Automating phase singularity localization in mathematical models of cardiac tissue dynamics.

Electrical wave-fronts are responsible for contraction in heart tissue. Rotary wave-fronts break up into daughter waves and it is this break up that is believed to underlie ventricular fibrillation. Mathematical methods abound for simulation of fibrillation, and localizing the core of rotary wave-fronts (the phase singularities) is key to characterizing the state of fibrillation and effectiveness of defibrillation in these models. We present a formal method for automating this process in these various models. Automation will allow for side-by-side comparisons of suggested mechanisms of fibrillation, comparison of various models of these mechanisms and faster evaluation of defibrillation strategies making use of these models.     

Effect of estradiol and progesterone on the low-dose endotoxin-induced glomerular inflammatory response of the female rat.

PROBLEM: Is the endotoxin-induced glomerular inflammatory response of the female rat under ovarian control? METHOD OF STUDY: Ovariectomized rats (OVX), with or without progesterone (OVX-P) or estradiol (OVX-E) treatment, as well as rats in the follicular or luteal phase of the ovulatory cycle were infused with endotoxin or saline and sacrificed 3 days later. Cryostat kidney sections were immunohistologically stained for the presence of neutrophils and monocytes (MØ) and the expression of adhesion molecules. RESULTS: After endotoxin, the glomerular number of neutrophils and the number of MAC-1 positive cells were increased in luteal-phase and in OVX-P rats, and the number of glomerular MØ was increased in luteal-phase, OVX, OVX-E, and OVX-P rats. Endotoxin increased ICAM-1 expression in all groups of rats, except in follicular-phase rats. The glomerular number of LFA-1– and VLA-4-positive cells following endotoxin were only increased in OVX rats. CONCLUSIONS: It is concluded that endotoxin-induced monocyte infiltration and ICAM-1 expression are inhibited by a factor produced during the follicular phase, probably by developing follicles. Infiltration of neutrophils and expression of MAC-1, LFA-1, VLA-4 seem to be under control of progesterone or estradiol.     

The usefulness of endometrial biopsy for luteal phase evaluation in infertility.

To assess the usefulness of the late luteal phase endometrial biopsy in infertility, we evaluated a total of 1492 biopsies performed in 1055 patients. Of these women, 699 underwent one biopsy during spontaneous ovulatory cycles, 288 had two, 57 had three, nine had four, and five biopsies were done in two patients. As controls we included 45 fertile women who were requesting contraception. We analysed histological dating of the endometrium and its abnormality rates in first and successive biopsy specimens, as well as the association of the pregnancy outcome with the endometrial patterns and treatment for luteal phase deficiency (LPD). Our results show firstly that diagnosis of LPD in both infertile and fertile women represents only a chance event; secondly, histological endometrial adequacy or inadequacy in the cycle of conception or in previous cycles is not related to the outcome of pregnancy in infertile patients. Finally, treatment of LPD does not improve pregnancy outcome in infertile women. Thus, luteal phase evaluation by histological dating of the endometrium is not worthwhile.     

Optimal fixation for total preanalytic phase evaluation in pathology laboratories. A comprehensive study including immunohistochemistry,DNA, and mRNA assays

The purpose of this study was to set the optimal preanalytical fixation protocol to enhance analytical and postanalytical phase accuracy and consistency. Twenty‐five normal colorectal tissues were fixed using various formalin concentrations, pHs, and fixation periods. All specimens were embedded in paraffin and 4 μm sections were used for immunohistochemistry of Ki‐67, and extraction and amplification of DNA and RNA. The Ki‐67 labeling index and the successful gene amplification rate for DNA and mRNA were evaluated and compared among variously fixed tissue samples. Ki‐67 positivity was enhanced by low pH and short fixation time, and was influenced by the type of antibody, but not by the staining (with or without using an autostainer) method. DNA amplification by PCR was strongly influenced by pH of formalin. cDNA amplification could be accomplished only with the shortest PCR fragment of 142 bp, and longer fixation times impaired the amplification. These data suggest that multiple different factors influence immunohistochemical results and gene amplification using DNA and mRNA. We recommend, based on data from this comprehensive analysis, a 10% neutral buffered formalin and fixation times of no longer than 1 week to produce consistent immunohistochemical slides and DNA amplification within 500 bp in pathology laboratories.     

The role of measurement of progestagen-associated endometrial protein in predicting adequate endometrial differentiation.

Late secretory endometrium synthesizes and secretes progestagen-associated endometrial protein (PEP), which is measurable in the serum of cycling women, and has been shown to increase in concentration during the luteal phase of the normal menstrual cycle. The purpose of this study was to determine the utility of serum PEP as a predictor of normal or inadequate luteal phase endometrial differentiation. One-hundred-and-twenty-five endometrial biopsies were taken within 4 days of a subsequent menstrual period, during the course of evaluation of infertility or recurrent abortion. Twenty-one of these biopsies demonstrated glandular/stromal asynchrony. Thirteen patients exhibited 'out-of-phase' endometrial biopsies and 91 patients had 'in-phase' biopsies. Mean PEP values significantly increased from the mid-luteal phase to the late luteal phase. Mean PEP values for patients with in-phase biopsies (43.92 units/ml) were not significantly different from those with out-of-phase biopsies (25.24 units/ml, P = 0.0942). PEP values for patients with asynchronous biopsies were intermediate. Use of clomiphene citrate did not affect these results.     

Enhancement of lectin pathway haemolysis by immunoglobulins.

We recently reported that indicator sheep erythrocytes (E) coated with mannan and sensitized with mannan-binding lectin (MBL) (E-M-MBL) are lysed by human serum in the absence of calcium via the lectin pathway of complement activation by a process which requires alternative pathway amplification and is associated with increased binding of and control by complement regulatory proteins C4 bp and factor H. In the present study, we investigated the effect of immunoglobulin (Ig) on this haemolysis. Co-sensitization of indicator E with anti-E haemolysin led to threefold enhancement of lectin pathway haemolysis in the absence of calcium, associated with increased binding of C3 and C5. Lysis was enhanced approximately twofold when E-M-MBL were chemically or immunologically coated with IgM or IgA, and fourfold when coated with IgG, prior to lysis in human serum-Mg-ethyleneglycol tetraacetic acid. The presence of haemolysin did not reduce the binding or inhibitory activity of C4 bp, and the enhancing activity of haemolysin was retained in serum depleted of C4 bp. By contrast, binding of factor H was greatly reduced in the presence of haemolysin, which had no enhancing effect in serum depleted of factor H. These experiments demonstrate the ability of IgG, IgM and IgA to enhance lectin pathway cytolysis, and that this enhancement occurs by neutralization of the inhibitory activity of factor H. Immunoglobulin enhancement of lectin pathway cytolysis represents another interaction between the innate and adaptive systems of immunity.     

Luteal phase support and severe ovarian hyperstimulation syndrome.

The incidence and statistical associations of the ovarian hyperstimulation syndrome (OHSS) were studied in 304 egg retrievals with gonadotrophin-releasing hormone agonist suppression, gonadotrophin administration and follicular aspiration. In addition to preserving corpus luteum function, the luteal phase administration of human chorionic gonadotrophin (HCG) was associated with a higher incidence of severe OHSS than was supplementation with progesterone alone (12 versus 0%, P less than 0.001). Severe OHSS occurred in 3.7% and 12% of retrievals without and with pregnancy respectively (P less than 0.01). Stepwise logistic regression showed that the occurrence of moderate or severe OHSS was statistically predicted by the log of the serum oestradiol on the day the initial HCG was given (P less than 0.0001), treatment with luteal phase HCG (P less than 0.0003), and fetal number (P less than 0.0079). In the late luteal phase of cycles without luteal HCG, the serum oestradiol concentration was one-tenth and the serum progesterone concentration was one-fifth of the luteal phase value with HCG support (P less than 0.001). Without luteal phase HCG, oestradiol was two-fold higher (P less than 0.001) and progesterone was 1.4-fold higher (P less than 0.005) in pregnant than in non-pregnant women. With luteal phase HCG, oestradiol was 1.4-fold higher in pregnant than in non-pregnant women (P less than 0.05), and progesterone was 1.7-fold higher (P less than 0.001). Oestradiol upper limits of 4400 and 14,700 pmol/l (1200 and 4000 pg/ml) for cycles with and without luteal phase HCG respectively correspond to approximately 5% risk of moderate or severe OHSS with a singleton pregnancy under these conditions.     

Early and late-phase asthmatic reactions: a hypothesis

Why might a foreign particle, exercise or fog inhalation precipitate two asthmatic reactions? It is reasonable to suspect that asthmatic patients develop two reactions because healthy subjects may also develop two physiological responses to the same stimuli. This suggestion is supported by the observation that living things have developed adaptative systems to confront either sudden or persistent changes in the environment or within the internal milieu. The results of several studies suggest that the early phase response (EPR) usually involves cells which are normal residents of the respiratory epithelium (mast cells) and pre-formed substances (histamine), whereas cells participating in the late phase reaction (LPR) are recruited from the circulation (eosinophils, basophils and T cells). Up to now most of the studies of the EPR and LPR have been addressed to detecting a cell or metabolite abnormality. This simplistic approach would probably not improve the knowledge of the mechanisms involved in asthmatic responses. Since the presence of isolated or dual responses seems to depend on the intensity and duration of the stimuli it is reasonable to suspect that EPR and LPR are the result of an excessive adaptative response of the bodies of asthmatics to sudden and prolonged/strong stimuli, respectively.     

Control of the rat's circadian self-stimulation rhythm by light-dark cycles.

Rats with hypothalamic and septal electrodes were maintained in continuous test environments where bar-press responses produced brief reinforcing electrical stimulations. Long-term trends in response emission were measured under continuous exposure to light, dark and 12 hr light-dark alternations. In addition, transient behavioral adjustment to sudden 180 degrees phase shifts in the light-dark schedule was studied. The ambient light condition was found to control the period and phase of the circadian rhythm of brain self-stimulation behavior, as quantified by Fourier analysis. The circadian period was greatest under constant light (up to 24.90 hr under dim illumination), and approximated 24.00 hr under constant dark. Successful nocturnal entrainment to 12 hr light-dark alternations was obtained, with the peak of the 24 hr Fourier fundamental occurring in the middle-to-late dark segments. Three to 11 days were required for re-entrainment to 180 degrees light-dark phase shifts, during which the behavioral oscillation period increased to values comparable to periods under constant light. The rate of re-entrainment appeared to be proportional to illumination intensity during light segments.     

Comparison of luteal phase profile in gonadotrophin stimulated cycles with or without a gonadotrophin-releasing hormone antagonist.

BACKGROUND: The aim of our study was to explore luteal phase hormone profiles in gonadotrophin-stimulated cycles with or without gonadotrophin-releasing hormone (GnRH) antagonist therapy during intrauterine insemination (IUI). Forty-one infertile couples were recruited in this randomized clinical study. METHODS: The 19 patients included in group A were treated for 21 cycles with recombinant FSH 150 IU/day starting from day 3 of the cycle and with the GnRH antagonist cetrorelix at the dose of 0.25 mg/day starting from the day in which a follicle with a mean diameter of > or =14 mm was seen at ultrasound scan. Cetrorelix was administered until human chorionic gonadotrophin (HCG) administration. The 22 patients included in group B were administered recombinant FSH alone at the same dosage for 27 cycles. RESULTS: The two treatment groups showed a similar increase in progesterone concentration during the luteal phase. In the mid-luteal phase (day 6 after HCG), oestradiol concentrations in group B were significantly higher compared with group A (P < 0.05) but the oestradiol:progesterone ratio was similar in the two groups. Serum LH was completely suppressed during the follicular phase only in group A, concomitantly with GnRH antagonist administration. A total of six pregnancies, all ongoing, were achieved (14.3% per patient and 12.2% per cycle), equally distributed in group A and in group B. CONCLUSION: GnRH antagonists can be safely administered in gonadotrophin-stimulated IUI cycles without luteal phase supplementation because no deleterious effects of GnRH antagonist administration were noted on luteal progesterone concentration or on the duration of the luteal phase.     

Pituitary gonadotrophin secretory capacity during the luteal phase in superovulation using GnRH-agonists and HMG in a desensitization or flare-up protocol.

Pituitary gonadotrophin reserve and basal gonadotrophin secretion were tested during the luteal phase in women superovulated with buserelin/human menopausal gonadotrophin (HMG) in a desensitization (n = 17) or flare-up protocol (n = 7). In the desensitization protocol the luteinizing hormone-releasing hormone (LHRH) stimulated serum LH and follicle stimulating hormone (FSH) concentrations remained impaired at least until day 14 after arrest of the agonist. In the flare-up protocol basal and stimulated LH secretion was still abnormal on days 14 and 15 after human chorionic gonadotrophin (HCG) injection. Normal basal serum FSH concentrations were measured at the end of the luteal phase in the flare-up protocol, but the response of FSH to LHRH injection was still subnormal. We conclude that gonadotrophin function remained impaired until the end of the luteal phase after desensitization and flare-up GnRH-agonist and HMG stimulation protocols. Corpus luteum stimulation with exogenous HCG or substitution therapy using natural progesterone are required to prevent the possible negative effects resulting from pituitary dysfunction after GnRH-agonist treatment.     

Integrated Laplacian‐based phase unwrapping and background phase removal for quantitative susceptibility mapping

Quantitative susceptibility mapping (QSM) is a recently developed MRI technique that provides a quantitative measure of tissue magnetic susceptibility. To compute tissue magnetic susceptibilities based on gradient echoes, QSM requires reliable unwrapping of the measured phase images and removal of contributions caused by background susceptibilities. Typically, the two steps are performed separately. Here, we present a method that simultaneously performs phase unwrapping and HARmonic (background) PhasE REmovaL using the LAplacian operator (HARPERELLA). Both numerical simulations and in vivo human brain images show that HARPERELLA effectively removes both phase wraps and background phase, whilst preserving all low spatial frequency components originating from brain tissues. When compared with other QSM phase preprocessing techniques, such as path‐based phase unwrapping followed by background phase removal, HARPERELLA preserves the tissue phase signal in gray matter, white matter and cerebrospinal fluid with excellent robustness, providing a convenient and accurate solution for QSM. The proposed algorithm is provided, together with QSM and susceptibility tensor imaging (STI) tools, in a shared software package named ‘STI Suite’. Copyright © 2013 John Wiley & Sons, Ltd.