Acanthosis nigricans in adolescents: a practical approach.

Acanthosis nigricans (AN) is a lesion affecting localized areas of the skin in persons with obesity and/or hyperinsulinemia. Biochemical mechanisms responsible for developing this hyperplastic lesion are unclear, but likely involve local cutaneous growth factors. It is associated with obesity, endocrinopathies (insulin resistance, diabetes mellitus, Cushing disease and acromegaly) and visceral malignancies. Clinicians should recognize AN because it may herald disorders ranging from endocrine disturbances to malignancy. Early recognition of these conditions is essential to identify children who are at highest risk for developing type 2 diabetes and further metabolic abnormalities.

Adrenal rest tumor of the liver causing Cushing's syndrome: treatment with ketoconazole preceding an apparent surgical cure.

Ketoconazole, an imidazole derivative known to inhibit cytochrome P450-dependent adrenal enzymes was given to a patient with a functioning adrenal rest tumor of the liver in preparation for surgery. The drug was administered in a stepwise manner for 42 days starting with 400 mg and reaching 1 g the last 4 weeks of the trial. Clear clinical improvement was evident early in the trial and was associated with evidence of amelioration of her hypercortisolism and striking changes in serum and urinary levels of steroid hormones and metabolites. Sex steroids in serum and urine fell dramatically from the first day to the end of the trial. Urinary 17-ketosteroid excretion fell from a basal average of 139 mg/24 h to near normal levels within a week of therapy; serum testosterone fell from a basal level of 2.4 to 0.18 ng/ml; serum 17 beta-estradiol fell likewise from 1096 to 150 pg/ml. In contrast, cortisol levels in serum and urine increased in the first 2 weeks of the trial and subsequently fell to values below the basal levels. Similarly, serum 17 alpha-OH-progesterone levels increased 63% above the basal levels by day 6 of the trial and declined afterwards. Nine months after successful tumor resection the patient is apparently cured as judged by steroid hormone levels and physical appearance. We conclude that ketoconazole was effective in blocking tumoral steroidogenesis which resulted in clinical benefit.

Leukocyte immunophenotypes in bronchoalveolar lavage fluid and peripheral blood of paracoccidioidomycosis, sarcoidosis and silicosis.

Leukocyte subsets in bronchoalveolar lavage (BAL) fluid and peripheral blood of patients with paraccoccidioidomycosis, sarcoidosis and silicosis were characterized using monoclonal antibodies and an immunoperoxidase technique. In paraccocidioidomycosis, the number of T-helper/inducer CD4-positive lymphocytes was lower in peripheral blood than in BAL fluid. Additional analysis showed that the expression of HLA-DR was very similar in alveolar macrophages, lung and blood T-cells. In sarcoidosis and silicosis there were higher proportions of T-helper/inducer cells in peripheral blood than in BAL fluid. The alterations in the T-helper/inducer/T-suppressor/cytoxic CD4/CD8 ratio in sarcoidosis and silicosis were more appreciable in peripheral blood than in BAL fluid, contrasting with the results in paracoccidioidomycosis. The expression of HLA-DR by alveolar macrophages in sarcoidosis was the highest of all the disease studied. No statistically significant differences were observed between chronic multifocal and chronic unifocal paracoccidioidomycosis disease, stage II and stage III sarcoidosis, and chronic and accelerated silicosis. The three granulomatous diseases analyzed had a few alveolar macrophages expressing the CD4 molecule on their surface. These findings and the technique of analyzing both peripheral blood and BAL leukocyte subsets may help to understand the pathogenesis of interstitial lung diseases.

Cyfra 21-1 marker in carcinoma of the cervix.

Cyfra 21-1 has been reported to be an effective tumor marker for epithelial carcinomas. The purpose of this investigation was to determine its value in evaluating response to treatment in patients with carcinoma of the cervix. Cyfra 21-1 levels were measured by immunoassay in the serum of 55 untreated patients with cervical cancer; a second sample was obtained in all of them after conventional treatment for association with clinical response. Pre-therapy levels were elevated in only 45% (25 of 55) of the patients, with a slight tendency to increase according to clinical stage: 33% (5/15) in stage I, 36% (8/22) in stage II and 67% (12/18) in stage III. In regards to association with response to therapy, and including patients with either normal or elevated pretreatment values, 46% (19/41) of women with a complete clinical response either persisted with or developed elevated levels after treatment completion. All 14 patients with persistent disease after therapy continued to have or developed elevated values. No patient with persistent disease had normal values after therapy, and all patients with negative values after treatment were truly complete clinical responders. The results of our study suggest that the test has a low sensitivity therefore and, despite our findings, a negative level after treatment may not be a safe indicator of disease-free status. On the other hand, an elevated post-treatment level is not a reliable indicator of persistence, proven by the fact that 46% of clinical responders fell in this category. Therefore, Cyfra 21-1 has a very limited role in correlating with response to treatment in carcinoma of the cervix.

Tacalcitol in psoriasis: a video-microscopy study.

Video-microscopy is a video-imaging system which permits direct visualization of the skin surface and capillaries, by using a microscope attached to a camera, a video-recorder and a printer. This technique provides information on the morphology of capillaries in vivo and has been used both for research into normal skin microcirculation and as a clinical method to detect capillary changes in psoriasis and other skin diseases. The aim of this study was to evaluate the morphology of capillaries in psoriatic plaques before and after treatment with tacalcitol, a new topical vitamin D3 analogue. Clinical evaluation was made after 3 and 6 weeks of therapy. After 3 weeks a reduction in erythema and scaling was noted; and areas in which capillaries were less tortuous became evident. After 6 weeks, capillaries were less dilated and tortuous in the whole plaque and had lost the large and tortuous appearance of active psoriasis.

Auricular involvement of a multifocal non-AIDS Kaposi's sarcoma: a case report.

Kaposi's sarcoma (KS) is a multicentric, malignant neoplastic vascular disease, mainly involving skin and mucosae, characterised by the proliferation of endothelial cells. The aetiology of KS still is unknown. Nonetheless, it has been reported that several epidemiological and environmental factors may play a role in its pathogenesis. Viral factors (i.e. human herpes virus 8, HHV-8) have also been claimed to play a role in the onset of KS. Four main clinical presentations of KS have been described: classic (sporadic), African (endemic), iatrogenic (immunosuppression-associated) and AIDS-associated (epidemic). The authors present a case of KS involving the external ear of a HIVnegative patient with a history of non-Hodgkin lymphoma and tuberculosis.

Physical and genetic mapping of amplified fragment length polymorphisms and the leaf rust resistance Lr3 gene on chromosome 6BL of wheat.

The Argentinian wheat cultivar Sinvalocho MA carries the Lr3 gene for leaf rust resistance on distal chromosome 6BL. In this cultivar, 33 spontaneous susceptible lines were isolated and cytogenetically characterized by C-banding. The analysis revealed deletions on chromosome 6BL in most lines. One line was nulli-6B, two lines were ditelo 6BS, two, three, and ten lines had long terminal deletions of 40, 30, and 20%, respectively, three lines showed very small terminal deletions, and one line had an intercalary deletion of 11%. Physical mapping of 55 amplified fragment length polymorphism (AFLP) markers detected differences between deletions and led to the division of 6BL into seven bins delimited by deletion breakpoints. The most distal bin, with a length smaller than 5% of 6BL, contained 22 AFLP markers and the Lr3 gene. Polymorphism for nine AFLPs between Sinvalocho MA and the rust leaf susceptible cultivar Gamma 6 was used to construct a linkage map of Lr3. This gene is at a genetic distance of 0.9 cM from a group of seven closely linked AFLPs. The location of the gene in a high recombinogenic region indicated a physical distance of approximately 1 Mb to the markers.

Preliminary results on the role of embryonic human chorionic gonadotrophin in corpus luteum rescue during early pregnancy and the relationship to abortion and ectopic pregnancy.

The precise mechanisms by which corpus luteum (CL) function is modulated during early pregnancy are not known. Evidence in failed pregnancies (ectopic, abortions), shows that factors other than human chorionic gonadotrophin (HCG) could be involved in its regulation. The objective of this study was to investigate the dynamics of beta-HCG, progesterone and oestradiol production in early pregnancy and its relation to embryonic quality and topographic localization. Plasma concentrations of progesterone, oestradiol and beta-HCG were studied between days +12 and +21 after an in-vitro fertilization (IVF) embryo transfer in 11 intrauterine pregnancies, 10 intrauterine abortions and seven tubal pregnancies. Tubal pregnancies and abortions were grouped according to doubling time (DT) of HCG. Results showed that oestradiol concentrations were apparently reduced in both ectopic pregnancies and abortions compared with normal pregnancies. The fall in oestradiol concentrations was seen in ectopic pregnancies with an abnormal DT for HCG and in all abortions. When the ectopic pregnancy had a normal DT, oestradiol and progesterone concentrations were normal. In abortions, the fall in oestradiol and progesterone concentrations was less influenced by the DT of HCG. These findings suggest that corpus luteum function depends on an adequate DT of HCG more than an absolute value, and with normal trophoblastic tissue the site of implantation does not affect CL function.

Ofuji papuloerythroderma: report of a European case.

The trunk and the limbs of an 82-year-old man were covered with large sheets of flat-topped erythematous papules arranged in a reticulate pattern which suddenly coalesced assuming erythroderma-like aspects. Body and positional folds were characteristically spared (deck chair sign). Mild eosinophilia was present. The histological and immunohistochemical examinations revealed an unspecific eczematous pattern. After systemic steroids and PUVA treatment the patient recovered from the dermatosis. Papuloerythroderma is a distinctive clinical entity, but it is not clear whether the dermatosis is the skin marker of systemic pathological conditions or a precursor of cutaneous lymphomas.

Validation of the dual analyte assay of the oestrone:pregnanediol ratio in monitoring ovarian function.

The purpose of this study was to validate the dual analyte system (Boots Celltech Ltd, Slough, UK) as a marker of ovarian function. For this purpose the urinary profile of the ratio of oestrone-3-glucuronide to pregnanediol-3-glucuronide in urine (E13G/PD3G) was compared with plasma concentrations of oestradiol, progesterone, luteinizing hormone (LH) and follicle stimulating hormone from day 8-24 of the menstrual cycle in 23 women. Daily transvaginal ultrasound was also performed from day 8 of the cycle until sonographic evidence of follicular rupture. The ratio of urinary metabolites exhibited a maximum value close to ovulation. In the majority of cases this coincided with the day of LH peak, and was followed by follicular rupture within the next 24 h in 74% of cases. The assay gives a good marker of ovulation, however, it is unlikely to help in detecting the initiation of the fertile period or the quality of the menstrual cycle.

Primary cutaneous CD30+ large T-cell lymphoma in a patient with psoriasis treated with cyclosporine.

We report the case of a 61-year-old woman who developed an anaplastic CD30+ cutaneous T-cell lymphoma during oral cyclosporine (CsA) therapy for recalcitrant psoriasis. Two months after CsA discontinuation, clinical and histological resolution of the lymphoma was observed. However, 3 years later extracutaneous involvement of the lymphoma could be detected. The association between CsA administration and the occurrence of the lymphoma may be casual, but a relationship with immunosuppression may also be hypothesized. We have reviewed all relevant data in the literature. To our knowledge, this is the first case of primary cutaneous CD30+ anaplastic large T-cell lymphoma in a patient treated with CsA for psoriasis.

Prenatal diagnosis of nonmosaic trisomy 9 in a fetus with severe renal disease.

We report a case of nonmosaic trisomy 9 presenting at 21 weeks of gestation with polycystic, echogenic horseshoe kidney, collapsed bladder, absent amniotic fluid, and intrauterine growth restriction. Color Doppler imaging demonstrated no blood flow signals from renal vessels. Fetal blood sampling confirmed a 47,XX,+9 karyotype, with no evidence of mosaicism, and increased serum beta2-microglobulin levels of 10.7 mg/l, consistent with severe renal failure. A repeat scan at 23 weeks also revealed a dysmorphic face, bilateral microphthalmia, and a cerebellar vermian defect. Follow-up examinations showed progressive growth restriction leading to fetal death at 33 weeks of gestation. This report demonstrates that fetuses with nonmosaic trisomy 9 may present with severe renal abnormalities and confirms that cases seen in the second and third trimesters usually have a dismal outcome.

The empty follicle syndrome: a pharmaceutical industry syndrome.

The purpose of this study is to provide evidence that empty follicle syndrome (EFS) is a result of an abnormality in the in-vivo biological activity of some batches of commercially available human chorionic gonadotrophin (HCG). This is a comparative study between six consecutive in-vitro fertilization (IVF) cases with EFS (study group) and 10 IVF pregnancy cycles (control group). Both groups received the same ovarian stimulation protocol consisting of leuprolide acetate and human menopausal gonadotrophin (HMG). An i.m. injection of 10,000 IU of HCG was administered once follicles had reached 18-20 mm and oestradiol/follicle > or = 16 mm was at least 900 pmol/l. Transvaginal aspiration was performed 36 h later. Plasma HCG prior to and 12 h after i.m. injection as well as the follicular fluid (FF) concentrations of oestradiol, progesterone, luteinizing hormone (LH) and HCG were determined in the study group and controls. The in-vitro biological activity of the batch of HCG used by the EFS cases and the control group was determined using a Leydig cell preparation from adult rats. Furthermore, the plasma clearance rate after i.v. injection of 5000 IU of HCG, from the same batches, was studied in three male volunteers. In the IVF cycles, no HCG was detected in plasma prior to the injection of commercial HCG. After 12 h, no HCG was detected in the study group compared to a mean of 207.5 IU/l (110-360) in controls. Mean FF concentration of LH, HCG, progesterone and oestradiol was 0.9 IU/l, 0 IU/l, 3.1 nmol/ml and 4.4 nmol/ml in EFS compared to 1.0, 98.3, 32.0 and 3.7 in pregnancy cycles. The in-vitro biological activity in both HCG batches was not significantly different; however, immunoreactive HCG used in EFS cases was undetectable in plasma of male volunteers as soon as 10 min after i.v. injection of 5000 IU of HCG. The endocrine abnormalities found in follicular fluids of EFS are not a consequence of an ovarian problem but the result of a lack of exposure to biologically active HCG. The rapid clearance of the drug after i.v. injection and the high affinity of desialylated HCG to liver cells suggest this to be a possible explanation for this infrequent but unfortunate event.

Predictive value of human chorionic gonadotrophin in the outcome of early pregnancy after in-vitro fertilization and spontaneous conception.

This prospective study analyses the value of the beta-subunit of human chorionic gonadotrophin (beta-HCG) in 120 pregnancies obtained after in-vitro fertilization (IVF)--embryo transfer. Spontaneous conception cycles (n = 16) were also analysed allowing a comparison between these two forms of conception. Of the 120 clinical pregnancies, 48 started as single gestations and 50 started with two or more sacs. There were 14 clinical abortions and eight ectopic pregnancies. All subjects had blood samples taken under a fixed protocol on days 11, 14, 17, 20 and 23 after follicular aspiration. Weekly samples were obtained thereafter until day 60 from ovum retrieval. Transvaginal ultrasounds were performed at weekly intervals, starting on day 23 after follicular aspiration. In spontaneous conception cycles blood samples were obtained daily, starting on the day of follicular rupture. In spontaneous conception cycles and in IVF-embryo transfer conceptions, the doubling time (DT) of beta-HCG was 1.4 +/- 0.3 and 1.6 +/- 0.4 days respectively. This difference was not significant. In multigestations, the DT was 1.5 +/- 0.3 days. The absolute values of beta-HCG in early spontaneous gestations were significantly higher than in IVF-embryo transfer cycles, suggesting that the blastocyst implants with less cellular mass when initiated in vitro as compared with the in-vivo condition. The early prediction of ectopic pregnancy and spontaneous clinical abortion was analysed by the beta-HCG profile as well as the absolute values in comparison to normal pregnancies. Both parameters showed significant differences as early as the interval between days 11 and 23 from follicular aspiration.(ABSTRACT TRUNCATED AT 250 WORDS)

The sensitivity of c-Jun and c-Fos proteins to calpains depends on conformational determinants of the monomers and not on formation of dimers.

Milli- and micro-calpains are ubiquitous cytoplasmic cysteine proteases activated by calcium. They display a relatively strict specificity for their substrates which they usually cleave at only a limited number of sites. Motifs responsible for recognition by calpains have not been characterized yet, and recently a role for PEST motifs in this process has been ruled out. c-Fos and c-Jun transcription factors are highly sensitive to calpains in vitro. They thus provide favourable protein contexts for studying the structural requirements for recognition and degradation by these proteases. Using in vitro degradation assays and site-directed mutagenesis, we report here that susceptibility to calpains is primarily determined by conformational determinants of the monomers and not by the quaternary structure of c-Fos and c-Jun proteins. The multiple cleavage sites borne by both proteins can be divided into at least two classes of sensitivity, the most sensitive ones being easily visualized in the presence of rate-limiting amounts of calpains. One site located at position 90-91 in c-Fos protein is extremely sensitive. However, efficient proteolysis did not have any strict dependence on the nature of the amino acids on either side of the scissile bond in the region extending from P2 to P'2. The structural integrity of the monomers is not crucial for recognition by calpains. Rather, sensitive sites can be recognized independently and their recognition is dependent on the local conformation of peptide regions that may span several tens of amino acids and maybe more in the case of the identified c-Fos hypersensitive site.

Pregnancy rate in an oocyte donation program.

Oocyte donation programs offer an alternative treatment for infertile women with ovarian failure or abnormal ovarian function. Seventeen cycles of in vitro fertilization and embryo transfer with donated oocytes were performed in 13 women, with a mean age of 34.8 years. The hormonal replacement therapy consisted of a fixed dose of oral estradiol valerate, 6 mg daily, and intramuscular progesterone in oil, 100 mg daily. Estrogen and progesterone were continued for 10 more weeks after embryo transfer if pregnancy was established. After 13 embryo transfers, 8 pregnancies were obtained, for a pregnancy rate per transfer of 61.5%. Today seven pregnancies are progressing normally, including one set of twins. This results suggest that an oocyte donation program using a fixed and simple hormonal replacement therapy is an adequate treatment for these infertile couples.