Primary infertility in women exposed to diethylstilboestrol in utero

Summary. In a selected group of 40 women who had been exposed to diethylstilboestrol in utero , 18 conceived without difficulty and 22 had primary infertility. Among those with primary infertility there was a significantly higher rate of anatomical structural defects and a greater tendency for menstrual disorders than in those without infertility. Thirteen (59%) of the women with primary infertility conceived, most after treatment with ovulation stimulating drugs. Spontaneous abortion and tuba1 pregnancy were frequent (47% and 10% respectively) and similar in both fertility groups. Of 13 infertile women examined, 4 (31%) had mild hyperprolactinemia—a hithero unreported finding for such women.     

Rescue of menotrophin cycles prone to develop ovarian hyperstimulation

Summary. In an attempt to prevent the loss of'overstimulated cycles' associated with human menopausal gonadotrophin (hMG)-induced ovulation, oestradiol levels and ovarian follicular state were monitored in 12 women with'overstimulated cycles' after withholding hMG for several days. Human chorionic gonadotrophin (hCG) was administered when oestradiol levels were 1700 pg/ml and the leading follicles between 17 and 22 mm in diameter. During the withholding period follicular growth continued in all patients, while oestradiol levels declined in all but three. These three patients conceived. Ovulation was observed in six additional women. Ovarian hyperstimulation did not occur in any of the 12 patients. We conclude that a rescue of'overstimulated cycles' is sometimes possible. Conception seems to depend on a continuing rise of E2 levels and early detection of'overstimulation'.     

CONJUNCTIVAL MELANOMAS

Background. The nomenclature and the clinical and pathologic features of cutaneous and conjunctival melanomas are different. A comparison is made to familiarize dermatologists and ophthalmologists with these differences. Methods. Five cases of conjunctival malignant melanoma from December 1983 to December 1990 were reviewed. Results. The nomenclature of primary acquired melanosis is not used for cutaneous melanomas, and terms such as dysplasia and Clark's nevus are not used for conjunctival melanomas. Technical difficulties exist in orienting thin conjunctival tissues because of a tendency to curl during fixation, resulting in tangential sectioning and making a false diagnosis of a prognostically ominous pagetoid spread for an otherwise banal basilar hyperplastic pattern. Excision, cryotherapy, and rarely exenteration are the therapeutic measures in managing conjunctival melanomas; these have far more serious consequences for the patient compared with the excision of a skin melanoma. Conclusion. Differences exist in several aspects between melanomas located in the skin and the eye.     

Binding of human serum amyloid A (hSAA) and its high-density Iipoprotein3 complex (hSAA-HDL3) to human neutrophils. Possible implication to the function of a protein of an unknown physiological role

Serum amyloid A (SAA) is an acute-phase serum protein which exists in the body in a complex with high-density lipoprotein (HDL₃). It is involved in chronic inflammation and neoplastic diseases in an as yet unknown manner. Toward an understanding of the possible physiological role of SAA we initiated a study of its association with blood proinflammatory cells with which it may interact functionally in vivo. In the following we describe the binding characteristics of recombinant human SAA to human neutrophils (polymorphonuclear leukocytes; PMNLs) and their plasma membranes. Scatchard analysis of rSAA binding and displacement curves revealed K_d in the nanomolar range. The C-terminal domain of the protein, i.e. amino acid residues 77-104, which might reside in serum following SAA degradation and amyloid A formation, was found to inhibit efficiently the binding of the whole protein to neutrophils. The interaction of SAA, and of its related peptides while complexed in HDL₃, with human PMNs was also studied. The results suggest that SAA may be involved, in an as yet unknown manner, in the neutrophil-associated inflammatory mechanism.     

How Can We Facilitate Spontaneous Termination of Ventricular Fibrillation and Prevent Sudden Cardiac Death? A Working Hypothesis

Spontaneous Ventricular Defibrillation. Ventricular fibrillation (VF) is one of the most life-threatening arrhythmias encountered in daily clinical practice. Its occurrence cannot be completely prevented by currently used antiarrhythmic drugs, and, in most instances, VF is sustained and leads lo the patient's death unless a successful DC defibrillation is applied. However, spontaneous reversion of VF to sinus rhythm has been observed in various animals and occasionally even in man. Hence, facilitation of self ventricular defibrillation must be explored as an alternative therapeutic approach. In experimental studies using several mammalian species, we have found that self ventricular defibrillation requires a good intercellular coupling and well synchronized electrical activity in the ventricles, which, in untreated animals, depend on their myocardial catecholamine content. It can then be hypothesized that any agent that elevates the catecholamine level during VF would facilitate spontaneous ventricular defibrillation, and drugs inhibiting extraneuronal catecholamine reuptake have indeed been shown to possess this ability. It is suggested that their effects are mediated by an increase in the intracellular cAMP level, and any compounds sharing this property could well prove efficacious in making VF transient and in reducing sudden cardiac death.     

Degradation of amyloid A and serum amyloid A by red blood cell haemolysate in patients with familial mediterranean fever

Enzymatic activity for the degradation of serum amyloid A (SAA) and amyloid A (AA) was detected in erythrolysates of normal subjects and patients with familial mediterranean fever. A significant difference between the activity of normal subjects and patients was not found. Serum inhibited the SAA (but not the AA) haemolysate proteolytic activity. Interindividual variation in the susceptibility of SAA to degradation by RBC haemolysates was shown. The original digestible fraction of SAA became gradually resistant to proteolytic cleavage over a 9 month period while the susceptibility of AA to degradation remained unchanged in this time period. These findings suggest that enzymatic degradation of SAA depends on the source of SAA, as well as inhibitory activity in serum.     

Mechanistic implications of cyanide binding to carboxypeptidase B

The putative metal coordinating ligand cyanide was used to study the effects of modifications of the metal coordination sphere on the spectral properties and catalytic activity of cobalt and zinc carboxypeptidases. The absorption spectra of Co²⁺-carboxypeptidase B in the presence of cyanide pointed to a direct interaction of the ligands with the metal. Gel-filtration experiments showed that the binding of one mole of ligand per mole of enzyme metal ion resulted in maximal spectral effects. Binding of cyanide to the metal ion as measured by absorption spectroscopy was inhibited by acetyl- L-arginine, a peptide pseudosubstrate, and by acetyl-D-arginine, a competitive peptide inhibitor. Addition of acetyl arginine to the enzyme-cyanide complex caused displacement of the ligand, as evidenced by the spectral parameters. Cyanide inhibited peptide hydrolysis in a partially noncompetitive manner, i.e. it did not prevent binding of the substrate to the enzyme but the enzyme-substrate-cyanide complex was hydrolyzed at a slower rate than the enzyme-substrate complex. The dissociation constant evaluated from kinetic studies for the binding of cyanide to Co²⁺-carboxy-peptidase B was in good agreement with that obtained from spectral measurements. Hydrolysis of the ester analog of the basic peptide substrate was not affected by cyanide. Based on these data a model is proposed in which the peptide carbonyl group displaces the water molecule from the metal coordination sphere during catalysis without increasing the coordination number.     

Primary infertility in women exposed to diethylstilboestrol in utero

Summary. In a selected group of 40 women who had been exposed to diethylstilboestrol in utero , 18 conceived without difficulty and 22 had primary infertility. Among those with primary infertility there was a significantly higher rate of anatomical structural defects and a greater tendency for menstrual disorders than in those without infertility. Thirteen (59%) of the women with primary infertility conceived, most after treatment with ovulation stimulating drugs. Spontaneous abortion and tuba1 pregnancy were frequent (47% and 10% respectively) and similar in both fertility groups. Of 13 infertile women examined, 4 (31%) had mild hyperprolactinemia—a hithero unreported finding for such women.     

Patterns of growth of uterine leiomyomas during pregnancy. A prospective longitudinal study

Summary. In a prospective study 32 leiomyomas (fibroids) in 29 pregnant women were examined with ultrasound every 3–8 weeks. Each patient had hetween 3 and 6 scans (mean 4.4) during the course of pregnancy, and 13 patients had a final scan at 6 weeks postpartum. An individual growth curve was established for each tumour and the patterns of growth were analysed. No increase in size during the pregnancy was observed in 25 fibroids (78%). Only 7 (22%) increased in size but by no more than 25% of the initial volume. At 4 weeks postpartum the size of the fibroids did not differ significantly from the size during pregnancy.     

Tyrosyl interactions at the active site of carboxypeptidase B

The phosphorescence emission spectra of native carboxypeptidase B and of chemically modified carboxypeptidase B (at arginyl residues) was measured in the presence and absence of peptide and ester substrates (acetyl-L-arginine and its hydroxy ester analog: acetyl-L-argininic acid). Ester binding did not affect the state of the tyrosyl residue as compared with its state in the substrate-free enzyme. In the modified enzyme, which is devoid of peptidase activity, binding of the peptide pseudosubstrate did not perturb the state of the tyrosyl residue. The luminescence spectra of Zn²⁺- and Co²⁺-carboxypeptidase B in the presence of the metal coordinating ligand cyanide, used to displace the water from the metal coordination sphere, is also described. Cyanide did not affect the luminescence spectra of the active-site tyrosyl residue in either Zn²⁺-or Co²⁺-carboxypeptidase, indicating that the tyrosyl residue was not interacting directly with the metal bound water. Hence, the effect of peptide on tyrosyl phosphorescence is not caused by the displacement of the tyrosyl from the coordination sphere, but rather by direct interaction of the peptide bond. The data are consistent with the proposition that the tyrosyl residue participates as a proton donor in amide but not in ester hydrolysis.