Purification and properties of human hepatic 3 alpha-hydroxysteroid dehydrogenase. 3 alpha-Hydroxysteroid dehydrogenase (3 alpha-HSD) was purified greater than 500-fold from human liver cytosol. The purification was monitored using 5 beta-[3H]dihydrocortisol (5 beta-DHF) as substrate. Electrophoretically homogeneous enzyme was obtained using a procedure that involved ammonium sulfate precipitation and three successive column chromatography steps: DEAE-cellulose, hydroxylapatite and Blue-Sepharose. The enzyme is a monomer since the native molecular weight was found to be 37,000, using a calibrated Sephadex G-75 column, and the denatured subunit molecular weight was determined to be 38,500, by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. The enzyme had a pI of 5.6-5.9. The 3-ketosteroids: cortisol, testosterone, progesterone and androstenedione, were not substrates for 3 alpha-HSD indicating that a saturated 4,5 double bond was required for substrate activity. The conformation at the 5 position, however, did not influence substrate activity since 5 alpha- and 5 beta-DHF and 5 alpha-dihydrotestosterone were all reduced at similar rates. The purified enzyme preferred NADPH to NADH as a cofactor and showed a broad peak of activity in the pH range of 6.8-7.4. The apparent Km for 5 beta-DHF was 18 microM. The enzyme was markedly stabilized by 50 mM phosphate buffer containing 10 to 20% glycerol at 4 degrees C. Freezing and thawing of the enzyme resulted in a large loss of activity during early stages of the purification. This is the first report of the purification to homogeneity of 3 alpha-HSD from human tissue.


Actions of acetyl-L-carnitine on the hypothalamo-pituitary-gonadal system in female rats. Acetyl-L-carnitine (ALC) is known to affect several aspects of neuronal activity. To evaluate the neuroendocrine actions of this compound, several endocrinological parameters were followed in ALC-treated and control animals during recovery from dark-induced anestrus. In treated animals, serum luteinizing hormone (LH) and prolactin levels were higher than those of controls during the proestrous and estrous phases of the cycle, and serum estradiol levels were higher during estrus. No significant changes were observed in serum levels of follicle-stimulating hormone and progesterone. Uterine weight was increased in ALC-treated rats during proestrus and estrus, but not in diestrus. The basal release of gonadotropin-releasing hormone (GnRH) from perifused hypothalamic slices of ALC-treated animals was elevated at proestrus and diestrus, and GnRH release elicited by high K+ was higher during all three phases of the cycle. The basal release of LH from perifused pituitaries of treated animals was elevated in diestrus, and the LH response to GnRH was higher in estrus and diestrus I. Depolarization with K+ caused increased LH secretion during proestrus and estrus in treated animals. In contrast to these effects of ALC treatment in vivo, no direct effects of ALC were observed during short- or long-term treatment of cultured pituitary cells. These results indicate that ALC treatment influences hypothalamo-pituitary function in a cycle stage-dependent manner, and increases the secretory activity of gonadotrophs and lactotrophs. Since no effects of ALC on basal and agonist-induced secretory responses of gonadotrophs were observed in vitro, it is probable that its effects on gonadotropin release are related to enhancement of GnRH neuronal function in the hypothalamus.


Familial and iatrogenic cortisol receptor resistance. Primary cortisol receptor resistance has been reported in 6 patients and 14 asymptomatic family members. We observed an additional 6 patients (2 males and 4 females). The male patients presented with hypertension. The female patients presented with acne, hirsutism and irregular menstruations. Dexamethasone therapy (1-1.5 mg/day) was of considerable clinical benefit. All 6 patients showed insufficient suppression of cortisol after 1 mg dexamethasone. The diurnal rhythm of ACTH and cortisol was intact, albeit at an elevated level. There was a normal increase of ACTH, cortisol, and GH to insulin-induced hypoglycemia, while cortisol production was (slightly) elevated. Adrenal androgen levels were increased in all patients. Glucocorticoid receptors measured in a whole cell dexamethasone binding assay in mononuclear leukocytes showed a lowered affinity in 1, and lowered numbers of receptors in 4 patients. In 1 patient no abnormalities were found. As a "bioassay" for glucocorticoid action dexamethasone suppressibility of mitogen-stimulated incorporation of [3H]thymidine in mononuclear leukocytes was measured. In this last patient dexamethasone suppressibility of [3H]thymidine incorporation was significantly lowered. Twelve months' treatment with 200 mg RU 486 per day in meningioma patients induced a similar biochemical picture as observed in primary cortisol receptor resistance. Partial cortisol receptor resistance might be less rare than previously thought. In the 6 patients presented at least 3 different forms can be recognized. Therapy with dexamethasone was successful in female patients with acne and hirsutism, as the secondary overproduction of adrenal androgens was effectively controlled. Chronic therapy with RU 486 causes a biochemical picture similar to primary cortisol receptor resistance.


Glucocorticoid receptors.

Glucocorticoid receptors. Glucocorticoid hormones are secreted uniquely from the zona fasciculata of the adrenal cortex, with marked circadian variation in basal levels and acute elevation in response to stress. Glucocorticoid receptors are almost ubiquitously distributed, and mediate a wide range of tissue-specific responses; in addition to classical, [3H]dexamethasone-binding GR (Type II receptors) there is excellent evidence that Type I sites (MR) act as mineralocorticoid receptors in some tissues but high affinity glucocorticoid receptors in others. Particular issues to be addressed in the presentation include: (i) the extent to which glucocorticoid receptor occupancy is modulated by extracellular (plasma-binding enzymes) or intracellular (proto-oncogenes) factors; (ii) whether or not there are specific response elements for Type I and II receptors; (iii) putative physiological roles for Type I, high affinity glucocorticoid receptors; (iv) evidence for glucocorticoid receptors other than classical GR and "MR". In summary, glucocorticoid receptors appear to be a final common pathway mediating and/or modulating circadian rhythms and stress responses. Cell-and tissue-specificity of response to a whole-body signal is determined by local pre-receptor, receptor and genomic differences. On the basis of previous studies on glucocorticoid secretion, and recent information on glucocorticoid action, it would at last appear possible to begin to construct a coherent physiology for glucocorticoid hormones.


Glucocorticoid-dependent hypertension.

Glucocorticoid-dependent hypertension. Glucocorticoid (GC) excess (Cushing's syndrome) is associated with hypertension in at least 70% of patients (in our series 89/130), independently of the subtype (pituitary or adrenal) and the duration, but not of the age of the patients. Cardiovascular damage is quite frequent in hypertensives, but is sometimes also present in normotensives. The mortality of patients with Cushing's syndrome is four times that of the general population when matched for age and sex, and much of this excess mortality is caused by cardiovascular disease. Hypertension remits in most of the patients after successful treatment, but may persist in some. Hypertension also occurs in 20% of patients treated with GC orally. The type of hypertension is independent of salt uptake, can not be controlled by spironolactone but is inhibited by a GC antagonist such as RU486. Experimentally-induced hypertension with oral cortisol (F) is associated with a rise in cardiac output, a fall in calculated total peripheral resistance, an increased forearm vascular responsiveness to exogenous norepinephrine, but no change in overall sympathetic tone, or in norepinephrine reuptake. The increased pressor responsiveness is probably due to local postsynaptic effector mechanisms in the resistance vessels, which could be important in phasic increases in neuronally mediated constrictor responses. Both in patients with Cushing's syndrome and in those on chronic GC treatment, the circadian blood pressure variations are absent or reversed. This may contribute to the deleterious effects of the GC excess on blood vessels. The vascular effects of the GC may be mediated by the activation of specific cardiovascular receptors, by modulating vascular transport systems, or by altered catecholamine or prostaglandin metabolism. GC may also act as mineralocorticoids (MC): in fact type 1 MC receptors are unable, in vitro, to distinguish between aldosterone and cortisol. The specificity-conferring mechanism of typical target organs for MC (e.g. kidney)--is thought to be due to the action of local 11-beta-hydroxysteroid dehydrogenase, which converts F to biologically inactive cortisone (E). When the activity of the enzyme is impaired (syndrome of apparent MC excess, liquorice or carbenoxolone administration), F acts as a MC and MC-hypertension with hypokalemia occurs.(ABSTRACT TRUNCATED AT 400 WORDS)


Bone and cartilage responsiveness to sex steroid hormones. Gonadal steroids influence the skeletal growth and metabolism both during the pubertal growth spurt and in adulthood with aging. It is now generally agreed that sex steroid effect on skeletal tissues is due to indirect and direct actions. In this presentation, in vitro effects of sex steroids on cartilage cells are reported by comparison with those observed on bone cells.


Sertoli-germ cells interactions in the human testis. In previous histoimmunochemical studies we reported that transferrin (TF) and insulin-like growth factor I (IGF-I) are present in the cytoplasm of the Sertoli cells of the adult human testis. Receptors for TF were found mainly in adluminal germ cells and type I receptors for IGF-I both in Sertoli and germ cells. Using electron microscopy, evidence of transfer of both TF and IGF-I from the Sertoli to the germ cells through a receptor-mediated endocytosis mechanism was also found. In this paper we report the results of the histoimmunochemical localization of alpha inhibin in the human fetal, prepubertal and adult testis. In 8- to 14-week-old fetal testes a positive immunostaining was found mainly in the interstitial cells, whereas no staining was found in the germ cords. In the prepubertal testis the immunostaining was present in the Sertoli cells but not in the interstitial cells. In the adult human testis the immunostaining was present not only in the Sertoli cells but also in the spermatocytes and in several Leydig cells. Using electron microscopy and immunogold labeling the presence of alpha inhibin immunoreactivity was found in the rough endoplasmic reticulum and in the Golgi cisternae of both Sertoli and Leydig cells. Moreover we found evidence of transfer of alpha inhibin from the Sertoli to the germ cells through receptor-mediated endocytosis.


Steroidal and non-steroidal factors in plasma sex hormone binding globulin regulation. Sex hormone binding globulin (SHBG) is a specific steroid-binding plasma glycoprotein regulated by several factors. Sex steroids are currently considered to be the main physiological regulators of this protein. SHBG levels, in fact, increase during estrogen treatment and decrease after androgen administration. It is well known, however, that in many physiological and pathological conditions SHBG concentrations cannot be explained only on the basis of steroidal control mechanisms. The regulation of SHBG levels is in fact more complex and other factors can also affect its plasma values. Between the steroidal factors our attention was focused on the role of androgens, of glandular and peripheral origin, in their capacity to lower SHBG plasma levels. We studied hyperandrogenic conditions in prepubertal (65 subjects with precocious adrenarche and 16 girls with prepubertal hypertrichosis, aged between 4 and 8 years) and in adult age (51 hirsute patients aged between 14-35 years and 51 acneic patients aged between 15-40 years). The effects of dexamethasone and ACTH administration on SHBG plasma levels were also evaluated. The results obtained showed that in adult hyperandrogenic patients SHBG levels, significantly lower than in controls, were not always inversely correlated with androgen levels, which, on the contrary, were higher than in controls. In patients with precocious adrenarche we found an inverse correlation only between SHBG, which was significantly lower than normal, and body mass index or bone age but not with androgens, suggesting that in this condition other factors may be more relevant than steroids in SHBG regulation. Between the non-steroidal factors our attention focused on insulin. We studied 40 non-obese hyperandrogenic patients with or without ultrasonographic evidence of polycystic ovaries, aged 18-39 years, and 35 obese patients, aged 19-37 years, with or without hyperandrogenism or evidence of PCO. Low levels of SHBG were found not only in hyperandrogenic obese patients but also in obese patients with normal androgens. It is possible to conclude that (1) several factors (calorie intake, energy balance and growth factors), other than steroids, may be involved in the regulation of SHBG levels in plasma; and (2) each regulating factor may act to a different extent depending on the various periods of the life cycle.


The potential relevance of cytokines to ovarian physiology. Elucidating the secrets of intraovarian intercellular communication constitutes a central area of investigation. While most attention has been directed thus far at the somatic cellular components of the ovary, the potential role(s) and relative importance of the resident ovarian white blood cell have received relatively limited attention. Efforts are currently under way to reconcile traditional ovarian physiology with observations relevant to intraovarian components of the white blood cell series. In this connection, it is important to note that unlike some gonadal compartments, the ovary does not constitute an immunologically privileged site. Thus, resident ovarian representatives of the white blood cell series can be observed at various stages of the ovarian life cycle. Current concepts suggest that regulatory cellular networks formerly viewed in immune terms now fall within the broad domain of endocrinology. Viewed in this light, resident ovarian representatives of the white blood cell series may constitute potential in situ modulators of ovarian function acting in all likelihood through the local secretion of regulatory cytokines. As the flow of information is probably multi directional, the very same cells are probably targeted for steroidal and peptidergic input in keeping with the existence of multiple autocrine and paracrine loops.


Control of steroidogenesis in Leydig cells. Luteinizing hormone (LH) interacts with its plasma membrane receptor to stimulate steroidogenesis not only via cyclic AMP but also other pathways which include arachidonic acid and leukotrienes and regulation of chloride and calcium channels. The same stimulatory pathways may lead to desensitization and down-regulation of the LH receptor and steroidogenesis. The LH receptor exists in a dynamic state, being truncated, or internalized, degraded or recycled. Desensitization is controlled by protein kinase C (PKC) in the rat and by cyclic AMP dependent protein kinase and PKC in the mouse Leydig cells. Using an adapted anti-sense oligonucleotide strategy we have shown that the cytoplasmic C-terminal sequence of the LH receptor is essential for desensitization to occur. In contrast, these sequences of the LH receptor are not required for the stimulation of cyclic AMP and steroid production. We have also shown that the extracellular domain of the LH receptor is secreted from the Leydig cell and may act as a LH-binding protein.


Ontogeny and subcellular localization of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in the human and rat adrenal, ovary and testis. Primates are unique in having adrenals that secrete large amounts of the precursor sex steroids (PSS) dehydroepiandrosterone (DHEA) and especially DHEA-sulfate. The adrenal PSS require the action of 3 beta-hydroxysteroid dehydrogenase/5-ene-4 ene isomerase (3 beta-HSD), 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), 5 alpha-reductase and/or aromatase to form the androgen dihydrotestosterone (DHT) or the estrogens 17 beta-estradiol and androst-5-ene-diol. Knowing the crucial role of 3 beta-HSD and 17 beta-HSD in sex steroid biosynthesis both in classical as well as in peripheral steroidogenic tissues, we have concentrated our efforts on the elucidation of the molecular structure of these enzyme families. We have thus characterized two types of human 3 beta-HSD cDNA clones and their corresponding genes which encode deduced proteins of 371 and 372 amino acids and share 93.5% homology. Human type I 3 beta-HSD is the almost exclusive mRNA species expressed in the placenta and skin, while human type II is the predominant mRNA species in the adrenals, ovaries and testes. We have also recently elucidated the structure of three types of rat 3 beta-HSD cDNAs which all encode a 372 amino acid protein. The predicted rat type I and II 3 beta-HSD proteins expressed adrenals, gonads and adipose tissue share 94% homology while they share 80% similarity with the liver-specific type III 3 beta-HSD. Transient expression of human type I and II as well as rat type I and II 3 beta-HSD cDNAs in HeLa human cervical carcinoma cells reveals that 3 beta-ol dehydrogenase and 5-ene-4-ene isomerase activities reside within a single protein and that these cDNAs encode functional 3 beta-HSD proteins. The expressed rat type III protein possesses a unique property catalyzing selectively the reduction of 3 beta-androstane 5 alpha-steroids such as DHT. Furthermore, we have also demonstrated by site-directed mutagenesis that the lower activity of expressed rat type II compared to rat type I 3 beta-HSD protein is due to a change of four amino acid residues potentially involved in a membrane-spanning domain. In parallel, we have characterized the complete nucleotide sequence of human 17 beta-HSD cDNA clones encoding a 327 amino acid protein as well as two in tandem 17 beta-HSD genes. Two major 17 beta-HSD mRNA species have been detected in several tissues due to a tissue-specific alternative site of initiation of transcription.(ABSTRACT TRUNCATED AT 400 WORDS)


Anabolic steroids: a review of their effects on the muscles, of their possible mechanisms of action and of their use in athletics. Anabolic steroids are synthetic molecules developed in the hope of obtaining a complete separation of the androgenic and myotrophic (anabolic) actions of testosterone. Such a goal has never been fully achieved. However, some synthetic steroids present a partial dissociation between these two activities. Since a single hormonal receptor apparently mediates the androgenic as well as the anabolic actions of testosterone, differences in patterns of androgen metabolization in the muscles and the sex accessory organs have been proposed as a possible cause of this phenomenon. Undoubtedly, androgens are able to exert a trophic effect on skeletal and cardiac muscle fibres in subjects with low circulating levels of testosterone such as prepubertal or hypogonadal males and females; however, the widespread use of anabolic steroids in male athletes to increase their physical performances poses the question of whether these compounds are active in the presence of normal circulating levels of testosterone. Most experimental animal studies indicate that anabolic steroids are ineffective in this situation. Since the results of the experiments performed in humans are largely contradictory, it is still not clear whether anabolic steroids are able to improve athletic performances. These and other relevant issues are reviewed.


Towards 3-D modelling of epithelia by computer simulation. The present work is a preliminary step towards dynamic 3-D modelling by computer graphics simulation of the structure of normal and pathological epithelia, using an expert system. In its present state, Esexsy (Epithelium Simulation by EXpert SYstem) allows the construction, through iterative steps, of a simple 3-D representation of the nasal epithelium, based on the positions, sizes and shapes of nuclei. The iterative process is based on statistical comparisons between distributions of parameter values calculated from real (2-D) histological sections and those issued from an equivalent computer 'section' through the simulated 3-D image. We show the results of attempts at simulating normal, metaplastic and dysplastic states of the nasal epithelium, the latter two being characterized by a progressive architectural disorganization, accompanied by nuclear size/shape alterations. The representation takes into account the size, shape, orientation and spatial arrangement of nuclei, with one or several layers from the basal lamina to the lumen. A modified Poisson point process is used at present to position the nuclei, which are modelled by bi-axial spheroids (from prolate to oblate through spherical), with random orientation and size/shape deviations. It should be possible to use the same computer program to simulate other types of epithelia and to achieve increasingly realistic representations by incorporating, notably, nuclear deformations and chromatin texture.


Determination of DNA ploidy in archival tissue from non-Hodgkin's lymphoma using flow and image cytometry. Paraffin-embedded tissue from a series of 40 cases of diffuse, large cell lymphoma was analyzed by both flow and image cytometry to compare the ability of these techniques to detect DNA aneuploid populations. Image cytometry (ICM) was performed both on nuclear suspensions and tissue sections. Twenty cases (50%) were non-diploid by at least one method of analysis. Twenty-five percent of the cases were aneuploid by flow cytometry (FCM) alone. The majority of these cases were near-diploid tumors which could not be resolved by ICM. Peri-tetraploid peaks were identified by ICM of tissue sections alone in 15% of the cases. There was an apparent loss of these peri-tetraploid cells during the preparation of the nuclear suspensions. The remaining cases showed a good correlation between all three methods in the determination of DNA ploidy. Flow and image cytometry are complimentary techniques when applied to archival tissue, however aneuploid populations may be missed if ICM is not performed on tissue sections.


DNA changes in progressive cervical intraepithelial neoplasia. Cervical intra-epithelial neoplasm (CIN) is treated as a progressive lesion, even though most CIN will not progress to invasive cancer if left untreated. This study focussed on DNA-cytometric analysis of cytologic smears of patients who had developed invasive cancer after initial smears showing CIN. The first part of the study aimed at describing the DNA-cytometric changes in these progressive ('malignant') CIN lesions. In the second part a cluster analysis was performed on 'malignant' CIN III lesions and CIN III lesions, with 'unknown' malignant potential. The results indicated that 'malignant' CIN lesions developed high DNA-index (DI) values during malignant transformation, as demonstrated by increasing mean DI values, a high percentage of DNA-aneuploidy and 2.5c Exceeding Rates. Furthermore, a trend-like pattern of texture feature values occurred in 'malignant' CIN lesions with increasing severity. These findings provide objective quantitative confirmation of the evolution of nuclear changes during malignant transformation. Cluster analysis showed that it was possible, using a set of four cytometric features, to subdivide the 'unknown' CIN III lesions into a cluster of lesions with feature values similar to the vast majority of the 'malignant' CIN III lesions, and a second cluster of lesions with feature values dissimilar to 'malignant' CIN III. It is argued that the profile of 'malignant' CIN has become clearer and that the results of this study may serve as a basis for a more objective cytopathologic subdivision of premalignant CIN. It may be justified to follow up patients whose lesions do not yet fit this 'malignant' profile. Not treating the non-progressive lesion group will avoid putting these patients at risk.


Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. A total of 178 patients with metastatic renal cell cancer were randomized to receive interferon alfa-2a (rIFN alfa-2a) or interferon alfa-2a+vinblastine (VLB). IFN alfa-2a was injected intramuscularly at a dose of 18 MIU 3 times a week and VLB was given intravenously at a dose of 0.1 mg/kg once every 3 weeks. The response rate was 11% for patients on monotherapy and 24% for those on combination treatment. The 5-year survival for 145 eligible patients was 9%, independently from the treatment arm. The performance status was significantly related to long-term prognosis, and 13% of the patients with performance status 0 were alive at 5 years, as compared to 6% and 0% for patients with a WHO grade of 1 and 2, respectively. The most frequent adverse events in both treatment arms were flu-like symptoms (95%), fatigue (70%) and gastrointestinal disturbances (68%). Leukopenia was observed more frequently with combination treatment (53%) than with IFN alfa-2a alone (30%). In conclusion, rIFN alfa-2a monotherapy at this dose and schedule has modest antitumor activity in metastatic renal cell cancer. The combination of rIFN alfa-2a+VLB results in a doubling of the response rate, but this does not translate into prolonged survival. Toxicity (except leukopenia) and tolerance were similar in both treatment arms.


Effective prevention of chemotherapy--induced phlebitis by low-dose heparin: a prospective randomised trial. In a prospective randomised trial patients receiving multiple-day chemotherapy and heparin had significantly fewer local complications at the site of venous access than patients who had chemotherapy alone. The need to move peripheral venous catheters to other sites was decreased significantly, from 36% to 6%. Prophylaxis of phlebitis with low-dose continuous heparin is safe, simple, cheap and effective. It facilitates administration of multiple-day chemotherapy for the patients, the nurses and the physicians.


A comparison of CA-549 with CA 15-3 and MCA in patients with metastatic breast cancer. CA 15-3, MCA, and CA-549 levels were determined in the serum of 56 patients with metastatic breast cancer, all of whom had visceral and/or bone metastases. CA 15-3 was positive in the serum of 37 patients, MCA in the serum of 38 patients, and CA-549 in the serum of 39 patients. All 3 markers were positive in 36 patients, and all 3 were negative in 16 patients. In the serum of 4 patients only 1 or 2 markers were slightly elevated. Thus, the results were identical in 52 of the 56 patients. It is concluded that CA 15-3, MCA, and CA-549 are sensitive markers for advanced breast cancer, and that no advantage can be expected by combining them.


Cisplatin-containing regimen in advanced or recurrent granulosa cell tumours of the ovary. The efficacy of combination chemotherapy in advanced or recurrent disease of granulosa cell tumours is still not well defined. Ten patients with advanced or recurrent granulosa cell tumours were treated with cisplatin, adriamycin and cyclophosphamide (CAP). Prior to chemotherapy all patients underwent surgical treatment. No patient received prior hormonochemotherapy or radiotherapy. Five complete responses (three pathologically documented) and one partial response were obtained for a total response rate of 60%. One pathologically-complete responder relapsed after 48 months from the onset of chemotherapy, but responded completely to debulking surgery and radiotherapy and remains well with no evidence of disease 87+ months. Five patients are still alive with no evidence of disease at 10+, 26+, 41+, 46+, 87+ months, 1 is still alive with disease and 4 have died at 20, 22, 28 and 60 months despite further treatment. Additional cooperative clinical trials are required to determine the exact efficacy of cisplatin chemotherapy in granulosa cell tumours.


Chemotherapy of head and neck cancer.

Chemotherapy of head and neck cancer. Numerous studies have shown cisplatin-based chemotherapy to be effective in the treatment of head and neck cancer. Cisplatin/5-fluorouracil (5-FU) is the most frequently used combination regimen, but neurotoxicity, ototoxicity, and renal toxicity limit repeated dosing (for long-term treatment of responding patients) and dose intensification. In studies to date, the analogue carboplatin appears to have activity similar to cisplatin, the advantage of no significant neurotoxicity, ototoxicity, or renal toxicity, and less emetic potential. Two randomized trials have shown cisplatin/5-FU and carboplatin/5-FU superior in terms of response rate compared to single-agent therapy. Treatment with combinations of carboplatin/methotrexate and carboplatin/cisplatin is feasible, but myelosuppression is dose-limiting. As an induction regimen, carboplatin/5-FU yields response rates similar to cisplatin/5-FU. Overall, carboplatin has a more favorable toxicity profile for treating head and neck cancer patients who often have multiple medical problems when presenting for palliation of cancer. Reversible myelosuppression is dose-limiting. However, the availability of hematopoietic growth factors may allow investigators to safely intensify dosing, particularly in combined-modality curative treatment regimens for the newly diagnosed patient.


High-dose progestin therapy for metastatic breast cancer. Progestin therapy has become an established endocrine modality for the treatment of metastatic breast cancer, with medroxyprogesterone acetate and megestrol acetate being the most widely used agents. Both drugs display similar effectiveness as initial and secondary therapy for patients with advanced disease, with combined complete and partial response rates of approximately 30% to 40%. Uncontrolled trials have suggested that high doses of medroxyprogesterone may be more effective than lower doses, but randomized trials have yielded conflicting results. Clinical trials of megestrol acetate have demonstrated it to be an affective, well-tolerated oral progestin, and a recent randomized trial has suggested that higher megestrol acetate doses may be associated with not only improved response but also improved time to disease progression and survival. Further trials of high-dose megestrol acetate for both initial and secondary therapy are under way, and their results will provide valuable information concerning the role of such treatment.


Use of ifosfamide in the management of breast cancer. Ifosfamide, a cytostatic drug highly active in vivo, has slight superiority over cyclophosphamide. It proved effective in experimental tumor systems including the C3H mammary carcinoma. Clinical studies of ifosfamide as monotherapy in breast cancer, begun in 1974 by Ahmann et al., reported a 20% objective response. Subsequent trials were conducted from 1974 through 1977 using ifosfamide as monotherapy, and ifosfamide was also combined with other chemotherapeutic agents. In 1975, Hartwich and coworkers used the combination ifosfamide/vincristine with a 25% overall response. With the introduction of the uroprotector mesna, more studies were instituted. In 1984, using the IMF combination (ifosfamide/methotrexate/5-fluorouracil), we reported a 25% overall response. Other groups also reported good results for ifosfamide-containing combinations, with overall responses ranging from 25% to 79%. Recently, Sanchiz and Milla used high-dose ifosfamide to treat metastatic breast cancer, with a 40% overall response. In conclusion, ifosfamide's efficacy in breast cancer has been confirmed and the drug is highly recommended in combination chemotherapy as a first-line treatment.


Carboplatin plus 5-fluorouracil and leucovorin in previously treated patients with metastatic breast cancer. The commonly reported second-line chemotherapy regimens administered for metastatic breast cancer usually induce few responses, which last no more than 4 to 8 months. We used carboplatin 50 mg/m2 on days 2, 3, and 4 of each course, leucovorin 500 mg/m2 on days 1 through 5 in 30-minute infusions, and 5-fluorouracil (5-FU) 375 mg/m2 intravenous bolus 1 hour after each leucovorin dose to treat 32 patients with metastatic breast cancer. Six patients had previously received treatment with only one cytotoxic chemotherapy regimen, usually CMF (cyclophosphamide/methotrexate/5-FU). Twenty-six patients had received treatment with two or more regimens of chemotherapy previously, and most of them also had received radiotherapy and endocrine manipulations. Fifteen patients had visceral deposits. In cases of excessive or persistent toxicity, single daily doses were not reduced, but the start of the next course was delayed or its duration reduced. Of 26 heavily pretreated patients, 12 responded, primarily those with disease in lymph nodes, skin, breast, and pleura. One patient with liver deposits had a complete remission confirmed at laparoscopy and echogram. Survival was probably prolonged, with a median duration of response of 5 months (range, 3 to 22+), and moderate side effects that did not compromise quality of life during treatment. The probability of response was not related to the type of pretreatment (with or without 5-FU) nor to response to previous treatments.


Carboplatin alone or in combination in high-risk acute nonlymphoblastic leukemia. The use of newly developed antileukemic agents is one of the therapeutic options available to overcome clinical resistance in refractory or other high-risk acute leukemias. Carboplatin is a second-generation platinum compound that has demonstrated significant activity against acute leukemia, particularly when administered via continuous intravenous infusion in phase I clinical trials. Based on the preliminary reports of these trials, we designed a phase II clinical trial to evaluate the efficacy and toxicity of carboplatin via continuous infusion (300 mg/m2/d for 5 days) for remission induction in adult patients with high-risk acute leukemia. Because of the significant antileukemic activity and the scarce extrahematologic toxicity noted in this trial, in order to increase the response rate, we were encouraged to try carboplatin in combination in a similar set of patients. A phase II study of carboplatin 300 mg/m2/d for 5 days in combination with etoposide 100 mg/m2/d for 3 to 4 days was designed by our group to treat patients with high-risk acute leukemia. This combination was chosen because (1) each drug has independent activity in acute nonlymphoblastic leukemia (ANLL) and (2) carboplatin/etoposide has been extensively tested in patients with small and non-small cell lung cancer, and therefore the toxicity and maximum tolerated dose are known. The complete remission rate achieved was somewhat higher (40%) than with carboplatin alone despite the increased incidence of extrahematologic toxicities, particularly gastrointestinal bleeding. At present, carboplatin should be considered as a new effective agent for the treatment of ANLL.(ABSTRACT TRUNCATED AT 250 WORDS)


Neoadjuvant combination of carboplatin and 5-FU in head and neck cancer: a randomized study. A prospective, randomized, multicenter study of patients with oropharyngeal and pharyngolaryngeal tumors compared locoregional treatment alone with neoadjuvant chemotherapy with carboplatin/5-fluorouracil (5-FU) followed by locoregional treatment. The aim of the study was to evaluate the role of chemotherapy on survival and on the need for mutilating surgery. Since 1988, 219 patients (105 with oropharyngeal and 114 with pharyngolaryngeal tumors) have entered the study. All patients randomized to neoadjuvant chemotherapy received three cycles of carboplatin 400 mg/m2 day 1 and 5-FU 1 g/m2/d as a continuous infusion days 1 through 5 every 3 weeks. Neoadjuvant chemotherapy was given to 108 patients. The 268 evaluable courses induced a low rate of grade 3 or 4 toxicity. Four patients (3.6%) died of major complications. The complete response (CR) rate was 31%, which represented a decrease in mutilating surgery of 30%. (Patients with CRs had radiotherapy alone instead of radiosurgical treatment as originally planned.) The objective response rate was 61%. Survival curves for the chemotherapy and chemotherapy-naive groups were not significantly different. The rate of nodal recurrence was significantly higher in the chemotherapy group, however, and chemotherapy did not decrease the rate of second primary tumors or distant metastases. Thus, the justification for neoadjuvant chemotherapy may be a decreased rate of mutilating surgery. These preliminary results are encouraging, but follow-up is as yet too short to allow definite conclusions.


Advances in the control of chemotherapy-induced emesis. Cancer patients consistently rank nausea and vomiting as the most feared side effects of treatment. Cisplatin, one of the most active chemotherapeutic agents, causes acute emesis and a delayed emesis syndrome, which also results in considerable patient morbidity. Despite the use of metoclopramide-containing combination regimens, approximately one third of cisplatin-treated patients continue to experience emesis. In recent years, considerable progress has been made in managing chemotherapy-induced emesis. This review discusses several factors that have contributed to improved antiemetic control, including standardization of antiemetic trial methodology, insight into the pathogenesis of chemotherapy-induced emesis, and the development of a new class of antiemetic agents, the serotonin antagonists. In clinical studies performed to date, these agents have generally proven to be both effective and safe. Three multicenter trials of the selective serotonin antagonist ondansetron in the prevention of nausea and vomiting from cisplatin are reviewed.


Efficacy of weekly cisplatin-based chemotherapy in recurrent and metastatic head and neck cancer. After disease recurrence or dissemination, patients who had been treated previously with radiation with or without surgery for cancer of the head and neck were given either cisplatin (16 patients), cisplatin/etoposide (15 patients), or cisplatin/etoposide/5-fluorouracil (5-FU) (19 patients) in an ambulatory care clinic. Intravenous (i.v.) cisplatin 25 mg/m2 was given weekly, while etoposide was given i.v. (80 mg/m2) on day 1 and orally (160 mg/m2) on day 2 of every odd-numbered week. In the three-drug regimen, 5-FU 500 mg/m2 i.v. was given every even-numbered week. Patients in all three groups received daily oral prednisone to decrease myelosuppression and oral co-trimoxazole and ketoconazole to prevent infection. The supportive drugs were given to all groups to keep these variables constant. As expected, myelosuppression did not occur in the cisplatin group, while the rates of severe neutropenia (less than 1.0 x 10(9)/L) in the two- and three-drug groups were 26% and 74%, respectively. The incidence of infection requiring hospitalization was low (2.5%). The response rate (complete plus partial) was lowest in the cisplatin group (6%) and higher in the cisplatin/etoposide (47%) and cisplatin/etoposide/5-FU (53%) groups. Because of the low response rate and the short time to progression (5 weeks) in the cisplatin group, 9 of these 16 patients were treated subsequently with cisplatin/etoposide. Time to progression and response duration were similar in the cisplatin/etoposide and cisplatin/etoposide/5-FU groups--12 and 14 weeks, and 12 and 9 weeks, respectively. Median survival times of the cisplatin and cisplatin/etoposide/5-FU groups were 36 and 34 weeks, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Cholesterol lowering and the reduction of CHD incidence and total mortality: results from a meta-analysis of randomized trials. This editorial reports on a meta-analysis done on cholesterol-lowering trials. Coronary heart disease incidence is reported for 16 trials and total mortality for 19 trials. The cholesterol benefit ratio, i.e., the percent risk reduction divided by the percent cholesterol reduction, was analyzed in terms of total vs. potential modifying factors. For coronary heart disease the benefit ratio was 2.8 (95% CL: 1.5, 4.2), and for total mortality it was 1.2 (95% CL: -0.1, 2.3). Cholesterol reduction had to be at least 8-9% to outweigh the negative impact of treatment on total mortality.


Cholesterol biosynthesis and metabolism. Cholesterol plays an essential role in cell membrane synthesis and in cell growth and differentiation. In mammalian cells, cholesterol can be synthesized from acetate precursors or taken up from dietary or exogenous sources. The major catabolic route for disposal of cholesterol involves conversion into excretable bile acids. The maintenance of cholesterol homeostasis is influenced and carefully controlled by multiple feedback mechanisms. The key regulatory targets of these feedback mechanisms are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in cholesterol biosynthesis, the low-density lipoprotein (LDL) receptor in cholesterol uptake, and cholesterol 7 alpha-hydroxylase in cholesterol catabolism. The elucidation of regulatory mechanisms in cholesterol metabolism has been greatly facilitated by the discovery of a new class of lipid-lowering drugs, the HMG-CoA reductase inhibitors. In addition to proving therapeutically useful in the treatment of hypercholesterolemia, these drugs have revealed novel regulatory steps in cholesterol metabolism and several new targets for future drug development. This manuscript reviews recent developments in the cholesterol biosynthetic pathway and the regulatory mechanisms that maintain cholesterol homeostasis.


Can we really justify the treatment of silent ischemia in 1992? No! Since the advent of ambulatory ST-segment monitoring, it has been established that silent ischemia is common in patients with various coronary artery disease syndromes, and such silent episodes represent up to 80% of all ischemic episodes. It appears to be associated with an adverse prognosis when compared with similarly characterized patients without silent ischemia during daily life. Silent ischemia does not, however, bother the patients, by virtue of the fact that it is silent, and therefore treatment of such ischemia must be justified by an improved outlook for the patient, rather than symptom relief. There is no direct evidence to date that silent ischemia is associated with acute myocardial infarction or sudden cardiac death in a cause-and-effect relationship, or that reduction or eradication of silent ischemia will lead to an improved prognosis for the patient; indeed, we have been unable to demonstrate any significant improvement in outlook when using the various antianginal/antiischemic agents at our disposal. Until we can demonstrate a benefit to the patient by detecting and treating silent ischemia, we should not waste large resources attempting to eradicate something whose significance we do not understand.


Advances in thrombolytic therapy.

Advances in thrombolytic therapy. Alteplase and saruplase are more fibrin-specific thrombolytic drugs than anistreplase. These and the thrombolytic drugs of the first generation (streptokinase and urokinase) have shortcomings and limitations. The prolonged intravenous maintenance infusions have been replaced by a bolus injection, accelerated infusions, or the combined intravenous administration of thrombolytic agents. Numerous truncated alteplase or saruplase molecules have been constructed by deletion and domain substitution or hybrids made of the two molecules without gaining in thrombolytic potency. Recombinant staphylokinase and plasminogen activator from bat saliva have some interesting properties and are being investigated. Thrombus-targeted thrombolytic drugs were constructed using monoclonal antibodies against fibrin fragments or against epitopes of activated platelets. Fibrin-specific thrombolytic drugs require the concomitant use of a potent antithrombotic drug to prevent reocclusion. Whether hirudin or synthetic thrombin inhibitors are superior to heparin and whether novel antiplatelet agents, including monoclonal antibodies to platelet receptors and disintegrins, are more effective than aspirin is under clinical investigation. The place of stable analogues of prostacyclin during thrombolytic treatment is still unsettled.


Cholesterol and coronary disease--outstanding questions. The role of raised blood cholesterol in causing coronary atheroma is established, and a high dietary intake of saturated fat is a leading cause of coronary disease. Reduction of hypercholesterolemia in middle-aged males reduces CHD incidence, mostly nonfatal myocardial infarction. But there are many unresolved questions that should lead to a selective and moderate approach to the management of hypercholesterolemia. These include lack of the exact knowledge of how raised cholesterol leads to atheroma, equivocal evidence of whether reduction of hypercholesterolemia causes regression of atheroma, uncertainty about how far down cholesterol levels can safely be reduced and whether the cost-benefit always justifies action, the fact that reduction of hypercholesterolemia does not reduce total mortality and may increase noncardiac mortality, and insufficient evidence as to whether the same policies should be adopted for women, the elderly, and adolescents as for middle-aged men.


Antihypertensive efficacy and effects of nitrendipine on cardiac and renal hemodynamics in mild to moderate hypertensive patients: randomized controlled trial versus hydrochlorothiazide. In this study antihypertensive efficacy, safety, and the effects of short-term nitrendipine administration on central and renal hemodynamics were evaluated in mild to moderate hypertensives. Our final goal was to ascertain whether the reduction in blood pressure induced by nitrendipine treatment was associated with maintained renal function. After a run-in period with placebo, 26 hypertensives without cardiac or renal disease were randomly assigned to a double-blind 8-week controlled trial with nitrendipine (N) 20 mg once a day (13 pts) or hydrochlorothiazide (HCT) 25 mg once a day (13 pts). Renal hemodynamic measurements included effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) by radionuclide study using I-131 hippuran and Tc-99m, according to the methods described by Schlegel and Gates, respectively. Effective renal blood flow [ERBF = ERPF/(1-Ht)], filtration fraction (FF = GFR/ERPF), and renal vascular resistance (RVR = MBP x 80/ERBF) were also calculated. Other hemodynamic measurements included cardiac index (CI), left ventricular (LV) ejection fraction (EF), and total peripheral resistance (TPR) measured by the first-pass radionuclide angiography technique. At the end of N or HCT administration significant decreases (p less than 0.001) in SBP, DBP, and MBP vs. baseline values were observed in both hypertensive groups. In the N group a significant decrease (p less than 0.01) in TPR and RVR, and significant increases (p less than 0.05) in CI, ERPF, and ERBF were observed. In the HCT group a significant decrease (p less than 0.05) in RVR was found without significant changes in other hemodynamic parameters. No important side effects were observed with either therapy. In conclusion, nitrendipine was effective in reducting blood pressure in mild to moderate hypertensive patients and exerted favorable effects on cardiac and renal function.


Regression of left ventricular hypertrophy in "previously untreated" hypertensive blacks after 6 months of blood pressure reduction with alpha- and beta-adrenergic blockade and thiazide therapy. In 10 hypertensive black patients who were "previously untreated" (defined as no antihypertensive therapy for a minimum of 12 months prior to enrollment) and who had LVH (defined by an increase in both wall thickness and echocardiographically determined LV mass), we studied the effects of treatment with either labetalol, an alpha- and beta-adrenergic blocker (three patients), or labetalol plus hydrochlorothiazide (seven patients). After 6 months of effective antihypertensive therapy, there was a 12% decrease in LV mass for the entire group. However, the extent of LVH regression was highly variable among individual patients.


Low-dose verapamil in middle-aged and elderly patients with angina pectoris: no evidence of increased susceptibility to the cardiac effects. This study investigated the cardiac responses and pharmacokinetics following the acute and chronic administration of verapamil in 14 middle-aged and elderly patients with ischemic heart disease (age range 42-76 years). There were small significant reductions in heart rate during chronic treatment, but there were no significant effects on the PR intervals following either single intravenous administration or after 4 weeks continued treatment. Left ventricular ejection fractions at rest or exercise were not significantly changed following either acute intravenous (rest 33%; exercise 38%) or chronic oral dosing with verapamil (rest 35%; exercise 43%) when compared with placebo (rest 34%; exercise 42%). There were no independent age-related effects on these indices of cardiac function, nor on apparent liver blood flow, nor on blood pressure and heart rate. The plasma clearance of verapamil was reduced from 1.3 l/min after acute dosing to 0.8 l/min during chronic treatment, but there was no significant independent age-related effect. The results of this study suggest that middle-aged and elderly patients with ischemic heart disease do not show enhanced cardiovascular responses to low doses (5 mg intravenously and 80 mg tid orally) of the calcium antagonist drug, verapamil.


Reduction of exercise-induced regional contractile dysfunction in dogs using a novel calcium channel blocker (Ro 40-5967). Ro 40-5967 is a calcium channel blocker with a novel chemical structure. The purpose of this study was to evaluate the effects of Ro 40-5967 on systemic hemodynamics and regional contractile function in a canine model of chronic coronary artery stenosis in which no contractile dysfunction is observed at rest, but dynamic exercise elicits regional myocardial ischemia and contractile dysfunction. Thirteen dogs were chronically instrumented with sonomicrometers for the measurement of wall thickness in the anterior and posterior left ventricular walls, a micromanometer for measuring left ventricular pressure (LVP) and its first derivative (dP/dt), and a catheter in the aorta for measuring systemic arterial pressure. An ameroid constrictor on the left circumflex coronary artery produced gradual constriction of the vessel such that treadmill exercise elicited regional contractile dysfunction. Runs were repeated 3 hours later after the administration of Ro 40-5967 (0.3 mg/kg, IV). During the control run, regional systolic wall thickening in the posterior wall fell from 25.5 +/- 6.3% (SD) to 15.9 +/- 5.1% (p less than 0.05). Ro 40-5967 did not change resting function in the poststenotic myocardium (26.9 +/- 8.4%) but improved regional function during the run to 18.2 +/- 6.2% (p less than 0.05). This improvement was associated with a slight decrease in the exercise heart rate (213 +/- 18 vs. 200 +/- 16 bpm, NS), no change in peak ventricular pressure (156 +/- 22 vs. 157 +/- 20 mmHg), mean aortic pressure (123 +/- 19 vs. 118 +/- 20 mmHg), dP/dt (5129 +/- 1143 vs. 5288 +/- 1120 mm Hg/sec), or systolic wall thickening in a distant control region.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of captopril with enalapril in the treatment of heart failure: influence on hemodynamics and measures of renal function. Twenty-nine patients with severe heart failure (NYHA III) were randomly assigned to receive therapy with an angiotensin converting enzyme inhibitor (ACE inhibitor), either captopril or enalapril. The mean daily dosage of captopril was 56 +/- 5 mg and of enalapril 9.5 +/- 0.4 mg. After a mean of 8 +/- 1 days, the influence of both ACE inhibitors on hemodynamics and renal function was compared. The mean arterial pressure in the group treated with captopril (Group A) fell by 9 +/- 3 mmHg (p less than 0.01), and in the group treated with enalapril (Group B) it fell by 12 +/- 3 mmHg (p less than 0.001). The difference between the groups was not significant. Heart rate decreased in both groups; however, the change was significant (p less than 0.05) only in patients treated with enalapril (-11 +/- 3 bpm in Group B vs. -7 +/- 4 bpm in Group A). Stroke volume index increased by 6 +/- 3 ml/m2 in Group A (p less than 0.05) vs. 10 +/- 2 ml/m2 in Group B (p less than 0.01). The increase in stroke volume index was not significantly different between the two groups. Mean decreases in pulmonary artery and right atrial pressure were also comparable in both groups. Thus, hemodynamic improvements were similar during therapy with either captopril or enalapril. Serum sodium and potassium before therapy were 137 +/- 1 mmol/l and 4.1 +/- 0.1 mmol/l, respectively, in group A and 139 +/- 1 mmol/l and 4.0 +/- 0.1 mmol/l, respectively, in group B.(ABSTRACT TRUNCATED AT 250 WORDS)


Long-term hemodynamic effects of nifedipine on congenital heart disease with Eisenmenger's mechanism in children. The hemodynamic effect of long-term nifedipine medication was studied in 10 children, 3-12 years of age, five with ventricular septal defect and five with complete atrioventricular septal defect; all had Eisenmenger's reaction, seven also had Down's syndrome. They underwent heart catheterization prior to and during 1-4 years of nifedipine therapy. Fick's principle was used to calculate the ratio of pulmonary arterial pressure to aortic pressure (PAP/PAO), the ratio of pulmonary flow to aortic flow (QP/QS), as well as the ratio of pulmonary vascular resistance to aortic vascular resistance (RP/RS). In the seven children under 8.8 years, nifedipine caused a significant drop in PAP/PAO (p less than 0.004), a slight increase in arterial O2 saturation, a significant increase in QP/QS (p less than 0.02), and a decrease in RP/RS (p less than 0.02). The nifedipine effect was age related. On nifedipine, breathing oxygen resulted in, independent of age, a significant increase in QP/QS (p less than 0.003) and a significant decrease in PAP/PAO (p less than 0.04) and in RP/RS (p less than 0.003). Direct O2 consumption measurements before and during oxygen breathing in six patients demonstrated no significant change in RP, RS, QP, or QS indices. Nifedipine had a relaxing effect on the pulmonary vascular bed, especially in the younger child with Eisenmenger's mechanism. On nifedipine therapy, O2 produced a more complex hemodynamic reaction that was not restricted to the pulmonary circulation alone.


Evaluation of bepridil efficacy by electrophysiologic testing in patients with recurrent ventricular tachycardia: comparison of two regimens. The purpose of the study was to evaluate this effect of different doses of intravenous and oral bepridil on the induction of ventricular tachycardia. Thirty-eight patients underwent electrophysiologic evaluation for recurrent ventricular tachycardia (VT). Sustained monomorphic VT was induced by programmed ventricular stimulation, using up to three extrastimuli in all patients. The effects of intravenous bepridil (2 mg/kg) were evaluated during the initial study. Intravenous bepridil prevented the induction of sustained VT in eight patients (21%). Electrophysiologic study was repeated after oral bepridil. In six patients the study was stopped because of adverse effects or VT recurrence. Thirty-two patients underwent repeat study 7 days later, taking oral bepridil, 500 mg/day (n = 16) or 900/day (n = 16). A dose of 500 mg/day of bepridil prevented the induction of sustained VT in only one patient. A dose of 900 mg/day of bepridil prevented the induction of sustained VT in eight patients. There were no significant clinical adverse effects, except in one patient receiving intravenous bepridil. The response to intravenous bepridil did not predict the response to oral bepridil. The response to intravenous or oral bepridil was not related to the plasma level of bepridil but was related to a higher left ventricular ejection fraction. Eight patients (21%) in whom VTs were noninducible on oral bepridil were discharged on 300 mg/day of bepridil if their initial loading dose was 500 mg/day or on 600 mg/day if their initial loading dose was 900 mg/day. They remained free of VT during a follow-up of at least 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)


Epithelial-specific gene expression during differentiation of stratified primary human keratinocyte cultures. Cultured epithelial cells are used to generate extensive patches of autologous skin equivalent for patients with burns or wounds and to investigate the growth and differentiation of epithelia in vitro. We have undertaken a comprehensive study of the morphological and molecular events that occur during culturing of human foreskin keratinocytes at the liquid-air interface on a dermal equivalent consisting of a collagen matrix containing fibroblasts. Using radioactively labeled RNA probes for mRNAs and monoclonal antibodies for proteins, we found that the expression of a comprehensive set of differentiation stage-specific genes was affected by the type of fibroblasts included in the matrix as well as by the age of the culture. The expression of these genes was not always coordinated and could not be predicted from the histological appearance of the stratified epithelium. Surprisingly, the mouse fibroblasts promoted epithelial differentiation much more closely resembling foreskin than did the homologous primary foreskin fibroblasts.


12-O-tetradecanoylphorbol-13-acetate induces transient cell cycle arrest in G1 and G2 in metastatic melanoma cells: inhibition of phosphorylation of p34cdc2. The growth of Demel human metastatic melanoma cells was inhibited by 12-O-tetradecanoylphorbol-13-acetate (TPA) and other nonphorbol tumor promoters including palytoxin and okadaic acid. Using flow cytometry, we have demonstrated that the cells arrested growth in G1 and G2 phases of the cell cycle. Detailed analysis of the kinetics of the growth arrest in unsynchronized cells showed that (a) the growth arrest was transient and peaked 16-20 h following addition of TPA; (b) effects of TPA on cell growth began within 1-2 h after the addition; and (c) cells completed S phase and arrested in G2. In addition, TPA induced a pronounced morphological change, which peaked by 1 h and gradually subsided over 24 h. In populations of cells synchronized in G1 using lovastatin, (a) addition of TPA blocked the onset of DNA synthesis up to the end of G1; (b) the lag between addition of the drug and onset of DNA synthesis was less than 30 min; and (c) addition of TPA at the end of G1 prevented the increased phosphorylation of p34cdc2, as determined by immunoprecipitation. The experiments reported here show that TPA transiently blocked the proliferation of Demel melanoma cells at the G1-S border and in G2, thus preventing cells from progressing through the cell cycle. These experiments suggest that pathways involving protein kinase C interact with and rapidly alter the molecular pathways involving p34cdc2 which regulate the onset of DNA synthesis and the G2-M transition.


Identification and characterization of the regulated pattern of expression of a novel mouse gene, meg1, during the meiotic cell cycle. The gene designated meg1 (meiosis expressed gene) is a new mouse gene identified during a search for mammalian genes potentially involved in meiotic processes. Two classes of complementary DNAs were isolated from an adult mouse testis complementary DNA library, which shared the same 3' end including the entire putative coding region but differed in their 5' ends. Only one of these complementary DNA classes appeared to correspond to the very abundant 0.75-kilobase testicular transcript of meg1. Sequence analysis predicts a 10.8-kilodalton protein which is highly charged and lysine rich. It is also relatively rich in potential phosphoacceptor amino acids (approximately 17%), several of which are located in phosphorylation consensus sequences. The pattern of expression of meg1 was studied utilizing a combined Northern blot and in situ hybridization analysis. Of the adult tissues examined, meg1 transcripts were detected exclusively in testis. Analysis of mRNA from testes of two germ cell deficient mutant strains did not reveal significant levels of meg1 transcripts. Analysis of RNA from enriched populations of spermatogenic cells from adult testes and localization by in situ hybridization revealed that meg1 transcripts are most abundant in pachytene spermatocytes. These results suggest a role for meg1 during germ cell differentiation, possibly during meiotic prophase.


Complementary DNA cloning of a novel epithelial cell marker protein, HME1, that may be down-regulated in neoplastic mammary cells. A full-length complementary DNA clone from a normal human mammary epithelial cell (strain 184) encoding a 25-kilodalton protein, HME1, was isolated. Expression of HME1 RNA appears to be limited to epithelial cells. The HME1 sequence has extensive sequence homology with bovine 14-3-3 protein, which is an activator of tyrosine and tryptophan hydroxylase. However, the tissue distribution, arrangement of charged amino acids, and location of potential phosphorylation sites of HME1 differ from those of 14-3-3. Compared with normal mammary epithelial cells, expression of HME1 RNA was dramatically low in two cell lines derived from human mammary carcinoma that were examined, and in a line of normal mammary epithelial cells transformed by oncogenes. HME1 therefore appears to be a cellular differentiation marker that may be down-regulated during neoplastic transformation.


Functional dissection of AP-1 transcription factors using the Gal4 adaptor assay. In the Gal4 adaptor assay, leucine zipper-containing proteins are tethered indirectly to the promoters of Gal4-responsive reporter genes via synthetic protein chimeras consisting of a Gal4 DNA-binding domain with an attached leucine zipper. Ternary complexes composed of the DNA binding site, the adaptor protein, and a leucine zipper factor can stimulate reporter gene activity, provided that the latter component possesses a transcriptional activation domain. This system is used to assay the transcriptional function and the interactions between various AP-1 factors.


Identification of a human chromosome 11 gene which is differentially regulated in tumorigenic and nontumorigenic somatic cell hybrids of HeLa cells. The tumorigenicity of HeLa cells in nude mice can be suppressed by the addition of a normal human chromosome 11 in somatic cell hybrids. We have attempted to identify specific genes involved in this phenomenon by transfecting a complementary DNA expression library into a tumorigenic HeLa-fibroblast hybrid. A cell line designated F2 was isolated which displayed morphological features of the nontumorigenic hybrids, demonstrated reduced tumorigenicity in nude mice, and showed an 85% reduction in alkaline phosphatase, a consistent marker of the tumorigenic phenotype in these cells. F2 contained a single exogenous complementary DNA, which was recovered by polymerase chain reaction and designated HTS1 because of its potential association with "HeLa tumor suppression." Northern blot studies suggested differential regulation of the HTS1 gene dependent on the tumorigenicity of the cell. In nontumorigenic hybrids, RNA species of 2.8, 3.1, and 4.6 kilobases were identified. In two tumorigenic hybrid lines, the 2.8-kilobase species was markedly reduced or absent. Similarly, three nontumorigenic human keratinocyte lines expressed all three RNA species, whereas several tumorigenic cervical carcinoma cell lines lacked the 2.8-kilobase species. Chromosome localization studies mapped the HTS1 gene to chromosome 11p15, a region of chromosome 11 that is believed to contain a tumor suppressor gene. These findings indicate that HTS1 represents a novel chromosome 11 gene which may be a target of the tumor suppressor gene active in this system.


Efficacy of twice daily versus three times daily oral ondansetron in the prevention of chemotherapy induced emesis: a randomized, single-blind, multicentre study. The Ondansetron International Emesis Study Group. Following a single intravenous dose given pre-chemotherapy, the efficacy and tolerability of oral ondansetron treatment given twice daily was compared with the established three times daily oral supplementary regimen in the prophylaxis of nausea and vomiting induced by cyclophosphamide (greater than or equal to 500 mg/m2) in combination with doxorubicin (greater than or equal to 40 mg/m2) or epirubicin (greater than or equal to 40 mg/m2). Oral ondansetron given twice daily or three times daily was equally effective in controlling nausea and emesis. The twice daily oral treatment prevented emesis in 73% of patients in the first 24 hours and in 65% of patients over 3 days. Both dose schedules were safe and were tolerated well. Twice daily oral ondansetron showed good efficacy for controlling emesis and nausea in oncology outpatients.


Multiple fractions in the treatment of head and neck cancer. Fifty-eight cases of head and neck cancer received hyperfractionated accelerated radiotherapy, with treatment three times daily to 47.5-54 Gy over 12-20 days. A total of 69% had a complete response within 3 months, and the actuarial survival was 52% at 1 year, 41% at 2 years, 43% at 3 years and 38% at 4 years. Acute reactions were rather more pronounced (31%) and late necrosis (15%) was more than would be expected with conventional fractionation. It is suggested that multiple fractions carried out by a small centre, are feasible and will reduce hospital stay.


Stage I seminoma of the testis: is post-orchidectomy surveillance a safe alternative to routine postoperative radiotherapy? Experience with the management of 128 patients with Stage I testicular seminoma over a 10-year period, 1980-1989, is presented. Fifty-six patients were treated with post-orchidectomy radiation therapy and 72 patients were put on surveillance. Patients thought to be at higher risk of relapse were generally treated with radiotherapy. There have been no tumour related deaths in this series; 5.4% of the irradiated group and 18% of patients on surveillance have relapsed to date. All relapses have been salvaged with further therapy and are currently in complete remission. In this interim analysis, surveillance appears to be a safe alternative to adjuvant radiation therapy provided regular, prolonged follow-up can be ensured. Surveillance is, however, time consuming and resource demanding, and should be undertaken only as part of a formal clinical study. Adjuvant post-orchidectomy radiotherapy should be considered the treatment of choice until further long-term data are available.


Radiotherapy for the treatment of recurrent craniopharyngioma. Twenty-five patients with craniopharyngioma received radiotherapy at the time of recurrence. The 10-year progression free survival and survival from the time of recurrence were 72% and 77% respectively. Nineteen patients underwent surgery prior to radiotherapy (6 partial excision, 4 decompression and 9 cyst aspiration). The extent of resection at the time of recurrence did not influence the outcome. Apart from pituitary failure there was no serious morbidity associated with this approach. The results of radiotherapy at recurrence are similar to those of conservative surgery and radiotherapy at the time of presentation. It suggests that radiotherapy remains an effective treatment modality at the time of recurrence of craniopharyngioma and it may therefore be delayed in situations where immediate radiation is not advisable. However, the high recurrence rate in incompletely excised craniopharyngioma, together with the potential risk of additional morbidity and mortality from undiagnosed progressive tumour and salvage surgery, would argue for a policy of radiotherapy as part of the initial treatment of incompletely excised craniopharyngioma.


Value of conformal planning in the radiotherapy of soft tissue sarcoma. The late complications and subsequent limb function seen following treatment of extremity sarcoma are related to the radiation dose used and the volume of tissue irradiated. The potential value of the use of 3D-planning and conformal blocking has been studied in 11 patients with lower limb sarcoma. Tumour, target and normal tissue volumes were reconstructed in 3D following a CT planning scan. Dose calculations were performed for conventional and conformal plans, using customized blocks with a margin of 6 mm around the target volume. No compromise of target dosimetry was permitted. The volumes of tissue receiving 50%, 80% and 90% of the prescribed dose were compared using cumulative volume dose histograms. The treatment volume was reduced in all patients, and by greater than 20% in four of five with thigh tumours. The mean volume of muscle outside the target volume which was irradiated to the 50% isodose was 4.2 litres. The volume irradiated to 90% or greater isodose was reduced by greater than 30% in five of eight patients with thigh and lower leg tumours. Similarly, the volumes of femur, tibia/fibula and ilium were reduced by 38%, 18% and 14% respectively by conformal blocking. Considerable sparing was achieved in the volumes of pelvic contents irradiated, including gonads and rectum. This simple, but time consuming, technique can achieve major reductions in normal tissue irradiation with potential improvements in limb function. To confirm its value and safety, prospective randomized trials must be performed and similar advances in patient immobilization and treatment verification are essential.


A comparison of manual and remote afterloading in the treatment of carcinoma of the cervix: increasing dose rate with a flexible applicator. A historical cohort design was used to assess the effect of introducing a remote afterloading system with a flexible applicator for the intracavitary treatment of cervical cancer. One hundred and sixty-eight patients treated for the 5 years prior to its introduction were compared to 84 patients treated for the first 3 years of its use. Patients were comparable with respect to age and stage. Treatment policies and techniques remained the same during the study period. Average dose rate to point A increased from 0.46 Gy/hr to 0.67 Gy/hr. The 3-year actuarial survival was equivalent between the two treatment modalities: 67.7% (manual), and 60.6% (remote). Patterns of local recurrence and distant failure were also equivalent between the two groups. Severe complication rates were comparable (8.3% manual, 6.3% remote) despite the increase in dose rate, confirming that the remote afterloading system can be safely adapted to a flexible applicator. The introduction of the remote afterloading system resulted in a 72% reduction in radiation exposure to staff.


Provision of cancer treatment services: the role of a district general hospital department of clinical oncology. Recent reports from the Royal College of Radiologists have highlighted the debate surrounding the provision of cancer services. This review describes the work of a district hospital based department of clinical oncology, emphasizing the access to and the outcome and scope of treatment. The findings indicate that district general hospital based cancer centres can provide a comprehensive, accessible, high quality consultant based service.


Radiation therapy: a long term cost benefit analysis in a North American region. The annual cost for a concentrated, high volume radiation therapy (RT) department during 1977 was 3.79 million Canadian dollars (C$). From a population of 1.14 million, 955 patients were treated with RT during 1977 at an average cost of C$3969 per patient. It is estimated that 225 will survive 15 years at a cost of C$1123 per survivor-year. The area under the RT survival curve presented indicates that RT given in 1977 will contribute to 5730 person-years of life at a cost of C$661 per person-year or C$1.82 per person-day (little more than the cost of a city bus ride). The cost to the community is C$3.32 per head per year. A 6 MV workhorse linear accelerator and its vault will contribute to one person-year of life at a cost of C$35.04 (or C$0.68 per person-week). RT is cheaper than various listed medical and surgical procedures in terms of cost per procedure or cost per year of life gained. All costs are adjusted to the 1988 C$.


Decision analysis in oncology: panacea or chimera? A review of the literature on the use of decision analysis in clinical oncology shows that, although these techniques have been available for more than 25 years, they have not been widely applied: only 19 decision analyses of therapeutic management in clinical oncology were found. The main disadvantages concern the difficulty of accurately assessing probabilities and defining measures of outcome. Time-consuming analysis may produce results that are either equivocal or simply confirm the expectations of common sense. If the basic design fails to include all relevant factors then any conclusions will be of little value. The main advantages are that, by demanding that problems be explicitly stated and analysed in a logical fashion, deficiencies in current knowledge, belief and practice are identified. The usefulness of these techniques lies in formulating management guidelines, either for treatment or for follow-up. They have only a limited role in decision making for individual patients.


Carboplatin and retroperitoneal fibrosis. A patient treated for ovarian epithelial cancer by total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), total omentectomy and five courses of single agent carboplatin chemotherapy, developed retroperitoneal fibrosis. This was diagnosed at exploratory laparotomy 6 months after completing treatment. No predisposing drug history existed in this patient. We believe that there have been no previous reports of an association between retro peritoneal fibrosis and carboplatin treatment.


Neurotoxic treatment in a patient with brachial neuritis associated with Hodgkin's disease. Brachial neuritis is a rare form of neuropathy associated with Hodgkin's disease. In the patient we describe, a brachial neuritis occurred during chemotherapy for Hodgkin's disease. He later developed a marked sensory peripheral neuropathy with vincristine. Lhermitte's sign also developed following modest doses of radiotherapy (35 Gy in 20 fractions to the whole cervical cord). We suggest that neurotoxic treatment must be given with extra care to patients with non-metastatic tumour induced neuropathies.


Enhanced normal tissue response to radiation in a patient with discoid lupus erythematosus. We report the case of a patient with discoid lupus erythematosus who developed a severe skin reaction whilst undergoing mantle irradiation for non-Hodgkin's lymphoma. Widespread moist desquamation occurred after a skin dose of only 17 Gy and was associated with an abscopal response outside the treatment area. The case illustrates the need for extreme caution when administering radiotherapy to patients with discoid or systemic lupus erythematosus.


Idiopathic epidural lipomatosis as a cause of pain and neurological symptoms attributed initially to radiation damage. Epidural lipomatosis is a rare condition in which overgrowth of extradural fat can lead to back pain, spinal cord compression and radiculopathy. A 51-year-old man developed back pain and reduced mobility following a standard course of radiotherapy for a Stage I seminoma. His symptoms and radiological appearances were initially attributed to radiation fibrosis. Further investigations and operative intervention revealed epidural lipomatosis. The excess lipomatous tissue was removed with complete resolution of his symptoms.


The concept of sign in the work of Vygotsky, Winnicott and Bakhtin: further integration of object relations theory and activity theory. In a recent paper Ryle introduced the idea of integrating object relations theory and activity theory, a conceptual tradition originated by Vygotsky and developed by a number of Soviet psychologists during the previous decades. A specific aspect of this integrative perspective will be examined, implied in Ryle's paper but not elaborated by him. It is the issue of sign mediation which was Vygotsky's primary contribution to the methodological problems of modern psychology. The aim is to show that object relations theory, especially the work of Winnicott, may bring fresh understanding into Vygotsky's early notions. It is further claimed that, by introducing the contribution of Mikhail Bakhtin and his circle to the notion of sign mediation, the profundity in Winnicott's understanding of the transitional object and of the potential space may be more fully appreciated. At the same time the ideas of Winnicott and Bakhtin will jointly clarify the limitations in Vygotsky's sign conception.


Mysticism and psychosis: the fate of Ben Zoma. This paper examines the link between psychosis and mystical study through the cases of four young men who 'entered the garden' of Jewish mystical speculation and subsequently became psychotic. The role of such study as a precipitating factor is suggested, as three had no signs of disturbance prior to their mystical studies. All had suffered personal losses, and their choice of mystical texts and rites showed that their attraction to mysticism included a search for atonement for guilt they felt over their loss. The features of normative mysticism are presented with each case and it is apparent that hallucinations, grandiose and paranoid delusions, and social withdrawal, are phenomena that do not distinguish the psychotic from the mystic. Diagnosis of psychosis is made on the basis of duration of the state, ability to control entry into the state and the associated deterioration of habits, particularly the neglect of daily religious duties. These findings emphasize the need for the examining psychiatrist to be aware of the cultural background, despite the presence of seemingly florid psychopathology. Four eminent Rabbis entered the garden of mystical speculation. Ben Azzai glimpsed and died. Ben Zoma glimpsed and was damaged (lost his sanity). Elisha ben Avuyah lost his faith. Rabbi Akiva departed in peace.


Human motivation objectively, experimentally analysed. The growth of validated objective devices, and of knowledge of ergic and sentiment structure has now, for 20 years, put new instruments (MAT and SMAT) in the hands of psychological practitioners. They have been slow to recognize, however, the theoretical powers in conflict measurement, decision theory, the general dynamic calculus, and structured learning theory which this has brought about. Illustration is given here of the experimental and clinical gains, with a view to the growth of several areas inaccessible to bivariate experiment.


Could 'objective, experimental' analysis of human motivation really improve psychotherapy? Cattell is a founding father of modern, multivariate psychological method and his paper is a fine introduction to his views on motivation which have perhaps received less attention in Britain than they deserve. However, it was the unanimous opinion of three referees that it needed to be followed by a dissenting voice. In this counterargument I suggest that Cattell's presentation is: (1) ingenuously confident of the power of multivariate statistical methods; (2) naïve about the interactive nature of the clinical relationship.


Comments on the objective analysis of motivation and psychotherapy. There are several important issues raised in the paper by Cattell and in the comments upon it: the empirical status of the Cattell factors; the experimental verification of factors; difficulties with confirmatory analysis and the value of P-analysis. The relevance of these points is explicated in this paper.


Causal beliefs about depression in depressed patients, clinical psychologists and lay persons. Non-depressed lay persons have been shown to have extensive and accurate knowledge about depression (Rippere, 1977, 1980 a, b, 1981 a) that is underpinned by a structure that resembles current academic theories of the disorder (Furnham & Kuyken, 1991). In this study a semi-structured interview schedule and a number of rating scales were used to determine and compare the nature and extent of depressed patients', clinical psychologists', and lay persons' beliefs about the causes of depression. We confirmed that depressed patients and non-depressed lay persons alike have relatively extensive beliefs about the causes of depression which are comparable to those held by clinical psychologists. However, depressed patients tend to endorse biological explanations of the causes of depression to a greater extent than clinical psychologists. In contrast, clinical psychologists assign a more important causal role to unconscious processes and childhood vulnerability factors than do either depressed patients or non-depressed lay controls.


The psychological well-being of infertile women after a failed IVF attempt: the effects of coping. One hundred infertile women and 73 female controls completed three measures of psychological well-being (depression, self-esteem and self-confidence) on two occasions (Times 1 and 2), coinciding with the beginning and end of a failed IVF attempt by the infertile women. At Time 2, the IVF women were also asked to indicate whether they had used a number of different coping responses, in relation to dealing with their failed IVF attempt. As predicted, IVF women were more depressed and had lower self-esteem than controls prior to the treatment cycle, and both before and after the treatment cycle they were less self-confident. After the failed IVF procedure, IVF women were more depressed and had lower levels of self-esteem than they did prior to the treatment cycle. In terms of the effects of coping on the post-attempt well-being of the IVF women, the use of problem-focused coping was associated with high levels of well-being, while the use of avoidance coping and seeking social support was associated with low levels of well-being.


Group therapy in the management of epilepsy. A pilot project using group therapy with patients from an epilepsy clinic is described. Observations of the group show that members were able to discuss their feelings about having epilepsy, and the difficulties the disorder caused in all areas of their lives, and to tolerate and learn from seizures which took place during group meetings. The greatest benefit was meeting others with epilepsy and sharing experiences in an environment that was not overprotective or overanxious, in contrast to their usual surroundings. The author suggests that groups of a similar nature could be a useful addition to the management of people with epilepsy.


Fibronectin as a prognostic indicator in portal hypertension. Plasma fibronectin levels were measured in 33 patients with portal hypertension and compared with modified Child's grading and a previously described prognostic index. Outcome at one year from blood sampling was recorded. Mean plasma fibronectin level was 304.1 mg/ml (sem 24.3) and significantly lower levels were found in patients who had had a variceal bleed within the previous seven days. Plasma fibronectin levels tended to be lower in patients with poor liver function as assessed by modified Child's grading but this did not achieve statistical significance. Plasma fibronectin alone was not an accurate predictor of one year survival in these patients but only one of seven patients who had a plasma fibronectin level below 300 mg/l in association with a poor prognostic index survived for one year.


Radiation stricture of the biliary ducts: an emerging new entity? Two patients with stricture of the extrahepatic biliary tree are described. Both patients presented with a clinical picture of obstructive jaundice one to two years following radiotherapy for a malignant condition. As no recurrent tumour was detected in either of the patients the strictures were considered to be the result of radiation therapy. Bilio-enteric decompression was performed in both patients who are well at follow up one and ten years after the procedure.


Studies in intestinal parasitic disease agents in stools of people in a rural area of Nigeria. A summary of 300 villagers who reported at the Parasitology Laboratory of the School of Medical Laboratory Technology (S.M.L.T) Vom, Plateau State, Nigeria was carried out for the presence of parasites' cysts, eggs, or larva. Of the 300 faecal samples examined using the light microscope after formal-ether centrifugation, 127 (42.3%) harboured one or more parasites. The parasites identified and their prevalent rates were: Entamoeba coli (19.0%) Necator americanus (17.0%); Entamoeba histolytica (4.7%); Schistosoma mansoni (3.0%); Giardia lamblia (2.3%); Trichuris trichuria (1.7%); Trichomonas hominis (1.0%); Ascaris lumbricoides (0.7%); Hymenolepsis nana (0.3%) Endolimax nana o. 3%); stercoralis (0.23%), and Iodamoeba butschlii (0.3%). The overall infection was 22.7% for the males and 19.7% for the females. Incidence was highest in villagers aged between 21 and 40 years.


Factors that may contribute to death from typhoid infection among Nigerians. Ninety-five cases of typhoid infection seen at autopsy at the University College Hospital, Ibadan, over a 10-year period were reviewed. They constituted 2.7% of 3,556 autopsies performed during this period. Apart from the associated conditions such as sickle cell disease, aplastic anaemia, schistosomiasis, liver cirrhosis and pregnancy which may lower the patients' immunity, a delay in seeking medical care, misdiagnoses, inappropriate therapy and a high complication rate were some of the factors that would appear to contribute to mortality. Therefore, in order to reduce death associated with these factors, it is essential to improve the health education of the people stressing the importance of personal communal hygiene and prompt hospital attendance from the onset of illness. There must also be improved clinical awareness of the disease to ensure early diagnosis and treatment. These are of great importance as the disease is treatable.


Kerosene poisoning in childhood: a 6-year prospective study at the University of Ilorin Teaching Hospital. In a 6-year prospective study of kerosene poisoning in children admitted to the Department of Paediatrics, University of Ilorin Teaching Hospital (UITH), between January 1982 and December 1987, 109 cases were seen. They were aged 6 months to 9 years, with a male: female ratio of 1.8:1. Majority (79.8%) were below 2 years. Many households (52.3%) stored the agent in familiar beverage or household containers placed on kitchen or bedroom floors, within easy reach of infants and toddlers. Seventy-six (69.7%) cases had home remedies, palm oil being the most common accounting for 55.3%. More than half of the cases (56.9%) presented within 12 hours of the accident due to persistent cough and dyspnoea. Respiratory complications viz pneumonia, pleural effusion and pulmonary oedema were the most common, evident in 67.3% of those who had chest radiographs. Approximately, three quarters (74.3%) of patients with radiologic abnormalities had palm oil alone or in combination with milk as home remedies. Severity of poisoning was influenced by the type of home remedy and the interval between accident and admission (P less than 0.05; P less than 0.01 respectively). Presence of radiological or CNS abnormality or both was associated with a higher morbidity. The only death in the study had complications referable to both systems. Ways of minimizing the risk of kerosene poisoning and its attendant morbidity are discussed.


Computerised axial tomographic scanning in neuropsychiatric disorders. The invention of the computerised tomography scanner - a product of modern bio-medical technology has significantly enhanced the diagnostic capability of physicians in the management of brain disorders such as cerebral atrophy, subdural haematoma, tuberous sclerosis, small calcifications and small intravascular clots. It is also useful in radiotherapy planning. The advantages of the CT scanner over the older conventional techniques, namely pneumoencephalography and arteriography are accuracy, reliability, and simplicity of operation. The major limitation is its diminished ability relative to angiography to precisely detect vascular disease, e.g. aneurysm. Furthermore, it is expensive and not precise in the differentiation of benign from malignant lesions. Despite the development of newer neuro-radiological equipment such as position emission tomography (PET) and nuclear magnetic resonance, the CT scanner remains a most invaluable diagnostic tool and should be given priority consideration in health vote allocation.


Pattern of pedestrian injuries from road traffic accidents in Nigerians. A prospective study of 108 Nigerian pedestrian road traffic accident (RTA) victims was conducted at the University of Ilorin Teaching Hospital in Nigeria between 1983 and 1984. Peak incidence occurred among 6 to 12 year old children while male/female ratio was 2.4/1. Multiple injuries occurred in 51.9% of the patients involving most frequently the chest with other body parts. Fifty-two patients (48.1%) required minor and major operations while the remaining 51.9% were treated non-operatively. Mortality was 12.0%. Only two of the thirteen dead patients were children. Socio-cultural, economic and clinical factors contributing to pedestrian RTA morbidity and mortality are reviewed as a basis for recommending preventive measure.


Assessment of minidose intrathecal morphine for analgesia after hemorroidectomy. The efficacy of 0.5kg intrathecal morphine was tested on 10 patients who had hemorrhoidectomy performed at the University College Hospital (UCH), Ibadan. They were anesthetized with 3 mls of 0.5% intrathecal bupivacine to which 0.5mg of morphine was added. Another 14 patients had intrathecal 3 mls of 0.5% bupivacine with normal saline. Post-operative analgesia was prolonged in the opiate group compared to the saline group up to 8th post-operative hour. Narcotic analgesic requirement was much less in the opiate group. There were no serious complications in either group. In view of the excellent analgesia in the immediate post-operative period and absence of delayed respiratory depression usually associated with higher doses of spinal opiates it is recommended that use of the technique be encouraged in similar surgical patients for pain relief.


Kaposis sarcoma report of a case with exclusive oral involvement. A case of Kaposis sarcoma presenting exclusively in the oral cavity is reported. Exclusive oral presentation of Kaposis sarcoma is considered extremely rare. At the U.C.H. Ibadan, a total of one hundred and two cases of Kaposis sarcoma were seen in the last 24 years. None of these presented exclusively or concomitantly in the oral cavity, until this case under review. The clinical and histological difficulties that were encountered in diagnosing this exclusive oral presentation are discussed. Literature review on possible pathogenesis is highlighted.


Infantile hypertrophic pyloric stenosis in Ghana. In a retrospective study of 84 Ghanaian infants with hypertrophic pyloric stenosis seen over a 15-year period between 1974 and 1988, the male/female incidence ratio was 9:1. First-born infants constituted 23.8% of the patient population. The incidence of associated congenital anomalies and jaundice were 10.7% and 3.6% respectively. About 33.3% of the infants started vomiting within the first week of life. The peak-age of presentation and diagnosis was between the second and sixth weeks of life. The operative mortality was 3.6%.


Invasive cervical carcinoma in two sisters. The occurrence of pre-invasive cervical carcinoma among siblings and in mother-daughter pairs has been reported previously in Europe. Invasive cervical cancer diagnosed in two Nigerian sisters within a period of three months is reported. It is suggested that sisters and daughters of patients with cervical cancer may be at a higher risk of developing the lesion because of similar socio-economic and cultural backgrounds and should therefore have regular cervical screening.


Acute intermittent [corrected] porphyria. An often forgotten diagnosis in acute abdomen. Three cases of Acute Intermittent Porphyria (AIP) are described. All presented with acute intermittent abdominal pains. One had grand-mal epilepsy as well. Two were diagnosed by chance. In the third case the diagnosis was thought of. It is suggested that AIP should always be considered as one of the differential diagnosis in Acute Abdomen in West Africa.


Weaning practices in Ilorin community, Nigeria. The paper examines the knowledge, attitude and practice of weaning in 516 mothers in Ilorin community, the capital of Kwara State of Nigeria. Women with a higher level of education and family income breastfed for a shorter period, and tended to wean earlier than the illiterate and low income group (p less than 0.05). Two hundred and twenty-eight mothers (44.2%) had commenced weaning by 3 months of age while 433 (83.9%) had done so by 6 months. Hunger, indicated by crying after a feed or demanding more frequent feeds, was the commonest reason for weaning (36.2%). Pap (maize or guineacorn gruel), an energy-sparse food remained the major weaning food irrespective of socio-economic characteristics. Fortification of pap was positively influenced by a high family income and education. Diarrhoea, associated with bottlefeeding or cow-pea diet, was the major cause of morbidity reported during weaning (55.8%). Ways of improving child health during the weaning period are suggested.


The neurotensin-related hexapeptide LANT6 is found in retinal ganglion cells and in their central projections in pigeons. Previous biochemical and immunohistochemical studies have shown that the neurotensin-related hexapeptide LANT6 is widespread and abundant in the avian nervous system. In the present study, immunohistochemical techniques were used to show that LANT6 is present in numerous cells of the retinal ganglion cell layer in pigeons. Consistent with the possibility that these LANT6+ retinal cells might be retinal ganglion cells, it was found that (1) the distribution of LANT6+ fibers and terminals in the central retinal target areas matched the distribution of central retinal projections; (2) the LANT6+ fibers and terminals are eliminated from retinal target areas by transection of the contralateral optic nerve; and (3) LANT6+ retinal cells in the ganglion cell layer can be retrogradely labeled by injections of fluorogold in the tectum. These results suggest that LANT6 may be utilized as a neuroactive substance by the central terminals of numerous retinal ganglion cells in birds. Similar anatomical findings have been previously reported for members of several other vertebrate groups, giving rise to the possibility that LANT6 (or its homologues in nonavians) may be a phylogenetically ubiquitous neuroactive substance used by retinal ganglion cells.


Spectral properties of short-wavelength (blue) cones in the turtle retina. Long- and medium-wavelength cones in the turtle retina participate in complex neural interactions. They are coupled via excitatory pathways to other cones and receive negative feedback inputs from luminosity-type horizontal cells. Little information has been collected on the S- (short-wavelength or blue) cones because they are scarce in the turtle retina and of smaller dimensions compared to the other cone types. In this paper, flash sensitivity action spectra and photoresponses of seven turtle S-cones were measured in the dark-adapted state and during chromatic background illuminations. The desensitizing action of monochromatic background lights was not uniform across the visible spectrum. A red background was most effective in desensitizing the S-cones to long-wavelength stimuli while a blue background light produced its strongest action on the photoresponses elicited by short-wavelength stimuli. The effects of chromatic adaptation on the S-cone action spectrum and on the kinetics of the small-amplitude photoresponses suggested that the S-cones in the turtle retina were involved in complex neural interactions. These included excitatory inputs probably originating in neighboring L-cones and inhibitory long-wavelength inputs probably mediated by L-type horizontal cells.


Development of vernier acuity and grating acuity in normally reared monkeys. The developmental time courses for vernier acuity and grating acuity were measured longitudinally in infant Macaca nemestrina monkeys. Behavioral measurements of vernier and grating acuity were made at regular intervals during development. Near birth, grating acuity is relatively more mature than vernier acuity. The proportional rate of vernier acuity development is faster than that for grating acuity. During the course of development, grating acuity improves approximately 15-fold whereas vernier acuity improves about 60-fold. Both visual functions approach adult levels at about the same age, around 40 weeks postnatally. Although grating acuity develops about four times faster in monkeys than in humans, vernier acuity development in monkeys and humans does not appear to reflect the same relationship. Adult levels of vernier acuity for the monkeys are about a factor of 2 poorer than are typically reported for humans. The differential development of vernier acuity and grating acuity does not necessarily reflect development at different levels of the visual system.