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[Spontaneous thrombosis of an iatrogenic pseudoaneurysm of the arterial brachiocephalic trunk following central venous catheterization].

Following the unsuccessful puncture of the right subclavian vein during central catheterism, a 80-year-old women developed a pseudoaneurysm on the external face of the brachiocephalic artery. Her symptomatology and haemodynamic status having remained steady, the patient was closely observed. The pseudoaneurysm itself thrombosed spontaneously and the foreseen endovascular procedure doesn't have been achieved. A review of the literature has been done concerning the venous catheterism complications and the pseudoaneurysm treatment.

Aged↗

PROGESTINS IN HORMONE REPLACEMENT THERAPY: IMPACT ON ENDOMETRIAL AND BREAST CANCER.

Unopposed estrogen replacement therapy (ERT) in non-hysterectomized women creates an unacceptably high risk of endometrial neoplasia that persists even after discontinuation of hormone replacement therapy (HRT). Normally progestin should be given in addition to ERT unless a contraindication to progestin exists: in this circumstance, endometrial surveillance is essential. Continuous combined progestin-estrogen therapy (PERT) appears to offer the greatest protection from endometrial cancer. Accumulated evidence now suggests that ERT has minimal impact on breast cancer risk, especially when compared to other known or suspected breast cancer risk factors. Women developing breast cancer while on ERT have improved survival compared to non-ERT users. Recent reports suggesting an increased breast cancer risk with PERT are based on limited data sets, and are reminiscent of early alarming reports about ERT, which have been largely refuted as larger data sets have become available. Further studies are required to clarify the true impact of PERT on breast cancer and breast cancer mortality.

Journal Article↗

Acanthamoeba keratitis after photorefractive keratectomy.

A 37-year-old women developed severe suppurative keratitis immediately after having photorefractive keratectomy in her left eye. The keratitis was unresponsive to intensive topical antibiotic agents and topical and systemic steroids. Although the differential diagnosis included nonmicrobial and fungal keratitis, the clinical course and confocal microscopy suggested, and subsequent histopathologic examination confirmed, a diagnosis of Acanthamoeba keratitis. The amebic contamination probably resulted from exposure of the deepithelialized cornea to contaminated freshwater in a northern Wisconsin marsh. This case emphasizes the importance of encouraging patients with epithelial defects and bandage soft contact lenses to avoid exposure to contaminated freshwater until reepithelialization is complete.

Acanthamoeba Keratitis↗

Polycystic ovary syndrome, androgen excess, and the impact on bone.

Polycystic ovary syndrome (PCOS) is a unique, natural model for the study of the influence of androgen excess on bone mass among women. Both thin and obese women develop PCOS, a presentation that allows for the evaluation of the effects of life-long obesity, alterations in body composition (central adiposity), and related metabolic abnormalities (hyperandrogenemia, hyperinsulinemia) on the skeleton. The relatively high prevalence of PCOS and its manifestation early in life render this disorder of particular importance in assessing the influence of androgens and androgen-estrogen balance on the attainment of maximal bone mass and subsequent development of osteoporosis later in life.

Female↗

Peptic ulcer and Helicobacter pylori.

Although there has been an explosion of data not only since the discovery of H. pylori in 1982, but also since the first comprehensive review of H. pylori in the Gastroenterology Clinics in 1993, much remains to be learned. In 1993, there were many skeptics doubting the importance of H. pylori in ulcer disease. Although this skepticism has dissipated, many ulcer patients infected with H. pylori still do not receive appropriate therapy. This situation possibly relates to the safety, efficacy, and simplicity of prescribing acid-suppressive therapy in contrast to the confusion regarding anti-H. pylori treatment regimens. Among the many continuing unanswered questions regarding the role of H. pylori and PUD are the still enigmatic nature of host, environmental, and H. pylori-related factors that determine outcome. Why do only some infected individuals (and why do more men than women) develop PUD, and what determines whether gastric ulcers or duodenal ulcers develop? What is the explanation for the seasonal variation in ulcer disease? Although PUD is an infectious disease, are other environmental factors critical for the manifestation of ulcers in association with infection? What factors govern the outcome of the combination of H. pylori infection and NSAID use? Has attention been too focused first on the pathophysiology of acid secretion and now on H. pylori? In curing H. pylori in association with PUD, are clinicians going to displace disease northward, substituting erosions, inflammation, and neoplasia (and associated symptoms) in the esophagus and gastroesophageal junction for an ulcer crater (and its associated symptoms) in the duodenum or stomach? The epidemiology of PUD is changing--in more recent reports of ulcer patients, H. pylori and NSAID use are less prevalent than in earlier reports. These questions and comments should not be misinterpreted as advocating a lack of aggressiveness in diagnosis and treatment of H. pylori in the setting of PUD, however. Nevertheless, the pendulum is swinging.

Anti-Ulcer Agents↗

A case of extracranial vertebral artery dissection with spontaneous recovery Diagnosis and follow-up by duplex and color Doppler.

A 47-year-old women developed an acute vestibular syndrome with a peripheral facial palsy not associated with any trauma. Magnetic resonance imaging showed an ischemic lesion in the territory of the posterior inferior cerebellar artery. Color Doppler ultrasonography detected an occlusion of the right vertebral artery and dissection of the artery was confirmed by a subsequent angiography. During follow-up Duplex-Doppler allowed a non-invasive monitoring of recanalization of the occluded artery. Copyright 1997 Elsevier Science Ireland Ltd.

Journal Article↗

Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families.

Spinal and bulbar muscular atrophy (Kennedy disease) is an adult form of X-linked motor neuron disease caused by the expansion of a polymorphic CAG-repeat sequence in the first exon of the androgen receptor gene. We studied clinical and molecular features of 36 patients and 19 heterozygous females. Phenotypic manifestations and disease severity broadly varied among our spinal and bulbar muscular atrophy patients. The size of CAG expansion significantly influences the age of disease onset, but neither clinical features nor disease severity. The majority of carrier women presented signs of chronic denervation at neurophysiological examination and, in three cases, low-amplitude sensory action potentials were recorded. Notably, a few women developed mild signs of bulbar motor neuron impairment later in life. The identification of a large number of patients by the use of the molecular test further supports the hypothesis that Kennedy disease had been previously underdiagnosed, probably because of the great variability of clinical presentation. Although an early diagnosis may not be crucial for treatment, given the lack of effective therapy, the molecular testing can be of great relevance for disease prognosis and genetic counseling.

Action Potentials↗

Endometrial resection and late reoperation in the treatment of menorrhagia.

STUDY OBJECTIVE: To evaluate the effectiveness of transcervical resection of the endometrium and indications for late reoperation. DESIGN: Retrospective study. SETTING: Central hospital in northern Norway. PATIENTS: Two hundred fifty women (age 30-59 yrs) with dysfunctional bleeding. INTERVENTIONS: Hysteroscopic transcervical resection of the endometrium. MEASUREMENTS AND MAIN RESULTS: Success as measured by patient satisfaction at 3-month follow-up was 97% and at 4 to 48 months was 91.6%. Mean observation time was 24 months. Twenty-one women required further surgery. Repeat resection was performed in eight women (3.2%), of whom 95% were satisfied. Thirteen women (5.2%) had a hysterectomy. Late reoperation was performed in 7 patients (2.8%) due to recurrent unacceptable vaginal bleeding and in 14 (5.6%) due to late onset of pain. CONCLUSION: After endometrial resection, a definite subgroup (8.4%) of women developed late onset of pain or bleeding requiring reoperation.

Adult↗

[Epidemiology of anal lesions (fissure and thrombosed external hemorroid) during pregnancy and post-partum].

Thrombosed external hemorrhoids (TEH) and anal fissure (AF) are 2 frequent sources of anal pains during childbirth. We are going to define their incidences as available in publications and in our experience in Bichat hospital. Then we will define their risk factors. According to Martin's and Corby's studies, AF was observed in 10% of the delivered women. In Bichat hospital we performed a proctological assessment to 165 pregnant women during the last third of pregnancy and within the 2 months following delivery. We observed 2 AF (1,2%) during the first period and 25 (15,2%) during the second. Rouillon et al. reported an incidence of TEH in 12,2% (20/164), while Pradel and al. reported 34% (18/52) of it. In Bichat hospital, 13 women (7,9%) were presenting with TEH during the last third of pregnancy and 33 (20%) in post-partum period. Two studies looked for a statistical correlation between AF and obstetrical, foetal or maternal factors. Corby et al. only pointed the role of constipation. In our study, terminal constipation was the most important risk factor for AF with 5.7 (2.7-12), odds ratio (95% confidence intervals). Rouillon et al. observed more TEH among women with a prolonged first stage labor and a big baby. In our study, a big baby and mother little lips tears were observed more often among women with TEH (P <0,05). Also, we observed only one TEH among the 25 women with caesarean section (4%). Finally, observation that TEH arise immediately after delivery is another argument to support the role of traumatic delivery. We also demonstrated the role of terminal constipation as risk factor for TEH after delivery. To conclude, 1/3 of pregnant women develop AF or TEH after delivery. These 2 pathologies are strongly correlated to terminal constipation. TEH seems equally furthered by traumatic delivery.

Anus Diseases↗

Synthesis and reactivity of the catechol metabolites from the equine estrogen, 8,9-dehydroestrone.

The risk factors for women developing breast and endometrial cancers are all associated with a lifetime of estrogen exposure. Estrogen replacement therapy in particular has been correlated with an increased cancer risk. Previously, we showed that the equine estrogens equilin and equilenin, which are major components of the widely prescribed estrogen replacement formulation Premarin, are metabolized to highly cytotoxic quinoids which caused oxidative stress and alkylation of DNA in vitro [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. Chem. Res. Toxicol. 1998, 11, 1113-1127]. In this study, we have synthesized 8,9-dehydroestrone (a third equine estrogen component of Premarin) and its potential catechol metabolites, 4-hydroxy-8,9-dehydroestrone and 2-hydroxy-8,9-dehydroestrone. Both 2-hydroxy-8,9-dehydroestrone and 4-hydroxy-8,9-dehydroestrone were oxidized by tyrosinase or rat liver microsomes to o-quinones which reacted with GSH to give one mono-GSH conjugate and two di-GSH conjugates. Like endogenous estrogens, 8,9-dehydroestrone was primarily converted by rat liver microsomes to the 2-hydroxylated rather than the 4-hydroxylated o-quinone GSH conjugates; the ratio of 2-hydroxy-8,9-dehydroestrone versus 4-hydroxy-8,9-dehydroestrone was 6:1. Also in contrast to experiments with equilin, 4-hydroxyequilenin was not observed in microsomal incubations with 8,9-dehydroestrone or its catechols. The behavior of 2-hydroxy-8,9-dehydroestrone was found to be more complex than 4-hydroxy-8,9-dehydroestrone as GSH conjugates resulting from 2-hydroxy-8,9-dehydroestrone were detected even without oxidative enzyme catalysis. Under physiological conditions, 2-hydroxy-8,9-dehydroestrone isomerized to 2-hydroxyequilenin to form the very stable 2-hydroxyequilenin catechol; however, 4-hydroxy-8,9-dehydroestrone was found to be stable under similar conditions. Finally, preliminary studies conducted with the human breast tumor S-30 cell lines demonstrated that the catechol metabolites of 8,9-dehydroestrone were much less toxic than 4-hydroxyequilenin (20-40-fold). These results suggest that the catechol metabolites of 8,9-dehydroestrone may have the ability to cause cytotoxicity in vivo primarily through formation of o-quinones; however, most of the adverse effects of Premarin estrogens are likely due to formation of 4-hydroxyequilenin o-quinone from equilin and equilenin.

Animals↗

Conformations of stereoisomeric base adducts to 4-hydroxyequilenin.

Exposure to estrogen through estrogen replacement therapy increases the risk of women developing cancer in hormone sensitive tissues. Premarin (Wyeth), which has been the most frequent choice for estrogen replacement therapy in the United States, contains the equine estrogens equilin and equilenin as major components. 4-Hydroxyequilenin (4-OHEN) is a phase I metabolite of both of these substances. This catechol estrogen autoxidizes to potent cytotoxic quinoids that can react with dG, dA, and dC to form unusual stereoisomeric cyclic adducts (Bolton, J. L., et al. (1998) Chem. Res. Toxicol. 11, 1113-1127). Like other bulky DNA adducts, these lesions may exhibit different susceptibilities to DNA repair and mutagenic potential, if not repaired in a structure-dependent manner. To ultimately gain insights into structure-function relationships, we computed conformations of stereoisomeric guanine, adenine, and cytosine base adducts using density functional theory. We find near mirror image conformations in stereoisomer adduct pairs for each modified base, suggesting opposite orientations with respect to the 5' --> 3' direction of the modified strand when the stereoisomer pairs are incorporated into duplex DNA. Such opposite orientations could cause stereoisomer pairs of lesions to respond differently to DNA replication and repair enzymes.

DNA Adducts↗

Inhibition of glutathione S-transferase activity by the quinoid metabolites of equine estrogens.

The risk factors for women developing breast and endometrium cancers are all associated with a lifetime of estrogen exposure. Estrogen replacement therapy (ERT) in particular has been correlated with a slight increased cancer risk, although the numerous benefits of ERT may negate this harmful side effect. Equilenin and equilin are equine estrogens which make up between 30% and 45% of the most widely prescribed estrogen replacement formulation, Premarin (Wyeth-Ayerst). In this study we have synthesized the catechol metabolites of equilenin [4-hydroxyequilenin (4-OHEN)] and equilin [4-hydroxyequilin (4-OHEQ)] and examined how changing unsaturation in the B ring affects the formation of o-quinone GSH conjugates and the ability of the o-quinones and/or GSH conjugates to inhibit glutathione S-transferase (GST). Interestingly, both 4-OHEN and 4-OHEQ autoxidized to o-quinones without the need of oxidative enzyme catalysis. 4-OHEN-o-quinone reacts with GSH to give two mono-GSH conjugates and one diadduct. The behavior of 4-OHEQ was found to be more complex than 4-OHEN as conjugates resulting from 4-OHEN were detected in addition to the 4-OHEQ GSH adducts. Both 4-OHEN and 4-OHEQ were found to be potent inhibitors of GST-catalyzed conjugation of GSH with 1-chloro-2,4-dinitrobenzene. In contrast, the endogenous catechol estrogens, 4-hydroxyestrone (4-OHE) and 2-hydroxyestrone (2-OHE), were without effect unless tyrosinase was present to convert the catechols to o-quinones. Scavengers of reactive oxygen species and metal chelators had no effect on GST inhibition by catechol estrogens with the exception of the catalase which protected GST activity. Kinetic studies showed that 4-OHEN was a potent irreversible inactivator of GST. Preincubation of the enzyme with 4-OHEN showed a time-dependent increase in inhibitory effect, and gel filtration did not restore GST activity confirming the irreversible nature of the enzyme inactivation. Analysis of the Kitz-Wilson plot gave a dissociation constant of the reversible enzyme-inhibitor complex (Ki = 620 microM) and a rate constant of conversion of the reversible enzyme-inhibitor complex to the irreversibly inhibited enzyme (k2 = 7.3 x 10(-)3 s-1). These data suggest that 4-OHEN is an irreversible inactivator with relatively low affinity for GST; however, once formed the 4-OHEN enzyme complex is rapidly converted to the irreversibly inhibited enzyme. The inhibition mechanism likely involves oxidation of the catechol estrogens to o-quinones and covalent modification and/or oxidation of critical amino acid residues on GST. In addition, hydrogen peroxide generated through redox cycling of the o-quinone and/or semiquinone radical and GSH could cause oxidative damage to GST.

Animals↗

The major metabolite of equilin, 4-hydroxyequilin, autoxidizes to an o-quinone which isomerizes to the potent cytotoxin 4-hydroxyequilenin-o-quinone.

The risk factors for women developing breast and endometrial cancers are all associated with a lifetime of estrogen exposure. Estrogen replacement therapy in particular has been correlated with a slight increased cancer risk. Previously, we showed that equilenin, a minor component of Premarin (Wyeth-Ayerst), was metabolized to highly cytotoxic quinoids which caused oxidative stress and alkylation of DNA in vitro [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. (1998) Chem. Res. Toxicol. 11, 1113-1127]. In this study, we have compared the chemistry of the major catechol metabolite of equilin (4-hydroxyequilin), which is found in several estrogen replacement formulations, to the equilenin catechol (4-hydroxyequilenin). Unlike endogenous catechol estrogens, both equilin and equilenin were primarily converted by rat liver microsomes to 4-hydroxylated rather than 2-hydroxylated o-quinone GSH conjugates. With equilin, a small amount of 2-hydroxyequilin GSH quinoids were detected (4-hydroxyequilin:2-hydroxyequilin ratio of 6:1); however, no peaks corresponding to 2-hydroxyequilenin were observed in incubations with equilenin. These data suggest that unsaturation in the B ring alters the regiochemistry of P450-catalyzed hydroxylation from primarily 2-hydroxylation for endogenous estrogens to 4-hydroxylation for equine estrogens. 4-Hydroxyequilenin-o-quinone reacts with GSH to give two mono-GSH conjugates and one di-adduct. The behavior of 4-hydroxyequilin was found to be more complex than 4-hydroxyequilenin as conjugates resulting from 4-hydroxyequilenin were detected in addition to the 4-hydroxyequilin-GSH adducts. The mechanism of decomposition of 4-hydroxyequilin likely involves isomerization to a quinone methide which readily aromatizes to 4-hydroxyequilenin followed by autoxidation to 4-hydroxyequilenin-o-quinone. Similar results were obtained with 2-hydroxyequilin, although, in contrast to 4-hydroxyequilenin, 2-hydroxyequilenin does not autoxidize and the reaction stops at the catechol. Since 4-hydroxyequilin is converted to 4-hydroxyequilenin and 4-hydroxyequilenin-o-quinone, similar effects were observed for this equine catechol, including consumption of NAD(P)H likely by the 4-hydroxyequilenin-o-quinone, depletion of molecular oxygen by 4-hydroxyequilenin or its semiquinone radical, and alkylation of deoxynucleosides and DNA by 4-hydroxyequilenin quinoids. Finally, preliminary studies conducted with the human breast tumor cell line MCF-7 demonstrated that the cytotoxic effects of the catechol estrogens from estrone, equilin, and 2-hydroxyequilenin were similar, whereas 4-hydroxyequilenin was a much more potent cytotoxin ( approximately 30-fold). These results suggest that the catechol metabolites of equine estrogens have the ability to cause alkylation/redox damage in vivo primarily through formation of 4-hydroxyequilenin quinoids.

Animals↗

Retrograde migration of starch in the genital tract of rabbits.

This study in a rabbit model simulates contamination with glove powder in association with a routine gynaecological examination. Large individual variations of powder contamination were found and there were no overall statistically significant differences between the control and experimental animals. The findings are supported by the observation that some but not all women develop adhesions after gynaecological surgery. Analyzes of variances indicate differences in the migration of starch particles in the genital tract with the highest amount of particles found three days after starch contamination of the vagina. Since no adhesions were observed, there would probably need to be an ongoing post surgical or post infectious inflammation in the tissue, when the starch particles are added. Starch powder from latex gloves can cause adhesions and increase the risk of latex allergy in healthcare workers. Retrograde migration in the genital tract cannot be excluded, powdered examination products should be eliminated from the gynecologicla examination room.

Animals↗

Identification of the breast cancer susceptibility gene BRCA2.

In Western Europe and the United States approximately 1 in 12 women develop breast cancer. A small proportion of breast cancer cases, in particular those arising at a young age, are attributable to a highly penetrant, autosomal dominant predisposition to the disease. The breast cancer susceptibility gene, BRCA2, was recently localized to chromosome 13q12-q13. Here we report the identification of a gene in which we have detected six different germline mutations in breast cancer families that are likely to be due to BRCA2. Each mutation causes serious disruption to the open reading frame of the transcriptional unit. The results indicate that this is the BRCA2 gene.

Amino Acid Sequence↗

A prospective study of the relationship between serum vitamins A and E and risk of breast cancer.

In an 8 year prospective study (1977-1985) on breast cancer, blood was taken from 5,086 women resident in Guernsey, and the serum stored at -20 degrees C. During this period 30 women developed the disease and their serum samples were analysed for vitamins A and E, and for retinol-binding protein (RBP). A further 288 age-matched control sera (up to 10 per pre-cancer case) were similarly analysed. No relationship was found between any of these substances and subsequent development of breast cancer. A significant correlation between increasing age and vitamin A (r = 0.46, P less than 0.001) and RBP (r = 0.36, P less than 0.001) concentrations was observed. There was also a trend for increased blood concentrations of vitamin E with age, but this was not significant. Serum RBP and vitamin A concentrations were highly correlated (r = 0.91, P less than 0.0001).

Adult↗

Serum M3/M21 in ovarian cancer patients.

Cytokeratins are polypeptides that constitute a subclass of intermediate filaments in epithelial cells. The aim of the present study was to evaluate the clinical usefulness of the serum evaluation of M3/M21 in patients with ovarian cancer. This retrospective study comprises 75 patients suffering from ovarian cancer FIGO stages Ia-III. M3/M21 reached a sensitivity of 78%, a specificity of 85%, a PPV of 89% and a NPV of 83% using a cut-off level of 45 U 1(-1). Forty-four women developed recurrent disease after complete remission during the observation period. M3/M21 showed lead time effects in 19 patients, ranging from 2 to 8 months (median 3.2 months). Elevated M3/M21 serum levels before therapy were associated with a poor overall survival (log-rank test, P = 0.02). Considering these preliminary results, the value of M3/M21 as a serum tumour marker, i.e. to evaluate the tumour burden, seems promising.

Adult↗

p16INK4A and p14ARF expression pattern by immunohistochemistry in human papillomavirus-related cervical neoplasia.

Human papillomavirus is known to play an important etiological role in the genesis of cervical cancer, but only a very small proportion of infected women develop invasive cervical cancer. The purpose of cervical cancer prevention is early diagnosis of its precursors. The molecular detection of human papillomavirus DNA as a diagnostic test to cervical carcinogenesis gave a low positive predictive value as compared to the use of biomarkers. p16INK4A and possibly p14ARF have been proposed as putative surrogate biomarkers that would allow identification of dysplastic cervical epithelia. Serial consecutive biopsies representing normal cervical epithelium to cervical intraepithelial neoplasia and/or invasive cervical cancer were stained with immunohistochemistry for p16INK4A, p14ARF and proliferating cell nuclear antigen. The positive rates of these markers were significantly higher in cervical intraepithelial neoplasia and in squamous cell carcinoma than in normal cervix (P<0.01). No significant difference was noted between lesions progressing from cervical intraepithelial neoplasia to squamous cell carcinoma for both p16INK4A and p14ARF expression (P>0.05). For both biomarkers, nuclear staining was predominantly seen. However, the cytoplasmic stain of p16INK4A increased with disease progression and the pattern of expression varied between different tumors and its location within the lesion. Both nuclear and cytoplasmic staining with p16INK4A and p14ARF of affected epithelial cells were considered positive. In the adjacent normal tissue to cervical neoplasia, the positive rates of p16INK4A, p14ARF and proliferating cell nuclear antigen expression were higher than those found distant to these lesions but the findings did not reach statistical significance. No correlation was seen between the human papillomavirus types detected and the expression of p16INK4a and p14ARF. In conclusion, overexpression of p16INK4A and p14ARF act as potential biomarkers for cervical cancer progression from premalignant lesions.

Adult↗