Clinical and Hemodynamic Outcomes of Balloon-Expandable Mitral Valve-in-Valve Positioning and Asymmetric Deployment: The VIVID Registry.

BACKGROUND: Mitral valve-in-valve (ViV) is associated with suboptimal hemodynamics and rare left ventricular outflow tract (LVOT) obstruction. OBJECTIVES: This study aimed to determine whether device position and asymmetry are associated with these outcomes. METHODS: Patients undergoing SAPIEN 3 (Edwards Lifesciences) mitral ViV included in the VIVID (Valve-in-Valve International Data) Registry were studied. Clinical endpoints are reported according to Mitral Valve Academic Research Consortium definitions. Residual mitral valve stenosis was defined as mean gradient ≥5 mm Hg. Depth of implantation (percentage of transcatheter heart valve [THV] atrial to the bioprosthesis ring) and asymmetry (ratio of 2 measures of THV height) were evaluated. RESULTS: A total of 222 patients meeting the criteria for optimal core lab evaluation were studied (age 74 ± 11.6 years; 61.9% female; STS score = 8.3 ± 7.1). Mean asymmetry was 6.2% ± 4.4%. Mean depth of implantation was 19.0% ± 10.3% atrial. Residual stenosis was common (50%; mean gradient 5.0 ± 2.6 mm Hg). LVOT obstruction occurred in 7 cases (3.2%). Implantation depth was not a predictor of residual stenosis (OR: 1.19 [95% CI: 0.92-1.55]; P = 0.184), but more atrial implantation was protective against LVOT obstruction (0.7% vs 7.1%; P = 0.009; per 10% atrial, OR: 0.48 [95% CI: 0.24-0.98]; P = 0.044). Asymmetry was found to be an independent predictor of residual stenosis (per 10% increase, OR: 2.30 [95% CI: 1.10-4.82]; P = 0.027). CONCLUSIONS: Valve stenosis is common after mitral ViV. Asymmetry was associated with residual stenosis. Depth of implantation on its own was not associated with residual stenosis but was associated with LVOT obstruction. Technical considerations to reduce postdeployment THV asymmetry should be considered.

Anxiety in youth at clinical high risk for psychosis: A case study and conceptual model.

Some individuals identified as being at clinical high risk (CHR) for developing psychosis may suffer substantial anxiety due to a fear of transitioning to psychosis. This can be associated with catastrophic misinterpretation of normal mental experiences, such as a momentary lapse in attention, as markers for psychosis, fueled by hypervigilance for mental experiences that may be perceived as signs of impending psychosis. This anxiety may only worsen due to the self-stigma triggered by admission to a psychiatric CHR clinic, independent of whether or not the individual transitions to psychosis. Based on a clinical case study, we propose a cognitive model for this anxiety, an extension of Clark's model of panic. Our model accounts for causal factors of this distress, such as self-stigma and maladaptive core beliefs. It also includes maintaining factors such as hypervigilance for mental experiences and catastrophic misinterpretation of normal mental experiences as anomalous and portending eventual psychosis. We outline assessment and treatment guidelines and offer suggestions for how this model could be empirically validated. We suggest that treatment with this model, under the neural diathesis-stress framework, may have the potential to lower the risk of transition to psychosis and that assessment for such anxiety should be part of standard CHR care.

Regional cerebellar volumes are related to early musical training and finger tapping performance.

The cerebellum has been associated with timing on the millisecond scale and with musical rhythm and beat processing. Early musical training (before age 7) is associated with enhanced rhythm synchronization performance and differences in cortical motor areas and the corpus callosum. In the present study, we examined the relationships between regional cerebellar volumes, early musical training, and timing performance. We tested adult musicians and non-musicians on a standard finger tapping task, and extracted cerebellar gray and white matter volumes using a novel multi-atlas automatic segmentation pipeline. We found that early-trained musicians had reduced volume in bilateral cerebellar white matter and right lobules IV, V and VI, compared to late-trained musicians. Strikingly, better timing performance, greater musical experience and an earlier age of start of musical training were associated with smaller cerebellar volumes. Better timing performance was specifically associated with smaller volumes of right lobule VI. Collectively, these findings support the sensitivity of the cerebellum to the age of initiation of musical training and suggest that lobule VI plays a role in timing. The smaller cerebellar volumes associated with musical training and timing performance may be a reflection of more efficiently implemented low-level timing and sensorimotor processes.

TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis.

Molecular subtypes of breast cancer are characterized by distinct patterns of gene expression that are predictive of outcome and response to therapy. The luminal breast cancer subtypes are defined by the expression of estrogen receptor-alpha (ERα)-associated genes, many of which are directly responsive to the transcription factor activator protein 2C (TFAP2C). TFAP2C participates in a gene regulatory network controlling cell growth and differentiation during ectodermal development and regulating ESR1/ERα and other luminal cell-associated genes in breast cancer. TFAP2C has been established as a prognostic factor in human breast cancer, however, its role in the establishment and maintenance of the luminal cell phenotype during carcinogenesis and mammary gland development have remained elusive. Herein, we demonstrate a critical role for TFAP2C in maintaining the luminal phenotype in human breast cancer and in influencing the luminal cell phenotype during normal mammary development. Knockdown of TFAP2C in luminal breast carcinoma cells induced epithelial-mesenchymal transition with morphological and phenotypic changes characterized by a loss of luminal-associated gene expression and a concomitant gain of basal-associated gene expression. Conditional knockout of the mouse homolog of TFAP2C, Tcfap2c, in mouse mammary epithelium driven by MMTV-Cre promoted aberrant growth of the mammary tree leading to a reduction in the CD24(hi)/CD49f(mid) luminal cell population and concomitant gain of the CD24(mid)/CD49f(hi) basal cell population at maturity. Our results establish TFAP2C as a key transcriptional regulator for maintaining the luminal phenotype in human breast carcinoma. Furthermore, Tcfap2c influences development of the luminal cell type during mammary development. The data suggest that TFAP2C has an important role in regulated luminal-specific genes and may be a viable therapeutic target in breast cancer.

The role of musical training in emergent and event-based timing.

INTRODUCTION: Musical performance is thought to rely predominantly on event-based timing involving a clock-like neural process and an explicit internal representation of the time interval. Some aspects of musical performance may rely on emergent timing, which is established through the optimization of movement kinematics, and can be maintained without reference to any explicit representation of the time interval. We predicted that musical training would have its largest effect on event-based timing, supporting the dissociability of these timing processes and the dominance of event-based timing in musical performance. MATERIALS AND METHODS: We compared 22 musicians and 17 non-musicians on the prototypical event-based timing task of finger tapping and on the typically emergently timed task of circle drawing. For each task, participants first responded in synchrony with a metronome (Paced) and then responded at the same rate without the metronome (Unpaced). RESULTS: Analyses of the Unpaced phase revealed that non-musicians were more variable in their inter-response intervals for finger tapping compared to circle drawing. Musicians did not differ between the two tasks. Between groups, non-musicians were more variable than musicians for tapping but not for drawing. We were able to show that the differences were due to less timer variability in musicians on the tapping task. Correlational analyses of movement jerk and inter-response interval variability revealed a negative association for tapping and a positive association for drawing in non-musicians only. DISCUSSION: These results suggest that musical training affects temporal variability in tapping but not drawing. Additionally, musicians and non-musicians may be employing different movement strategies to maintain accurate timing in the two tasks. These findings add to our understanding of how musical training affects timing and support the dissociability of event-based and emergent timing modes.

Contributions of severe burn and disuse to bone structure and strength in rats.

Burn and disuse results in metabolic and bone changes associated with substantial and sustained bone loss. Such loss can lead to an increased fracture incidence and osteopenia. We studied the independent effects of burn and disuse on bone morphology, composition and strength, and microstructure of the bone alterations 14days after injury. Sprague-Dawley rats were randomized into four groups: Sham/Ambulatory (SA), Burn/Ambulatory (BA), Sham/Hindlimb Unloaded (SH) and Burn/Hindlimb Unloaded (BH). Burn groups received a 40% total body surface area full-thickness scald burn. Disuse by hindlimb unloading was initiated immediately following injury. Bone turnover was determined in plasma and urine. Femur biomechanical parameters were measured by three-point bending tests and bone microarchitecture was determined by micro-computed tomography (uCT). On day 14, a significant reduction in body mass was observed as a result of burn, disuse and a combination of both. In terms of bone health, disuse alone and in combination affected femur weight, length and bone mineral content. Bending failure energy, an index of femur strength, was significantly reduced in all groups and maximum bending stress was lower when burn and disuse were combined. Osteocalcin was reduced in BA compared to the other groups, indicating influence of burn. The reductions observed in femur weight, BMC, biomechanical parameters and indices of bone formation are primarily responses to the combination of burn and disuse. These results offer insight into bone degradation following severe injury and disuse.

Benefits of pulsatile flow in pediatric cardiopulmonary bypass procedures: from conception to conduction.

This review on the benefits of pulsatile flow includes not only experimental and clinical data, but also attempts to further illuminate the major factors as to why this debate has continued during the past 55 years. Every single component of the cardiopulmonary bypass (CPB) circuitry is equally important for generating adequate quality of pulsatility, not only the pump. Therefore, translational research is a necessity to select the best components for the circuit. Generation of pulsatile flow depends on an energy gradient; precise quantification in terms of hemodynamic energy levels is, therefore, a necessity, not an option. Comparisons between perfusion modes should be done after these basic steps have been taken. We have also included experimental and clinical data for direct comparisons between the perfusion modes. In addition, we included several suggestions for future clinical trials for other interested investigators.

Successful treatment of peripartum cardiomyopathy with extracorporeal membrane oxygenation.

A 24-year-old female developed heart failure within four months of delivering her first child. Echocardiogram revealed a moderately dilated left ventricle with severely reduced systolic function. She continued to decompensate, requiring intubation and inotropic support. When the use of an intra-aortic balloon pump failed to stabilize the patient, the decision was made to place her on ECMO. The circuit consisted of a Quadrox D membrane oxygenator and a CentriMag centrifugal pump. After 11 days of support, the patient met the weaning criteria and was successfully removed from ECMO. She was discharged one month after her admission. The new technology available allows for ECMO to be considered as an earlier option for the treatment and management of these patients as a bridge to recovery.

A screening and prevention programme serving an ethnically diverse population of women at high risk of developing breast and/or ovarian cancer.

INTRODUCTION: We describe a screening and prevention programme primarily targeting under-served minority women at high risk of breast and/or ovarian cancer. Women attending this Bellevue Hospital Center (BHC) Clinic were either self-referred from a variety of special outreach programmes or referred internally by medical professionals caring for relatives or friends. Our objective was to delineate referral sources and preliminary risk-assessment findings in relation to demographic features in this population. METHODS: Following a detailed family and personal history intake and physical examination, each woman on her initial visit is categorized into a low (standard) risk, high-risk or indeterminate-risk group. Women found to be at high risk of developing breast and/or ovarian cancers are referred for further testing, additional screening measures, or participation in chemoprevention trials. All other women are counselled concerning follow-up and lifestyle issues. RESULT: Between 2003 and 2007, 171 women for whom complete information was obtained were analysed. Thirty-four of the women were Caucasians (19.8%) and 137 (80.2%) were ethnically diverse minority women. Sixty-two (36.2%) were found to be at high risk with a median age of 42 years. The majority of the high-risk women were referred to the clinic by medical professionals (58%), most of whom were from within the BHC health care system. In fact, one-fourth of the referrals were women who carried a diagnosis of cancer, mostly arising in the breast, and who were concerned with risks to other family members. Trends in genetic testing results indicate fewer mutations among high-risk Asians than among other ethnicities. CONCLUSION: Accurate risk assessments and implementation of screening and prevention measures have been challenging during the first few years of operation. Nevertheless, the need for providing consultation from internal referrals and the potential for genetic and psychosocial research in an ethnically diverse population are powerful incentives for continuing to evolve these services.

Tissue-specific variation in expression of prolactin receptor gene subtypes in hypergravity-exposed rats.

Prolactin (PRL) effects are mediated by membrane receptors (PRLR) of which the long (PRLR-L) and short form (PRLR-S) predominate. Our objective was to compare the distribution pattern of PRLR-L and PRLR-S transcripts and their ratio in adipose (AD), liver (LV), mammary (MG) and pituitary (PG) tissues of stationary (SC, n = 8) and hypergravity (HG, n = 8) exposed periparturient rats. Pregnant rats were exposed to 2 g force from day 11 of gestation (G11) through post partum day 1 (P1). PRLR-L mRNA expression compared to PRLR-S was greater (P < 0.001) in AD, MG and PG but was lower (P < 0.001) in LV in both HG and SC animals at P1. The ratio of PRLR-L/PRLR-S mRNA in the AD, LV, MG and PG was not different between HG and SC rats. In summary, these data reveal that the hypergravity-induced downregulation of PRLR is not directly triggered by deranged distribution of PRLR isoforms.

Homocysteine levels and glucose metabolism in non-obese, non-diabetic chronic schizophrenia.

OBJECTIVE: We studied a sample of schizophrenia out-patients to test the hypotheses that serum homocysteine concentrations would correlate positively with measures of glucose metabolism. METHOD: Subjects underwent a nutritional assessment and fasting plasma, serum insulin and homocysteine tests. RESULTS: Males had a significantly higher homocysteine levels than females (7.69 +/- 1.42 microM vs. 6.63 +/- 1.40 microM; P = 0.02). Comparing subjects with normal fasting glucose (NFG) (glucose < 100 mg/dl) and impaired fasting glucose (IFG) (> or = 100 mg/dl) subjects with IFG (mean 8.2 +/- 1.5 microM) had significantly higher homocysteine levels than those with NFG (mean 7.2 +/- 1.4 microM, P = 0.03). IFG was also associated with greater mean values for a Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) (P = 0.002) and diastolic blood pressure (P = 0.045). CONCLUSION: The group with IFG had higher fasting serum homocysteine concentrations than those with NFG which supports a connection to an important cardiovascular risk factor.

Association between gravitational force and tissue metabolism in periparturient rats.

Recently, interest in mammalian reproduction and offspring survival in altered gravity has been growing. Because successful lactation is critical for mammalian neonate survival, we have been studying the effect of gravity metabolism. We have shown an exponential relationship between glucose metabolic rate in mammary tissue of periparturient rats and an increase in gravity load. In this study we showed that changes in mammary metabolic rate due to gravity force were accompanied by a decrease in glucose metabolism in adipose tissue and by a reduced size of adipocytes. We assume that these changes are likely due to changes in prolactin or leptin levels related to altered gravity load.

Effects of hypergravity on mammary metabolic function: gravity acts as a continuum.

Mammary metabolic activity in pregnant rats is significantly increased in response to spaceflight. To determine whether changes in mammary metabolism are related to gravity load, we exposed pregnant rats to hypergravity and measured mammary metabolic activity. From days 11-20 of gestation (G), animals were centrifuged (20 rpm; 1.5, 1.75, or 2.0 x gravity) or were maintained at 1 G. On G20, five rats from each group were removed from the centrifuge and euthanized. The remaining dams (n = 5/treatment) were housed at 1 G until parturition. After 2 h of nursing by the pups, the postpartum dams were euthanized (G22). Glucose oxidation to CO2 and incorporation into lipids was measured. Mammary glands from dams euthanized on G20 revealed a strong negative correlation between metabolic rate and increased G load. Approximately 98% of the variation in glucose oxidation and 94% of the variation in glucose incorporation into lipids can be accounted for by differences in G load. Differences in metabolic activity disappeared in the postpartum dams. When we combined previous data from the microgravity with hypergravity environments and plotted the ratio of mammary metabolic rate vs. G load, there was a significant exponential relationship (r2 = 0.99). These data demonstrate a remarkable continuum of response across the microgravity and hypergravity environments and support the concept that gravitational load influences mammary tissue metabolism.

Body mass, energy intake, and water consumption of rats and humans during space flight.

Alteration of metabolism has been suggested as a major limiting factor to long-term space flight. In humans and primates, a negative energy balance has been reported. The metabolic response of rats to space flight has been suggested to result in a negative energy balance. We hypothesized that rats flown in space would maintain energy balance as indicated by maintenance of caloric intake and body mass gain. Further, the metabolism of the rat would be similar to that of laboratory-reared animals. We studied the results from 15 space flights lasting 4 to 19 d. There was no difference in average body weight (206 +/- 13.9 versus 206 +/- 14.8 g), body weight gain (5.8 +/- 0.48 versus 5.9 +/- 0.56 g/d), caloric intake (309 +/- 21.0 versus 309 +/- 20.1 kcal/kg of body mass per day), or water intake (200 +/- 8.6 versus 199 +/- 9.3 mL/kg of body mass per day) between flight and ground control animals. Compared with standard laboratory animals of similar body mass, no differences were noted. The observations suggested that the negative balance observed in humans and non-human primates may be due to other factors in the space-flight environment.

Rate controlling steps in fatty acid oxidation by unloaded rodent soleus muscle.

In response to decreased usage skeletal muscle undergoes an adaptive reductive remodeling due to the decrease in tension on the weight bearing components of the musculo-skeletal system. Accompanying a shift in fiber type is an increased reliance of carbohydrate metabolism and decreased reliance on fat for energy. These responses have been found with both space flight and ground based models of disuse atrophy including the chronically adapted rodent hind limb suspended (HLS) rat (1, 4-7, 10, 11). In addition, after space flight, the ability of soleus muscle homogenates to oxidize palmitate is decreased. We have previously shown that expression of the mRNA of enzymes involved in beta-oxidation is reduced in the soleus muscle of HLS rats. At the same time mRNA expression of enzymes involved in glycolysis was increased. This study extends these observations to address the question of whether the decrease in beta-oxidation is caused by a reduction in the capacity of the pathway to oxidize fat or the regulation is effected before fatty acids enter the mitochondria, i.e. the reduced capacity of the fatty acid oxidation pathway is because less fat is available for oxidation. The two key steps involved in fatty acid uptake into the cells are lipoprotein lipase and the transport of the free fatty acids produced by lipoprotein lipase into the cell via the carnitine acyltransferase system.

The Skin Picking Impact Scale (SPIS): scale development and psychometric analyses.

The Skin Picking Impact Scale (SPIS) is a self-report instrument developed to assess the psychosocial consequences of repetitive skin picking. An initial 28-item scale was administered to 31 individuals with severe self-injurious skin picking and 78 individuals with non-self-injurious skin picking. Item difficulty levels and part-whole correlations resulted in a 10-item scale with good internal consistency. SPIS scores for those with self-injurious skin picking were significantly higher than for those with non-self-injurious skin picking. SPIS scores for those with self-injurious skin picking correlated with duration of daily picking, satisfaction during picking, and shame subsequent to picking, as well as Beck Depression Inventory and Beck Anxiety Inventory scores. Sensitivity and specificity analyses indicate that a scale cutoff score of 7 optimally discriminates individuals with self-injurious skin picking from those with non-self-injurious skin picking.

Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for obsessive compulsive disorder.

BACKGROUND: As interventions for severe, treatment-refractory obsessive compulsive disorder (OCD), neurosurgical procedures are associated with only modest efficacy. The purpose of this study was to identify cerebral metabolic correlates as potential predictors of treatment response to anterior cingulotomy for OCD. METHODS: Clinical data were analyzed in the context of a retrospective design. Subjects were 11 patients who underwent stereotactic anterior cingulotomy for OCD. Symptom severity was measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) before and at approximately 6 months postoperative. Preoperative F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) data were available. Statistical parametric mapping methods were used to identify loci of significant correlation between preoperative regional cerebral metabolism and postoperative reduction in Y-BOCS scores. RESULTS: One locus within right posterior cingulate cortex was identified, where preoperative metabolism was significantly correlated with improvement in OCD symptom severity following cingulotomy. Specifically, higher preoperative rates of metabolism at that locus were associated with better postoperative outcome. CONCLUSIONS: A possible predictor of treatment response was identified for patients with OCD undergoing anterior cingulotomy. Further research, utilizing a prospective design, is indicated to determine the validity and reliability of this finding. If confirmed, an index for noninvasively predicting response to cingulotomy for OCD would be of great value.