Andrology: Acrosome reaction inducibility predicts fertilization success at in-vitro fertilization

We prospectively studied the ability of acrosome reaction (AR)inducibility to predict fertilization success in a group of232 infertile patients presenting sequentially for in-vitrofertilization (IVF). The median percentage of eggs fertilizedfor the overall patient population was 25% (interquartile range5–58%), with one to 29 oocytes available for insemination(median, five oocytes). The median percentage of eggs fertilizedat IVF increased as the percentage of spermatozoa able to undergoAR became greater: spermatozoa with a failed AR (5%) fertilizedonly 12% of eggs, while spermatozoa with AR values>9% fertilized50% of eggs. The assay had a specificity of 0.75, a sensitivityof 0.55 and an odds ratio of 2.9; thus, AR-positive patientsare 2.9 times more likely to achieve fertilization than patientswith a failed AR. Receiver operator characteristic (ROC) curveswere constructed for AR, sperm concentration and percentageof normal forms in semen. All three parameters proved to bepotentially useful in predicting the occurrence of fertilization,although AR and morphology appeared to be better than spermconcentration by ROC analysis. Patients were divided into fourclearly defined subgroups according to their traditional semencharacteristics, including morphology. The median percentageof eggs fertilized decreased as traditional semen characteristicsdeteriorated, from a median of 46% for patients with excellentsperm concentration, motility and morphology, to a median of29% for patients with suboptimal semen quality and a medianof 0% for patients with severely impaired semen. Within eachpatient subgroup, the median percentage of eggs fertilized was3-to 4-fold higher for individuals with a positive AR than forthose with a failed AR, indicating that AR has a greater effecton fertilization rate than traditional semen parameters includingmorphology. We now recognize that some men with good semen characteristicshave an unexpectedly poor AR and a markedly reduced fertilizationrate, while other men with poor traditional semen characteristicsunexpectedly retain AR and perform relatively well at IVF. Bycontrast to AR, morphology seemed to have little effect on fertilizationsuccess (two-way analysis of variance not significant). Thewife's age and oocyte quality were evenly distributed amongthe different patient subgroups, indicating that differencesin fertilization rate could not be attributed to either parameter.Our data indicate that AR has a much higher predictive valuefor IVF success than traditional semen parameters includingmorphology. We propose that AR assessment is a clinically usefuldiagnostic tool in determining a patient's likelihood of achievingfertilization at IVF.     

Extracellular taurine increase in rat hippocampus evoked by specific glutamate receptor activation is related to the excitatory potency of glutamate agonists

Taurine increases in brain extracellular space due to glutamate agonists were studied in vivo in the rat hippocampus using a dialysis technique, both in the absence and in the presence of glutamate receptor antagonists. Extracellular taurine levels increased during perfusions of agonists, listed in descending order of potency: kainate (KA), N-methyl-D-aspartate (NMDA), and quisqualate (QA). While taurine increases due to KA or QA perfusions were inhibited by 6,7-dinitro-quinoxaline-2,3-dione (DNQX), those induced by NMDA were abolished in the presence of 3-(carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). These results indicate that increases in extracellular taurine levels evoked by NMDA, KA or QA in the rat hippocampus are caused by activation of their specific receptors. Field potentials, concomitantly recorded, were quickly abolished during NMDA or KA perfusions (0.1 mM), while QA (0.25 mM) induced the appearance of bicuculline-like evoked responses. Since taurine has been proposed as an osmoregulatory substance in the rat brain, and cell swelling is known to be an early component of glutamate agonists neurotoxicity, the increases in extracellular taurine reported here could be due to taurine released through an osmoregulatory process, counteracting the neurotoxic cellular oedema induced by glutamate agonists.     

Pretreatment prognostic factors for survival in small-cell lung cancer: A new prognostic index and validation of three known prognostic indices on 341 patients

Aims: a) To identify which pretreatment clinical or blood parameters werepredictive of patient survival in small-cell lung cancer (SCLC) in aretrospective analysis. b) To validate three known prognostic indices: RoyalMarsden Model (index 1), London Group (index 2) and Manchester Score (index3).Patients and methods: From 1981 to 1993, 341 SCLC patients were treatedwith chemotherapy with or without surgery or radiotherapy. Univariate andmultiple regression analyses of survival were performed and the feasibilityof these models was explored, index 1: Karnofsky index, albumin, sodium andalkaline phosphatase; index 2: ECOG performance status (PS), albumin andalanine transaminase; and index 3: lactate dehydrogenase (LDH), diseaseextent, sodium, Karnofsky index, alkaline phosphatase and bicarbonate.Results: Significant prognostic factors for survival after univariate andmultiple regression analysis were: disease extent, PS, creatine kinase,neutrophilia, LDH, hypoalbuminemia, hyperglycemia and bicarbonate. A newprognostic index was performed that included LDH, hypoalbuminemia,neutrophilia, disease extent and PS. It defined three prognostic groups (PG).Median survival and two-year survival for these PG were 12.3, 8 and 3.4 monthsand 16.5%, 2.3% and 0%, respectively. The following PGwere identified after application of the three models proposed: Index 1identified two PG with 0% and 16.6% two-year survival (P <0.001); index 2 detected three PG with 0%, 5% and 15.7%two-year survival (P < 0.001) and index 3 detected three PG with 0%,2.5% and 16.2% two-year survivals, respectively (P < 0.001).Conclusion: A new prognostic index is proposed allowing identification ofthree different PG. The feasibility of three known prognostic models wasvalidated and demonstrated. Variables other than disease extent or PS (albuminor LDH) should be taken into account in designing future clinical trials.     

In-111 octreotide scan in a case of a neuroendocrine tumor of unknown origin

Major neuroendocrine tumors contain many somatostatin receptors. This feature allows for the localization of primary tumors and tumor metastases by scintigraphy with the radiolabeled somatostatin analog octreotide. We describe a patient with nonspecific clinical data and ultrasonography and CT that showed an isolated focal lesion in the liver. In-111 octreotide scintigraphy was essential in establishing the diagnosis of liver metastasis from a neuroendocrine tumor confirmed by pathologic findings. Because clinical symptoms recurred, ultrasonography and CT were performed a few months after surgery. Both were negative. However, In-111 octreotide scintigraphy suggested multiple bone metastases and established the diagnosis of bone metastases from a neuroendocrine tumor, which was confirmed by Tc-99m MDP bone scans and MRI.     

Two cases of acute pulmonary edema secondary to laryngospasm

We report two cases of acute pulmonary edema attributable to episodes of postextubation laryngospasm appearing when two young patients awoke after appendectomies under general anesthesia. Both patients improved in less than 48 hours with diuretics, oxygen therapy and liquid restriction, making tracheal intubation unnecessary. The pathophysiology and clinical and radiological signs of pulmonary edema are reviewed.     

5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK(1) receptor antagonists: structural modifications at the tryptophan domain

Analogues of the previously reported potent and highly selective CCK(1) receptor antagonist (4aS, 5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido-[1, 2-c]pyrimidine (2a) were prepared to explore the structural requirements at the Boc-tryptophan domain for CCK(1) receptor affinity. Structural modifications of 2a involved the Trp side chain, its conformational freedom, the Boc group, and the carboxamide bond. Results of the CCK binding and in vitro functional activity evaluation showed three highly strict structural requirements: the type and orientation of the Trp side chain, the H-bonding acceptor carbonyl group of the carboxamide bond, and the presence of the Trp amino protection Boc. Replacement of this acid-labile group with 3, 3-dimethylbutyryl or tert-butylaminocarbonyl conferred acid stability to analogues 14a and 15a, which retained a high potency and selectivity in binding to CCK(1) receptors, as well as an in vivo antagonist activity against the acute pancreatitis induced by caerulein in rats. Oral administration of compounds 14a and 15a also produced a lasting antagonism to the hypomotility induced by CCK-8 in mice, suggesting a good bioavailability and metabolic stability.     

Lamotrigine serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drugs and dosage implications

Using bivariate and multivariate methods, we retrospectively analyzed the influence of patient age and the use of concomitant antiepileptic drugs (AEDs) on the lamotrigine (LTG) concentration-to-dose (C/D) ratio in samples from 164 patients (68 children, 96 adults) with epilepsy receiving LTG alone (n = 28) or in combination with various antiepileptic drugs (n = 136). The LTG C/D ratio increased with age in children receiving LTG alone (r = 0.60, p < 0.01), but decreased with age in adults receiving LTG and inducers (r = -0.42, p < 0.001). In patients receiving LTG and inducers, the ratio was statistically lower in those younger than 9 years of age (0.23 +/- 0.08) and older than 30 years of age (0.32 +/- 0.15) than it was in those between 9 and 30 years of age (0.44 +/- 0.15). The mean LTG C/D ratio was 0.37 +/- 0.15 in patients receiving LTG and inducers (n = 92), 0.84 +/- 0.41 in patients receiving LTG alone (n = 28), 1.09 +/- 0.44 in those receiving LTG with VPA plus inducers (n = 17), and 3.41 +/- 1.18 in those receiving LTG and VPA (n = 27). Differences in the LTG C/D ratio between treatment groups were similar in children and in adults. We reached the following conclusions: The LTG C/D ratio increased with age in children but may decrease with age in adults receiving concomitant enzyme-inducing AEDs; the LTG C/D ratio was 10 times lower in patients receiving LTG and inducers than in those receiving LTG and VPA (in both children and adults), and this difference was higher than the four-fold difference described for LTG half-life and the two-fold differences currently used in LTG dosage.