What's Now and What's Next for Surgical Endometriosis Management in the Infertile Patient? An Evidence-Based Review for the General OB/GYN.

Endometriosis is a significant contributor to female infertility, and its complex nature and varied phenotypes lead to questions regarding the value of surgical management. In this manuscript, we summarize current evidence and recommendations regarding surgical treatment for infertility in peritoneal disease, endometriomas, adenomyosis, and deep endometriosis, and highlight recent evidence regarding perinatal outcomes in women with endometriosis. Our purpose is to provide a concise "user's guide" for decisions regarding the surgical management of endometriosis in patients with infertility and generate awareness of recent perinatal outcome data.

Deconvoluting the Innocent vs. Non-innocent Behavior of N,N-diethylphenylazothioformamide Ligands with Copper Sources.

Redox-active ligands lead to ambiguity in often clearly defined oxidation states of both the metal centre and the ligand. The arylazothioformamide (ATF) ligand class represents a redox-active ligand with three possible redox states (neutral, singly reduced, and doubly reduced). ATF-metal interactions result in strong colorimetric transitions allowing for the use of ATFs in metal detection and/or separations. While previous reports have discussed dissolution of zerovalent metals, the resulting oxidation states of coordination complexes have proved difficult to interpret through X-ray crystallographic analysis alone. This report describes the X-ray crystallographic analysis combined with computational modelling of the ATF ligand and metal complexes to deconvolute the metal and ligand oxidation state of metal-ATF complexes. Metal(ATF)2 complexes that originated from zerovalent metals were found to exist as dicationic metal centers containing two singly reduced ATF ligands. When employing Cu(I) salts instead of Cu(0) to generate copper-ATF complexes, the resulting complexes remained Cu(I) and the ATF ligand remained "innocent", existing in its neutral state. Although the use of CuX (where X = Br or I) or [Cu(NCMe)4]Y (where Y = BF4 or PF6) generated species of the type: [(ATF)Cu(µ-X)]2 and [Cu(ATF)2]Y, respectively, the ATF ligand remained in its neutral state for each species type.

Abnormal differentiation of dopaminergic neurons in zebrafish trpm7 mutant larvae impairs development of the motor pattern.

Transient receptor potential, melastatin-like 7 (Trpm7) is a combined ion channel and kinase implicated in the differentiation or function of many cell types. Early lethality in mice and frogs depleted of the corresponding gene impedes investigation of the functions of this protein particularly during later stages of development. By contrast, zebrafish trpm7 mutant larvae undergo early morphogenesis normally and thus do not have this limitation. The mutant larvae are characterized by multiple defects including melanocyte cell death, transient paralysis, and an ion imbalance that leads to the development of kidney stones. Here we report a requirement for Trpm7 in differentiation or function of dopaminergic neurons in vivo. First, trpm7 mutant larvae are hypomotile and fail to make a dopamine-dependent developmental transition in swim-bout length. Both of these deficits are partially rescued by the application of levodopa or dopamine. Second, histological analysis reveals that in trpm7 mutants a significant fraction of dopaminergic neurons lack expression of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Third, trpm7 mutants are unusually sensitive to the neurotoxin 1-methyl-4-phenylpyridinium, an oxidative stressor, and their motility is partially rescued by application of the iron chelator deferoxamine, an anti-oxidant. Finally, in SH-SY5Y cells, which model aspects of human dopaminergic neurons, forced expression of a channel-dead variant of TRPM7 causes cell death. In summary, a forward genetic screen in zebrafish has revealed that both melanocytes and dopaminergic neurons depend on the ion channel Trpm7. The mechanistic underpinning of this dependence requires further investigation.

Anatomy of the lamprey ear: morphological evidence for occurrence of horizontal semicircular ducts in the labyrinth of Petromyzon marinus.

In jawed (gnathostome) vertebrates, the inner ears have three semicircular canals arranged orthogonally in the three Cartesian planes: one horizontal (lateral) and two vertical canals. They function as detectors for angular acceleration in their respective planes. Living jawless craniates, cyclostomes (hagfish and lamprey) and their fossil records seemingly lack a lateral horizontal canal. The jawless vertebrate hagfish inner ear is described as a torus or doughnut, having one vertical canal, and the jawless vertebrate lamprey having two. These observations on the anatomy of the cyclostome (jawless vertebrate) inner ear have been unchallenged for over a century, and the question of how these jawless vertebrates perceive angular acceleration in the yaw (horizontal) planes has remained open. To provide an answer to this open question we reevaluated the anatomy of the inner ear in the lamprey, using stereoscopic dissection and scanning electron microscopy. The present study reveals a novel observation: the lamprey has two horizontal semicircular ducts in each labyrinth. Furthermore, the horizontal ducts in the lamprey, in contrast to those of jawed vertebrates, are located on the medial surface in the labyrinth rather than on the lateral surface. Our data on the lamprey horizontal duct suggest that the appearance of the horizontal canal characteristic of gnathostomes (lateral) and lampreys (medial) are mutually exclusive and indicate a parallel evolution of both systems, one in cyclostomes and one in gnathostome ancestors.

Celsr3 is required for normal development of GABA circuits in the inner retina.

The identity of the specific molecules required for the process of retinal circuitry formation is largely unknown. Here we report a newly identified zebrafish mutant in which the absence of the atypical cadherin, Celsr3, leads to a specific defect in the development of GABAergic signaling in the inner retina. This mutant lacks an optokinetic response (OKR), the ability to visually track rotating illuminated stripes, and develops a super-normal b-wave in the electroretinogram (ERG). We find that celsr3 mRNA is abundant in the amacrine and ganglion cells of the retina, however its loss does not affect synaptic lamination within the inner plexiform layer (IPL) or amacrine cell number. We localize the ERG defect pharmacologically to a late-stage disruption in GABAergic modulation of ON-bipolar cell pathway and find that the DNQX-sensitive fast b1 component of the ERG is specifically affected in this mutant. Consistently, we find an increase in GABA receptors on mutant ON-bipolar terminals, providing a direct link between the observed physiological changes and alterations in GABA signaling components. Finally, using blastula transplantation, we show that the lack of an OKR is due, at least partially, to Celsr3-mediated defects within the brain. These findings support the previously postulated inner retina origin for the b1 component and reveal a new role for Celsr3 in the normal development of ON visual pathway circuitry in the inner retina.

A chemical-genetic approach to studying neurotrophin signaling.

Trk tyrosine kinases are receptors for members of the neurotrophin family and are crucial for growth and survival of specific populations of neurons. Yet, the functions of neurotrophin-Trk signaling in postnatal development as well as maintenance and plasticity of the adult nervous system are less clear. We report here the generation of mice harboring Trk knockin alleles that allow for pharmacological control of Trk kinase activity. Nanomolar concentrations of either 1NMPP1 or 1NaPP1, derivatives of the general kinase inhibitor PP1, inhibit NGF and BDNF signaling in TrkA(F592A) and TrkB(F616A) neurons, respectively, while no such Trk inhibition is observed in wild-type neurons. Moreover, oral administration of 1NMPP1 leads to specific inhibition of TrkA(F592A), TrkB(F616A), and TrkC(F167A) signaling in vivo. Thus, Trk knockin mice provide valuable tools for selective, rapid, and reversible inhibition of neurotrophin signaling in vitro and in vivo.

Anion-Caffeine Interactions Studied by 13C and 1H NMR and ATR-FTIR Spectroscopy.

This work investigates the interactions of a series of 11 anions with caffeine by utilizing 13C and 1H NMR and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. The aim of this study is to elucidate the molecular mechanisms of ion interactions with caffeine and to study how these interactions affect caffeine aggregation in aqueous solution. The chemical shift changes of caffeine 13C and 1H in the presence of salts provide a measure for anions' salting-out/salting-in abilities on individual carbon and hydrogen atoms in caffeine. The relative influences of anions on the chemical shift of individual atoms in the caffeine molecule are quantified. It is observed that strongly hydrated anions are excluded from the carbons on the six-member ring in caffeine and promote caffeine aggregation. On the other hand, weakly hydrated anions decrease caffeine aggregation by accumulating around the periphery of the caffeine molecule and binding to the ring structure. The ATR-FTIR results demonstrate that strongly hydrated anions desolvate the caffeine molecule and increase aggregation, while weakly hydrated anions have the opposite effects and salt caffeine into solution.

Influence of cardiac autonomic neuropathy on heart rate dependence of ventricular repolarization in diabetic patients.

OBJECTIVE: Prolongation of the QT interval and increased QT dispersion are associated with a poor cardiac prognosis. The goal of this study was to assess the long-term influence of the autonomic nervous system on the heart rate dependence of ventricular repolarization in patients with diabetic autonomic neuropathy (DAN). RESEARCH DESIGN AND METHODS: We studied 27 subjects (mean age 51.8 years) divided into three age- and sex-matched groups: nine control subjects, nine diabetic subjects with DAN (mostly at a mild stage; DAN+), and nine diabetic subjects without DAN (DAN-). DAN was assessed on heart rate variations during standard maneuvers (Valsalva, deep-breathing, and lying-to-standing maneuvers). No subject had coronary artery disease or left ventricular dysfunction or hypertrophy, and no subject was taking any drugs known to prolong the QT interval. All subjects underwent electrocardiogram and 24-h Holter recordings for heart rate variations (time and frequency domain) and QT analysis (selective beat averaging QT/RR relation, nocturnal QT lengthening). RESULTS: Rate-corrected QT intervals (Bazett formula) did not differ significantly between the three groups. The diurnal and nocturnal levels of low frequency/high frequency, an index of sympathovagal balance, were significantly reduced in DAN+ subjects. Using the selective beat-averaging technique, a day-night modulation of the QT/RR relation was evidenced in control and DAN- subjects. This long-term modulation was significantly different in DAN+ subjects, with a reversed day-night pattern and an increased nocturnal QT rate dependence. CONCLUSIONS: In diabetic patients with mild parasympathetic denervation, QT heart rate dependence was found to be impaired, as determined by noninvasive assessment using Holter data. Analysis of ventricular repolarization could represent a sensitive index of the progression of neuropathy. The potential prognostic impact of a reversed day-night pattern with steep nocturnal QT/RR relation still remains to be defined.