients, including those with Tay-Sachs disease and Gaucher disease. To obtain insight into the mechanism of accumulation and its pathological role, the subcellular distribution of saposins in brain from Tay-Sachs disease and in spleen of Gaucher disease were compared with that of GM2 ganglioside and glucocerebroside, respectively. In both Tay-Sachs brain and Gaucher spleen, saposins were found predominantly in light-density fractions while most of the GM2 ganglioside and glucocerebroside, respectively, were found in heavy-density fractions. These studies indicate that saposins that accumulate in these pathological tissues are not tightly associated with GM2 ganglioside or glucocerebroside.