Menstrual disorders and infertility caused by inactivating mutations of the luteinizing hormone receptor gene

OBJECTIVE: To review clinical findings, hormone levels, and DNA analyses in genetic males and females with inactivating mutations of the LH receptor gene. DESIGN: Review of reported cases. SETTING: A university hospital. PATIENT(S): Genetic males and females with inactivating mutations of the LH receptor gene. RESULT(S): The clinical presentation in genetic males ranged from female genitalia to male genitalia with micropenis caused by Leydig cell hypoplasia. Genetic females presented with amenorrhea or oligomenorrhea, enlarged cystic ovaries, and infertility. Both males and females had elevated LH levels and LH/FSH ratios. Sequencing of genomic DNA revealed homozygous or compound heterozygous deletions, nonsense mutations, or missense mutations in the LH receptor gene. CONCLUSION(S): This study of patients with inactivating mutations of the LH receptor indicates that in genetic males, the action of hCG and LH is necessary for the normal development of primary and secondary sexual characteristics. In contrast, secondary sexual characteristics develop in genetic females in the absence of LH action, but they fail to ovulate.     

Is it possible to anticipate seizure onset by non-linear analysis of intracerebral EEG in human partial epilepsies?

Detection of electrophysiological features preceding and indicative of imminent seizures in patients with epilepsy would be a major breakthrough with immense scientific and clinical implications. The definition of a "pre-ictal state" several minutes prior to seizure onset would open a new time window for studying mechanisms of seizure generation as well as for possible therapeutic interventions. In this review we present recent findings from nonlinear time series analysis of intracranially recorded EEG that may allow to forecast seizure onset in patients with partial epilepsy.     

17Beta-hydroxysteroid dehydrogenase 3 deficiency in women

In genetic males, mutation of the 17beta-hydroxysteroid dehydrogenase 3 (17HSD3)gene that is normally expressed in the testes impairs testosterone formation and causes development of male pseudohermaphroditism. We have ascertained seven women who are sisters of men with 17HSD3 deficiency and who are either homozygotes or compound heterozygotes for the same mutations as their affected brothers. Our findings confirm the concept that women with such mutations are asymptomatic.     

Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene

Familial glucocorticoid resistance is characterized by increased cortisol secretion without clinical evidence of hypercortisolism, but with manifestations of androgen and mineralocorticoid excess. This condition is mainly caused by mutations of the GR gene that cause inadequate transduction of the glucocorticoid signal in glucocorticoid target tissues. The clinical features of glucocorticoid resistance in females include hirsutism, acne, male pattern baldness, oligomenorrhea, and oligoanovulation. We describe here a new phenotype, female pseudohermaphroditism and severe hypokalemia, caused by a homozygous inactivating mutation of the GR gene. The proband was born with ambiguous genitalia from consanguineous parents and was mistreated as a 21-hydroxylase deficiency case since the age of 5 yr. She had very high levels of plasma ACTH (759 pg/ml or 167 pmol/liter) and high levels of cortisol (28-54 microg/dl or 772-1490 nmol/liter), androstenedione (5-14 ng/ml or 17-48 nmol/liter), T (174-235 ng/dl or 7-8 nmol/liter), and 17-hydroxyprogesterone (8-12 ng/ml or 24-36 nmol/liter). Her cortisol and 17-hydroxyprogesterone levels were not compatible with the diagnosis of classic congenital adrenal hyperplasia; furthermore, cortisol was not properly suppressed after dexamethasone administration (28 microg/d or 772 nmol/liter). Her laboratory evaluation indicated a diagnosis of glucocorticoid resistance. To investigate this puzzling clinical and biochemical picture, we analyzed both GR and CYP21 genes. Indeed, a homozygous T to C substitution at nucleotide 1844 in exon 5 of the GR gene was identified in the patient that caused a valine to alanine substitution at amino acid 571 in the ligand domain of the receptor. Her parents and an older sister were heterozygous for this mutation. A whole Epstein-Barr virus-transformed cell dexamethasone-binding assay revealed that this Ala(571) mutant had a 6-fold reduction in binding affinity compared with the wild-type receptor. In a functional assay using mouse mammary tumor virus promoter-driven luciferase reporter gene, the mutant receptor displayed 10- to 50-fold less trans-activation activity than the wild-type receptor. In addition, a large heterozygous CYP21 conversion was identified in the patient and her father. In conclusion, we described the first case of female pseudohermaphroditism caused by a novel homozygous GR gene mutation. This phenotype indicates that pre- and postnatal virilization can occur in females with the glucocorticoid resistance syndrome.     

Primary Sclerosing Cholangitis: A Clinical Review

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by fibro-obliterative inflammation of the entire biliary tree. It is a slowly progressive disease with an undulating course, resulting in terminal biliary cirrhosis after a median period of about 12 years after diagnosis. The etiology of the disease is unknown and there is no effective therapy that can halt disease progression. Around 8% of PSC patients develop cholangiocarcinoma, which, by the time it is diagnosed, cannot be treated curatively. The purpose of this article is to review the current knowledge about primary sclerosing cholangitis and to speculate on future strategies to address the issues of etiology and therapy.     

Heme oxygenase-2 immunoreactivity in developing and mature bovine olfactory epithelium

In the present study the localization of heme oxygenase-2 (HO-2) in developing and mature olfactory epithelium of the bovine is investigated using immunohistochemistry and post embedding immunogold labelling. HO-2 immunoreactivity is first seen in epithelial cells localized along the luminal surface of the olfactory pit. Up to midgestation the number of HO-2 immunoreactive cells increases throughout all layers of the developing olfactory epithelium. From midgestation through adulthood immunostaining is restricted to perinuclear cytoplasm and axons of mature olfactory receptor neurons localized in intermediate epithelial regions. The temporal and spatial expression patterns of HO-2 immunohistochemistry support the notion that CO plays a role in neuronal differentiation while its presence in mature neurons might be functionally related to olfactory transduction.     

Procalcitonin (PCT) im Verlauf einer disseminierten Aspergillus-Infektion bei einem Intensivstationspatienten – Ein Fallbericht

Modern diagnostic methods of systemic bacterial infections or sepsis include the inflammatory marker procalcitonin (PCT). However, the significance of PCT in patients with severe systemic fungal infection is unclear. Reports of the diagnostic and predictive value of PCT in systemic fungal infections are limited. This is a report of a 14-day PCT-course for an intensive care patient with lethal disseminated Aspergillosis. PCT plasma levels were measured by an immunoluminometric assay (the normal range <0.5 ng/ml). A 59-year-old male with a history of COPD, diabetes mellitus and coronary heart disease presented with acute bronchopneumonia. Microbiological and mycological investigations were performed. Nocardia spp.(blood culture and bronchoalveolar lavage) and Aspergillus fumigatus(bronchoalveolar lavage) were isolated by culture. After systemic therapy with antibiotics and antifungal drugs, PCT levels decreased from 39.5 ng/ml (day 1) to 0.58 ng/ml (day 11). On day 13 of intensive care, Enterococcus faeciumwas isolated from a blood culture and PCT plasma levels increased up to 81.7 ng/ml. The patient died one day later. Autopsy revealed the cause of death as meningoencephalitis and pneumonia due to Aspergillus. Procalcitonin (PCT) is well established as a diagnostic and prognostic marker in systemic bacterial infections. However this marker proved unsatisfactory in assessing the course of disease in this patient with Aspergillosis. While the patient still had disseminated aspergillosis, the plasma level of PCT decreased to almost normal values. At this time severe systemic aspergillosis was still present as demonstrated by autopsy. This leads us to conclude that PCT serum concentration does not serve as an accurate marker for aspergillosis.