[Use of laparoscopy in gynecology].

Paper concerns 1822 performed laparoscopies. The most frequent indications to laparoscopy were: sterility, adnexal mass, tubal pregnancy and pelvic pain syndrome. In 80% cases of sterility we found pathologic findings, which could be the cause of sterility. adnexal mass, tubal pregnancy and pelvic pain syndrome. In 80% cases of sterility we found pathologic findings, which could be the cause of sterility. In 75% of cases we confirmed adnexal mass, which were operated by laparoscopy or by laparotomy. In 17 cases we confirmed unruptured tubal pregnancy, which were conservatively operated by laparoscopy or by laparotomy. Laparoscopy is useful method in gynecology, especially in diagnostically difficult cases of gynecologic disease.


[Laparoscopic surgery in gynecologic practice].

Paper concerns 293 laparoscopic operations. The most frequent types of laparoscopic operations in presented material were: adhesion lysis in minor pelvis (33.8% cases), cystectomy and cyst-ovariectomy (27.6%) and electrocoagulation of ovarian capsule. Operative laparoscopy because of small injury is useful method in the treatment some gynecological disease.


[Complications of endoscopy in gynecology].

The paper concerns the complications which appeared during 1822 laparoscopies and 141 hysteroscopies. The overall percentage of complications in presented material was 0.82% for laparoscopy and 2.8% for hysteroscopy. The most frequent complication during performance of laparoscopy was subcutaneous emphysema (8 cases). The most frequent complication during hysteroscopy was uterine wall perforation, which appeared in 3 cases during incision of dense and massive intrauterine adhesions. All patients with complications of gynecologic endoscopy recovered well.


[Use of diagnostic and operative hysteroscopy in clinical practice].

In the paper authors present indications and results of 141 hysteroscopies. The most frequent indications were: sterility, Asherman syndrome suspected, infertility and abnormal uterine bleeding. 55 diagnostic and 86 operative hysteroscopies were performed. In sterility and infertility group of patients were present 49.6% pathological findings of uterine cavity, between them the most frequent were: uterine septa and intrauterine adhesions. In the remaining cases the intrauterine pathology were present in 75.8% cases, between of them the most frequent were intrauterine adhesions and endometrial hyperplasia. Hysteroscopy should be the method of choice in some cases of gynecological pathology.


[Diagnosis and treatment of uterine changes effecting fertility using hysteroscopy].

The aim of this study was evaluation of uterine factors in sterility and infertility using hysterosalpingographic and hysteroscopic techniques. Sixty five women ranged in age from 22 to 40 years were included in this study. The results of performed hysterosalpingographies and hysteroscopies were compared. Intrauterine changes found during diagnostic procedures were removed in operative hysteroscopy and the effectiveness of this treatment was estimated by pregnancy rate. The most frequent changes found within cervical canal and uterine cavity were adhesions and endometrial polyps. The rate of uterine septa and submucous myomas were considerable lower. Hysteroscopy was found the best diagnostic method in evaluation of intrauterine conditions for fertility and considerably increased the range of information about the type and location of uterine abnormalities. The removal of those changes during operative hysteroscopy increased the fertility rate in women treated with this procedure.


[Usefulness of hysteroscopy in diagnosing sterility].

Sterility is a severe social problem. Using hysteroscopy, which is possible thanks to development of medical technology, seems to be an important improvement in diagnostics and therapy of sterility. The aim of this study is evaluation of the usefulness of hysteroscopy in diagnostics of sterility. There was a group of 106 women with diagnosed primary sterility and 82 women with secondary sterility. Wolf and Storz hysteroscopes were used during examinations, whereas the uterine cavity was dilated by CO2 using Wolf Metrometer 2121. During this examination a normal uterine cavity was found in most cases (32.9%). The next findings were: endometrial polyps (27.6%), intrauterine adhesions (23.4%), sub-serous myomas (14.3%), and congenital uterine abnormalities (1.5%). Comparing outcomes of hysteroscopy in both groups of sterile women, the high rate of intrauterine adhesions in the secondary sterility (43.9%) was detected. Performing hysteroscopy in patients with sterility increases considerably the range of informations about reproductive organs. Also the possibility of eye-controlled biopsy, deliberation of intrauterine adhesions or removing of endometrial polyps during endoscopic procedure increases the value of hysteroscopy.


[Evaluating the possibility of performing diagnostic and operative hysteroscopy depending on the type of hysteroscopy and agent used for filling the uterine cavity].

The aim of the paper is to present own experiences concerning diagnostic and operative hysteroscopy performed with 4 types of hysteroscopes. Flexible hysteroscope HYP 1T, rigid hysteroscope 5 mm in diameter with single flow, operative hysteroscope 8 mm in diameter with constant flow, hysteroresectoscope 9 mm in diameter with constant flow produced by Olympus; for filling the uterine cavity CO2 0.2% NaCl, 5% glucose, Purisol, Hyskon were implemented. In even case the degree of hardship of the procedure, traumatism for the patient, degree of operated-on patient's safety during the procedure, possibility of applied in the presence of bleeding, price of instrument and agents applied for filling the uterine cavity were estimated. It has been found out that the use of rigid hysteroscope 5 mm in diameter and operative hysteroscope 8 mm in diameter with constant flow and utilization of CO2 as well as Purisol and Hyskon solutions provide possibility of extensive diagnosis and therapy.


[Diagnosis of fetal hemolytic disease and therapeutic possibilities].

The possibility of fetal blood sampling and direct blood transfusion into fetal circulation began the new direction in diagnostics and treatment of fetal haemolytic disease. Early diagnostics and possibilities of intrauterine treatment of the fetus enabled effective treatment also in severe hydrops cases. In the article diagnostic and therapeutic scheme introduced in the I Department of Obstetrics and Gynaecology and Central Rh-disease Unit in Warsaw was presented.


[Vaginal delivery after previous cesarean section].

Data concerning frequency of cesarean section as well as frequency of vaginal delivery after cesarean section in Poznań region in years 1990-1991 were presented. During last years we observed significant increase of spontaneous deliveries after cesarean section. The indications for the previous cesarean section and the outcome of the present pregnancy are discussed.


[Pharmacokinetics of phenazone after bilateral ovariectomy in female rabbits].

The aim of this study was to evaluate the influence of female sex hormones on phenazone pharmacokinetics using as an experimental model female rabbits after a bilateral ovariectomy. Eighteen female rabbits divided into two groups: control animals and experimental rabbits, that underwent ovariectomy, were used in the study. Pharmacokinetic assays were performed in all animals: prior to the study, after 1 month and after 2 months. Blood was sampled within 24 hours after intragastric administration of phenazone at a dose 50 mg/kg b.w. Two compartment open model was used for calculations. Significant increase in AUC and prolongation of phenazone halflife as well as a decrease in the total body clearance were noted. The study demonstrated the possible inhibition of the microsomal mixed-function oxidase system by oestrogens.


[Sinusoidal and pseudo-sinusoidal patterns in cardiotocography--differentiation and prognosis].

Examples of cardiotocograms looks like a graph of a sine function were presented. The differentiation of these various patterns was discussed. The most usefull parameters were amplitude and frequency of long-term variability and its relation to the uterine contractions and short-term variability.


[The course of pregnancy with placenta praevia diagnosed in the 2nd and 3rd trimester].

Selected clinical features of the course of pregnancy in 118 gravidas with placenta praevia diagnosed ultrasonographically on the first breeding were compared. The clinical features significantly connected with bleeding and the prognostic features for the way of delivery were stated. The longest bleeding was observed in patients with partial or marginal placenta praevia. The most common anterior location of low placenta praevia was connected with the lowest risk as regards the cesarean section due to hemorrhage. The earlier occurrence of the bleeding was associated with its longer duration. The time of the occurrence of the first bleeding and its duration were associated with a duration of the pregnancy and a body mass of the newborn. The recurrence of bleeding was of no prognostic importance. The appearance of the first bleeding after the 28th week of pregnancy was significantly connected with the necessity of performing a cesarean section due to hemorrhage in case of central, partial or marginal placenta praevia. In case of low-lying placenta the way on delivery was significantly related to the time of appearance of the first bleeding and the distance between the placenta and the internal os. Fisher's linear discriminative function of the two features allowed for the determination of a mathematical formula for the prognosis of the way of delivery in case of a low-lying placenta.


[Comparison of mammography and sonography in diagnosis of breast cysts].

Mammography and sonography were done in 479 women. In mammography cysts were suspected in 10 cases, in 20 cases solid lumps and in 49 cases no changes were detected. In sonography in 7 cases cysts were found in 23 solid lumps, in 49 no changes were detected. It was proved that sonography is much more accurate in detecting cysts than mammography.


[Thyroid carcinoma from material of the surgery department at the oncology clinic, Medical Academy in Poznan].

From among 612 cases of various kinds of thyroid diseases operated in the Surgical Department of the Oncological Clinic, we present here 24 cases (3.92%) of thyroid carcinoma. They are divided according to sex, staged to TNM system and histopathologic diagnosis. Discussed were the range of performed operations which depended on the results of histopathologic examinations. They were compared with the current principles of thyroid carcinoma treatment. Owing to the significance of inter-operational examination, in order to establish the range of the operation, the authors suggest that necessity of surgical treatment in cases of thyroid carcinoma, in centers which have at their disposal a histopathological laboratory.


[Role of gynecology in etiopathogenesis of cervical carcinoma].

Cancer as a natural stochastic phenomenon and disease can be promoted by many non-specific factors, including also such gynecological ones as: 1. faulty prediction and determination of birth date: 2. instrumental instead of possible natural labor; 3. reduction rather prolongation of lactation; 4. acceptation of early sexual life; 5. wrong hormonal therapy; 6. longlasting prescription of pills; 7. infrequent diagnosis and wrong therapy of hypothalamic conditioned abortions and premature deliveries; 8. clinical, colposcopic and cytologic false negative diagnosis of cervical cancer; 9. eradication of neoplastic lesion without normalization of environment, and 10, too radical and aggressive treatment of precancerous states. Medicine as no other field of human activity requires from the gynecologists the specific responsibility for conscientious constant acquisition of general knowledge to ensure the future of human species especially in conquering "cancer of mothers" and preventing "cancer of early sexual life".


[Treatment of tubal pregnancy laparoscopically].

Five cases of unruptured tubal pregnancy treated laparoscopically are described. Basing on the clinical evaluation of them we concluded, that selected cases of unruptured tubal pregnancy may be successfully treated using the laparoscopic technics. The use of this technics is less traumatic for patient, shorted the time of her stay in the hospital and lower the costs of therapy.


[Subpopulations of t lymphocytes and lymphocyte proliferative activity in normal pregnancy].

T lymphocyte subpopulations (CD3+, CD4+, CD8+) and the lymphocyte proliferative responses to mitogens (PHA, Con A, PWM), in the environment of fetal calf serum (FCS) were examined in 16 normal primigravidas in the third trimester of pregnancy and in 15 healthy nonpregnant women. In normal pregnant women significantly lower absolute and percentage numbers of CD3+ and CD4+ T cells and almost twice reduced CD4+/CD8+ ratio were found, in comparison with nonpregnant subjects. Despite the shifts among particular T lymphocyte subsets in the peripheral blood, non disorders were found in the lymphocyte proliferative responses to mitogens in normal pregnancy.


[Immunomodulating properties of sera in normal pregnant women].

The purpose of this study was to analyze the immunosuppressive properties of sera of normal pregnant women. Effects of pregnancy sera on the proliferation of mitogen (PHA, Con A, PWM)-induced lymphocytes were examined in healthy primiparas. The sera of normal pregnant women inhibited the proliferation of PHA- and Con A- induced both autologous and allogenic lymphocytes (obtained from nonpregnant and pre-eclamptic women), while remaining neutral towards the proliferation of PWM- induced lymphocytes in comparison with fetal calf serum. The basic immunomodulatory activity of the sera in pregnant women was contained in the heat-stable fraction.


[Evaluating the usefulness of qualitative analysis of latex c-reactive protein for diagnosing neonatal sepsis].

We analyzed the results of determinations C-reactive protein (Latex Test Dialab firm) of 136 newborns. We divided them into three groups: with generalized infections, with infection without sepsis and without infection. Sensitivity of method for neonates with septicaemia was 60%, for neonates with infection without sepsis--81.25%, together for all infections--66.1%. After overlooking sepsis caused by Staphylococcus epidermidis sensitivity for sepsis was 81.8% and for all infections--81.6%.


[Method of delivery and obstetric records of premature labour in material from the Polish Mother's Health Center Memorial Hospital].

526 premature labours between the 28th and the 36th week of pregnancy were recorded at the Polish Mother's Health Centre Memorial Hospital during the period between April 1989 to September 1991. The mortality rates of newborns were analysed in the group of vaginal and abdominal delivery in the following pregnancy stages: the 28th--the 31st week, the 32nd--the 34th week, the 35th--the 36th week. 23 pregnant delivered abdominally by rapid indications were excluded from the study. In this group cesarean section was caused by placental complications or severe gestosis. This group, as a group of a high obstetric risk, was directly incomparable with vaginal delivery group, that of a low obstetric risk. Newborns with congenital malformations were also excluded from the study. Our analysis allows to assume that cesarean section, when applied in the premature labour between the 32nd and the 34th week of pregnancy, gives much better chances for newborn's survival than vaginal delivery.


[Monitoring hormones during the menstrual cycle among sterile women. I].

This paper attempts to estimate the endocrinological function of the following glands: pituitary, thyroid, adrenal, pancreas, and ovary. An examination only once of their hormones was made between the 8th and 10th day of the follicular phase of the menstrual cycle. This examination was performed on 22 sterile women with monophasic menstrual cycle, 119 sterile women with biphasic menstrual cycle and 17 women who delivered at least one child without previous treatment (control group). Radioimmunoassays (RIA) of 11 hormones: LH, FSH, PRL, estradiol, progesterone, cortisol, aldosterone, insulin, T3, T4, and testosterone were made. It was confirmed that the marked differences showed only the examinations of LH and estradiol among sterile women with monophasic menstrual cycle in comparison to the group of sterile women with biphasic cycle and the control group. RIA of the concentrations of the thyroid, pancreas and adrenal hormones among women without endocrinopathy have not a mark diagnostical value. RIA of the level of the testosterone is not appropriate in clinical cases which do not carry symptoms a hyperandrogenism.


[Hormonal monitoring during the menstrual cycle among sterile women. II].

This paper attempts to assess the value of the dynamical examinations of the concentrations of the pituitary gonadotropin LH, FSH, PRL in the menstrual cycle. RIA were made on 22 sterile women with monophasic cycle and 119 sterile women with biphasic cycle in comparison with 17 women who delivered at least one child without previous treatment (control group). The dynamical RIA were made on all women between the 5th and the 26th day of the menstrual cycle. The results of these assays were compared in the 8th, 14th, 15th, 16th, 21st and 25th day of the menstrual cycle. It was confirmed that the lower levels of PRL are maintained through all the time of the menstrual cycle among sterile women with monophasic cycle. It is shown that higher level of LH is maintained through all the time of the menstrual cycle but it is particularly higher in the secretary phase of the cycle among sterile women with monophasic cycle. A lower level of FSH was observed at the beginning of the follicular phase of the cycle and a markedly higher concentration of FSH was found on the secretary phase of the cycle among sterile women with monophasic cycle.


[Hormonal monitoring of the menstrual cycle among sterile women. III].

This paper attempts to assess the value of the dynamical examinations of the concentrations of the ovary hormones progesterone and estradiol in the menstrual cycle. RIA were made on 22 sterile women with the monophasic cycle and 119 sterile women with the biphasic cycle in comparison with 17 women who delivered at least one child without previous treatment (control group). The dynamical RIA were made on all women between the 5th and 26th day of the menstrual cycle. The results of these assays were compared on the 8th, 14th, 15th, 16th, 21st and 25th day of the menstrual cycle. The examinations confirmed a markedly lower concentrations of estradiol throughout all the time of the cycle among sterile women with the monophasic cycle and a little higher concentrations among sterile women with the biphasic cycle. Markedly lower concentrations of progesterone were observed throughout all the time of the cycle among sterile women with the monophasic cycle and a little higher concentrations of it were found among sterile women with the biphasic menstrual cycle.


[Malignant melanoma coexisting with pregnancy].

An extremely rare case of melanoma amelanoticum coexisting with pregnancy has been discussed. Pregnant A. Ch., age 42, was admitted to the Polish Mother's Health Centre Memorial Hospital on the 22nd of August, 1990 with a diagnosis of the 5th pregnancy, the 2nd delivery, the 30th week of gestation, state after cesarean section. Suspected malignant melanoma. Stomach ulceration. Thrombophlebitis of left lower extremity. General condition--medium hard. For the last three days she did not report fetal movements, fetal heartbeat was not detected either. Us examination confirmed fetal death. On the 24th of August, 1990, spontaneous vaginal delivery terminated the pregnancy, giving a dead, macerated female fetus, body weight of 1500 g. On the 3rd day after delivery the patient died with growing circulation-respiratory insufficiency. Autopsy revealed melanoma malignum amelanoticum disseminatum. Neither an autopsy of the fetus nor histopathological examinations of the secundines were performed for the advanced maceration. The coexistence of pregnancy with malignant melanoma in this case brought a tragic end both for the mother and the fetus.


Lateralization of the grasp reflex in male and female human newborns.

The lateralization of the grasp reflex was studied in male and female newborns. The mean grasp-reflex strength of the right hand was found to be higher than that of the left hand in males, but the difference was not significant. The mean grasp-reflex strength of the right hand was found to be significantly higher than that of the left hand in females. There was no significant difference between the mean grasp-reflex strengths of the right hand in the male and female subjects. The mean reflex strength of the left hand was found to be higher in males than females; the difference was only marginally significant. The right minus left (R - L) reflex strength showed a significant positive linear relation to the right-and left-reflex strengths in both sexes. This was, however, much more pronounced for the right-reflex than the left-reflex. There was a significantly positive linear correlation between the reflex strengths of the right and left hands and the body weight in males. The females did not show such a relationship between reflex strength and body weight. These sex-related differences in the grasp reflex in newborns were discussed in light of cerebral lateralization and its hormonal modulation.


The relationships between the degree of grasp-reflex asymmetry, grasp-reflex strength from the right and left hands, and body weight in the male and female newborn with and without familial sinistrality.

The relation of the degree of grasp-reflex asymmetry to the strength of right- and left-hand grasp-reflex strength and body weight was studied in human newborn. In the total sample (N = 103), the right minus left (R-L) reflex strength was found to be positively linearly related to the grasp-reflex strengths from the right and left hands in FS-subjects; the correlation was higher for the right hand than the left hand. In FS+ subjects (N = 17), there was not a significant correlation between R-L and right-reflex strength; left-reflex strength was found to be negatively linearly related to the R-L reflex strength. In FS- subjects, the right- and left-reflex strengths showed a positive linear correlation with body weight. In FS+ subjects, only the left-reflex showed a positive linear correlation with body weight. The R-L reflex tended to be positively correlated with body weight in FS- subjects and negatively correlated in FS+ subjects. In females (N = 58), the relation of R-L to right and left reflex was similar to that for the total sample. There was no significant correlation between grasp reflex and body weight in FS- females. In FS+ females (N = 8), there was a positive linear correlation between the right grasp-reflex and body weight; the left grasp-reflex did not show such a significant correlation. The R-L grasp-reflex strength was not correlated with body weight in females.(ABSTRACT TRUNCATED AT 250 WORDS)


Changes in psychopathological symptoms in sleep apnea patients after treatment with nasal continuous positive airway pressure.

To evaluate the psychological disturbances associated with obstructive sleep apnea (OSA) and the effect of nasal continuous positive airway pressure (NCPAP) treatment on these alterations, personality patterns and psychosocial adjustment were assessed in patients hypnopolygraphically diagnosed with OSA before and after different periods of NCPAP therapy. Prior to treatment, MMPI results for 23 patients showed significant elevations (p < .01) on five clinical scales compared to those of 17 normal controls. Apneics' personality patterns were predominantly of a "neurotic-mixed" type, indicating an anxiety reaction with paranoid features. Depression, schizophrenia, and hypochondriasis were the highest scales. Most patients had severe psychosocial maladjustment. In the follow-up study during the NCPAP treatment, there was a progressive reduction of the psychopathological signs along with a generalized improvement in psychosocial adaptation. These changes were remarkably significant after about a year's treatment, in particular for depression (p < .01) and total adjustment degree (p < .01). It was concluded that severe OSA is associated with serious psychosocial alterations that improve gradually with NCPAP.


Right-, left-dominance and ambidexterity in grasp reflex in human newborn: importance of left brain in cerebral lateralization.

The grasp reflex was studied in human newborn without familial sinistrality. Of 60 females, 26 (43.3%) were right-handed and 34 (56.7%) ambidextrous. Of 62 males, 20 (32.3%) were right-handed, 39 (62.9%) ambidextrous, and 3 (4.8%) left-handed. There was a nonsignificant preponderance of right-dominance in females and a significant preponderance of nonright-handedness in males. In right-handers, the mean right minus left (R-L) grasp-reflex showed a positive linear correlation with the grasp-reflex from the right and left hands, with a higher correlation for the right hand. In ambidexters, the R-L grasp reflex did not show any significant correlation with the grasp reflex from the right and left hands. The mean grasp-reflex from right and left were found to be significantly smaller in ambidextrous males and females then right-handed males and females, with a much higher significance for the right hand. It was concluded that females tended to have a more pronounced reflex lateralization than males. The results also indicated that the left brain may be more important than the right brain for the development of a spinocerebral motor lateralization in humans.


Anoxic encephalopathy: a case study of an eight-year-old male with no residual cognitive deficits.

Anoxia is generally associated with impaired learning, memory, attention, and planning. We present a case of near-drowning (5-15 minute anoxia) with subsequent 15 hour coma that is extremely unique because of (1) the absence of neuropsychological and neurological deficits 3 1/2 months post-injury, and (2) the availability of pre-injury intelligence testing for comparison. Findings are important as previous research has suggested residual deficits will be evident after much briefer coma. The present findings suggest anoxic encephalopathy does not automatically result in neurological or cognitive impairment.


Is postmenopausal osteoporosis related to pineal gland functions?

There is currently considerable interest in the pathogenesis of postmenopausal osteoporosis, which is the most common metabolic bone disease. Osteoporosis affects approximately 20 million persons in the United States, 90% of whom are postmenopausal women. Although there is evidence that estrogen deficiency is an important contributory factor, the pathogenesis of osteoporosis is multifactorial and presently poorly understood. There is evidence that pineal melatonin is an anti-aging hormone and that the menopause is associated with a substantial decline in melatonin secretion and an increased rate of pineal calcification. Animal data indicate that pineal melatonin is involved in the regulation of calcium and phosphorus metabolism by stimulating the activity of the parathyroid glands and by inhibiting calcitonin release and inhibiting prostaglandin synthesis. Hence, the pineal gland may function as a "fine tuner" of calcium homeostasis. In the following communication, we propose that the fall of melatonin plasma levels during the early stage of menopause may be an important contributory factor in the development of postmenopausal osteoporosis. Consequently, plasma melatonin levels taken in the early menopause could be used as an indicator or perhaps as a marker for susceptibility to postmenopausal osteoporosis. Moreover, light therapy, administration of oral melatonin (2.5 mg at night) or agents which induce a sustained release of melatonin secretion such as 5-methoxypsoralen, could be useful agents in the prophylaxis and treatment of postmenopausal osteoporosis. Finally, since application of external artificial magnetic fields has been shown to synchronize melatonin secretion in experimental animals and humans, we propose that treatment with artificial magnetic fields may be beneficial for postmenopausal osteoporosis.


The pineal gland and spontaneous abortions: implications for therapy with melatonin and magnetic field.

Spontaneous abortion, the termination of pregnancy prior to 20 weeks of gestation, is estimated to occur in 40%-50% of all pregnancies and in 12%-15% of identified pregnancies. The causes of spontaneous abortion can be divided into two main categories: those arising from chromosomal anomalies and those arising from abnormalities in the intrauterine environment. In the following communication, we propose that deficient pineal melatonin functions in early pregnancy may be causally related to the development of spontaneous abortions in cases where chromosomal anomalies or structural abnormalities of the uterus have been excluded. This hypothesis is based on the findings that: (a) melatonin plasma levels normally increase by 200%-300% in the first 20 weeks of pregnancy; (b) melatonin decreases uterine contractility in the rat; (c) melatonin stimulates the secretion of progesterone, which decreases uterine contractility and prevents immunological rejection of the trophoblast; (d) melatonin inhibits the synthesis of prostaglandins, which are potent inducers of uterine contractility and labor, and (e) pinealectomy increases the number of spontaneous abortions in pregnant rats. In addition, since melatonin is a hormone with immunosuppressant properties, we propose that the increased melatonin production in early pregnancy may contribute to a state of "transplantation immunity" to the paternal histocompatibility antigens preventing immunological rejection of the trophoblast. If this hypothesis is correct, then plasma melatonin, levels during early pregnancy could be used as an indicator for increased risk of spontaneous abortions.(ABSTRACT TRUNCATED AT 250 WORDS)


Seasonal panic disorder: a possible variant of seasonal affective disorder.

The present communication concerns a 30 year-old female patient with panic disorder in whom panic attacks appeared to be seasonally-related. Characteristically, attacks were more frequent and severe during the months of October to May with spontaneous remissions during the months of June to September. Since 70% of patients with seasonal affective disorder (SAD), a variant of affective illness characterized by recurrent winter depressions with remissions in summer, suffer from anxiety disorders, we propose that seasonal panic disorder may be a variant of SAD. Since SAD is associated with phase delay of circadian rhythms, some forms of panic disorder may be related to phase instability of circadian rhythms. Moreover, since administration of artificial bright light therapy is currently the most effective treatment for SAD, it is suggested that patients with panic disorder should be questioned as to whether their symptoms are seasonally related. If a positive association is established, these patients should be offered treatment with light therapy prior to or coincident with the institution of pharmacotherapy.


The inhibitory effect of the muscarinic agonist pilocarpine on lymphocyte activation involves the IL-2 pathway and the increase in suppressor cell function.

The inhibition of lymphocyte DNA synthesis by the cholinergic muscarinic agonist pilocarpine (5 x 10(-4) M) was not reversed by addition of exogenous recombinant Interleukin-2 (100-1000 IU/ml). Pilocarpine did not inhibit Interleukin-2 (IL-2) production by human peripheral blood mononuclear cells but decreased the number of interleukin-2 receptor bearing cells (TAC positive cells). Furthermore, pilocarpine increased the CD8:CD4 T lymphocyte ratio enhancing the suppressor cell function. All these effects were blocked by the muscarinic antagonist atropine (1 x 10(-6) M). As described for the specific lymphocyte nicotinic stimulation, the pure cholinergic muscarinic stimulation inhibits lymphocyte proliferation by enhancing suppressor activity.


Fc gamma receptors are expressed on human neuroblastoma cell lines: lack of correlation with N-myc oncogene activity.

FcRs (Fc Receptors) have been detected on the cell surface of two human neuroblastoma cell lines; IMR 32 and SK-N-SH, by immunocytochemistry and flow cytometric analysis, using a previously characterized polyclonal antiserum raised against the Fc gamma R isolated from a human CLL line (Gorini, Medgyesi, Garavini, Dorrington and Down, 1987; Rozsnay, Sarmay, Szabo, Medgyesi, Gorini and Gergely, 1990). FcR is expressed on all the cells of both lines at least at the same level as on the HL60 promyelocyte cell line used as positive control. Two electrophoretic components displaying apparent molecular masses of 70 and 43 kDa respectively have been identified by SDS-PAGE followed by Western blotting analysis of crude cell membranes. In addition, "in situ" hybridization experiments seem to exclude a correlation between FcR expression and N-myc oncogene activity. The presence of FcR in neuroblastoma could be related to a possible functional role even on these cells which do not belong to the immune system; moreover, they could also be exploited for a diagnostic characterization of this tumor.


"Positive" and "negative" movement disorders in schizophrenia.

Investigations aimed at identifying the clinical characteristics that discriminate tardive dyskinesia (TD) from non-TD patients have yielded disparate findings. We have suggested, based on pharmacological and neuroradiological studies, that TD in schizophrenia may be a covariate of positive symptoms while drug-induced parkinsonism (DIP) may relate to negative symptoms. To investigate this hypothesis, we examined in 47 institutionalized schizophrenic patients the relationship of TD and DIP with psychopathology clusters rated on the Positive and Negative Syndrome Scale. We found that involuntary movements of TD were significantly associated with the activation cluster (p < .01), whereas DIP was significantly associated with the anergia cluster (p < .01). These findings thus support the position that TD is a specific facet of the positive syndrome in schizophrenia, while DIP is a specific feature of the negative syndrome. Clinically, the data suggest that schizophrenic patients with predominant positive symptoms may be at increased risk for TD, while those with prominent negative features could be at increased risk for DIP. In analogy with the positive/negative dichotomy, we propose that TD could be regarded as a "positive," while DIP as a "negative" movement disorder.


Pattern of CBF in the rehabilitation of visuospatial neglect.

The CBF was assessed in seven patients before and after rehabilitation for visuospatial neglect. Two months of treatment produced an increased perfusion both in the right posterior and left anterior areas of the brain. However, only the left anterior CBF increase was correlated with the neglect disorders. The left anterior improvement in CBF was inversely correlated with right-left cerebellum asymmetry in pre- and post-treatment. The present data suggest the role of the frontal eye-fields in the mechanism of recovery of visual exploration in patients with severe neglect.


Similarities between sylvian fissure asymmetries in cat brain and planum temporale asymmetries in human brain.

Galaburda et al. (1987) have suggested that asymmetry of planum temporale in men would result from an asymmetrical neuronal loss; symmetry would implicate a failure of asymmetrical cell loss. There are several reports indicating a similarity between men and animal in cerebral lateralization. In the present work, a morphological analysis was performed in sylvian fissure (SF) of cats. Asymmetry coefficients (AC) were distributed symmetrically and normally with a mean of zero. However, female cats exhibited a relatively stronger leftward asymmetry (left SF > right SF), and male cats a relatively stronger rightward asymmetry in SF. The results generally supported those of Galaburda and his coworkers. Deviations from their results depended mainly on paw preference. The similarity between human brain and animal brain was accentuated once more concerning cerebral lateralization. The results were not appropriate to conclude about the mechanisms of cerebral lateralization. Testosterone in males and estrogen in females were suggested to be the main hormones contributing to the emergence of cerebral lateralization.


Associations among right minus left brain weight, right- and left-brain weight and the degree of paw preference in right- and left-preferent male and female cats.

The relation of right and left brain weight to right minus left (R-L) brain weight and the relation of R-L paw use to brain weight were studied in adults cats. The R-L brain weight was significantly larger than zero in right-pawed (RH) male and left-pawed (LH) females. The R-L brain weight was significantly smaller than zero in LH males, not significantly different from zero in RH females. The R-L brain weight was negatively linearly correlated with the left-brain weight in RH and LH males (no significant correlations in females). The R-L paw use showed a significant positive linear correlation with the R-L brain weight in RH male and females. There was a significant negative linear correlation between R-L paw use and R-L brain weight especially in LH males. Total brain weight showed a significant negative linear correlation with R-L paw use in RH males, and a positive linear correlation in LH males (no correlations in female cats). These results indicated that intermanual difference in paw use is associated with interhemispheric weight difference and total brain weight, especially in male cats; the left brain seems to be of importance in cerebral lateralization.


Lateral orientation, eye movements and dichotic listening.

Past studies have found that lateral orientation (eye or head turn) may influence hemispheric asymmetry on the dichotic listening task. The present work studied the effects of forced head and eye turn on a consonant-vowel dichotic test. Spontaneous conjugate lateral eye movements (CLEM) in response to questions were also measured. The subjects were 29 male and 25 female right-handed university students. The dichotic test was administered using a forced-attention method rather than free recall in order to control for attentional bias. As predicted, right lookers on the CLEM test, showed an enhanced right ear advantage while left lookers showed a diminished right ear advantage. This suggests that characteristic hemispheric arousal may enhance or inhibit asymmetry on perceptual laterality tests. No relationship was found between dichotic listening and forced head or eye turning. It was noted that past experiments may have failed to control for the attentional bias introduced by having the head or eyes turned to one direction.


Hemispheric priming: effect of response mode on a position replication task.

Ten male and ten female dextral subjects performed a kinesthetic position replication task under two response mode conditions; in one block, subjects indicated their decision by a lateralized verbal response and in the other block, by a midline chin-lift response. Response mode was found to interact with arm, excursion length, end position, and sex. This interaction is interpreted to reflect the influence of verbal preparation on the relative balance between a left hemisphere-biased strategy of kinesthetic positioning and a right hemisphere-biased strategy involving a spatial reference system.


Magnetic fields in the therapy of parkinsonism.

In a recent Editorial published in this Journal, I presented a new and revolutionary method for the treatment of Parkinson's disease (PD). I reported that extracranial treatment with picoTesla magnetic fields (MF) is a highly effective, safe, and revolutionary modality in the symptomatic management of PD. My conclusion was based on experience gained following the successful treatment of over 20 Parkinsonian patients, two of whom had levodopa-induced dyskinesias. None of the patients developed side effects during a several month period of follow-up. In the present communication, I present two reports. The first concerns four Parkinsonian patients in whom picoTesla MF produced a remarkable and sustained improvement in disability. Three of the patients had idiopathic PD and the fourth patient developed a Parkinsonian syndrome following an anoxic episode. In all patients, treatment with MF was applied as an adjunct to antiParkinsonian medication. The improvement noted in these patients attests to the efficacy of picoTesla MF as an additional, noninvasive modality in the therapy of the disease. The second report concerns two demented Parkinsonian patients in whom treatment with picoTesla MF rapidly reversed visuospatial impairment as demonstrated by the Clock Drawing Test. These findings demonstrate, for the first time, the efficacy of these MF in the amelioration of cognitive deficits in Parkinson's disease. Since Alzheimer's pathology frequently coexists with the dementia of Parkinsonism, these observations underscore the potential efficacy of picoTesla MF in the treatment of dementias of various etiologies.


Successful treatment of multiple sclerosis with magnetic fields.

The present communication concerns a 50 year-old woman with a 15 year history of chronic-progressive multiple sclerosis (MS) in whom extracranial application of picoTesla magnetic fields (MF) produced a dramatic and sustained improvement in disability. In contrast, administration of melatonin (3 mg, P.O.) produced in this patient a rapid exacerbation of disability which was reversed subsequently by treatment with MF. It is hypothesized that the therapeutic effects of picoTesla MF involve the mediation of the pineal gland which is known to act as a magnetosensor. The report demonstrates, for the first time, the remarkable efficacy of weak MF in the symptomatic treatment of chronic-progressive MS and underscores the pivotal role of the pineal gland in the pathophysiology of MS. If confirmed by a larger cohort of patients, extracranial application of picoTesla MF may prove as an extremely efficacious, nonpharmacological modality for the treatment of MS.


Parenchymal "damage" in transient ischemic attacks (TIAs) and prolonged reversible ischemic neurologic deficits (PRINDs):--the role of cranial CT and EEG.

Over a period of 6 years (1985-1990) we reviewed records of patients with one or more TIAs or PRINDs (196 TIAs, 63 PRINDs). 111 patients (42.9%) suffered from TIAs/PRINDs of the anterior circulation. In all cranial CT scanning (CCT) was performed, whereas only in 79 EEG was recorded after recovery from the symptoms. 25 patients (22.5%) out of the 111 showed low density areas of recent onset in CCT made responsible for the attack. Among the EEGs of the 79 patients 35 (44.3%) revealed corresponding electrical abnormalities. Out of the 79 patients investigated by both methods in 14 (17.7%) a lesion was demonstrated in CCT and focal abnormality in EEG. In 11 (13.9%) EEG was normal despite a lesion manifested in CCT. Vice versa 21 patients (26.6%) showed normal CCTs but focal abnormalities in EEG. By far most cases (43%) had normal CCTs and EEGs. These results may contribute to a redefinition of TIA and PRIND as clinically defined syndromes in prae-CT-area.


Low-dimensional chaos in event-related brain potentials.

The quantification of a chaotic system, such as the nervous system, can be made by calculating the correlation dimension (D2) from a sample of the data it generates. The encephalogram was recorded from the vertex during an auditory "odd-ball" paradigm and was signal-averaged to reveal the event-related potentials (ERPs). A new method for continuously estimating D2, the "Point-D2" (PD2), was determined from the same data, and it also was signal-averaged. The PD2 method was found to be more accurate than others currently used for investigating finite data; it also was found to track nonstationarities that arise within the data. A significant (p < .001) PD2-decrease accompanied the ERPs evoked by target stimuli; the PD2 onset-latency and peak did not correlate with any ERPs. The very short latency suggests that the PD2-decrease may be associated with "selective stimulus set," an interpretation that has been related to early cortical ERP components.


Age-related changes in attended and unattended P3 latency in normal subjects.

Event-related potentials to visual attended and unattended stimuli were studied in 37 normal subjects between the ages of 19 and 91. The components of the P3 responses to rare nontarget stimuli and rare target stimuli were measured as P3a and P3b, respectively. Both the P3a and P3b latencies were significantly and positively correlated with age. The N2 finding of age-related latency prolongation was comparable to the P3a changes with age. From the standpoint of the theory of automatic and controlled processing, these results suggest that both automatic processing, as reflected by the P3a, and attentional controlled processing, as reflected by the P3b, are impaired with normal aging.


Pineal calcification in relation to menopause in schizophrenia.

I have suggested that critical changes in melatonin secretion, as mediated by the pineal gland, may exert a crucial role in the onset and pathogenesis of schizophrenia. Since pineal calcification (PC) is thought to reflect the metabolic and secretory activity of the gland, I investigated in 29 randomly selected chronic institutionalized female schizophrenic patients the association of PC on CT scan with premenopausal (prior to age 40) versus menopausal (ages 40-55) onset of illness. The premenopausal patients were found to show a significantly higher prevalence of PC than the menopausal patients (55.5% vs. 18.1%; X2 = 3.93, df = 1, p < .05). Since PC was unrelated to historical, demographic, and treatment variables, these findings highlight the importance of the pineal gland for the timing of the onset of schizophrenia, particularly in relation to the female reproductive state. The results carry theoretical implications on the pathogenesis of schizophrenia and suggest that the pineal gland may exert a protective effect against its onset.


Influence of education on WCST performances in schizophrenic patients.

Schizophrenic patients have been widely reported to fail in performing Wisconsin Card Sorting Test (WCST). These data have been mostly interpreted as cognitive difficulties and/or neurofunctional impairment inherent to schizophrenia. Nevertheless, checking sample characteristics, the importance of variables as education appears relevant. In our study we examined schizophrenic patients and controls with low and high educational levels respectively. ANOVA results show significant differences on WCST performances for the variable diagnosis (schizophrenics and controls) and for the variable educational level (low and high educational level). It therefore seems necessary call for caution in interpreting WCST results in schizophrenic patients when educational level is not considered.


Electroacupuncture accelerated the expression of c-fos protooncogene in serotonergic neurons of nucleus raphe dorsalis.

It has been proposed that the FOS protein encoded by c-fos protooncogene functions as a nuclear "third messenger" molecule that couples short-term extracellular signals to long-term alterations in cell function, by regulating the expression of specific target genes. In the present study, immunocytochemical double staining technique was used to investigate the effects of electroacupuncture on the expression of c-fos oncogene in the serotonergic neurons in the nucleus raphe dorsalis (NRD) that has been known to play an important role in the endogenous analgesic system of the brain. The number of FOS positive serotonergic cells in the NRD increased significantly after the electroacupuncture stimulation. These results indicate that electroacupuncture can activate central serotonergic neurons at gene expression level.


Inverse correlation between right-paw use and body weight in right-pawed male cats and left-pawed female cats.

The association between paw preference and body weight was studied in cats. In right-pawed males, the right minus left (R-L) paw use significantly decreased as the body weight increased. There was no significant correlation between these parameters in left-pawed males as well as in right-pawed females. In left-pawed females, the frequency of the left-paw use increased as the body weight increased. These results partly supported those in humans (Tan, in press). It was suggested that hormonal factors affecting body weight may also influence cerebral lateralization and consequently paw preference. The best possibility for these hormones appears to be testosterone.


The influence of the pineal gland on migraine and cluster headaches and effects of treatment with picoTesla magnetic fields.

For over half a century the generally accepted views on the pathogenesis of migraine were based on the theories of Harold Wolff implicating changes in cerebral vascular tone in the development of migraine. Recent studies, which are based on Leao's concept of spreading depression, favor primary neuronal injury with secondary involvement of the cerebral circulation. In contrast to migraine, the pathogenesis of cluster headache (CH) remains entirely elusive. Both migraine and CH are cyclical disorders which are characterised by spontaneous exacerbations and remissions, seasonal variability of symptoms, and a relationship to a variety of environmental trigger factors. CH in particular has a strong circadian and seasonal regularity. It is now well established that the pineal gland is an adaptive organ which maintains and regulates cerebral homeostasis by "fine tuning" biological rhythms through the mediation of melatonin. Since migraine and CH reflect abnormal adaptive responses to environmental influences resulting in heightened neurovascular reactivity, I propose that the pineal gland is a critical mediator in their pathogenesis. This novel hypothesis provides a framework for future research and development of new therapeutic modalities for these chronic headache syndromes. The successful treatment of a patient with an acute migraine attack with external magnetic fields, which acutely inhibit melatonin secretion in animals and humans, attests to the importance of the pineal gland in the pathogenesis of migraine headache.


L-tryptophan in neuropsychiatric disorders: a review.

Animal data indicate that serotonin (5-HT) is a major neurotransmitter involved in the control of numerous central nervous system functions including mood, aggression, pain, anxiety, sleep, memory, eating behavior, addictive behavior, temperature control, endocrine regulation, and motor behavior. Moreover, there is evidence that abnormalities of 5-HT functions are related to the pathophysiology of diverse neurological conditions including Parkinson's disease, tardive dyskinesia, akathisia, dystonia, Huntington's disease, familial tremor, restless legs syndrome, myoclonus, Gilles de la Tourette's syndrome, multiple sclerosis, sleep disorders, and dementia. The psychiatric disorders of schizophrenia, mania, depression, aggressive and self-injurious behavior, obsessive compulsive disorder, seasonal affective disorder, substance abuse, hypersexuality, anxiety disorders, bulimia, childhood hyperactivity, and behavioral disorders in geriatric patients have been linked to impaired central 5-HT functions. Tryptophan, the natural amino acid precursor in 5-HT biosynthesis, increases 5-HT synthesis in the brain and, therefore, may stimulate 5-HT release and function. Since it is a natural constituent of the diet, tryptophan should have low toxicity and produce few side effects. Based on these advantages, dietary tryptophan supplementation has been used in the management of neuropsychiatric disorders with variable success. This review summarizes current clinical use of tryptophan supplementation in neuropsychiatric disorders.


Auditory brainstem response (ABR) latency: relative importance of age, sex and sensorineural hearing-loss using a mathematical model of the audiogram.

Influences of age, sex and audiogram on ABR latencies have been studied. Using a mathematical model of audiogram, the analysis of data finds a relative importance of age, sex and audiogram similar to previous studies. Audiogram slope was correlated only with the latencies of waves I and V, and multiple regression analyses indicate the slope effect is relatively weak compared to that of the other parameters. Using a mathematical model of audiogram did not improve the ABR variance across subjects, underscoring the need to discover other relevant variables to explain ABR latency.


Nocturnal plasma melatonin and alpha-melanocyte stimulating hormone levels during exacerbation of multiple sclerosis.

The pineal gland has been implicated recently in the pathogenesis of multiple sclerosis (MS). To investigate this hypothesis further, we studied nocturnal plasma melatonin levels and the presence or absence of pineal calcification (PC) on CT scan in a cohort of 25 patients (5 men, 20 women; mean age: 41.1 years; SD = 11.1; range: 27-72) who were admitted to a hospital Neurology service for exacerbation of symptoms. Plasma alpha-melanocyte stimulating hormone (alpha-MSH) estimations were included in the study since there is evidence for a feedback inhibition between alpha-MSH and melatonin secretion. Abnormal melatonin levels were found in 13 patients (52.0%), 11 of whom had nocturnal levels which were below the daytime values (i.e., < 25 pg/ml). Although melatonin levels were unrelated to the patient's age and sex, there was a positive correlation with age of onset of symptoms (p < .0001) and an inverse correlation with the duration of illness (p < .05). PC was noted in 24 of 25 patients (96%) underscoring the pathogenetic relationship between MS and the pineal gland. Alpha-MSH levels were undetectable in 15 patients (60.0%), low in two patients (8.0%), normal in seven patients (28.0%), and elevated in one patient (4.0%). Collectively, abnormal alpha-MSH levels were found in over 70% of patients. These findings support the hypothesis that MS may be associated with pineal failure and suggest, furthermore, that alterations in the secretion of alpha-MSH also occur during exacerbation of symptoms. The relevance of these findings to the pathogenesis of MS are discussed.


The direction of the conditioned natural killer cell response can be re-directed with indomethacin and/or handling.

We have used the pairing of camphor odor conditioned stimulus (CS) and injection of poly I:C unconditioned stimulus (US) in a short 3 day single trial conditioning paradigm. Conditioning was done by exposing mice to the CS/US combination on day 0 and reexposing the conditioned animals to the CS on day 2. This results in a conditioned augmentation of the natural killer (NK) cell response. Indomethacin treatment and/or handling stress induced by simply measuring rectal temperature was found to dramatically alter the direction of the conditioned NK cell response. Conditioning of indomethacin treated mice produced a conditioned suppression of the NK cell response mimicking a conditioned tolerance response. If handling stress was superimposed on day 2 the conditioned suppression response was replaced by a conditioned augmentation of the NK cell response. Even with one trial conditioning, drugs and handling stress can serve as additional cues to alter the direction of the conditioned response. The studies also show that the conditioning of the fever response is independent of conditioning of the NK cell response.


Event-related prolongation of induced EEG rhythmicities in experiments with a cognitive task.

Since we consider evoked potentials (EPs) and event-related potentials (ERPs) as an ensemble of induced rhythmicities we investigated "sensory" evoked potentials (EPs) and "cognitive" event-related potentials (ERPs) with respect to their frequency components (around 5 Hz and around 10 Hz). "Sensory" EP sessions consisted in standard EP measurements with tone bursts of 2000 Hz frequency. Prior to the subsequent "cognitive" sessions, the subjects were instructed to expect frequent 2000 Hz tones and rare 1950 Hz tones, the rare tones thus being difficult to detect. A further instruction was to count the number of the "rare" stimuli. Not a single tone of different frequency, however, was presented. The single trials were then analyzed with respect to their 5 Hz and 10 Hz components. Time-locking was investigated using a modified single sweep wave identification (SSWI) method. Depending on features of the prestimulus EEG, it was observed that theta (4-7 Hz) and alpha (7-13 Hz) responses were prolonged in the case of "cognitive" sessions. We believe that the prolonged endogenous ERP components are induced rhythmicities triggered by additional information processing, when a high degree of uncertainty has to be resolved during our experimental conditions. For the analysis and visualization of these phenomena, the combination of digital filtering and SSWI showed relevant advantages in comparison to other methods.


Pineal and habenula calcification in schizophrenia.

Animal data indicate that melatonin secretion is stimulated by the paraventricular nucleus (PVN) of the hypothalamus and that lesions of the PVN mimic the endocrine effects of pinealectomy. Since the PVN lies adjacent to the third ventricle, I propose that periventricular damage, which is found in schizophrenia and may account for the third ventricular dilatation seen on computed tomographic (CT), may disrupt PVN-pineal interactions and ultimately enhance the process of pineal calcification (PC). To investigate this hypothesis, I conducted CT study on the relationship of PC size to third ventricular width (TVW) in 12 chronic schizophrenic patients (mean age: 33.7 years; SD = 7.3). For comparison, I also studied the relationship of PC size to the ventricular brain ratio and prefrontal cortical atrophy. As predicted, there was a significant correlation between PC size and TVW (r pbi = .61, p < .05), whereas PC was unrelated to the control neuroradiological measures. The findings support the hypothesis that periventricular damage may be involved in the process of PC in schizophrenia and may indirectly implicate damage to the PVN in the mechanisms underlying dysfunction of the pineal gland in schizophrenia. In a second study, I investigated the prevalence of habenular calcification (HAC) on CT in a cohort of 23 chronic schizophrenic-patients (mean age: 31.2 years; SD = 5.95). In this sample HAC was present in 20 patients (87%). Since the prevalence of HAC in a control population of similar age is only 15% these data reveal an almost 6-fold higher prevalence of HAC (X2 = 84.01, p < .0001) in chronic schizophrenia as compared to normal controls. The implications of HAC for the pathophysiology of schizophrenia are discussed in light of the central role of the habenula in the regulation of limbic functions.


An audit of resuscitation and anaesthesia during Operation 'Safe Haven'.

The Royal Navy combined Surgical Support Team deployed for six weeks to Northern Iraq. Eighteen casualties of civilian and military trauma required active resuscitation, 10 of whom were under the age of 16. Three died. Triage of multiple casualties was necessary on three occasions. The principles of Advanced Trauma Life Support (ATLS) were adopted and the experience is described under the ABCDE headings of the primary survey. Deficiencies of training and equipment are identified. Seventy one anaesthetics, administered to 52 patients, were audited prospectively in detail. Systolic blood pressure was significantly higher with isoflurane and controlled ventilation (ICV), compared with halothane and trichloroethylene (HTCV) (P < 0.05). ICV patients recovered more quickly than with HTCV (P < 0.05), but were significantly older and heavier (P < 0.05). Isoflurane should replace the standard halothane/trichloroethylene combination. Controlled ventilation or ketamine anaesthesia allowed satisfactory SpO2 on air alone. With controlled ventilation, anaesthesia was entirely satisfactory for children down to 6.5 kg. Local anaesthetic procedures were useful. The entire anaesthetic drug cost was only 127 pounds. Three patients received a degree of intensive care. Recommendations are made to improve future outcome, but sophisticated resuscitation, anaesthesia and monitoring is now possible in the front line.


The effect of manpower and medical facility reduction on surgical practice during the Gulf Conflict 1991.

The General Surgical admissions to Royal Naval Hospital, Stonehouse from 1 April 1990-31 March 1991 were audited. This period included the Gulf War. There remained throughout the build-up to Operation Desert Storm, and during the actual conflict, a requirement to treat Service personnel as well as maintaining surgical training. This paper shows that both criteria were met despite reduced medical manpower and facilities.


Anaphylactic shock in neuropsychoimmunological research.

Anaphylaxis appears to be an excellent experimental model for investigating the interactions between central nervous system (CNS) and immune system. Both afferent and efferent regulatory pathways of anaphylactic response are well characterized. The potent mediators of anaphylactic shock, such as histamine and serotonin, are at the same time neurotransmitters, acting in the CNS, and regulators/modulators of the immune system, since receptors for these substances exist on the membrane of the cells of the immune system. In this article the results of studies on the relationship between anaphylaxis and CNS, performed by both pioneers and contemporary investigators, are briefly reviewed. Recent experiments done in our laboratory are presented, which showed that (a) anaphylactic shock can be induced by intracerebroventricular administration of the shocking dose of antigen; (b) rats can learn to associate the induction of anaphylactic shock with neutral stimuli from the environment; and (c) stress in the form of electric tail-shocks reduces the intensity of anaphylactic shock.


Asymmetrical relationships between the right and left heights of the sylvian end points in right- and left-pawed male and female cats: similarities with planum temporale asymmetries in human brain.

Asymmetry in the height of the right (R) and left (L) Sylvian end points was studied in right- (RH) and left-pawed (LH) male and female cats. Sylvian height was described relatively to brain weight. An asymmetry coefficient (AC) was estimated (R - L/.5*R + L). There was no significant relationship between R + L Sylvian height and AC, in the total sample and in AC- (leftward asymmetry) brains. In AC+ brains (rightward asymmetry), R + L Sylvian height showed an inverse correlation with AC in RH cats, and a direct correlation in LH cats. There was an inverse correlation between left Sylvian height and AC in RH cats, but no correlation in LH cats. There was a direct correlation between right and left Sylvian height and AC. In AC- brains, left Sylvian height had no relation to AC, but there was a direct correlation between right Sylvian height and AC. In AC+ brains, left Sylvian height showed an inverse correlation with AC in RH males and females; a direct correlation only in LH male cats. Right Sylvian height showed a direct relation to AC+ values in RH and LH males and LH females (no correlation in RH females). The results supported the generalization that a brain symmetrical in a given region has more combined cortex than a brain that is asymmetrical for this region, only for RH cats, however (Galaburda et al., 1987).


Enkephalins, brain and immunity: modulation of immune responses by methionine-enkephalin injected into the cerebral cavity.

There is a large number of interactions at molecular and cellular levels between the nervous system and the immune system. It has been demonstrated that the opioid neuropentapeptide methionine-enkephalin (Met-Enk) is involved in humoral and cell-mediated immune reactions. Met-Enk injected peripherally produces a dual and dose-dependent immunomodulatory effect: high doses suppress, whereas low doses potentiate the immune reactivity. The present mini-review concerns the immunological activity of Met-Enk after its administration into the lateral ventricles of the rat brain, and describes the extraordinary capacity of centrally applied Met-Enk to regulate/modulate the immune function. This survey is composed of sections dealing with (a) the role of opioid peptides in the central nervous system (CNS); (b) the activity of opioid peptides in the immune system; (c) the application of Met-Enk into the cerebral cavity; (d) the influence of centrally administered Met-Enk on nonspecific local inflammatory reaction; (e) the effect of Met-Enk injected intracerebroventricularly (i.c.v.) on specific delayed hypersensitivity skin reaction, experimental allergic encephalomyelitis, anaphylactic shock, plaque-forming cell response, and hemagglutinin production; (f) the central antagonizing action of quaternary naltrexone, an opioid antagonist that does not cross the brain-blood barrier, on Met-Enk-induced immunomodulation; (g) the alteration of immune responsiveness by i.c.v. injection of enkephalinase-degrading enzymes; (h) the participation of the brain-blood/blood-brain barrier in the CNS-immune system interaction; and (i) the role of opioid receptors in immunological activity of Met-Enk. A hypothesis has been advanced for the reaction of Met-Enk and opioid receptor sitting on the cell membrane. This concept suggests that the constellation of chemical residues of enkephalin and receptor in the microenvironment determines the binding between the opioid partners. The plurality of conformational structures of enkephalins and receptors makes possible their involvement in a variety of processes which occur in different physiological systems, including the nervous system and the immune system, and intercommunications between the two systems.


Rhegmatogenous retinal detachment in Royal Naval personnel: a retrospective study.

A retrospective study was conducted to assess the various factors thought to influence the outcome of retinal detachment in RN personnel. A description of retinal detachment and its management, aimed at non-specialists, is given in the introduction. In the study period eight Servicemen had rhegmatogenous retinal detachments. All underwent conventional detachment surgery, but two required two further operations including vitrectomy. Important features of each patient's detachment are discussed, as is post-operative progress. All patients spent a considerable time away from duty and three were discharged from the Service on medical grounds. Poor outcome could be related to myopia, trauma, delay in presentation to primary care, the number of operations performed and to post-operative complications. Advice is given regarding assessment and management of suspected cases by non-specialists. It is hoped that reporting this study will increase awareness within the RN of retinal detachment as a sight-threatening condition.


The pineal gland and the mode of onset of schizophrenia.

Recent studies suggest that abnormal melatonin functions may be implicated in the pathophysiology of schizophrenia. Since there is evidence that the presence of pineal calcification (PC) may relate, among other factors, to disturbances in melatonin secretion, I investigated in 23 chronic institutionalized schizophrenic patients the relationship of PC size on CT scan to the mode of onset of schizophrenia which carries both developmental and prognostic significance. Patients with gradual onset schizophrenia had PC size that was significantly larger than those with sudden onset (8.94 +/- 3.96 mm vs. 4.80 +/- 1.75 mm p < .025). These findings suggest that the nature of onset of schizophrenia may be influenced by the activity of the pineal gland, which may exert a role in the development and prognosis of the illness.


The obstetric course of elderly primigravidae--a review.

An increasingly large number of women are now delaying the start of their families until they reach the age of 35 years or older. They are then known as elderly primigravidae in obstetric parlance. This paper reviews recent literature and reports on a retrospective survey conducted by the author of such women at an RAF hospital and presents the findings concerning their ante-natal, intra-partum, post-partum and neonatal outcomes.


State-dependent peculiarities of cocaine-induced behavioral sensitization and their possible reasons.

To study determinants and possible reasons of cocaine-induced behavioral sensitization, locomotor effects of the drug (COC, 15 mg/kg, IP; 5 daily injections followed by a "challenge," four days later) and various stimuli associated (procedure of injection, placement in the test cage) and nonassociated (tail-pinch) with its administration were measured in rats under different experimental conditions. When COC was injected in quite conditions, two hours after animal habituation to the test cages, locomotor response to the first drug injection was only slightly higher compared to one of saline and these responses were relatively stable following repeated treatment (no sensitization). An enhanced locomotor response to the procedure of injection (needle prick) without changes in responsivity to other stimuli used were found in these COC-treated rats. When COC was injected in activated conditions (animal placement in test cages), locomotor response to the first drug administration was significantly higher compared to one of saline and COC used in the quiet state and it was enhanced following repeated treatment (sensitization). More intense locomotion associated with placement in test cages without any changes in responses to other stimuli was found in rats after this procedure of treatment. Thus, locomotor effects of COC and dynamics of its changes following repeated treatment depend upon the organism's functional state accompanying the drug's effect. Reinforcing action of COC determining development of interinfluence of its effects and ones triggered by environmental variables (learning based on conditioning) is considered as a proposed initial cause and a main mechanism both for enhanced reactivity to cocaine administered under conditions of its previous use and to various environmental events associated with previous cocaine effects.


The genetic basis of cancer.

The genetic basis of human cancer is well established, although much work remains to be done to unravel the mechanisms of carcinogenesis. Multiple genetic alterations appear to the hallmark in the adult cancers. Molecular cloning and characterization of the amplified proto-oncogenes and mutated recessive oncogenes would shed light on the mechanisms involved in the initiation and progression of human cancer. New tests are likely to be available in the near future (for specific oncogenes) for the diagnosis and management of various forms of human cancer.


Stealing in children.

Stealing is a common behavioural problem in children. The causes of stealing include a desire for possession, attention-seeking behaviour, revenge, a lack of discipline, poor parental role models, or significant psychological or psychiatric problems. With proper management, the tendency to steal resolves in most children.


Cephalosporins in childhood bacterial meningitis.

Bacterial meningitis remains one of the most common life threatening infections of childhood. There exists a conventional therapy for this disease. However, with the increasing incidence of Haemophilus strains resistant to ampicillin and chloramphenicol and Streptococcus pneumonia strains relatively resistant to penicillin, alteration of current therapeutic regimens for meningitis may become necessary. Cephalosporins were considered as alternatives to the conventional therapy for the treatment of bacterial meningitis during the past decade. However, there are still some discrepancies on the use of these against some organisms despite the advent of the cephalosporins. Thus, a review article analyzing quite a number of reliable clinical trials related to cephalosporins for the treatment of bacterial meningitis during the past decade to date is introduced.


Approaching "asthma" in pre-school children.

Respiratory illnesses are the most common cause of morbidity throughout childhood. In the pre-school age group, there is uncertainty about when to attribute symptoms to asthma and when to use asthma therapy. This article reviews these problems and suggests a basis for the use of medication.


Non-surgical closure of patent ductus arteriosus with the Rashkind PDA occluder system.

Transcatheter closure of Patent Ductus Arteriosus (PDA) was done in 18 children using the USCI Rashkind PDA occluder system. Patient age ranged from 1.2 to 14 years and their weights ranged from 8 to 36 kg. Isolated restrictive PDA was present in 15 patients; 3 had additional cardiac defects. The diameter of the PDA ranged from 2 to 6 mm as determined by lateral aortogram. PDA occlusion was successfully done in all 18 children. Ten 12 mm and eight 17 mm occluders were implanted with no complications. Post-implant aortogram showed complete ductal closure in 6 and trivial or small residual ductal flow in 12 cases. Doppler color flow mapping done within 3 days of the procedure showed complete ductal closure in 9, 8 had trivial ductal flow and 1 had small ductal flow. Transcatheter technique using a Rashkind PDA occluder system is a safe and effective method of non-surgical PDA occlusion.


The use of blood glucose/cerebrospinal fluid glucose ratio in the diagnosis of central nervous system infection in infants and children.

The diagnosis of bacterial meningitis can be difficult nowadays when antibiotics are freely used in infants and children with fever due to infection, so that a positive smear or culture may be difficult to achieve. In areas where sophisticated methods of diagnosis may be hard to come by, the simple procedure of simultaneously estimating the blood and cerebrospinal fluid (CSF) glucose levels may be helpful in distinguishing bacterial meningitis from viral meningitis. 74 proven cases of bacterial meningitis and aseptic meningitis were investigated prior to treatment. There were 36 cases of bacterial meningitis and 38 cases of aseptic meningitis. The CSF glucose/plasma glucose ratio was calculated for each patient. The cases were divided into two groups; Group A with CSF glucose/plasma glucose ratio of (0.38-2.0) and Group B with CSF glucose/plasma glucose ratio of (0.1-0.35). In Group A, two out of 59 cases died while in Group B, nine out of 15 died (p < 0.01). 44 out of 59 in Group A recovered fully while only two out of 15 in Group B were cured (p < 0.01). It was also found that 54.2% in Group A were admitted in deep coma compared with 86.7% in Group B (p < 0.05) and 25.4% in Group A were admitted with seizures while 66.7% in Group B had convulsion (p < 0.01). Hence, a low CSF glucose/plasma glucose ratio was associated with a poor outcome. The mechanisms responsible for these findings are discussed especially with reference to the blood-brain barrier (BBB).(ABSTRACT TRUNCATED AT 250 WORDS)


Birth trauma and nasal septal deformity in neonates.

The prevalence of nasal septal deformity and its relationship with the different types and difficulty of delivery were studied in a randomised group of newborns at the Maternity Hospital Kuala Lumpur between 1st November 1989 to 31st January 1990. Out of a total of 674 noses examined using the otoscope, 147 (21.8%) were found to have nasal septal deformity. There was no significant difference in the prevalence of nasal septal deformity in the different types of delivery. There was also no significant increase in the prevalence of nasal septal deformity with increasing degree of difficulty of the delivery. Therefore, we cannot then attribute parturition pressures or birth trauma as the etiology of these congenital nasal septal deformity. Nevertheless a policy of routine screening in view of early correction is advocated to decrease the morbidity associated with this deformity in newborns and children.


A clinical study of obstructive jaundice among Singapore infants.

Fifty infants with obstructive jaundice were reviewed. Other than jaundice, hepatomegaly and splenomegaly were the other common presentations. The mean age of referral was 9.4 weeks. This was unsatisfactory as the prognosis depends on the age of corrective surgery. Majority of the non surgical cholestasis were due to idiopathic hepatitis. These patients did well as all of them were asymptomic and had no evidence of liver disease at 2 years of age.


Long term endocrine complications of acute leukemia therapy--a case report.

We report a patient with acute lymphoblastic leukemia who underwent treatment comprising chemotherapy, radiotherapy (cranial and testicular) and then a bone marrow transplant from an identical twin. He was cured of his leukemia and has been disease-free for nine years. With long term survival, there were problems, notably those of growth and endocrine insufficiency, which needed special considerations in management.


Etretinate treatment for Harlequin baby.

This report of a Harlequin foetus surviving is due essentially to two factors. a) the intensive care provided to the erythrodermic infant, looking after its nutrition, temperature control and controls of infection and b) the use of a new synthetic Vitamin A acid--Etretinate in the management of dyskeratinisation syndromes. As this is of autosomal recessive inheritance, besides genetic counselling, Singapore has to develop its prenatal diagnostic techniques viz-amniocentesis and ultrasound studies of the skin, to detect dermatological problems.


Anhidrotic ectodermal dysplasia (Christ-Siemens-Touraine syndrome)--a case report and review.

We report two brothers with anhidrotic ectodermal dysplasia (AED). AED is characterised by a triad of inability to sweat dental abnormalities and hypotrichosis. Although rare, it is important to diagnose this condition as it may lead to considerable morbidity and mortality if unrecognised. The typical features of this entity as described in the literature and as seen in our patients are emphasized as increased awareness can lead to early diagnosis and better prognosis.


The Moebius sequence--report of a case and a short annotation.

A Malay baby with multiple cranial nerve involvement consistent with the Moebius sequence (syndrome) is reported. He also had many non-Central Nervous System (CNS) related defects which include limb reduction defects and the Poland sequence. A short annotation and the spectrum of this disorder are presented. In view of many reported related disorders, Moebius sequence may occur as a part of a broader pattern of malformation.


The pressure-dependent nature of the rash in Henoch Schönlein purpura.

A 10 month old girl with Henoch-Schönlein purpura (HSP) developed a rash predominantly on the anterior aspect of the knees. The authors speculate that this distribution of the rash was due to the pressure effects consequent to crawling and propose that the distribution of the rash in HSP should be described as pressure-dependent rather than merely gravity-dependent. The therapeutic implications of pressure-dependency in HSP are discussed.


Post-streptococcal glomerulonephritis with minimal abnormalities in the urinary sediment.

Post-streptococcal glomerulonephritis (PSGN) classically presents with hypertension, edema, macroscopic hematuria, acute renal failure, proteinuria, and an active urine sediment with red blood cells and red blood cell casts. A patient who developed PSGN but who had only minimal and transient abnormalities in the urinalysis is reported. Physicians should be aware that a normal urinalysis does not rule out the diagnosis of PSGN.


Efficacy of Zaditen (ketotifen) in wheezy infants and young children.

This was a double-blind, randomised evaluation of the efficacy and safety of Zaditen in comparison with placebo in infants and young children (aged 6-36 months). These children either had (i) at least 2 episodes of wheezing over 8 weeks, or (ii) persistent wheeze over 4 weeks, prior to entering into the study. In the doctor's opinion, the group treated with Zaditen had more improvement in symptomatology (p < 0.05). They were more likely to have reduced or discontinued bronchodilators. They showed trends of improvement of symptom scores in night cough, wheeze and sputum production. These differences, however, did not reach statistical significance. There were no major adverse reaction of note.


Development of chemopreventive agents for bladder cancer.

The term cancer chemoprevention refers to the prevention or prolongation of carcinogenesis by intervention with drugs prior to the malignant (i.e., invasive) stage. The development of chemopreventive drugs is the major objective of the Chemoprevention Branch of the National Cancer Institute. Neoplastic lesions of the urinary bladder present a unique opportunity for evaluating chemopreventive agents because of (1) the accessibility of the lesions to observation and biopsy, and (2) those patients who have been successfully treated for a primary lesion represent a population at unusually high risk for recurrence and/or progression. Although 70-80% of bladder cancers initially present as superficial, papillary transitional cell neoplasms with limited potential for invasion, the incidence of recurrence is high after resection (60-75%). Recurrent tumors are highly unpredictable, and may be of higher grade or stage (progression). Although recurrence is responsible for high treatment-related morbidity, progression represents the greatest potential for mortality. Thus, potential chemopreventive agents considered here would modulate bladder carcinogenesis from initiation of normal-appearing tissue through progression of superficial tumors. Clinical trials of chemopreventive drugs involve healthy target populations, and the endpoints are reduced cancer incidence or mortality, reduced/eliminated precancerous lesions or increased latency, with none to minimal toxicity. Since cancers may not appear for 20-30 years, two of the most difficult aspects of testing these drugs in intervention trials are the long observation periods and large study populations required to measure cancer incidence reduction. However, observing the regression or recurrence of superficial bladder lesions (TIS, T1, Ta) requires relatively short time periods. Thus, these lesions lend themselves to the investigation of intermediate biomarkers, defined as morphologic and/or molecular alterations in tissue between initiation and tumor invasion. It is hypothesized that modulation of one or more biomarkers would interrupt carcinogenesis and result in a decrease in cancer incidence. Thus, evaluation of biomarkers as surrogate endpoints would allow bladder trials to be of even shorter duration, use fewer subjects and be lower in cost. In addition, intermediate biomarkers could predict which superficial lesions (or normal-appearing tissue) have the greatest potential for neoplastic progression. Development of strategies for the design of intervention trials for bladder cancer and review of the current status of intermediate biomarkers in the bladder, and methods for their validation, are major objectives of this workshop.


Intravesical BCG: current results, natural history and implications for urothelial cancer prevention.

Bacillus Calmette-Guerin (BCG) has been shown in randomized trials to be the most effective agent against superficial bladder tumors. BCG therapy prevents or reduces tumor recurrences, abrogates tumor progression and improves survival over surgery alone. The optimal BCG schedule varies among patients, reflecting a heterogeneous tumor population. Multifocality, high grade (G2,3) and T1 tumors are risk factors for tumor recurrence or invasion. Patients presenting with such features are most likely to benefit from BCG. An incomplete response to BCG portends a high risk of tumor progression. Non-responders have a 40-60% risk of developing muscle invasion or metastases within 10 years, compared with 10-15% for BCG responders. Further, 80% of non-responders progress in the bladder within 3-5 years. After 5 years, relapses are more common in the prostate (13-35%) and upper collecting system (15-33%); one-half of these are invasive tumors. This suggests that intense therapy directed at premalignant and early bladder lesions coupled with a chemoprevention strategy designed to protect the whole urothelium will be required to reverse a pan-urothelial tumor diathesis.


Superficial bladder cancer: diagnosis, surveillance and treatment.

Approximately 70% of all bladder cancers are superficial at the time of presentation. Superficial bladder cancer includes tumors confined to the urothelium (clinical stage Ta) or lamina propria (stage T1) and flat carcinoma in situ (stage Tis). Because the biological behavior of bladder neoplasms is variable, several important prognostic factors must be addressed. Multivariate analyses have shown that factors predictive of tumor recurrence and tumor progression include multifocal tumors, high grade tumors, T1 tumors and positive urinary cytology after transurethral resection (TUR). The patient with superficial bladder cancer should be monitored via endoscopy supplemented by urinary cytology, using either voided or bladder irrigation specimens and urinalysis. Frequent intravenous urography is not required, even in high grade tumors, as long as the clinical and pathologic studies remain negative and the patient is asymptomatic. The "gold standard" of treatment for superficial bladder carcinoma is TUR of the entire tumor. Despite TUR, new tumors will occur in approximately 50% of all patients; those at highest risk for tumor recurrence and progression require adjuvant intravesical therapy after TUR. A variety of drugs are used as intravesical therapy, including thiotepa, mitomycin C, doxorubicin hydrochloride, Bacillus Calmette-Guerin (BCG), epirubicin, and interferon. Although associated with the most toxicity, BCG appears to be the most efficacious agent in increasing the time to recurrence and progression and in reducing the recurrence rate.


Chemotherapy resistant transitional cell carcinoma as a target for chemoprevention.

alpha-Interferon combined with 5-fluorouracil results in significant antitumoral activity in metastatic bladder carcinoma refractory to standard MVAC chemotherapy. As a single agent, alpha-interferon is ineffective for invasive or metastatic disease, but appears to contribute to the increased response rate of patients with invasive chemotherapy-refractory disease. Although most patients with superficial bladder carcinoma will not develop invasive disease, patients in complete remission from invasive disease are at high risk for relapse. In vitro assays indicate that fenretinide (4-HPR), alpha-interferon, and 5-fluorouracil possess significant antitumoral activity in human transitional cell carcinoma (TCC) lines. Some features of postchemotherapy-refractory TCC are similar to those of initial superficial disease (sensitivity to biological therapy). The biological study of patients with residual postchemotherapy disease may permit the development of strategies which will prevent the recurrence of malignancy within the bladder following an initial complete remission, in addition to developing strategies for the selection and treatment of patients with high risk superficial disease.


New opportunities for screening and early detection of bladder cancer.

In the United States, over 51,000 new cases of urinary bladder tumors are diagnosed annually. Approximately 75-85% of all newly diagnosed cases are superficial transitional cell carcinomas (TCCs). Incidence is highest (80% of the cases) in the 50-79 year age group. Recent studies have reported that 21-25% of risk for bladder cancer among United States white males is due to occupational exposure. The DuPont Chambers Works in Deepwater, New Jersey, was a major producer of two chemicals now known to be human bladder carcinogens (beta-naphthylamine and benzidine) as well as two suspected human bladder carcinogens [ortho-toluidine and 4,4'-methylene- bis,2-chloroaniline (MOCA)]. Between 1954 and 1982, DuPont screened 1723 exposed employees annually at the Chambers Works using the Papanicolaou test for urinary cytology and microscopic urinalysis. A review of the prior screening program found that employees who developed bladder cancer during this time period were approximately twice as likely to have had hematuria than those comparably exposed who did not develop bladder cancer. Building on this finding, a three-year screening study evaluated a home self-test for microscopic hematuria to aid early detection of treatable urologic conditions among exposed workers at this chemical plant. Every six months, subjects tested their urine at home for 14 consecutive days, for the presence of blood. A high degree of adherence to our protocol (over 92% completed and returned the self-testing record) as well as high compliance with repeat screening (85% returned for screening in subsequent quarters) demonstrated good acceptance and performance of the recommended schedule of self-testing. Through the first 7 periods of screening, two new cases and one recurrence of TCC of the bladder were detected.


Chemoprevention of experimental bladder cancer.

The chemopreventive efficacy of several compounds was evaluated in the N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder cancer model using C57BL/6 x DBA/2F1 (BDF) male mice. Compounds were administered in a defined semipurified diet (AIN-76-A) either as single agents or in combination. As single agents and at the doses employed, 2-alpha-difluoromethylornithine (DFMO), piroxicam, oltipraz, and sodium molybdate effectively inhibited the incidence of transitional cell carcinoma (TCC). 4-Hydroxyphenyl retinamide (4-HPR) was ineffective. Body weight gain and survival was not affected by the doses of agents used. Combinations of two agents which increased efficacy were 4-HPR+DFMO, DFMO+piroxicam, 4-HPR+oltipraz, and DFMO+oltipraz. Three-agent combinations which showed enhanced efficacy against TCC induction were 4-HPR+Na molybdate+DFMO, 4-HPR+DFMO+piroxicam, and 4-HPR+DFMO+oltipraz. Although the three-agent combinations were, for the most part, no more effective than the two-agent combinations at the doses employed, all combination regimens significantly reduced bladder cancer incidence even when single agent administration did not.


Activity of 4-HPR in superficial bladder cancer using DNA flow cytometry as an intermediate endpoint.

The ability of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) to affect the outcome of previously resected superficial bladder cancer was investigated in a pilot study using DNA content flow cytometry and conventional cytology as intermediate endpoints. Twelve patients were treated with oral 4-HPR (200 mg daily) and compared with 17 non-randomized, untreated controls. The median interval between transurethral resection and 4-HPR administration was 5.5 months (range 0-36). The median follow-up period was 12 months (range 3-31) in the 4-HPR group and 9 months (range 2-22) in the control group. The proportion of patients with DNA aneuploid stemlines in bladder-washed cells decreased from 7/12 (58%) to 5/11 (45%) in the 4-HPR group, but increased from 7/17 (41%) to 10/17 (59%) in the control group. In patients with stable diploid profiles, mean (+/- SE) S-phase and G2+M-phase fractions decreased in the course of retinoid treatment from basal levels of 15.2 +/- 4.1% to 7.5 +/- 3.3% and 10.3 +/- 2.2% to 5.2 +/- 0.4%, respectively. The same parameters in the control group changed from basal levels of 14.6 +/- 3.4% to 12.4 +/- 2.7% and 9.8 +/- 1.6% to 12.6 +/- 1.6%, respectively. Positive or suspicious cytologic examinations were present in 3/12 (25%) treated cases prior to 4-HPR administration and all subsequently reverted to normal. The same parameter in the control group increased from 4/17 (24%) to 6/17 (35%) during follow-up. Impaired adaptation to darkness was recorded in 4 patients, and transient dermatologic alterations were observed in one-third of the patients, requiring dose reduction in one case.(ABSTRACT TRUNCATED AT 250 WORDS)


13-cis-retinoic acid in chemoprevention of superficial bladder cancer. The National Bladder Cancer Group.

Animal studies indicate that 13-cis-retinoic acid (CRA) inhibits bladder tumor growth and is effective in treating patients with serious dermatologic disorders. A trial of CRA in patients at high risk for recurrent Ta, T1 tumors was initiated at an experimental dose of 0.5 mg/kg/d in three divided doses, increasing to 1 mg/kg/d at four weeks. Treatment of twenty eligible patients lasted for six months with an additional 24 month follow-up period. One patient was later excluded due to toxicity resulting in an early dose reduction. Eight patients stopped treatment before three months; of these five, had recurrences within three months, one developed pulmonary metastasis, and one developed a T2G3 tumor. Four patients stopped treatment between three and six months; three of them had recurrences before one year and one had no evidence of disease at seven years. Seven patients completed the course; of these three had recurrences within six months, and three more had recurrences at 8, 15, and 45 months, respectively. Toxicity was nearly universal; cheilosis, conjunctivitis, pruritus, joint and eye pain, flashing lights, and erythrocyte sedimentation rate (ESR) over 60 were all noted. The lack of positive results and the frequency and severity of toxicity led to termination of the study.


A prospective clinical trial of difluoromethylornithine (DFMO) in patients with resected superficial bladder cancer.

Difluoromethylornithine (DFMO) is a promising chemopreventive agent which is excreted unchanged in the urine, is active in vivo against superficial bladder cancer in animal tumor model systems, and has cytotoxic activity in vitro against superficial bladder cancer cells. Thus, DFMO may be particularly efficacious in preventing the development of bladder tumors and/or for the therapy of established superficial bladder cancer. To examine this hypothesis, an intergroup clinical trial is currently accruing patients with cystoscopically resected superficial bladder cancer (who would otherwise simply be observed). While the primary goal of this protocol is to define a daily dose of DFMO having little or no toxicity for use in future randomized chemoprevention trials, the rate of recurrent bladder tumors will also be followed in the hope that DFMO will inhibit the development of recurrent bladder cancers.


Piroxicam and other cyclooxygenase inhibitors: potential for cancer chemoprevention.

Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) widely used for treatment of inflammatory arthritis. Recent experimental and clinical studies suggest that piroxicam, as well as other NSAIDs, may be useful for chemoprevention of colon cancer. While there is less information regarding NSAIDs for chemoprevention of urinary bladder malignancy, there are compelling data which suggest that this should be evaluated. A major effect of NSAIDs is inhibition of cyclooxygenase, the rate-limiting enzyme for conversion of arachidonic acid to important signal molecules, including prostaglandins, which profoundly affect cellular functions in many tissues. The initial enzyme reaction leading to formation of prostaglandin H can be accompanied by cooxidation of xenobiotics resulting in extrahepatic and local tissue production of reactive products which are carcinogenic. The end product prostaglandins, especially prostaglandin E2 (PGE2), are biological modifiers which can significantly affect cell proliferation and tumor growth. High levels of PGE2 stimulate growth of certain tumor cell lines while inhibition of prostaglandin synthesis with indomethacin or piroxicam can cause suppression. The mechanisms for this effect are unclear. Studies in cultured cells exposed to indomethacin show inhibition of G1-to-S phase progression of the cell cycle and a reduction in overall DNA synthesis. It is unclear whether this effect on cell growth results from some direct action of the NSAID or a reduction in prostaglandins or indirectly from modulation of important control signals, such as calcium flux. In addition to cyclooxygenase, NSAIDs can inhibit activity of other enzymes, including phosphodiesterases and cyclic GMP-AMP protein kinases, which may be central to cancer initiation and promotion. NSAIDs can also interfere with transmembrane ion fluxes and with cell-to-cell binding. Prostaglandins can modulate a variety of immunological responses and thereby play an important role in host antitumor immunity. For example, high levels of tissue PGE2 are frequently associated with suppression of immune surveillance and killing of malignant cells. Conversely, immune responses are generally enhanced by drugs that inhibit prostaglandin synthesis. PGE2 can act as a feedback inhibitor for cellular immune processes, such as T-cell proliferation, lymphokine production, and cytotoxicity. This effect is also seen for macrophage activity and natural killer cell toxicity. In general, either increased production of PGE2 or increased sensitivity to normal amounts of PGE2 results in depressed cellular immunity. Cyclooxygenase inhibitors (NSAIDs) such as piroxicam which decrease PGE2 production can stimulate cellular immune function both in vitro and in vivo. A variety of tumor cell lines and human malignancies produce large quantities of prostaglandins.(ABSTRACT TRUNCATED AT 400 WORDS)