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Biomedical subjects

C Simone

Publications and source records attributed to C Simone.

At least 19 recordsLinked to original sources
PubMed1998

STK11 mutations in Peutz-Jeghers syndrome and sporadic colon cancer.

A potential tumor suppressor gene, STK11 , encoding a serine threonine kinase, has recently been identified on chromosome 19p13. Germ-line mutations of this gene have been found in patients with Peutz-Jeghers syndrome (PJS). To further investigate the relevance of STK11 mutations in PJS, we analyzed its coding sequence in nine patients and identified two deletions and three missense mutations. Because intestinal carcinomas have been observed to develop in association with PJS, we analyzed tumors from 71 patients for allelic deletions (loss of heterozygosity) and STK11 gene mutations, to elucidate the etiological role of STK11 gene in sporadic colorectal cancer. Loss of heterozygosity, evaluated using the microsatellite D19S886, was observed in 10 of 52 informative cases. No somatic mutations were detected except for a missense alteration in one tumor. Our data indicate the heterogeneity of PJS and the infrequent involvement of the STK11 gene in colorectal cancer.

AMP-Activated Protein Kinase Kinases↗
PubMed1998

Transplacental transfer and biotransformation studies of nicotine in the human placental cotyledon perfused in vitro.

Our objective was to study the characteristics of transfer and biotransformation of nicotine in the human term placenta. Nicotine transfer was studied by dually perfusing an isolated cotyledon of the human placenta in vitro. Nicotine metabolism to cotinine was investigated in intact tissue during perfusion and in placental microsomal fractions. Following the addition of nicotine (40 ng/ml) to the maternal side of the placenta, distribution into placental tissue (0.43 +/- 0.13 ng/ml/min) was three times higher than transfer to the fetal side of the placenta (0.15 +/- 0.01 ng/ml/min). The steady-state maternal-to-fetal transfer of nicotine was approximately 90% that of antipyrine (a marker of flow-dependent transfer). There was no evidence of nicotine metabolism to cotinine by intact placental tissue or in microsomal fractions. The observation that nicotine readily crosses the human placenta with no evidence of metabolism suggests that nicotine has the potential to cause adverse affects on the developing fetus.

Biological Transport↗
PubMed1996

Cocaine inhibits hCG secretion by the human term placental cotyledon perfused in vitro.

Cocaine has been shown to adversely affect pregnancy outcome in humans, but the mechanism(s) are not well understood. Using the technique of perfusing the human term placental cotyledon in vitro, we measured the rate of hCG appearance in the maternal circulation in the presence and absence of cocaine in the maternal circulation. At a dose of 0.80 microgram/mL, hCG secretion was reduced by 46%. This reduction in hCG concentration in the maternal circulation may effect normal steroidogenesis required to maintain pregnancy and may contribute to our understanding of the reproductive toxicology of cocaine.

Chorionic Gonadotropin↗
PubMed1994

Correlation of local changes in cerebral blood flow, capillary density, and cytochrome oxidase during development.

Although elevations in cerebral metabolic demand during development may induce angiogenesis, the correlation among ontogenic changes in local cerebral blood flow, cytochrome oxidase activity (an index of oxidative capacity) and capillary density have not been examined previously. We measured these parameters in selected regions of the brains of anesthetized rabbits of various ages. Increases in all three parameters occurred postnatally within the cerebral cortex and striatum, whereas in the medulla, values at birth were similar to those in adults. In newborns, the pattern of distribution of blood flow within the parietal cortex was such that levels were maximal in the outer layers and declined in deeper layers. This distribution correlated closely with that of capillary density, whereas cytochrome oxidase activity was maximal at levels deeper in the cortex. By postnatal day 17, the distribution for all three parameters was similar to that of cytochrome oxidase activity in young animals. A regression analysis of the regional values demonstrated a positive correlation between capillary density and blood flow in young (< or = postnatal day 8) and old (> or = postnatal day 17) animals. In contrast, cytochrome oxidase activity and capillary density were poorly correlated in young animals but positively correlated in older animals, with the slopes being markedly different (P < 0.005). The results suggest that early in postnatal development, the pattern of cytochrome oxidase activity is relatively mature compared with that of capillary density. By postnatal day 17, microvascular anatomy is closely associated to oxidative capacity, likely reflecting a steady state regulation of capillary density to metabolic requirements.

Animals↗
PubMed1994

Transfer of cocaine and benzoylecgonine across the perfused human placental cotyledon.

OBJECTIVE: Our aim was to measure the transfer of cocaine and its major metabolite benzoylecgonine across the human term placenta. STUDY DESIGN: By means of in vitro perfusion of the human term placental cotyledon the transfer of these compounds was measured. RESULTS: The steady-state maternal-to-fetal transfer of cocaine (0.18 +/- 0.05 microgram/ml/min) was significantly greater than benzoylecgonine transfer (0.02 +/- 0.01 microgram/ml/min) (p < 0.05). When the perfused tissue was analyzed 32% +/- 7% of the maternal cocaine dose was retained by the placental tissue, whereas only 12% +/- 12% of the maternal benzoylecgonine dose was retained by the placental compartment. CONCLUSIONS: These results suggest (1) the placenta may serve as a depot for large amounts of cocaine, thus offering some degree of fetal protection after bolus administration; (2) fetal exposure may be prolonged by placental retention and subsequent release of cocaine and benzoylecgonine; and (3) benzoylecgonine does not cross the placenta as readily as does cocaine. Variability in placental handling of cocaine and benzoylecgonine may therefore determine fetal exposure to these agents.

Biological Transport↗
PubMed1994

Drug transfer across the placenta. Considerations in treatment and research.

Using the pregnant woman as a means to medicate her fetus represents a new and exciting therapeutic approach in clinical pharmacology. In years to come, we will see an increase in the use of the currently accepted fetal therapies and an increase in the number of therapies available to the caregiver or clinician aimed at assisting the unborn child. The pharmacologist, through in vitro research that aids our understanding of the role of the placenta in fetal drug therapy, can contribute to the growth of this new field within the realm of obstetric medicine.

Animals↗
PubMed1994

Acetylcholinesterase and butyrylcholinesterase activity in the human term placenta: implications for fetal cocaine exposure.

The characterization of the enzymes responsible for drug metabolism in the human placenta is of great importance in determining the possible role the placenta plays in protecting the fetus from potentially fetotoxic drugs. We speculate that the placenta metabolizes cocaine, serving to protect the fetus from the drug's ill effects. Cholinesterase, the principle enzyme that metabolizes cocaine, has been hypothesized to be present yet is not well characterized in the human placenta. The purpose of this study was to quantify human placental acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity. Human placentas were obtained from elective cesarean sections, and several lobules were thoroughly perfused with cold buffer to ensure minimal contamination from erythrocyte AChE. Subcellular fractions were then prepared from these lobules by using standard differential centrifugation techniques. Microsomes and cytosol were assayed for AChE and BChE activity by using a spectrophotometric assay. BChE activity was found in the cytosolic fraction of the placental villous tissue, whereas AChE activity was measured in the microsomal fraction. By demonstrating that BChE activity is present in human term placenta we have shown that this organ has the capacity to metabolize cocaine and may therefore serve as a metabolic barrier to fetal exposure to cocaine.

Acetylcholinesterase↗
PubMed1992

Local blood-brain barrier in the newborn rabbit: postnatal changes in alpha-aminoisobutyric acid transfer within medulla, cortex, and selected brain areas.

Postnatal changes in local permeability of the blood-brain barrier to an inert neutral amino acid (alpha-[14C]-aminoisobutyric acid) were investigated in 25 rabbits. The local transfer constant (K) for this tracer was measured with quantitative autoradiographic techniques at postnatal ages of 1, 3, 8, and 17 days, and adult. In adults, the amino acid penetrated the blood-brain barrier poorly in most regions examined (K less than 1 microliter.g-1.min-1) except within and in proximity to structures with a relatively leaky blood-brain barrier such as area postrema and choroid plexus. The rate of tracer entry into "impermeable" regions was seven- to 10-fold greater in 1-day-old rabbits than adults and not dependent on active transport. In young animals, there was a pronounced regional variation in K with the lowest values occurring in white matter and the highest in gray matter such as cerebral cortex, posterior thalamus, and hippocampus. During postnatal development, K decreased (p less than 0.01) with most regions having values near those of adults by 17 days of age. The results indicate that the blood-brain barrier of the newborn rabbit is relatively leaky to a small hydrophilic nonelectrolyte with a distribution that is heterogeneous regionally. Irrespective of age, such blood-borne substances can accumulate in certain brain areas considered to have impermeable vessels (e.g., nucleus tractus solitarii).

Aging↗
PubMed1984

Toxicity of WR-2721 administered in single and multiple doses.

Two hundred forty-three patients have received WR-2721 in Phase I-II studies. Separate studies were conducted in which patients with advanced malignancies received WR-2721 before single or multiple doses of radiotherapy or in single doses prior to cyclophosphamide, nitrogen mustard or cis-platinum. Single doses were escalated from 25 to 1330 mg/m2. An Acceptable Tolerated Dose (ATD) of 740 mg/m2 infused in 15 minutes has been established and is currently used in Phase II studies. Significant persistent hypotension (greater than 20 torr systolic) as a dose-limiting toxicity has occurred in 5% of patients in the single dose study. Fifty-five patients have been entered in the multiple dose trial. Dose levels of 340 mg/m2, four times a week for three weeks, and 250 mg/m2, four times a week for six weeks have been reached. There were five idiosynchratic reactions (fever, chills, rash, hypotension), one of which was severe. Some patients withdrew from the multiple dose study because of vomiting after each injection, or fear. No deaths nor any long-term untoward effects were observed. There is no suggestion of tumor protection.

Amifostine↗
PubMed1982

Osteosclerosis in leprosy.

The literature contains little reference to the phenomenon of osteosclerosis in leprosy. The aim of the authors' investigations was to determine: a) the incidence of osteosclerosis as part of the radiographic picture in the distal extremities of the limbs; b) the pathological substratum; c) the possible clinical significance. The research was carried out on 233 leprosy patients at the Colonia Hanseniana di Gioia del Colle (Bari). The authors examined 260 radiographs of the hands and 1310 radiographs of the feet. A number of biopsy samples of bone were taken from four patients and examined by means of microradiography using ultraviolet fluorescent light and also by historadiography. The basic radiographic features indicative of osteosclerosis were: a) reactive osteosclerosis; b) sclerosing periostosis; c) massive osteosclerosis. The authors observed a preponderance of osteosclerosis in the bones of the first digital ray, both in the phalanges and metatarsals or metacarpals. The sesamoid bones were affected more commonly in those of the first digit than those of the fifth. The radiographic findings were confirmed microscopically. It is difficult to assess the possible clinical significance because of the transient nature of the osteosclerosis in the evolution of the lepromatous lesions with time.

Adult↗