Biomedical subjects

J M Brandes

Publications and source records attributed to J M Brandes.

At least 19 recordsLinked to original sources

PubMed1995

Dopa reaction of fetal melanocytes before and after skin transplantation on to nude mice.

We have previously demonstrated that human fetal epidermal melanocytes are dopa-negative. The present study was conducted to test the hypothesis that human fetal melanocytes can be activated to produce melanin under conditions differing from their natural in utero environment. To address this question, dopa staining activity of fetal epidermal sheets, obtained from seven aborted fetuses with estimated gestational ages of 13-20 weeks, was evaluated before and after engraftment on to nude mice. Dopa staining became positive 7 days post-engraftment. The intensity of the dopa reaction and the mean number of melanocytes increased by day 14 post-engraftment, and these changes were even greater by day 30. These observations indicate that human fetal melanocytes, potentially capable of synthesizing melanin under conditions differing from their normal in utero environment, are either inhibited, or not stimulated to do so.

Adult↗

PubMed1994

Failure of meiotic competence in human oocytes.

The administration of hCG to women undergoing in vitro fertilization and embryo transfer (IVF/ET) results in the meiotic maturation of cumulus-oocyte complexes (COC). Sometimes oocytes being aspirated for IVF/ET fail to resume meiosis in vivo and even after a subsequent 20-h incubation in vitro and are thus defined as meiotic competence failure (MCF) oocytes. The relationship between the proportion of MCF oocytes and other IVF/ET outcomes was studied over 3 years in 703 tested cycles of 487 women. Women yielding one or more MCF oocytes in at least one menstrual cycle represented 8.6% of this population and were defined as MCF women. Cumulus state in the MCF oocyte population was characterized as mature in 57.4 +/- 6.7%, intermediate in 13.9 +/- 4.0%, immature in 24.1 +/- 8.7%, and atretic in 4.6 +/- 2.7%. These values differed significantly, by 0.6-, 2.9-, 7.1-, and 4.6-fold, respectively, as compared to the corresponding COC aspirated from women yielding only meiotically competent (MC) oocytes. In a menstrual cycle yielding both MC and MCF oocytes, the IVF/ET variables were evaluated in the MC oocytes. Thus, in such cases the incidence of fertilization or cleavage and the number of blastomeres per embryo were significantly reduced concomitant with the increase in percentage of MCF oocytes. When the percentage of MCF oocytes was 25% or more, no pregnancy was achieved. Various follicular parameters and serum 17 beta-estradiol (E2) and progesterone (P4) levels were compared in MC and MCF women over the four days preceding day of aspiration.(ABSTRACT TRUNCATED AT 250 WORDS)

Chorionic Gonadotropin↗

PubMed1994

Actigraphic home-monitoring of the sleep patterns of in vitro fertilization children and their matched controls.

The sleep patterns of 35 in vitro fertilization (IVF) children aged 19 to 57 months and their matched controls were evaluated by actigraphic home-monitoring for three consecutive nights. Actigraphic data were analysed by an automated scoring procedure developed in the authors' laboratory. There were no significant differences in activity levels between IVF multiple-birth subjects and their matched controls or between IVF singletons and their matched controls. In contrast, multiple-birth subjects had higher activity levels during sleep and lower sleep efficiency than singletons in both IVF and control groups. Sleep measures showed night-to-night stability in all groups.

Age Factors↗

PubMed1994

Transvaginal sonography, color flow imaging, computed tomographic scanning, and CA 125 as a routine follow-up examination in women with pelvic tumor: detection of recurrent disease.

We were trying to determine whether transvaginal sonography combined with color flow imaging should be used routinely for detecting recurrent pelvic tumors in patients treated for pelvic cancer. Eighteen patients who had completed their treatment for pelvic tumor were examined every 6 months by gynecologic examination, a CT scan, serum CA 125 levels, and transvaginal sonography with color flow imaging. Laparotomy or fine-needle biopsy was performed when a recurrent pelvic mass was observed or suspected on CT scans or transvaginal sonography. In nine of 18 patients a recurrent pelvic tumor was observed or suspected on CT scans or on transvaginal sonography. A recurrent pelvic tumor was diagnosed on laparotomy in five patients. In four patients, only a fine-needle biopsy was performed and only two of them had positive results. The highest sensitivity and specificity for detecting recurrent pelvic tumors were achieved by transvaginal sonography (100 and 91%, respectively) and by color flow imaging (86 and 100%, respectively). Intratumoral blood vessels were detected in all cases with recurrent pelvic tumors, and in only one of these cases the PI was high. We recommend a routine follow-up with transvaginal sonography in women completing their treatment for pelvic tumors. When a recurrence of tumor is only suspected on transvaginal sonography, color flow imaging may be used as an additional diagnostic tool.

Aged↗

PubMed1993

Use of a sealed minichamber for direct observation and evaluation of the in vitro effect of cigarette smoke on sperm motility.

OBJECTIVE: To determine the in vitro effect of cigarette smoke on sperm motility and survival in an attempt to find a possible association with clinical studies that had pointed to the existence of such an effect in vivo. DESIGN: Laboratory experiments in which the effect of cigarette smoke on human sperm placed in a sealed minichamber was directly observed and determined by motion analysis. PATIENTS: High-quality fresh semen specimens were obtained from healthy donors and used for the experimental studies. INTERVENTIONS: Various doses of filtered and nonfiltered cigarette smoke, collected by an improvised manual smoking machine, were streamed at a rate of 2 mL/s into sealed chambers containing samples of washed spermatozoa. Evaluation of the changes in sperm motility was performed in real time by direct microscopical observation and repeated determinations by the multiple exposure photography technique until their complete immobilization. RESULTS: Streaming of 100 mL of cigarette smoke induced a dramatic drop in sperm motility, which caused sperm immobilization in about 15 minutes. This effect showed a clear dose-response relationship either with the amounts streamed or with the time during which sperm were exposed to cigarette smoke. The harmful effect was almost the same whether sperm were exposed to filtered or nonfiltered cigarette smoke. The role of carbon monoxide and hydrogen cyanide on these findings was studied separately, and it was shown that the inhibitory effect was not due to the presence of these two important components of cigarette smoke. CONCLUSIONS: The clear evidence of the in vitro harmful effect of crude cigarette smoke on sperm motility points to the possibility that in heavy smokers certain toxic agents may reach mature spermatozoa or their precursors via the blood stream and induce their harmful effect on sperm motility in vivo.

Carbon Monoxide↗

PubMed1993

Premature ovarian failure--the prognostic application of autoimmunity on conception after ovulation induction.

OBJECTIVE: To assess whether the presence of autoimmune activity in patients with premature ovarian failure (POF) can predict the response to ovulation induction and conception. DESIGN: Assessment of autoimmune activity in patients with POF, correlating the response to ovulation induction with this autoreactivity. SETTING: Tertiary care academic center. PATIENTS: Forty women with POF, 15 of them treated by ovulation induction because of infertility. INTERVENTIONS: All patients were tested for the presence of autoimmune activity, antibodies against various tissues, and 15 of them were treated with combinations of hMG/hCG, glucocorticosteroids as immunosuppressant, and some of them also with a long-acting GnRH agonist. Those patients not interested in infertility were put on hormone replacement therapy (HRT). MAIN OUTCOME MEASURES: Serum E2 and P were measured during ovulation induction as well as follicular diameter monitoring by transvaginal sonography. Achievement of gestations and their outcome were monitored in the group in which ovulation induction was accomplished. RESULTS: Antibodies against thyroglobulin, nuclear antigens, heart, tissue gluten, or increased levels of immunoglobulin (Ig)M, or decreased levels of complement C3 and C4 were significantly different in the patients with POF than in the control population. Autoreactivity of at least one class of the tested antibodies was found in 31 of 40 patients (77%). In 15 patients with autoimmune activity who have undergone ovulation induction using hMG/hCG, 14 pregnancies were achieved in 8 patients. Two of the pregnancies were spontaneous, and 12 were generated by hMG/hCG and fluocortolone, with or without pretreatment with GnRH-a. Twelve healthy babies were generated by 10 gestations, 3 ended in spontaneous abortions (23%), and 1 is ongoing. All the nonspontaneous pregnancies were achieved in the first three cycles of ovulation induction. CONCLUSIONS: Patients with POF and autoimmune activity, suggesting an autoimmune etiology to the ovarian failure, may respond to ovulation induction and have a conception rate of approximately 40% in three cycles. Those who do not conceive in three treatment cycles have a very low probability to conceive; therefore, further attempts of ovulation induction should be discouraged. However, some patients may spontaneously conceive in association with HRT.

Adult↗

PubMed1993

Presence of sperm in the perivitelline space predicts fertilization rate after partial zona dissection.

OBJECTIVE: To examine the association of the number of spermatozoa present in the perivitelline space and sperm parameters with fertilization after partial zona dissection in male factor patients. DESIGN: Partial zona dissection was applied in 62 couples (84 cycles). A total of 524 oocytes underwent partial zona dissection (1/8 of the zona circumference) (partial zona dissection group) and 171 sibling oocytes were not manipulated (control group). A total of 326 manipulated oocytes were examined for the presence of spermatozoa in the perivitelline space. SETTING: University-based in vitro fertilization (IVF) program. PATIENTS: Fifty-four (87%) couples had at least one complete failure of fertilization, and 8 (13%) couples had low fertilization rate (< 10%) in previous routine IVF attempts. MAIN OUTCOME MEASURES: Fertilization rate, cleavage rate, and the number of spermatozoa present in the perivitelline space after partial zona dissection. RESULTS: Monospermic and polyspermic fertilization rates were 22.3% and 6.7% in the partial zona dissection oocytes and 8.8% and 0.6% in the nonmanipulated oocytes, respectively. The cleavage rate was similar in the partial zona dissection and control group (69.2% and 66.6%, respectively). A total of 81 partial zona dissection embryos and 10 nonmanipulated embryos were transferred to the uterus of 34 women (39 cycles), resulting in four pregnancies. In 46% (18 of 39) of the patients who had both partial zona dissection and control oocytes, only the manipulated oocytes fertilized. In only 48.8% of partial zona dissection oocytes, spermatozoa were detected in the perivitelline space; in this group of oocytes the fertilization rate was 56.6%. Sperm count and morphology were not clearly correlated with the outcome of partial zona dissection. CONCLUSIONS: The partial zona dissection technique enhances fertilization of subfertile sperm. However, the low efficiency of the procedure, apart from being associated with a high polyspermic rate, is related to the failure of sperm to traverse the slit in the zona pellucida in approximately one half of the manipulated oocytes.

Adult↗

PubMed1993

Injury severity scoring and length of stay in hospital of war casualties--demonstration of an association and possible selection bias.

The Injury Severity Score (ISS) is a widely used measure of anatomical injury. It is the sum of squares of the highest scores on the Abbreviated Injury Scale (AIS) in each of the three most severely injured body regions. This study was designed to describe the relationship between ISS and length of stay (LOS) in hospital. The ISS was independently determined by four physicians who studied 491 war casualties, excluding dead on arrival and non-trauma patients. The study demonstrates non-linear and non-homogeneous relationships between ISS and LOS. Exclusion of fatalities resulted in biased (higher) estimates of LOS among those with ISS scores of 25-66. The patients could be grouped into five categories according to their maximal AIS (MAIS): (1) Slight injury--i.e. those with injuries appropriate for AIS scores 1 or 2 that lead to an LOS of median 5 days; (2) Moderate injury--i.e. those with injuries appropriate to AIS scores of 3, with an expected median LOS of 10 days; (3) Severe injuries--i.e. those with injuries appropriate to AIS scores of 4, with expected median LOS of about 17 days; (4) Very severe injuries--i.e. those with one injury appropriate to an AIS score of 5; and (5) Multiple severe injuries--those who are severely wounded in two or more body regions, i.e. those with two or more injuries appropriate to AIS scores of 5 and 4, with a median LOS of 39 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗

PubMed1993

Increasing progesterone secretion in human granulosa-luteal cells induced by human follicular fluid.

Increasing evidence suggests that local ovarian agents play a central role in the regulation of follicular maturation and corpus luteum formation. In previous studies, we have shown that porcine follicular fluid induces granulosa cell luteinization in sow, human and rat. In the present study, the effect was investigated of either human follicular fluid (FF) alone, human follicle-stimulating hormone (FSH) alone, or both upon progesterone secretion of human granulosa-luteal cells. Granulosa-luteal cells were cultured in the presence of either FSH (5, 50 and 250 ng/ml), lyophilized FF (50 and 250 micrograms/ml) or both. Secretion of progesterone increased from a minimum of 2.5-fold to a maximum of 23-fold in the presence of FSH alone and, significantly less (approximately 2-fold) in the presence of FF alone, compared to cells cultured in medium alone. The co-administration of FSH and FF was significantly more effective than either alone, while addition of both FSH (250 ng/ml) and FF (250 micrograms/ml) gave maximal progesterone secretion. In granulosa-luteal cells pre-cultured with both FSH and FF, subsequent exposure to human chorionic gonadotrophin (HCG) alone increased progesterone secretion 1.6-fold to 11-fold, compared to cells pre-cultured with FSH alone. The effect of FF from individual follicles was also studied. FF from follicles yielding mature cumulus-oocyte complexes was 4.2-fold more effective, than FF obtained from follicles yielding immature cumulus-oocyte complexes in enhancing the FSH stimulation of progesterone secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗

PubMed1993

Investigation in real time of the effect of gravitation on human spermatozoa and their tendency to swim-up and swim-down.

To investigate in real time if and how natural gravity affects rates of swim-up and swim-down of human spermatozoa, samples of motile or immobilized spermatozoa in a sealed mini-chamber were placed vertically on a 90 degrees tilted microscope. The mode of their sedimentation, as well as the difference in the rate of their swimming up and down, were observed directly over 30 min and analysed from photomicrographs. Under the influence of natural gravity force, most immobilized spermatozoa turned their heads down in about 5 min and then sank slowly at an average speed of 0.2 mu/s. The number of motile spermatozoa that swam down was 5-6 times more than those swimming up. It can be implied that in spite of the mild force exerted by 1 g on suspended spermatozoa in comparison to the high g force obtained by centrifugation, the overall effect of gravity on the rate of swimming up or down becomes dominant. Gravity causes the sperm heads to turn downward after which the oriented spermatozoa continue to move down by their own tail movements, causing accumulation of motile spermatozoa at the bottom. This may explain why in some recent studies swim-down was superior to the swim-up procedure during sperm separation by self-migration.

Gravitation↗

PubMed1993

Uterine artery flow velocity waveforms and color flow imaging in women with perimenopausal and postmenopausal bleeding. Correlation to endometrial histopathology.

We performed Doppler studies of the uterine artery in 85 women with postmenopausal and perimenopausal bleeding. Sixty-six women had non-malignant changes and 19 women had malignant changes on histologic examination of the endometrium. Uterine fibroids were detected in 30 women. When malignant changes were detected in the endometrium, uterine artery resistance index was always below 0.83. The mean uterine artery resistance index was significantly lower in the group of women with pathologic changes of the endometrium (RI = 0.77 +/- 0.03) compared to the group with non pathologic changes (RI = 0.85 +/- 0.08 p < 0.01), excluding the women with uterine fibroids. The lowest mean resistance index in the uterine artery was observed in the group of women with uterine fibroids (RI = 0.60 +/- 0.09 p < 0.001). In five of six patients with endometrial carcinoma blood vessels were detected around the myometrium by using color flow imaging. Their RI was always less than 0.5. In five patients, blood vessels were detected in uterine fibroids but their RI was always more than 0.5. All six women with endometrial carcinoma but only seven of 13 women with endometrial hyperplasia, had endometrial thickness greater than 5 mm. Doppler velocimetry of the uterine artery carries a high sensitivity (100%) in detecting pathological changes of the endometrium in patients presenting with postmenopausal or perimenopausal bleeding. The presence of high resistance in this vessel, may allow a more conservative approach in this group of patients.

Aged↗

PubMed1993

Screening for ovarian cancer in women with breast cancer with transvaginal sonography and color flow imaging.

The aim of the present study was to determine the efficacy of transvaginal color flow imaging as a screening tool for ovarian cancer. Six hundred patients with previous breast carcinoma were screened for ovarian cancer. Screening was performed using transvaginal sonography with color flow imaging. Serum CA 125 levels were measured in patients with abnormal sonographic findings. Eighty-three percent of the ovaries were detected in the premenopausal patients by ultrasonographic scanning and only 26% of the ovaries were detected in the postmenopausal patients. Intraovarian blood vessels were detected in 11% of the premenopausal women. The PI was less than 1 in 80% of these ovaries, but, on repeated examinations, the values of PI increased in all the blood vessels to greater than 1. Intraovarian blood vessels were detected in 1.8% of the normal ovaries observed in the postmenopausal women, but PI was always greater than 1. Eleven women with complex ovarian cysts (not simple) and one woman with enlarged ovaries underwent explorative laparotomy. In three women, primary malignant ovarian tumors were diagnosed and in one woman metastatic ovarian cancer was diagnosed. The specificity of sonography in detecting malignant ovarian tumors was 97.5% and the positive predictive value was 25%. The specificity of color flow imaging in detecting primary malignant ovarian tumors was 99.8% and the positive predictive value was 60%. In selected groups of women, screening for ovarian cancer with transvaginal color flow imaging may be justified.

Adult↗

PubMed1992

Secretion of human chorionic gonadotropin in superfused young placental tissue exposed to cadmium.

The effect of various concentrations of cadmium (Cd) in levels ranging from 0.75 to 12 micrograms/ml medium, on the secretion of human chorionic gonadotropin (hCG) in first-trimester placental explants, after 6 or 24 h incubation, employing both static and dynamic systems was examined. Later the unbound Cd was washed for 45 min with fresh medium devoid of Cd, followed by superfusion with the latter medium for 75 min, during which time samples were collected for hCG assay. For the superfusion experiments the parameters used for evaluating the hCG secretion pattern were: mean peak amplitude (MPA), pulse frequency (PF) and the area under the hCG secretion curve (AUC). The results indicate that in the dynamic system the hCG secretion increased significantly, and this increase was dose dependent. There was also a dose-related increase in mean total hCG secreted by the explants exposed to Cd. Maximal hCG secretion was observed after 24 h exposure of explants to 6 micrograms of the metal/ml. Both the MPA and AUC parameters showed a statistically significant increase for this dose level. At 12 micrograms/ml, the pulsatile secretion of hCG decreased, the value for the mean hCG secretion being comparable to that observed for 0.75 micrograms/ml. After 6 h incubation, however, there were no significant changes from the control, as judged by all of the above parameters. The levels of hCG secreted by the explants into the media in the static system were not significantly different from their respective controls, for both incubation periods and Cd levels. These results indicate that Cd may affect the normal placental function, as reflected in its hCG secretion pattern.

Cadmium↗

PubMed1992

In vitro exposure to mercury and cadmium alters term human placental membrane fluidity.

The effect of incubation with mercury (Hg) as HgCl2 and cadmium (Cd) as CdCl2, at levels of 6 or 12 micrograms/ml of medium, on explants of term human placental microvillus membrane fluidity were studied. After incubation for 6 or 24 hr explants for each dose level were pooled and washed with fresh medium to remove any unbound metal. Placental membranes were separated by differential centrifugation and fluidity was studied by steady-state fluorescence polarization, expressed as the fluorescence anisotropy, r, with 1,6-diphenyl-1,3,5-hexatriene as a probe. The results show that membranes derived from explants incubated for 24 hr with either 6 or 12 micrograms/ml medium of either metal showed fluorescence anisotropy values (i.e., decreased fluidity) significantly higher than that of their respective controls. With 6 micrograms/ml of either metal the decrease in fluidity was highly significant for both metals and with 12 micrograms/ml a further decrease in membrane fluidity was observed with either metal. Both metals accumulated in placental membranes in proportion to their level in the medium. Membrane accumulation of Cd was higher than that of Hg. The cholesterol, phospholipid, and cholesterol-to-phospholipid mole ratios in membranes derived from metal-treated explants were unchanged, compared to their respective controls. However, no changes in membrane fluidity were observed in the samples incubated for 6 hr. In conclusion, exposure of placental cells to Hg and Cd caused accumulation of the metals in the membranes and lowered the membrane fluidity, which may affect membrane function and cause damage to the developing fetus.

Alkaline Phosphatase↗

PubMed1992

Effect of cadmium on some enzyme activities in first-trimester human placentae.

Explants from first-trimester placentae obtained from non-smoking women were incubated with doses of 0, 0.75, 1.5, 3, 6 and 12 micrograms of cadmium (Cd) as CdCl2 for 6 or 24 h. At the end of the incubation period, the activities of placental aryl hydrocarbon hydroxylase (AHH) (a phase I enzyme), quinone reductase (QR) and catecholamine-O-methyltransferase (COMT) (both phase II enzymes) and glucose-6-phosphate dehydrogenase (G-6-PD) were determined. Cd at low dose levels increased significantly the activities of placental phases I and II enzymes in a time- and dose-dependent manner. Of the first 3 enzymes, only AHH showed a biphasic response for the two time periods, with the activities of QR and COMT continually increasing at all the dose levels tested for the two incubation periods. However, the G-6-PD activity was inhibited at all the dose levels of Cd, the effect being very drastic after exposure to 0.75 ppm Cd for both incubation periods.

Aryl Hydrocarbon Hydroxylases↗

PubMed1992

Effect of inorganic mercury on in vitro placental nutrient transfer and oxygen consumption.

The effect of mercury (HgCl2) on placental amino acid and glucose transfer as determined by the use of their nonmetabolizable radioactive analogues, aminoisobutyric acid (AIB) and 3-o-methyl glucose (3MG), respectively, was studied in an in vitro perfusion model of a term human placenta. Hg2+ was found to decrease the transfer and accumulation of AIB without affecting 3MG transfer. It was also found to decrease the placental oxygen consumption rate. Placental circulation and tissue morphology remained intact, as demonstrated by the antipyrine transfer rate, and by electron microscopy, respectively. The mechanism by which Hg2+ may interfere with placental amino acid transfer and accumulation is discussed. Although much higher concentrations than those found in the ordinary polluted environment were used, this is the first report showing that Hg2+ interferes with an essential human placental function in a system employing a whole human placental cotyledon. This finding may indicate the possible involvement of Hg2+ in impaired organogenesis in early pregnancy or deranged fetal growth during the last trimester.

3-O-Methylglucose↗

PubMed1992

In vitro effect of mercury on enzyme activities and its accumulation in the first-trimester human placenta.

The effect of incubating young placental explants with HgCl2 on the activities of aryl hydrocarbon hydroxylase (AHH) (a phase I enzyme), quinone reductase (QR), catecholamine-O-methyltransferase (COMT) (both phase II enzymes), and glucose-6-phosphate dehydrogenase (G-6-PD) is described. Mercury (Hg) at low doses significantly elevated placental phase I and phase II enzyme activities, but decreased the activity of G-6-PD. The increase in activities, which was time- and dose-dependent, was higher in explants incubated for 24 hr than in those incubated for 6 hr. The decrease in placental G-6-PD activity was drastic at low Hg dose levels but at higher levels the inhibitory effect was milder for both incubation periods. Placental explants accumulated Hg in amounts proportional to its concentration in the incubation medium and this accumulation was greater in explants incubated for 24 hr. The data suggest that contamination with low Hg levels from the environment during pregnancy may affect placental enzymatic activity. The accumulation of Hg during short incubation indicates a strong placental cell affinity for Hg, which could affect its other metabolic functions. The system used in sensitive, as it shows alteration in enzyme activity even with relatively low concentrations of the metal and the response is dose-related.

Analysis of Variance↗

PubMed1992

Gonadotropin-releasing hormone analogues for dysfunctional bleeding in women after liver transplantation: a new application.

A new clinical indication for GnRH agonists treatment seems to exist in addition to the many indications known so far (4, 5). These previously mentioned indications include: uterine fibroids, precocious puberty, endometriosis, polycystic ovarian disease, ovulation induction for assisted fertilization (in vitro or in vivo), treatment of various tumors such as prostatic, breast, pancreatic, ovarian, and pituitary tumors, and various catamenial disorders such as premenstrual syndrome and porphyria. Women after liver transplantation, who are in the reproductive age and who experience menometrorrhagia or dysfunctional bleeding, seem to be a new indication for application of these useful GnRH analogues. This application may prevent the potential hepatotoxicity or cholestasis of E-P combinations usually used for treatment of dysfunctional bleeding. The recommended treatment is of relatively short duration (3 to 6 months), within the first 2 years of the transplantation, after which a more prolonged treatment should be considered. This treatment may also spare the need for contraception during its administration because both oral contraceptives and intrauterine device are relatively contraindicated in these patients (the latter because of the immunocompromised state). We believe this application to become more common because of increasing numbers of liver transplantations and improved survival rate. It may be looked at as a "new application of a relatively new drug for a new and enlarging situation."

Adult↗