Caffeine does not cause override of the G2/M block induced by UVc or gamma radiation in normal human skin fibroblasts

Caffeine has for many years been known to be involved in the sensitization of DNA to damage. One potential mechanism recently put forward is an override of the G2/M block induced by irradiation, which would leave the cells less time for DNA repair prior to mitosis. However, different cell types display a variety of responses and no clear pathway has yet emerged, especially as little is known about the capacity of this agent to enhance DNA damage in normal, untransformed cells. Continuous exposure to commonly used caffeine concentrations (1-5 mM) inhibited the proliferation of normal human fibroblasts (NHFs) in a dose-dependent manner to up to 80% at 5 mM. Exposure of exponentially growing NHFs to UVc radiation (20 J m(-2)) or gamma radiation (2.5-8 Gy) led to a 45-60% inhibition of proliferation and protracted accumulation of cells in the G2/M phase. Addition of 2 mM caffeine after irradiation induced slowing of the S phase passage, with a resultant delay in G2/M accumulation mimicking a G2/M block override. These results were confirmed by stathmokinetic studies, which showed delayed entry of the cells into mitosis in the presence of caffeine. Our data demonstrate that caffeine primarily inhibits replicative DNA synthesis and suggest that, at least in normal cells, caffeine potentiates the cytotoxicity of radiation by intervening in DNA repair rather than by overriding the G2/M block.     

Citalopram and demethylcitalopram in human milk; distribution, excretion and effects in breast fed infants

AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for citalopram and demethylcitalopram, in breast-feeding women taking citalopram for the treatment of depression, and to determine the plasma concentration and effects of these drugs in their infants. METHODS: Seven women (mean age 30.6 years) taking citalopram (median dose 0.36 mg kg(-1) day(-1)) and their infants (mean age 4.1 months) were studied. Citalopram and demethylcitalopram in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval. Infant exposure was estimated (two separate methods) as the product of milk production rate and drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/PAUC values of 1.8 (range 1.2-3) and 1.8 (range 1.0-2.5) were calculated for citalopram and demethylcitalopram, respectively. The mean maximum concentrations of citalopram and demethylcitalopram in milk were 154 (95% CI, 102-207) microg l(-1) and 50 (23-77) microg l(-1). Depending on the method of calculation, mean infant exposure was 3.2 or 3.7% for citalopram and 1.2 or 1.4% for demethylcitalopram. Citalopram (2.0, 2.3 and 2.3 microg l(-1)) was detected in three of the seven infants. Demethylcitalopram (2.2 and 2.2 microg l(-1) was detected in plasma from two of the same infants. No adverse effects were seen in the infants, all were within appropriate percentile limits for weight and all had normal Denver developmental quotients. CONCLUSIONS: The mean combined dose of citalopram and demethylcitalopram (4.4-5.1% as citalopram equivalents) transmitted to infants via breast milk is below the 10% notional level of concern. Plasma concentrations of these drugs in the infants were very low or absent and there were no adverse effects. These data support the safety of the use of citalopram in breast feeding women. Nevertheless, each decision to breast feed should always be made as an individual risk:benefit analysis.     

Establishment of a cell line of human endometrial adenocarcinoma in vitro

A new in vitro cell system, Line human endometrial cancer-one (HEC-1), derived from adenocarcinoma of human endometrium has been established and has successfully proved stable proliferation in continuous tissue culture since May, 1968. The cytologic findings of HEC-1 reveal such anaplastic features as anisonucleosis, nucleolar pleomorphism, and piling-up tendency in cellular arrangement. Distribution of the chromosome number is found at the diploid range, and the apparent marker chromosome has been identified without exception. When transplanted into a hamster cheek pouch, HEC-1 demonstrates a definite tumor formation whose histologic picture reveals papillary adenocarcinoma. The original characteristics of endometrial cancer have been precisely maintained in this in vitro culture system.     

Epidural analgesia for obstetrics: a maternal, fetal, and neonatal study

The effect of lumbar epidural (LE) and caudal epidural (CE) analgesia on the fetal heart rate and fetal acid-base status (pH and base excess) of 41 patients was studied during first- and second-stage analgesia in a controlled research delivery room environment. All patients had baseline parameters which made it possible to observe the effects of the epidural technique upon the fetal heart rate, pH, and base excess. Certain neonatal parameters were recorded to evaluate the epidural effect upon the neonate's postdelivery period. These included Apgar scores at 1 and 5 minutes, umbilical cord arterial and venous blood gases, and neonatal blood gases from the umbilical artery in the first hour after birth. There was an increase in late deceleration after epidural block despite segmental analgesia with minimal lidocaine dosages and the absence of hypotension. However, unless second-stage embarrassment or hypotension occurred, no significant deterioration of the acid-base status was noted. The greatest incidence of late deceleration was noted when epidural analgesia was combined with oxytocin. For the few toxemia patients studied, the epidural technique did not prove hazardous. These intrapartum regional analgesic techniques (LE and CE) do not appear to present a hazard to the normal fetus or the fetus at mild risk. Nevertheless, discretion would dictate that these techniques be restricted with evidence of combined antepartum and intrapartum fetal compromise.     

Response of pituitary LH and FSH to synthetic LH-releasing hormone in normal subjects and patients with Sheehan's syndrome

Serum levels of LH and FSH were determined by radioimmunoassay in seven patients with Sheehan's syndrome, eight women with normal menstrual cycles, and five normal men following intravenous injection of synthetic luteinizing hormone-releasing hormone (LH-RH) in a dose of 100 μg. The mean maximum increases of LH (M. ± S.E. mI.U./ml.) were in the following order: 279.4 ± 87.6 at the preovulatory phase, 69.2 ± 12.6 in normal males, 48.2 ± 3.5 at the midluteal phase, and 29.9 ± 4.9 at the early follicular phase. The response of serum levels of FSH was found to parallel the change in the levels of LH, but these changes were less pronounced. No response of LH and FSH to LH-RH was observed in five patients with Sheehan's syndrome while the remaining two patients showed an increase of LH around normal lower limits. These findings seem to indicate that LH-RH test is useful for the evaluation of pituitary reserve function of gonadotropin secretion.     

Clinical experiences with fetal heart rate monitoring of one thousand patients in labor

A series of 1,000 labor patients has been monitored electronically, and their records reviewed. Monitoring provides accurate objective evidence that fetal condition is good and that tolerance for labor is normal. With a normal record, the likelihood is strong that a normal baby will be delivered. Electronic fetal heart rate monitoring is unreliable in the prediction of babies born in poor condition. It does, however, provide an excellent screening test for selection of patients for scalp pH determinations. Electronic monitoring of fetal heart rate provides early evidence of fetal anoxia. It should be carried out in all patients receiving oxytocin during labor to avoid episodes of fetal anoxia. External monitoring methods currently available permit routine monitoring of all patients in labor. Whether monitoring all normal patients will improve fetal health and survival is still an unanswered question.     

Sentinel lymph nodes in vulvar cancer: Management dilemmas in patients with positive nodes and larger tumors

Background

Although sentinel lymph node (SLN) biopsy has been routinely used in the treatment of invasive squamous cell carcinoma (SCC), questions still remain regarding the management of patients with positive nodes, as well as its use in patients with larger tumors.