Congenic mapping and genotyping of the tetrahydrobiopterin-deficient hph-1 mouse

The hph-1 ENU-mutant mouse provides a model of tetrahydrobiopterin deficiency for studying hyperphenylalaninaemia, dopa-response dystonia, and vascular dysfunction. We have successively localized the hph-1 mutation to a congenic interval of 1.6-2.8 Mb, containing the GCH gene encoding GTP cyclohydrolase I (GTP-CH I). We used these data to establish a PCR method for genotyping wild type, hph-1 and heterozygote mice, and found that heterozygote animals have partial tetrahydrobiopterin deficiency. These new findings will extend the utility of the hph-1 mouse in studies of GTP-CH I deficiency.     

The effect of isotretinoin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone

BACKGROUND: Isotretinoin is a known teratogen, and when it is prescribed to women of childbearing potential, 2 forms of contraception must be used, commonly including hormonal contraception. Although isotretinoin and estradiol are metabolized largely by cytochrome P450 (CYP) 3A4 and glucuronidation, the potential for clinical drug interaction, with subsequent pharmacodynamic impact, has not been evaluated. METHODS: We enrolled 26 healthy women who were to receive isotretinoin for the treatment of severe, recalcitrant nodular acne and who were taking or planning to take oral contraceptives. The pharmacokinetics of ethinyl estradiol and norethindrone (INN, norethisterone) (the components of Ortho Novum 7/7/7; Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ) and pharmacodynamic assessments of oral contraceptive effectiveness (concentrations of serum progesterone, luteinizing hormone, and follicle-stimulating hormone) were determined on days 6 and 20 of 2 separate oral contraceptive cycles, before and during isotretinoin treatment. RESULTS: The addition of isotretinoin to the oral contraceptive regimen resulted in small and inconsistent, although statistically significant (P <.04), decreases in the concentrations of both ethinyl estradiol (9% decrease in area under the plasma concentration-time curve from time 0 to 24 hours after the dose on day 6) and norethindrone (11% decrease in maximum plasma concentration on day 20). Isotretinoin did not cause any statistically significant increases in pharmacodynamic markers, although a majority of women had increases in these measures. Although there was no correlation between isotretinoin (or metabolite) levels and oral contraceptive levels (P >.05), there was a correlation between progesterone level and oral contraceptive levels (P <.05). Variability was large for both pharmacokinetic measures (median coefficients of variation of 44%-69% [for each time point within a study period]) and pharmacodynamic measures (median coefficients of variation of 64%-114%). One woman in each study phase, one before and one during isotretinoin treatment, had a progesterone elevation consistent with possible ovulation. No serious or unexpected adverse events were observed. CONCLUSIONS: The small reduction in ethinyl estradiol and norethindrone levels associated with isotretinoin was not associated with any pharmacodynamic changes in our study. The combination of the teratogenic risk of isotretinoin and the large variability of and correlation between oral contraceptive levels and pharmacodynamic measures, however, strongly reinforces the necessity of additional contraceptive methods during concomitant administration of these drugs.     

A British Second World War veteran with disseminated strongyloidiasis

A case is described of a 78-year-old British veteran of the Second World War (1939-45) who was stationed in Southeast Asia and who developed a recurrent pneumonia with blood eosinophilia. He was treated with steroids, and eventually died with a severe Pseudomonas pneumonia. Just prior to death, larvae of Strongyloides stercoralis were identified in his sputum, and a specific serum ELISA test was later positive. At autopsy no other organs were involved, but bronchoalveolar carcinoma was found. Longstanding (57 years) chronic strongyloidiasis in a veteran who served in Southeast Asia but who was not a prisoner of war is very unusual. The pattern of dissemination was also not that of a true hyperinfection syndrome, and the case demonstrates the continued need for diagnostic vigilance amongst former soldiers who were based in the Far East.     

The dietary glycemic index during pregnancy: influence on infant birth weight, fetal growth, and biomarkers of carbohydrate metabolism

During pregnancy, lower levels of maternal glucose before and during a glucose load have been associated with reduced infant birth weight and an increased risk of small-for-gestational-age births. A lower incremental area under the glucose response curve defines a low glycemic diet. Thus, during pregnancy the maternal diet, as measured by the glycemic index, may influence fetal growth and infant birth weight. A total of 1,082 gravidas who enrolled in the Camden Study between August 1996 and October 2002 were followed prospectively during pregnancy. The dietary glycemic index was computed from three 24-hour recalls in the course of pregnancy. Samples for plasma glucose and for glycosylated hemoglobin were obtained at 24-28 weeks' gestation. The glycemic index was positively and significantly related to maternal glycosylated hemoglobin and plasma glucose. There were as well significant linear trends for dietary fat intake to decrease and for intakes of carbohydrate, sucrose, fiber, and folate to increase as the glycemic index declined. Gravidas with a low dietary glycemic index had reduced infant birth weight and approximately a twofold increased risk of a small-for-gestational-age birth. Consistent with data on maternal plasma glucose, data in this study show that the type of carbohydrate in the diet of urban, low-income women influences fetal growth and infant birth weight.     

Atypical squamous cells of undetermined significance on cervical smears: follow-up study of an Asian screening population

BACKGROUND: The current study reports on the significance of cervical smears identified as atypical squamous cells of undetermined significance (ASCUS) in the largest Asian screening population to date. METHODS: From January 1998 to December 1999, 190,000 cervical smears were evaluated by the cervical cytology laboratory at the University of Hong Kong (Hong Kong, China). From these smears, 5579 ASCUS were identified. Follow-up cytology and histology findings were analyzed. RESULTS: Follow-up cytology or biopsy results were retrieved for 3601 women (64.5%). Of these, 544 (9.8%) and 96 women (1.7%) were found to have low-grade (LSIL) and high-grade (HSIL) squamous intraepithelial lesions, respectively. Biopsy results were obtained for 198 (36.4%) of the 544 women with LSIL. One hundred seventy-nine (32.9%) and 19 women (3.5%) were confirmed to have cervical intraepithelial neoplasia (CIN)-1 and CIN-2-CIN-3, respectively. Biopsy results were retrieved for 53 (55.2%) women with HSIL. Forty patients (41.7%) were confirmed to have CIN-2-CIN-3, whereas CIN-1 was found in the remaining patients. One woman with squamous cell carcinoma was diagnosed by colposcopic biopsy after immediate referral following a diagnosis of ASCUS. There was a significantly larger proportion of LSIL or HSIL (P < 0.0001) or higher-grade findings in women with ASCUS compared with the general screening population. Infective organisms were identified in 412 women (7.4%) with ASCUS. These women had a decreased risk of subsequent development of LSIL (P < 0.0001) or HSIL (P = 0.027). CONCLUSIONS: ASCUS smears indicated an increased risk of HSIL or carcinoma. The authors suggested careful patient follow-up in such cases.     

Anal canal cancer and chemoradiation treatment in two patients with systemic lupus erythematosus treated by chronic therapeutic immunosuppression

Two case reports of anal cancer developing during chronic therapeutic immunosuppression for systemic lupus erythematosus (SLE) and their cancer management are presented. The complex issues of delivery of curative chemoradiation treatment for anal cancer in the context of co-existing autoimmune connective tissue disease (AICD) are discussed. These two cases show that combined chemotherapy and radiation regimens are possible in patients with SLE. However, frequent, careful assessment with judicious and prompt management of haematological and other complications during treatment is important.     

A meiotic recombination in a new isolated familial somatotropinoma kindred

We report here the genetic findings of a new isolated familial somatotropinoma (IFS) kindred in which the mother (subject I:2) and one daughter (subject II:2) are affected; their ages at diagnosis were 25 and 14 years respectively. Additionally, patient I:2 developed virilization due to an androgen-secreting adrenocortical mass, presenting clinical and molecular features of sporadic adrenal carcinoma. To genotype this family and to narrow down the candidate interval of the putative IFS gene at 11q13, we performed haplotyping on the DNA from all five members of the family and allelotyping of one available somatotropinoma using polymorphic microsatellite markers from chromosome region 11q12.1-11q13.5. Results indicated that the disease haplotype, between markers D11S956 and D11S527, was transmitted from subject I:2 only to subject II:2. A meiotic recombination event was detected in the fraternal twin sister of II:2 (subject II:1), but her disease status is unknown. Since she is only 18 years old this genetic event cannot yet narrow down the area involved in the pathogenesis of IFS. Allelotyping of the somatotropinoma from II:2 revealed loss of the chromosome carrying the wild-type copy of the putative IFS gene inherited from her father. These results support the involvement of a tumor suppressor gene at 11q13.1-q13.3 in the pathogenesis of IFS.     

Coexisting epithelioid trophoblastic tumor and choriocarcinoma of the uterus following a chemoresistant hydatidiform mole

The epithelioid trophoblastic tumor is an unusual type of trophoblastic tumor. Herein, we describe a patient with coexisting epithelioid trophoblastic tumor and choriocarcinoma in the uterus. The patient had a history of hydatidiform mole with recurrent elevation of human chorionic gonadotrophin level that is resistant to chemotherapy. Histopathologic and immunohistochemical examination showed distinctive differences between the 2 trophoblastic tumors. The development of epithelioid trophoblastic tumor may be related to the persistence of locally invasive disease, which was unresponsive to chemotherapy. The patient responded well to surgery. The presence of an epithelioid trophoblastic tumor should be considered in chemoresistant gestational trophoblast tumor.     

Clinical aspects of gestational trophoblastic disease: a review based partly on 25-year experience of a statewide registry

BACKGROUND: Gestational trophoblastic disease is a fascinating group of pregnancy disorders characterised by abnormal proliferation of trophoblast, ranging from benign to malignant. Because the disease is uncommon, there is a need to formulate management with the assistance of collective information. METHODOLOGY: A review of available information from English written literature was undertaken, especially data reported by registries around the world (Charing Cross Hospital in England, the North-western University and the New England area in the USA as well as our own experience in Queensland, Australia). Where possible, collated data from relevant studies were analysed to answer some of the questions posed in clinical practice, with reference to metastatic disease to liver and brain, twinning of molar gestation and coexisting fetus, and placental-site tumour. RESULTS: We found that molar gestation can be classified according to its clinical presentation which influences the time taken to reach human chorionic gonadotropin (HCG) 'negativity' and the risk of persisting disease. Categorisation of risk is the basis for choice of chemotherapy to achieve good outcomes. Metastases to liver and brain remain problems in management; the development of 'new' metastases during chemotherapy is a very poor prognostic factor. In the variant of twinning with molar gestation and coexisting fetus, it is important to elucidate the fetal karyotype in planning management: a 69XXX fetus is not salvageable but a normal 46XX or 46XY fetus faces the prospect of early preterm delivery. The placental-site tumour is very rare; localised disease is curable by surgery; chemotherapy is less effective in disseminated disease. From collated worldwide data, the recurrence rate after one mole is 1.3% and after two or more is 20%. Reproductive outcome in subsequent pregnancies, even after multidrug chemotherapy, is not different from the general population. Because of the increased risk long-term of second tumours after multidrug chemotherapy a closer surveillance of these patients is necessary. CONCLUSION: In general, the disease in its persisting or malignant form is 'a cancer model par excellence' because of an identifiable precursor condition, a reliable HCG marker, and sensitivity of the disease to cytotoxic drugs. With current management, retention of fertility is possible and normal reproductive outcome assured.