The relationship between anti-Müllerian hormone in women receiving fertility assessments and age at menopause in subfertile women: evidence from large population studies.

CONTEXT: Anti-Müllerian hormone (AMH) concentration reflects ovarian aging and is argued to be a useful predictor of age at menopause (AMP). It is hypothesized that AMH falling below a critical threshold corresponds to follicle depletion, which results in menopause. With this threshold, theoretical predictions of AMP can be made. Comparisons of such predictions with observed AMP from population studies support the role for AMH as a forecaster of menopause. OBJECTIVE: The objective of the study was to investigate whether previous relationships between AMH and AMP are valid using a much larger data set. SETTING: AMH was measured in 27 563 women attending fertility clinics. STUDY DESIGN: From these data a model of age-related AMH change was constructed using a robust regression analysis. Data on AMP from subfertile women were obtained from the population-based Prospect-European Prospective Investigation into Cancer and Nutrition (Prospect-EPIC) cohort (n = 2249). By constructing a probability distribution of age at which AMH falls below a critical threshold and fitting this to Prospect-EPIC menopausal age data using maximum likelihood, such a threshold was estimated. MAIN OUTCOME: The main outcome was conformity between observed and predicted AMP. RESULTS: To get a distribution of AMH-predicted AMP that fit the Prospect-EPIC data, we found the critical AMH threshold should vary among women in such a way that women with low age-specific AMH would have lower thresholds, whereas women with high age-specific AMH would have higher thresholds (mean 0.075 ng/mL; interquartile range 0.038-0.15 ng/mL). Such a varying AMH threshold for menopause is a novel and biologically plausible finding. AMH became undetectable (<0.2 ng/mL) approximately 5 years before the occurrence of menopause, in line with a previous report. CONCLUSIONS: The conformity of the observed and predicted distributions of AMP supports the hypothesis that declining population averages of AMH are associated with menopause, making AMH an excellent candidate biomarker for AMP prediction. Further research will help establish the accuracy of AMH levels to predict AMP within individuals.

External validation of nomogram for the decline in serum anti-Müllerian hormone in women: a population study of 15,834 infertility patients.

The value of anti-müllerian hormone (AMH) as a marker of the ovarian reserve is becoming clear in a range of clinical contexts.This study reports the external validation of a quadratic model-based AMH­age nomogram using a cohort of 15,834 US women. All models previously investigated for the decline in ovarian reserve (i.e. linear, bi-linear, decay curve, power and quadratic models) tended to overestimate AMH by approximately 11% versus the published nomogram, indicating some between-population heterogeneity. Bootstrapping of 1000 datasets indicated that the quadratic model provided the best fit, confirming the choice of this model in the AMH­age nomogram. This nomogram can therefore be used with confidence for the interpretation of AMH in clinical populations.

Antigenic variation in Treponema pallidum: TprK sequence diversity accumulates in response to immune pressure during experimental syphilis.

Pathogens that cause chronic infections often employ antigenic variation to evade the immune response and persist in the host. In Treponema pallidum (T. pallidum), the causative agent of syphilis, the TprK Ag undergoes variation of seven V regions (V1-V7) by nonreciprocal recombination of silent donor cassettes with the tprK expression site. These V regions are the targets of the host humoral immune response during experimental infection. The present study addresses the causal role of the acquired immune response in the selection of TprK variants in two ways: 1) by investigating TprK variants arising in immunocompetent versus immunosuppressed hosts; and 2) by investigating the effect of prior specific immunization on selection of TprK variants during infection. V region diversity, particularly in V6, accumulates more rapidly in immunocompetent rabbits than in pharmacologically immunosuppressed rabbits (treated with weekly injections of methylprednisolone acetate). In a complementary experiment, rabbits preimmunized with V6 region synthetic peptides had more rapid accumulation of V6 variant treponemes than control rabbits. These studies demonstrate that the host immune response selects against specific TprK epitopes expressed on T. pallidum, resulting in immune selection of new TprK variants during infection, confirming a role for antigenic variation in syphilis.

Lipophosphoglycan is a virulence factor distinct from related glycoconjugates in the protozoan parasite Leishmania major.

Protozoan parasites of the genus Leishmania undergo a complex life cycle involving transmission by biting sand flies and replication within mammalian macrophage phagolysosomes. A major component of the Leishmania surface coat is the glycosylphosphatidylinositol (GPI)-anchored polysaccharide called lipophosphoglycan (LPG). LPG has been proposed to play many roles in the infectious cycle, including protection against complement and oxidants, serving as the major ligand for macrophage adhesion, and as a key factor mitigating host responses by deactivation of macrophage signaling pathways. However, all structural domains of LPG are shared by other major surface or secretory products, providing a biochemical redundancy that compromises the ability of in vitro tests to establish whether LPG itself is a virulence factor. To study truly lpg(-) parasites, we generated Leishmania major lacking the gene LPG1 [encoding a putative galactofuranosyl (Gal(f)) transferase] by targeted gene disruption. The lpg1(-) parasites lacked LPG but contained normal levels of related glycoconjugates and GPI-anchored proteins. Infections of susceptible mice and macrophages in vitro showed that these lpg(-) Leishmania were highly attenuated. Significantly and in contrast to previous LPG mutants, reintroduction of LPG1 into the lpg(-) parasites restored virulence. Thus, genetic approaches allow dissection of the roles of this complex family of interrelated parasite virulence factors, and definitively establish the role of LPG itself as a parasite virulence factor. Because the lpg1(-) mutant continue to synthesize bulk GPI-anchored Gal(f)-containing glycolipids other than LPG, a second pathway distinct from the Golgi-associated LPG synthetic compartment must exist.

Formin-2, a novel formin homology protein of the cappuccino subfamily, is highly expressed in the developing and adult central nervous system.

Formin-1 is the founding member of a family of genes of emerging biological and medical importance that share specific domains of homology, allowing them to be classified together as the formin homology proteins. Although deficiency mutations in formin-1 lead to profound developmental defects in limb and kidney formation, similar deficiency mutations in more distantly related members of this family (diaphanous and cappuccino in Drosophila and BNI1 in yeast) have ostensibly unrelated phenotypes. Here we describe murine and human formin-2 (Fmn2), a gene which bears a high degree of similarity to formin-1 and cappuccino. The mouse gene, which encodes a putative 1567-amino-acid open reading frame and maps to mouse Chromosome 1, is expressed almost exclusively in the developing and mature central nervous system. Expression begins at embryonic day 9. 5 in the developing spinal cord and brain structures and continues in neonatal and adult brain structures including the olfactory bulb, cortex, thalamus, hypothalamus, hippocampus and cerebellum. Human formin-2 has a similar expression pattern.

Sequence determinants for regulated degradation of yeast 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein.

The degradation rate of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-R), a key enzyme of the mevalonate pathway, is regulated through a feedback mechanism by the mevalonate pathway. To discover the intrinsic determinants involved in the regulated degradation of the yeast HMG-R isozyme Hmg2p, we replaced small regions of the Hmg2p transmembrane domain with the corresponding regions from the other, stable yeast HMG-R isozyme Hmg1p. When the first 26 amino acids of Hmg2p were replaced with the same region from Hmg1p, Hmg2p was stabilized. The stability of this mutant was not due to mislocalization, but rather to an inability to be recognized for degradation. When amino acid residues 27-54 of Hmg2p were replaced with those from Hmg1p, the mutant was still degraded, but its degradation rate was poorly regulated. The degradation of this mutant was still dependent on the first 26 amino acid residues and on the function of the HRD genes. These mutants showed altered ubiquitination levels that were well correlated with their degradative phenotypes. Neither determinant was sufficient to impart regulated degradation to Hmg1p. These studies provide evidence that there are sequence determinants in Hmg2p necessary for degradation and optimal regulation, and that independent processes may be involved in Hmg2p degradation and its regulation.

Trabeculectomy vs. nonpenetrating trabeculectomy: a retrospective study of two procedures in phakic patients with glaucoma.

In a retrospective study we compared the efficacy and safety of trabeculectomy and nonpenetrating trabeculectomy (NPT). In the latter procedure under a thin scleral flap, juxtacanalicular trabecular meshwork with Schlemm's canal is excised leaving the innermost trabecular meshwork behind. Trabeculectomy was performed on 86 eyes (66 blacks, 20 whites), whereas 71 eyes underwent NPT (44 blacks, 27 whites). The mean follow-up period was 1.7 years. Postoperatively at one year, trabeculectomy controlled 70.3% of patients with no or topical antiglaucoma medication, whereas 83.7% of NPT patients were similarly controlled. There was a difference in the number and severity of complications between trabeculectomy and NPT. Postoperative flat anterior chamber, uveitis, hyphema, vitreous loss, and choroidal detachment occurred more frequently after trabeculectomy.

Effectiveness of nonpenetrating trabeculectomy in aphakic patients with glaucoma.

Nonpenetrating trabeculectomy was performed on 28 aphakic eyes consisting of 18 with chronic open-angle glaucoma and 10 with secondary and/or complicated glaucoma. The canal of Schlemm and the juxtacanalicular trabecular meshwork were excised for a length of 4 mm beneath a 6 mm x 6 mm scleral flap. At one year postoperatively, 72.0% of all patients were controlled, 24% required no antiglaucoma medications. However, 88% of chronic simple glaucoma patients were satisfactorily controlled. The mean follow-up period was 1.4 years. Minimal complications have been encountered to date. Nonpenetrating trabeculectomy may be valuable as an initial procedure in aphakic patients who require glaucoma filtration surgery.

Hemiplegic writing in severe aphasia.

Three patients with severe aphasia and right hemiplegia are described who could write to dictation with the right arm using a limb prosthesis though agraphic with the "intact" left hand. The phenomenon of "hemiplegic writing" is explained as an access to submerged or preprocessing levels in language and action structure, through the use of older proximal motor systems. This interpretation has implications for our understanding of language and brain function, as well as for approaches to the treatment of patients with severe language disorders.

Potential side effects of timolol therapy in the treatment of glaucoma.

The literature concerning the clinical and pharmacologic studies of systemically administered timolol in 2233 patients was reviewed. Side effects reported were correlated with dosage levels and estimated plasma levels. Most adverse effects occurred with levels much higher than would be expected after the topical use of timolol to control glaucoma. The table of potential complications and adverse effects seen with the use of systemic timolol is meant to focus attention on expected and unexpected side effects. All could occur and should be looked for with the topical use of this drug. The goal of this paper is to define better what physicians should look for in evaluating the clinical safety of this drug and what can be realistically expected to be seen as the use of this drug becomes more widespread.