Embryo quality but not pronuclear score is associated with clinical pregnancy following IVF.

PURPOSE: The association between pronuclear (PN) scoring of embryos from assisted reproductive technology (ART) and clinical pregnancy remains controversial. We hypothesized that embryos with PNs scored on the day of fertilization check offer better embryo selection on day 3 and higher CPR compared to non-PN scored embryos. METHODS: Patients (19-46 years) undergoing IVF/ICSI cycles at Montefiore's Institute for Reproductive Medicine and Health between January 2006 and December 2009 were included in our study. We analyzed fresh day 3 cycles only with autologous oocytes and partner's fresh sperm (n = 344). A total of 1,899 embryos were included. We compared CPR from non-PN scored embryos (Group 1, n = 835) with PN scored embryos (Group 2, n = 1,064). Composite scores by patient were developed based on embryo disposition. We also assessed traditional embryo grading derived from cell number, fragmentation and cell symmetry. Data analysis included chi square and t test to determine if PN scoring was associated with improved CPR, and to compare the additional variables. RESULTS: CPR between Group 1 and Group 2 were not different (p = 0.91). CPR was significantly associated with female age, number of mature oocytes retrieved, number of day 3 embryos and grade of embryos transferred on day 3 (p < 0.05). CONCLUSION: PN scoring was not associated with improved CPR in day 3 embryo transfers. Mean grade of transferred embryos continues to be a well-established, independent predictor of CPR. We conclude that further refinement of embryo grading by PN scoring is not beneficial.

Leptin suppresses anti-Mullerian hormone gene expression through the JAK2/STAT3 pathway in luteinized granulosa cells of women undergoing IVF.

STUDY QUESTION: Do the adipocytokines, leptin and adiponectin affect the granulosa cell expression of anti-Mullerian hormone (AMH) and its receptor (AMHR-II)? SUMMARY ANSWER: Leptin suppresses AMH mRNA levels in human luteinized granulosa cells through the JAK2/STAT3 pathway, while adiponectin has no such effect. WHAT IS KNOWN ALREADY: AMH is one of the most reliable markers of ovarian reserve. Serum AMH levels decline with obesity. Obesity is associated with elevated leptin and reduced adiponectin levels. STUDY DESIGN, SIZE AND DURATION: This prospective study included 60 infertile women undergoing fresh IVF and ICSI cycles utilizing autologous oocytes at Montefiore's Institute for Reproductive Medicine and Health between July 2010 and April 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Follicular fluid was collected from small (SFs; <14 mm) and large follicles (LFs; ≥14 mm) from 38 participants. Total RNA was extracted separately from mural and cumulus granulosa cells and mRNA levels were measured by RT-PCR. In an additional group of participants (N = 22), primary cumulus and mural granulosa cells (pooled SFs and LFs) were cultured in media alone or with addition of either leptin (N = 7), adiponectin (N = 8) or JAK2/STAT3 inhibitor + leptin (N = 7), and AMH and AMHR-II mRNA levels measured. Levels of AMH, leptin and adiponectin protein were measured in follicular fluid. MAIN RESULTS AND THE ROLE OF CHANCE: AMH and AMHR-II mRNA and follicular fluid AMH protein levels were inversely correlated with age. AMH mRNA expression was six times higher in cumulus compared with mural granulosa cells in SFs (P< 0.05) and eight times higher in cumulus compared with mural granulosa cells in LFs (P < 0.001). In follicular fluid, leptin protein level positively correlated (r = 0.7, P = 0.03), while adiponectin protein level inversely correlated (r = -0.46, P = 0.02) with BMI. Leptin treatment suppressed AMH and AMHR-II mRNA in both cumulus and mural granulosa cells (all P < 0.05). In the presence of JAK2/STAT3 inhibitor, leptin treatment did not alter AMH but continued to suppress AMHR-II mRNA in cumulus cells (P = 0.02). Adiponectin treatment did not alter AMH or AMHR-II mRNA levels. LIMITATIONS, REASONS FOR CAUTION: This study included a luteinized granulosa cell model as these cells were collected from women who were hyperstimulated with gonadotrophins. The results obtained may not fully extrapolate to non-luteinized granulosa cells. WIDER IMPLICATIONS OF THE FINDINGS: Leptin may program abnormal AMH signaling, thereby resulting in ovarian dysfunction. This study opens a new perspective for understanding the low ovarian reserve seen in obese women and provides new insights into potential mechanisms that explain the lower AMH seen in obese women. Whether our findings explain the worse response to ovulation induction observed in obese women needs to be further elucidated.

Constructive and destructive addition of forward and reflected arterial pulse waves.

Although the physics of arterial pulse wave propagation and reflection is well understood, there is considerable debate as to the effect of reflection on vascular input impedance (Z(in)), pulsatile pressure, and stroke work (SW). This may be related to how reflection is studied. Conventionally, reflection is experimentally abolished (thus radically changing unrelated parameters), or a specific model is assumed from which reflection can be removed (yielding model-dependent results). The present work proposes a simple, model-independent method to evaluate the effect of reflection directly from measured pulsatile pressure (P) and flow (Q). Because characteristic impedance (Z(0)) is Z(in) in the absence of reflection, the P with reflection theoretically removed can be calculated from Q x Z(0). Applying this insight to an illustrative case indicates that reflection has the least effect on P and SW at normal pressure but a greater effect with vasodilation and vasoconstriction. Z(in), P, and SW are increased or decreased depending on the relative amount of constructive and destructive addition of forward and reflected arterial pulse waves.

True arterial system compliance estimated from apparent arterial compliance.

A new method has been developed to estimate total arterial compliance from measured input pressure and flow. In contrast to other methods, this method does not rely on fitting the elements of a lumped model to measured data. Instead, it relies on measured input impedance and peripheral resistance to calculate the relationship of arterial blood volume to input pressure. Generally, this transfer function is a complex function of frequency and is called the apparent arterial compliance. At very low frequencies, the confounding effect of pulse wave reflection disappears, and apparent compliance becomes total arterial compliance. This study reveals that frequency components of pressure and flow below heart rate are generally necessary to obtain a valid estimate of compliance. Thus, the ubiquitous practice of estimating total arterial compliance from a single cardiac cycle is suspect under most circumstances, since a single cardiac cycle does not contain these frequencies.

Disparate effects of three types of extracellular acidosis on left ventricular function.

Effects of acidosis on muscle contractile function have been studied extensively. However, the relative effects of different types of extracellular acidosis on left ventricular (LV) contractile function, especially the temporal features of contraction, have not been investigated in a single model. We constituted perfusion buffers of identical ionic composition, including Ca2+ concentration ([Ca2+]), to mimic physiological control condition (pH 7.40) and three types of acidosis with pH of 7.03: inorganic (IA), respiratory (RA), and lactic (LA). Isolated rabbit hearts (n = 9) were perfused with acidotic buffers chosen at random, each preceded by the control buffer. Under steady-state conditions, instantaneous LV pressure (Pv) and volume (Vv) were recorded for a range of Vv. The results were as follows. 1) LV passive (end-diastolic) elastance increased with IA and RA. However, this increase may not be a direct effect of acidosis; it can be explained on the basis of myocardial turgor. 2) Although LV inotropic state (peak active Pv and elastance) was depressed by all three acidotic buffers, the magnitude of inotropic depression was significantly less for LA. 3) Temporal features of Pv were altered differently. Whereas IA and RA reduced time to peak Pv (tmax) and hastened isovolumic relaxation at a common level of LV wall stress, LA significantly increased tmax and retarded relaxation. These results and a model-based interpretation suggest that cooperative feedback (i.e., force-activation interaction) plays an important role in acidosis-induced changes in LV contractile function. Furthermore, it is proposed that LA-induced responses comprise two components, one due to intracellular acidosis and the other due to pH-independent effects of lactate ions.

Apparent arterial compliance.

Recently, there has been renewed interest in estimating total arterial compliance. Because it cannot be measured directly, a lumped model is usually applied to derive compliance from aortic pressure and flow. The archetypical model, the classical two-element windkessel, assumes 1) system linearity and 2) infinite pulse wave velocity. To generalize this model, investigators have added more elements and have incorporated nonlinearities. A different approach is taken here. It is assumed that the arterial system 1) is linear and 2) has finite pulse wave velocity. In doing so, the windkessel is generalized by describing compliance as a complex function of frequency that relates input pressure to volume stored. By applying transmission theory, this relationship is shown to be a function of heart rate, peripheral resistance, and pulse wave reflection. Because this pressure-volume relationship is generally not equal to total arterial compliance, it is termed "apparent compliance." This new concept forms the natural counterpart to the established concept of apparent pulse wave velocity.

Understanding and managing resistance.

AIDS: As many as 25 to 45 percent of patients using triple therapy with protease inhibitors will develop resistance due to a change in the genetic HIV code. However, patients who develop resistance may still benefit clinically when protease inhibitors are used in combination with other antiretrovirals. These patients may not have undetectable viral loads although they may have stable T4-cell counts. Resistance does not always lead to disease progression. Newer drugs under development or available through compassionate track programs may benefit people with resistance. DMP-266 (Sustiva) is a non-nucleoside reverse transcriptase inhibitor that shows promise for these patients. Other drugs in development include Compound 141, 1592, and adefovir.^ieng

Serial assessment of the cardiovascular system in normal pregnancy. Role of arterial compliance and pulsatile arterial load.

BACKGROUND: Temporal changes in systemic arterial compliance and wave propagation properties (pulsatile arterial load) and their role in ventricular-systemic arterial coupling during gestation have not been explored. Noninvasive methods combined with recently developed mathematical modeling techniques were used to characterize vascular and left ventricular (LV) mechanical adaptations during normal gestation. METHODS AND RESULTS: Fourteen healthy women were studied at each trimester of pregnancy and again postpartum. Experimental measurements included instantaneous aortic pressure (subclavian pulse tracings) and flow (aortic Doppler velocities) and echocardiographic imaging of the LV. A small increase in LV muscle mass and end-diastolic chamber dimension occurred by late gestation, with no significant alterations in myocardial contractility. Cardiac output increased and the steady component of arterial load (total vascular resistance) decreased during pregnancy. Several changes in pulsatile arterial load were noted: Global arterial compliance increased (approximately 30%) during the first trimester and remained elevated thereafter. The magnitude of peripheral wave reflections at the aorta was reduced. The mathematical model-based analysis revealed that peripheral wave reflections at the aorta were delayed and that both conduit and peripheral vessels contributed to the increased arterial compliance. Finally, coordinated changes in the pulsatile arterial load and LV properties were responsible for maintaining the efficiency of LV-to-arterial system energy transfer. CONCLUSIONS: The rapid time course of compliance changes and the involvement of both conduit and peripheral vessels are consistent with reduced vascular tone as being the main underlying mechanism. The pulsatile arterial load alterations during normal pregnancy are adaptive in that they help to accommodate the increased intravascular volume while maintaining the efficiency of ventricular-arterial coupling and diastolic perfusion pressure.

Ejection has both positive and negative effects on left ventricular isovolumic relaxation.

In isovolumically beating hearts, the speed of left ventricular (LV) relaxation is uniquely determined by peak active stress (sigma max). In contrast, such a succinct description of relaxation is lacking for the ejection beats, although ejection is generally thought to hasten relaxation. We set out to determine how ejection modifies the relaxation-sigma max relationship obtained in the isovolumically beating hearts. Experiments were performed on five isolated rabbit hearts subjected to various loading conditions. Instantaneous LV pressure and volume were recorded and converted to active stress, from which isovolumic relaxation time (Tr) was defined as the time for stress to fall from 75 to 25% of sigma max (isovolumic beats) or its end-ejection value (ejection beats). Steady-state and transient isovolumic beat and steady-state ejection beat data were used to develop a multiple regression model. This model identified stress, current beat ejection, and previous beat ejection history as independent predictor variables of Tr and fit the data well in all hearts (r2 > 0.98). Furthermore, this model could predict relaxation in transient ejection beats (r2 = 0.30 for all hearts). Whereas the coefficient for the current beat ejection was negative (i.e., negative effect or hastening relaxation), the ejection history coefficient was positive (i.e., positive effect or slowing relaxation). The sum of these two coefficients was negative, corresponding to the commonly observed net negative effect of ejection on relaxation. The expected positive inotropic effect of ejection was also observed. The dissipations of both positive inotropic and relaxation effects were slow, suggesting a nonmechanical underlying mechanism(s). We postulate that these two effects are linked and caused by ejection-mediated changes in myofilament Ca2+ sensitivity.

Acute primary human immunodeficiency virus type 1 infection in a patient with concomitant cytomegalovirus encephalitis.

We report what we believe is the first case of primary human immunodeficiency virus type 1 (HIV-1) infection and simultaneous cytomegalovirus (CMV) encephalitis, which was confirmed by detection of CMV DNA in the patient's cerebrospinal fluid with use of the polymerase chain reaction. This coinfection had an unusual course, and the patient's clinical status deteriorated despite administration of combination antiretroviral therapy. The patient responded clinically only after therapy for CMV infection was added to his combination antiretroviral regimen. An atypical course and duration of symptomatic primary HIV-1 infection should suggest a possible coincident infection with other opportunistic agents that are normally expected to cause disease later in the course of HIV-1 infection. Current recommendations from the Centers for Disease Control and Prevention list CMV encephalitis as an AIDS-defining event.

Wave propagation in coupled left ventricle-arterial system. Implications for aortic pressure.

The objective of this study was to examine the effects of wave propagation properties (global reflection coefficient gamma IG; pulse wave velocity, c(ph); and characteristic impedance zeta(o) on the mechanical performance of the coupled left ventricle-arterial system. Specifically, we sought to quantify effects on aortic pressure (P(ao)) and flow Q(ao) while keeping constant other determinants of P(ao) and Q(ao) (left ventricular end-diastolic volume, V(ed), and contractility, heart rate, and peripheral resistance, R(s)). Isolated rabbit hearts were subjected to real-time, computer-controlled physiological loading. The arterial circulation was modeled with a lossless tube terminating in a complex load. The loading system allowed for precise and independent control of all arterial properties as evidenced by accurate reproduction of desired input impedances and computed left ventricular volume changes. While propagation phenomena affected P(ao) and Q(ao) morphologies as expected, their effects on absolute P(ao) values were often contrary to the current understanding. Diastolic (Pd) and mean (Pm) P(ao) and stroke volume decrease monotonically with increases in gamma G, c(ph), or zeta(o) over wide ranges. In contrast, these increase had variable effects on peak systolic P(ao) (Ps): decreasing with gamma G, biphasic with c(ph), and increasing with zeta(o). There was an interaction between gamma G and c(ph) such that gamma G effects on P(m) and P(d) were augmented a higher C(ph) and vice versa. Despite large changes in system parameters, effects on Pm and Ps were modest ( < 10% and < 5%, respectively); effects on Pd were always two to four times greater. Similar results were obtained when the single-tube model of the arterial system was replaced by an asymmetrical T-tube configuration. Our data do not support the prevailing hypothesis that P(s) (and therefore ventricular load) can be selectively and significantly altered by manipulating gamma G, c(ph), and/or zeta o.

Combating malnutrition in HIV infection.

Physicians should use nutrition as adjunctive therapy for all patients affected by HIV disease. However, when wasting is already present, a thorough evaluation (examination and labs) to elucidate and treat the underlying causes of malnutrition should be initiated, dietary counseling made available, and nutritional and vitamin/mineral supplementation encouraged. Appetite stimulants may be helpful when appropriate. If wasting syndrome develops despite intervention, enteral or parenteral nutrition may be considered. Clinical trials are currently underway to assess the utility of anabolic therapies and cytokine inhibitors as additional options. Malnutrition is a leading cause of morbidity in HIV disease. With continued research and early nutritional interventions (i.e., prevention as well as treatment strategies), the task of preventing wasting may eventually become "a piece of cake."

Arterial wave propagation phenomena, ventricular work, and power dissipation.

The effects of wave propagation phenomena, namely global reflection coefficient (gamma G[omega]) and pulse wave velocity (Cph), are studied in a model of the coupled left ventricle/arterial system. The left ventricle consists of a time-varying elastance, while the arterial system is modeled as a single, uniform, elastic tube terminating in a complex load. Manipulation of model parameters allowed for the precise control of gamma G(omega) and Cph independent of each other, peripheral resistance, and characteristic impedance. Reduction of gamma G(omega) and Cph were achieved through increases in load compliance and tube compliance, respectively. The equations describing the system were solved for left ventricular and aortic pressures and aortic flow. From these, stroke volume (SV), left ventricular stroke work (SW), and steady (Ws), oscillatory (Wo), and total power dissipation (Wt) in the arterial system were calculated. An index of arterial system efficiency was the ratio Wo/Wt (%Wo), with lower values indicating higher efficiency. Reduction of gamma G(omega) yielded initial increases in Ws, while Wo increased for the entire range of gamma G(omega), resulting in increased %Wo. This reduced efficiency is imposed on the ventricle, resulting in increased SW without increased SV. On the other hand, decreased Cph yielded in a steady increase in Ws and a biphasic response in Wo, resulting in reduced %Wo for most of the range of reduced Cph. These results suggest that differential effects on arterial system efficiency can result from reductions of gamma G(omega) and Cph. In terms of compliance, changes in arterial compliance can have different effects on efficiency, depending on where the compliance change takes place. Reasons for these results are suggested, and the role of distributed compliances is raised as a new problem.

Physiological relevance of T-tube model parameters with emphasis on arterial compliances.

The T-tube model of systemic arterial circulation was examined with respect to the physiological relevance of model parameters. root aortic pressure [Pao(t)] and flow [Qao(t)] and descending aortic flow [Qb(t)] were measured in anesthetized, open-chest dogs under control conditions, during inflation of a balloon positioned in the left external iliac artery (n = 5), and during infusion of vasoactive drugs nitroprusside (NTP, n = 4) and phenylephrine (PHL, n = 5). With Pao(t) as the input, the model accurately predicted both Qao(t) and Qb(t) under all conditions (r2 > 0.96). The balloon inflation data established the ability of the model to discriminate between proximal and distal arterial mechanical properties. Furthermore, proximal properties (i.e., tube characteristic impedances and transit times) were independent of distal properties such as terminal compliances and resistances (or equivalently, wave reflections). The effects of NTP and PHL were pharmacologically consistent and served to further validate this model. NTP primarily affected distal (load) properties, whereas PHL altered both load and tube parameters. Physiological interpretation of model parameters, particularly compliance, is also discussed. The ability of the model to correctly discriminate between proximal and distal arterial properties is relevant because these properties may affect cardiovascular function differently.

Alterations in systemic arterial mechanical properties during septic shock: role of fluid resuscitation.

The effects of septic shock (endotoxin; EDTX) on arterial mechanical properties were studied in anesthetized rabbits, both in the absence (EDTX alone) and presence (EDTX + fluids) of fluid resuscitation. Aortic pressure-flow (n = 20) and pressure-diameter (n = 10) measurements were used to calculate systemic arterial and regional aortic mechanical properties. At 3 h of EDTX shock, EDTX-alone rabbits had elevated total peripheral resistance (TPR, + 30%, P < 0.05), reduced cardiac output (CO, -40%, P < 0.05), and increased aortic characteristic impedance (Zc, +78%, P < 0.05). In contrast, the EDTX + fluids group responded with decreased TPR (-30%, P < 0.05), a tendency to increase CO (+23%), and elevated Zc (+46%, P < 0.05). A reduction in aortic diameter (-20%, P < 0.05) and an increase in elastic modulus (+50%, P < 0.05) and water content (+23%, P < 0.02) of the aortic wall were observed following endotoxemia. Thus following EDTX 1) "hyperdynamic" septic shock profile (i.e., low TPR, high CO) was observed only when concomitant fluid replacement was provided, 2) aortic wall stiffening was present due to both increased smooth muscle tone and vessel wall edema, and 3) fluid resuscitation resulted in discordant changes in TPR and Zc, suggesting differential flow-induced vasodilation between arteriolar and aortic smooth muscle.