Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response.

Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis. Pyridostigmine is also recommended by most Western armies for use as pretreatment under threat of chemical warfare, because of its protective effect against organophosphate poisoning. Because of this drug's quaternary ammonium group, which prevents its penetration through the blood-brain barrier, the symptoms associated with its routine use primarily reflect perturbations in peripheral nervous system functions. Unexpectedly, under a similar regimen, pyridostigmine administration during the Persian Gulf War resulted in a greater than threefold increase in the frequency of reported central nervous system symptoms. This increase was not due to enhanced absorption (or decreased elimination) of the drug, because the inhibition efficacy of serum butyryl-cholinesterase was not modified. Because previous animal studies have shown stress-induced disruption of the blood-brain barrier, an alternative possibility was that the stress situation associated with war allowed pyridostigmine penetration into the brain. Here we report that after mice were subjected to a forced swim protocol (shown previously to simulate stress), an increase in blood-brain barrier permeability reduced the pyridostigmine dose required to inhibit mouse brain AChE activity by 50% to less than 1/100th of the usual dose. Under these conditions, peripherally administered pyridostigmine increased the brain levels of c-fos oncogene and AChE mRNAs. Moreover, in vitro exposure to pyridostigmine increased both electrical excitability and c-fos mRNA levels in brain slices, demonstrating that the observed changes could be directly induced by pyridostigmine. These findings suggest that peripherally acting drugs administered under stress may reach the brain and affect centrally controlled functions.

PGD for all cystic fibrosis carrier couples: novel strategy for preventive medicine and cost analysis.

Over 1000 children affected with cystic fibrosis (CF) are born annually in the USA. Since IVF with preimplantation genetic diagnosis (PGD) is an alternative to raising a sick child or to aborting an affected fetus, a cost-benefit analysis was performed for a national IVF-PGD program for preventing CF. The amount spent to deliver healthy children for all CF carrier-couples by IVF-PGD was compared with the average annual and lifetime direct medical costs per CF patient avoided. Treating annually about 4000 CF carrier-couples with IVF-PGD would result in 3715 deliveries of non-affected children at a cost of $57,467 per baby. Because the average annual direct medical cost per CF patient was $63,127 and life expectancy is 37 years, savings would be $2.3 million per patient and $2.2 billion for all new CF patients annually in lifetime treatment costs. Cumulated net saving of an IVF-PGD program for all carrier-couples for 37 years would be $33.3 billion. A total of 618,714 cumulative years of patients suffering because of CF and thousands of abortions could be prevented. A national IVF-PGD program is a highly cost-effective novel modality of preventive medicine and would avoid most births of individuals affected with debilitating genetic disease.

Sperm capacitation is, after all, a prerequisite for both partial and complete acrosome reaction.

The acrosome reaction (AR) - an essential step in mammalian fertilization - can occur, according to the consensus, only in capacitated spermatozoa. In apparent contrast, recent reports have demonstrated that human spermatozoa incubated in vitro in an albumin-free medium and therefore believed to be non-capacitated, do undergo the AR. With the aim of determining unequivocally whether or not capacitation is required for the AR and whether albumin is essential for capacitation, we compared the potential to undergo partial and complete AR (induced by phorbol myristate ester or by the Ca2+ ionophore A23187) between human spermatozoa incubated in a capacitating medium, albumin-free medium, and non-capacitating medium. The results clearly demonstrate that capacitation is, after all, a prerequisite for both partial and complete AR. Albumin, on the other hand, is essential only for acquiring the capacity to undergo complete, not partial AR.

Ciliary ultrastructure of respiratory and fallopian tube epithelium in a sterile woman with Kartagener's syndrome. A quantitative estimation.

Ciliary ultrastructure was studied and quantitatively estimated in a 27-year-old sterile woman suffering from complete KS. Ciliated epithelium was obtained from both nasal mucosa and a fallopian tube. Cilia from both locations were devoid of DA. Various MT abnormalities were found in 16 percent of respiratory epithelial and 21 percent of fallopian tube ciliary cross-sections. The abnormality related to radial spoke defect was frequently seen. The findings in the fallopian tubes were compared to three normal control cases. In these, DA were visible, and MT defects were mainly of excess or missing microtubules. The relevance of these findings to fertility is not clear.

Pooled sequential ejaculates: a way to increase the total number of motile sperm from oligozoospermic men.

We investigated the yield of total number of motile spermatozoa from oligozoospermic men by pooling two closely spaced sequential ejaculates. Semen characteristics were compared between sequential ejaculates (within a period of 1 to 4 hours) of 18 oligozoospermic males (sperm concentration less than 20 X 10(6)/mL and total sperm count less than 40 X 10(6) in the ejaculate) and a control group of 16 normozoospermic men. Whereas the median total number of motile sperm of normozoospermic males significantly decreased from 70 X 10(6) in the first ejaculate to 23 X 10(6) in the second sequential ejaculate, such a decrease was not detected in oligozoospermic males, 3.6 X 10(6) and 3.1 X 10(6), respectively. The percent of normozoospermic and oligozoospermic men who demonstrated a decreased (less than 50%), a comparable (50% to 150%), or an increased (greater than 150%) total motile sperm count in the second ejaculate in comparison with the first ejaculate were 69%, 31%, and 0 versus 39%, 28%, and 33%, respectively. Consequently, pooling of two sequential ejaculates significantly increased the median total number of motile sperm from normozoospermic males by 144% and from oligozoospermic males by 329%, (to 10.2 X 10(6]. We suggest that pooling of two sequential ejaculates from oligozoospermic males is a simple and cost effective method to increase significantly the total number of motile sperm for intrauterine insemination, in vitro fertilization, gamete intrafallopian transfer, or semen cryopreservation.

Reduction of peritoneal adhesion formation by colchicine: a comparative study in the rat.

Colchicine inhibits processes known to be involved in the pathogenesis of peritoneal adhesions. Daily administration of 50 micrograms of colchicine to 22 rats significantly diminished adhesion formation, as compared with dexamethasone-treated and untreated rats. Rats that developed at least three adhesions of grade 3 (scale 0 to 4) were strikingly less prevalent among the colchicine-treated animals than the untreated group (9.1% versus 40.9%, P less than 0.001). The double product of the number and grading of adhesions was significantly lower (P less than 0.05) in the colchicine group. Colchicine is more effective than dexamethasone in inhibiting adhesion formation in the rat.

How often should infertile men have intercourse to achieve conception?

OBJECTIVE: To clarify how often infertile men should have intercourse to achieve conception, the effect of sequential ejaculation on total motile sperm counts was investigated. DESIGN: Case-control study. SETTING: Infertility and IVF unit, tertiary care center. PARTICIPANTS: Five hundred seventy-six men who produced two closely spaced sequential ejaculates. MAIN OUTCOME MEASURE: The total motile sperm counts of the second ejaculates were compared with the total motile sperm counts of the first ejaculates. RESULTS: In normospermic men (n = 359), the total motile sperm counts decreased significantly from 93 (18 to 601) (median [minimum to maximum] x 10(6)) in the first ejaculate to 42 (1.2 to 387) in the second ejaculate, produced 24 hours later. In contrast to the normospermic men, in the asthenospermic group (24 hours difference, n = 81) and in both oligospermic groups, (1 to 4 hours difference, n = 27; and 24 hours difference, n = 45), there were no significant changes in the total motile sperm counts (24 [5.9 to 229] versus 30 [0.8 to 150], 6 [0.8 to 18] versus 3.6 [0.1 to 63] and 13 [2.5 to 32] versus 10 [0.1 to 66], respectively). Moreover, in both oligoasthenospermic groups (1 to 4 hours difference, n = 23; and 24 hours difference, n = 41) the total motile sperm counts increased significantly (3.2 [0.6 to 7.9] versus 8 [0.4 to 48] and 4 [0.2 to 13] versus 4 [0.1 to 101], respectively). In all groups, pooling sequential ejaculates significantly increased the total motile sperm counts, over and above that of the first ejaculate, by 49% in the normospermic group, 95% in the asthenospermic group, 67% and 75% in the oligospermic groups (1 to 4 hours and 24 hours difference, respectively), and 233% and 139% in the oligoasthenospermic groups (1 to 4 hours and 24 hours difference, respectively). CONCLUSIONS: Sequential ejaculation may overcome the impaired sperm transport causing low total motile sperm counts observed in some oligospermic and/or asthenospermic men. Most of these infertile men may significantly increase their fertility potential, assessed by the total motile sperm counts, either by pooling sequential ejaculates for IUI, GIFT, and IVF, or by having intercourse every day or even twice a day, at the time of ovulation.

Ovarian stimulation protocol for in vitro fertilization with gonadotropin-releasing hormone agonist widens the implantation window.

Pregnancy rates vary considerably with the type of ovarian stimulation used for in vitro fertilization and embryo transfer (IVF-ET). The window of implantation may represent one of the rate-limiting steps in IVF success. We therefore investigated estimated implantation times of 10 consecutive IVF singleton pregnancies, achieved using pituitary suppression with gonadotropin-releasing hormone agonist (GnRH-a) before and during ovarian stimulation with human menopausal gonadotropins (hMG), and compared those with 9 consecutive IVF pregnancies achieved by hMG stimulation only. Estimated implantation times were calculated by regression analysis of serial human chorionic gonadotropin (hCG) measurements between days 7 and 16 after ET. The GnRH-a/hMG pregnancies implanted between days 7 and 11, whereas hMG pregnancies implanted between days 7 and 9 after ET. The hCG regression curve for the GnRH-a/hMG pregnancies revealed a delay of 1.5 days in estimated implantation time compared with the hMG only group. There were no significant differences in pretransfer in vitro embryos development between the two groups. Thus, the delay in hCG rise probably reflects a delay in embryo implantation. We therefore conclude that a GnRH-a/hMG stimulation protocol appears to widen the implantation window in comparison with a hMG only protocol. This observation may at least in part explain the improved IVF pregnancy success with GnRH-a/hMG stimulation protocols.

The role of gonadotropins in the etiology of ectopic pregnancy.

Our study indicates that the high rate of EP in MAP(+) patients, treated with hMG/hCG, is due to the fact that it is a selected group of infertile patients with probable additional underlying tubal disease. Absence of EP in MAP(-) patients indirectly support the theory that a mechanical factor is at work. It is, therefore, our opinion, that the cause of ectopic pregnancy lies in the patient and not in the drug (hMG/hCG).

Distribution of serum creatine kinase activity in young healthy persons.

The normal distribution of serum creatine kinase (CK) was determined in 428 men (mean age = 21.5) and 540 women (mean age = 20.2). The bootstrap method was employed to obtain statistical parameters of CK reference range and correlations with physical activity habits, BMI, cigarette smoking and alcohol consumption. CK distribution was non-Gaussian and skewed toward the higher values; 18.9% of the men and 4.6% of the women had values above the upper reference limits defined for the commercial assay kit. The median 97.5 percentile value was 532 u/l for men and 248 u/l for women (95% confidence interval of 384-738 u/l and 184-340 u/l, respectively). A significant correlation was found only between CK and alcohol consumption in men. Myoglobin level in a representative group of subjects correlated well with CK activity for both genders. Our findings define the range of CK values in a healthy, young, heterogeneous population. We suggest that only CK levels above the determined 97.5 percentile should warrant further clinical investigation.

Thyroid hormone levels in cord blood of infants with acidemia at birth.

OBJECTIVE: To study the funic thyroid hormone levels in cases were fetal distress during labor resulted in acidemia at birth. MATERIAL AND METHODS: Arterial and venous levels of TSH, total T4, free T4 and total T3 obtained from cord blood at birth of twelve acidemic fetuses were compared with normal controls. RESULTS: Acidemic fetuses had a significanly higher TSH levels than controls (16.5+/-2. 1 microI/dl vs. 9.6+/-1.4 microI/dl, P=0.01). Total T3 levels were significantly lower in acidemic fetuses (49.2+/-2.9 ng/dl vs. 63+/-5. 5 ng/dl, P=0.04). Total and free T4 levels were similar and there was no difference between arterial and venous levels of the hormones. CONCLUSIONS: Birth acidemia from fetal distress during labor is associated with higher TSH levels and lower T3 levels.

Fertility in anovulatory patients after primary cesarean section.

OBJECTIVE: To evaluate the fertility potential after primary cesarean section (CS) in anovulatory patients treated for ovulation induction with gonadotropins. STUDY DESIGN: A controlled, prospective study was conducted on 97 anovulatory patients who delivered a neonate either abdominally or vaginally after ovulation induction with human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG). After four cycles of hMG/hCG therapy, cumulative pregnancy rates and abortions were observed. In both groups, patients who did not conceive underwent hysterosalpingography to evaluate uterine and tubal patency. RESULTS: The cumulative pregnancy rate in the anovulatory, post-cesarean section patients treated with hMG/hCG was 61.9%, as compared to 59.6% in the control group (statistically nonsignificant). The abortion rate was similar in both groups. CONCLUSION: The risk of uterine or tubal infertility is probably not substantially increased in patients on whom uncomplicated cesarean sections have been performed. Anovulatory patients who conceive after treatment with gonadotropins and deliver abdominally should be referred for medical treatment before evaluation of any uterine or tubal infertility.

Catalytic antibodies: generation, nature, and possible role as chemical warfare scavengers.

Nearly three decades have passed since the idea was proposed that antibodies may provide catalytic activity as enzymes. Since then the term "catalytic antibodies" has gained more and more popularity. Numerous antibodies enhancing the rate of reactions have been described. This review will address the basic biological considerations involved in the genesis of catalytic antibodies and explore their possible role in the future providing protection in chemical warfare.