Extended haplotype with rs41524547-G defines the ancestral origin of SCA10.

Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant ataxia caused by a large expansion of the (ATTCT)n repeat in ATXN10. SCA10 was described in Native American and Asian individuals which prompted a search for an expanded haplotype to confirm a common ancestral origin for the expansion event. All patients with SCA10 expansions in our cohort share a single haplotype defined at the 5'-end by the minor allele of rs41524547, located ~35 kb upstream of the SCA10 expansion. Intriguingly, rs41524547 is located within the miRNA gene, MIR4762, within its DROSHA cleavage site and just outside the seed sequence for mir4792-5p. The world-wide frequency of rs41524547-G is less than 5% and found almost exclusively in the Americas and East Asia-a geographic distribution that mirrors reported SCA10 cases. We identified rs41524547-G(+) DNA from the 1000 Genomes/International Genome Sample Resource and our own general population samples and identified SCA10 repeat expansions in up to 25% of these samples. The reduced penetrance of these SCA10 expansions may be explained by a young (pre-onset) age at sample collection, a small repeat size, purity of repeat units, or the disruption of miR4762-5p function. We conclude that rs41524547-G is the most robust at-risk SNP allele for SCA10, is useful for screening of SCA10 expansions in population genetics studies and provides the most compelling evidence to date for a single, prehistoric origin of SCA10 expansions sometime prior to or during the migration of individuals across the Bering Land Bridge into the Americas.

Postsynaptic NMDA Receptor Expression Is Required for Visual Corticocollicular Projection Refinement in the Mouse Superior Colliculus.

Efficient sensory processing of spatial information is facilitated through the organization of neuronal connections into topographic maps of space. In integrative sensory centers, converging topographic maps must be aligned to merge spatially congruent information. The superior colliculus (SC) receives topographically ordered visual inputs from retinal ganglion cells (RGCs) in the eye and layer 5 neurons in the primary visual cortex (L5-V1). Previous studies suggest that RGCs instruct the alignment of later-arriving L5-V1 inputs in an activity-dependent manner. However, the molecular mechanisms underlying this remain unclear. Here, we explored the role of NMDA receptors in visual map alignment in the SC using a conditional genetic knockout approach. We leveraged a novel knock-in mouse line that expresses tamoxifen-inducible Cre recombinase under the control of the Tal1 gene (Tal1CreERT2 ), which we show allows for specific recombination in the superficial layers of the SC. We used Tal1CreERT2 mice of either sex to conditionally delete the obligate GluN1 subunit of the NMDA receptor (SC-cKO) during the period of visual map alignment. We observed a significant disruption of L5-V1 axon terminal organization in the SC of SC-cKO mice. Importantly, retinocollicular topography was unaffected in this context, suggesting that alignment is also disrupted. Time-course experiments suggest that NMDA receptors may play a critical role in the refinement of L5-V1 inputs in the SC. Together, these data implicate NMDA receptors as critical mediators of activity-dependent visual map alignment in the SC.SIGNIFICANCE STATEMENT Alignment of topographic inputs is critical for integration of spatially congruent sensory information; however, little is known about the mechanisms underlying this complex process. Here, we took a conditional genetic approach to explore the role of NMDA receptors in the alignment of retinal and cortical visual inputs in the superior colliculus. We characterize a novel mouse line providing spatial and temporal control of recombination in the superior colliculus and reveal a critical role for NMDA expression in visual map alignment. These data support a role for neuronal activity in visual map alignment and provide mechanistic insight into this complex developmental process.

Blood pressure reactivity to psychological stress is associated with clinical outcomes in patients with heart failure.

INTRODUCTION: Cardiovascular (CV) reactivity to psychological stress has been implicated in the development and exacerbation of cardiovascular disease (CVD). Although high CV reactivity traditionally is thought to convey greater risk of CVD, the relationship between reactivity and clinical outcomes is inconsistent and may depend on the patient population under investigation. The present study examined CV reactivity in patients with heart failure (HF) and its potential association with long-term clinical outcomes. METHODS: One hundred ninety-nine outpatients diagnosed with HF, with ejection fraction ≤40%, underwent an evaluation of blood pressure (BP) and heart rate reactivity to a laboratory-based simulated public-speaking stressor. Cox proportional hazards regression models were used to examine the prospective association between BP and heart rate reactivity on a combined end point of death or CV hospitalization over a 5-year median follow-up period. RESULTS: Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) reactivity, quantified as continuous variables, were inversely related to risk of death or CV hospitalization (Ps < .01) after controlling for established risk factors, including HF disease severity and etiology. In similar models, heart rate reactivity was unrelated to outcome (P = .12). In models with tertiles of reactivity, high SBP reactivity, compared with intermediate SBP reactivity, was associated with lower risk (hazard ratio [HR] = .498, 95% CI .335-.742, P =.001), whereas low SBP reactivity did not differ from intermediate reactivity. For DBP, high reactivity was marginally associated with lower risk compared with intermediate DBP reactivity (HR = .767, 95% CI .515-1.14, P =.193), whereas low DBP reactivity was associated with greater risk (HR = 1.49, 95% CI 1.027-2.155, P =.0359). No relationship of heart rate reactivity to outcome was identified. CONCLUSIONS: For HF patients with reduced ejection fraction, a robust increase in BP evoked by a laboratory-based psychological challenge was associated with lower risk for adverse CVD events and may be a novel and unique marker of left ventricular systolic reserve that is accompanied by a more favorable long-term prognosis.

Depressive symptoms are associated with clinical outcomes in heart failure with reduced ejection fraction.

AIMS: The objective of this study was to examine associations between elevated depressive symptoms and increased risk of adverse clinical events patients with heart failure and reduced ejection fraction (HFrEF), as well as the potential contribution of health behaviours. METHODS AND RESULTS: One hundred forty-two men and women with HFrEF were enrolled through heart failure (HF) clinics and followed over time. At baseline and 6 months, depressive symptoms were assessed by the Beck Depression Inventory-II (BDI-II) and HFrEF disease activity by B-type natriuretic peptide (BNP). The Self-Care of Heart Failure Index (SCHFI) was used to assess HF self-care behaviours. Proportional hazards regression models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. Over a median follow-up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10-point higher baseline BDI-II score was associated with a 35% greater risk of death or cardiovascular hospitalization. Higher baseline BDI-II scores were associated with poorer HF self-care maintenance behaviours (R = -0.30, P < 0.001) and fewer daily steps (R = -0.19, P = 0.04), suggesting that elevated depressive symptoms may diminish important health behaviours. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI-II and plasma BNP over 6 months were positively related (R = 0.25, P = 0.004). CONCLUSIONS: This study confirms that elevated depressive symptoms are associated with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Poor health behaviours may contribute to the adverse association of elevated depressive symptoms with the increased hazard of adverse clinical outcomes.

Cognitive behavior therapy for insomnia for untreated hypertension with comorbid insomnia disorder: The SLEEPRIGHT clinical trial.

Insomnia and poor sleep are associated with an increased risk of developing cardiovascular disease (CVD) and its precursors, including hypertension. In 2022, the American Heart Association (AHA) added inadequate sleep to its list of health behaviors that increase the risk for CVD. It remains unknown, however, whether the successful treatment of insomnia and inadequate sleep can reduce heightened CVD risk. SLEEPRIGHT is a single-site, prospective clinical trial designed to evaluate whether the successful treatment of insomnia results in improved markers of CVD risk in patients with untreated hypertension and comorbid insomnia disorder. Participants (N = 150) will undergo baseline assessments, followed by a 6-week run-in period after which they will receive cognitive behavior therapy for insomnia (CBT-I), comprised of 6 hourly sessions with an experienced CBT-I therapist over a 6-week period. In addition to measures of insomnia severity, as well as both subjective and objective measures of sleep, the primary outcome measures are nighttime blood pressure (BP) and BP dipping assessed by 24-h ambulatory BP monitoring (ABPM). Secondary outcomes include several CVD risk biomarkers, including clinic BP, lipid profile, vascular endothelial function, arterial stiffness, and sympathetic nervous system (SNS) activity. Data analysis will evaluate the association between improvements in insomnia and sleep with primary and secondary CVD risk biomarker outcomes. The SLEEPRIGHT trial (ClinicalTrials.Gov NCT04009447) will utilize CBT-I, the current gold standard treatment for insomnia disorder, to evaluate whether reducing insomnia severity and improving sleep are accompanied by improved biomarkers of CVD risk in patients with untreated hypertension.

Association of Depression Symptoms and Biomarkers of Risk on Clinical Outcomes in HFrEF.

BACKGROUND: Prior studies have demonstrated an association of depression with adverse clinical outcomes in patients with HFrEF, but the possible mechanisms responsible for the association are not unserstood. METHODS: 142 men and women with HFrEF were enrolled through HF clinics and followed over time. At baseline and 6-months, depression was assessed by the Beck Depression Inventory (BDI-II) and disease activity by B-type natriuretic peptide (BNP). Proportional Hazards Regression Models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. RESULTS: Over a median follow-up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10-point higher baseline BDI-II score was associated with a 35% higher hazard of death or cardiovascular hospitalization. Greater baseline BDI-II scores were associated with poorer HF self-care maintenance (R=-0.30, p<0.001) and fewer daily steps (R=-0.19, p=0.04), suggesting that depression may adversely affect important health behaviors. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI-II score and plasma BNP over 6 months were positively correlated (R=0.25, p=0.004). CONCLUSIONS: This study underscores the importance of elevated depression symptoms and their association with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Health behaviors may play a greater role than direct biobehavioral pathways in the adverse effects of depression on the HF disease trajectory and resultant clinical outcomes.

Coping effectively with heart failure (COPE-HF): design and rationale of a telephone-based coping skills intervention.

BACKGROUND: Coping Effectively with Heart Failure (COPE-HF) is an ongoing randomized clinical trial funded by the National Institutes of Health to evaluate if a coping skills training (CST) intervention will result in improved health status and quality of life as well as reduced mortality and hospitalizations compared with a heart failure education (HFE) intervention. METHODS AND RESULTS: Two hundred heart failure (HF) patients recruited from the Duke University Medical Center and the University of North Carolina Hospital system will be randomized to a CST intervention (16 weekly 30-minute telephone counseling sessions including motivational interviewing and individually tailored cognitive behavioral therapy) or to an HFE intervention (16 weekly 30-minute telephone sessions including education and symptom monitoring). Primary outcomes will include postintervention effects on HF biomarkers (B-type natriuretic peptide, ejection fraction) and quality of life, as well as long-term clinical outcomes (hospitalizations and death). Secondary analyses will include an evaluation of treatment effects across subpopulations, and potential mechanisms by which CST may improve clinical outcomes. CONCLUSIONS: COPE-HF is a proof-of-concept study that should provide important insights into the health benefits of a CST intervention designed to enhance HF self-management, improve health behaviors, and reduce psychologic distress.

Wiring subcortical image-forming centers: Topography, laminar targeting, and map alignment.

Efficient sensory processing is a complex and important function for species survival. As such, sensory circuits are highly organized to facilitate rapid detection of salient stimuli and initiate motor responses. For decades, the retina's projections to image-forming centers have served as useful models to elucidate the mechanisms by which such exquisite circuitry is wired. In this chapter, we review the roles of molecular cues, neuronal activity, and axon-axon competition in the development of topographically ordered retinal ganglion cell (RGC) projections to the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN). Further, we discuss our current state of understanding regarding the laminar-specific targeting of subclasses of RGCs in the SC and its homolog, the optic tectum (OT). Finally, we cover recent studies examining the alignment of projections from primary visual cortex with RGCs that monitor the same region of space in the SC.

NMDA Receptor Expression by Retinal Ganglion Cells Is Not Required for Retinofugal Map Formation nor Eye-Specific Segregation in the Mouse.

Retinal ganglion cells (RGCs) project topographically to the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN). Spontaneous activity plays a critical role in retinotopic mapping in both regions; however, the molecular mechanisms underlying activity-dependent refinement remain unclear. Previous pharmacologic studies implicate NMDA receptors (NMDARs) in the establishment of retinotopy. In other brain regions, NMDARs are expressed on both the presynaptic and postsynaptic side of the synapse, and recent work suggests that presynaptic and postsynaptic NMDARs play distinct roles in retinotectal developmental dynamics. To directly test the role of NMDARs expressed by RGCs in retinofugal map formation, we took a conditional genetic knock-out approach to delete the obligate GluN1 subunit of NMDARs in RGCs. Here, we demonstrate reduced GluN1 expression in the retina of Chrnb3-Cre;GluN1flox/flox (pre-cKO) mice without altered expression in the SC. Anatomical tracing experiments revealed no significant changes in termination zone size in the SC and dLGN of pre-cKO mice, suggesting NMDAR function in RGCs is not an absolute requirement for topographic refinement. Further, we observed no change in the eye-specific organization of retinal inputs to the SC nor dLGN. To verify that NMDA induces activity in RGC terminals, we restricted GCaMP5 expression to RGCs and confirmed induction of calcium transients in RGC terminals. Together, these findings demonstrate that NMDARs expressed by RGCs are not required for retinofugal topographic map formation nor eye-specific segregation in the mouse.

Vascular α1-Adrenergic Receptor Responsiveness in Masked Hypertension.

BACKGROUND: Masked hypertension (nonhypertensive in the clinic setting but hypertensive outside the clinic during wakefulness) is characterized by increased blood pressure in response to physical and emotional stressors that activate the sympathetic nervous system (SNS). However, no studies have assessed vascular reactivity to a pharmacological SNS challenge in individuals with masked hypertension. METHODS: We analyzed data from 161 adults aged 25 to 45 years (mean ± standard deviation age 33 ± 6 years; 48% were African American and 43% were female). Participants completed ambulatory blood pressure monitoring, and a standardized α 1-adrenergic agonist phenylephrine test that determines the dose of phenylephrine required to increase a participant's mean arterial pressure by 25 mm Hg (PD25). RESULTS: Twenty-one participants were considered to have masked hypertension (clinic systolic blood pressure (SBP) <140 and diastolic blood pressure (DBP) <90 mm Hg but awake SBP ≥135 or DBP ≥85 mm Hg), 28 had sustained hypertension (clinic SBP ≥140 or DBP ≥90 mm Hg and awake SBP ≥135 or DBP ≥85 mm Hg), and 106 had sustained normotension (clinic SBP <140 and DBP <90 mm Hg and awake SBP <135 and DBP <85 mm Hg). After multivariable adjustment, the mean (±SE) PD25 was less in participants with masked hypertension compared with their counterparts with sustained normotension (222.1 ± 33.2 vs. 328.7 ± 15.0; P = 0.012), but similar to that observed in subjects with sustained hypertension (254.8 ± 31.0; P =0.12). CONCLUSIONS: Among young and middle-aged adults, masked hypertension is associated with increased vascular reactivity to a SNS challenge, which may contribute to elevated awake BPs as well as to increased cardiovascular disease risk.

The modifying effects of social support on psychological outcomes in patients with heart failure.

OBJECTIVE: We examined the modifying effects of social support on depressive symptoms and health-related quality of life (QoL) in patients receiving coping skills training (CST). METHOD: We considered the modifying effects of social support in the Coping Effectively with Heart Failure clinical trial, which randomized 179 heart failure (HF) patients to either 4 months of CST or usual care enhanced by HF education (HFE). CST involved training in specific coping techniques, whereas HFE involved education about HF self-management. Social support was assessed by the Enhancing Recovery in Coronary Heart Disease (ENRICHD) Social Support Inventory, QoL was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ), and depression was assessed with the Beck Depression Inventory-II (BDI-II). RESULTS: Linear regression models revealed a significant Intervention Group × Baseline Social Support interaction for change in KCCQ total scores (p = .006) and BDI-II scores (p < .001). Participants with low social support assigned to the CST intervention showed large improvements in KCCQ scores (M = 11.2, 95% CI [5.7, 16.8]), whereas low-social-support patients assigned to the HFE controls showed no significant change (M = -0.8, 95% CI [-7.2, 5.6]). Similarly, BDI-II scores in participants with low social support in the CST group showed large reductions (M = -8.7, 95% CI [-11.3, -6.1]) compared with low-social-support HFE participants (M = -3.0, 95% CI [-6.0, -0.1]). CONCLUSIONS: HF patients with low social support benefit substantially from telephone-based CST interventions. Targeting HF patients with low social support for behavioral interventions could prove to be a cost-effective strategy for improving QoL and reducing depression. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Relationship of depression to death or hospitalization in patients with heart failure.

BACKGROUND: Depression is widely recognized as a risk factor in patients with coronary heart disease. However, patients with heart failure (HF) have been less frequently studied, and the effect of depression on prognosis, independent of disease severity, is uncertain. METHODS: Two hundred four outpatients having a diagnosis of HF, with a ventricular ejection fraction of 40% or less, underwent baseline assessments including evaluation of depressive symptoms using the Beck Depression Inventory and of HF severity determined by plasma N-terminal pro-B-type natriuretic peptide. Cox proportional hazards regression analyses were used to examine the effects of depressive symptoms on a combined primary end point of death and hospitalizations because of cardiovascular disease (hereafter referred to as cardiovascular hospitalization) during a median follow-up of 3 years. RESULTS: Symptoms of depression (Beck Depression Inventory score) were associated with risk of death or cardiovascular hospitalization (P<.001) after controlling for established risk factors including HF disease severity, ejection fraction, HF etiology, age, and medications. Clinically significant symptoms of depression (Beck Depression Inventory score >/=10) were associated with a hazard ratio of 1.56 (95% confidence interval, 1.07-2.29) for the combined end point of death or cardiovascular hospitalization. Contrary to our expectation, antidepressant medication use was associated with increased likelihood of death or cardiovascular hospitalization (hazard ratio, 1.75; 95% confidence interval,1.14-2.68, P =.01) after controlling for severity of depressive symptoms and for established risk factors. CONCLUSIONS: Symptoms of depression were associated with an adverse prognosis in patients with HF after controlling for HF severity. The unexpected association of antidepressant medications with worse clinical outcome suggests that patients with HF requiring an antidepressant medication may need to be monitored more closely.

Teaching for Practice: The Impact of a Large-Scale Interprofessional Foundational Program.

PURPOSE: The University of Kansas Medical Center has developed an interprofessional education (IPE) foundational program using TeamSTEPPS, a curriculum designed to improve patient care through effective communication and teamwork. The purpose of this study was to understand the impact of the Level 1 program on learners as they develop the attitudes, knowledge, and skills related to interprofessional collaborative practice. METHODS: Learners (n=715) representing 15 professions participated in the Level 1 program. A mixed-methods approach was used to assess achievement of learning objectives, learner reactions, modifications of perceptions and attitudes, acquisition of knowledge and skills, and anticipated behaviors. RESULTS: Learners (n=585, 81.8%) agreed that the program was valuable. Positive changes in attitudes were significant pre-post (p<0.001). An average of 80.3% of learners who responded (n=196, 27.4%) correctly answered knowledge survey questions. Furthermore, analysis of open-ended questions suggested that learners gained an increased appreciation for interprofessional communication and better understanding of the roles of other healthcare professions. CONCLUSIONS: Based on positive learner reactions, changes in attitudes and knowledge, and anticipated behaviors associated with this program, similar approaches that incorporate TeamSTEPPS early in professional curricula may be useful for foundational IPE programming due to the intentional alignment with collaborative practice and orientation towards the Quadruple Aim.

Race and sex differences in cardiovascular α-adrenergic and ß-adrenergic receptor responsiveness in men and women with high blood pressure.

OBJECTIVE: Hypertension is associated with unfavorable changes in adrenergic receptor responsiveness, but the relationship of race and sex to adrenergic receptor responsiveness in the development of cardiovascular disease is unclear. This study examined α-adrenergic and ß-adrenergic receptor responsiveness in African-American and white men and women with untreated high blood pressure (BP) (HBP) and with normal BP. METHODS AND RESULTS: The study sample comprised 161 African-American and white men and women in the age range 25-45 years. Isoproterenol, a nonselective ß-adrenergic receptor agonist, was administered intravenously to determine the bolus dose required to increase heart rate by 25 bpm, an index of ß-adrenergic receptor responsiveness. Similarly, phenylephrine, an α1-adrenergic receptor agonist, was administered to determine the bolus dose required to increase BP by 25 mmHg, an index of vascular α1-adrenergic receptor responsiveness. HBP (P < 0.01), male sex (P = 0.04), and higher BMI (P < 0.01) were all associated with reduced ß-adrenergic receptor responsiveness, with a similar trend observed for African-American race (P = 0.07). Conversely, α1-adrenergic receptor responsiveness was increased in association with HBP (P < 0.01), female sex (P < 0.01), and African-American race (P < 0.01). CONCLUSION: In the early stages of hypertension, cardiovascular ß-adrenergic receptors demonstrate blunted responsiveness, whereas conversely α1-adrenergic receptors exhibit increased responsiveness. This pattern of receptor changes is especially evident in men and African-Americans, is exacerbated by obesity, and may contribute to the development of cardiovascular disease.

Effects of Coping Skills Training on Quality of Life, Disease Biomarkers, and Clinical Outcomes in Patients With Heart Failure: A Randomized Clinical Trial.

BACKGROUND: Heart failure (HF) is a chronic disease that compromises patients' quality of life (QoL). Interventions designed to reduce distress and improve disease self-management are needed. We evaluated the efficacy of a telephone-based coping skills training (CST) intervention. METHODS AND RESULTS: This randomized clinical trial involved 180 HF outpatients with reduced ejection fraction. Participants ranged in age from 29 to 87 years (mean=58 years); 27% were women, and 47% were nonwhite. Participants were randomized to either a CST intervention or heart failure education, both delivered over 16 weeks. The primary outcomes were (1) postintervention effects on QoL and HF disease biomarkers (both with α=0.01), and (2) a composite measure of time to death or first hospitalization (with α=0.03) over a median follow-up period of 3 years. CST resulted in greater improvements in QoL compared with heart failure education (P<0.01), including the Kansas City Cardiomyopathy Questionnaire (P=0.009), depressive symptoms (P=0.027), and the 6-minute walk test (P=0.012). However, it did not differentially improve HF disease biomarkers or reduce risk of all-cause hospitalizations or death (hazard ratio=0.84 [95% confidence interval, 0.59-1.12]). Interestingly, exploratory analyses showed that participants randomized to CST experienced a reduction in the composite end point of worsening HF hospitalization or death during the 3-year follow-up period (hazard ratio=0.65 [95% confidence interval, 0.44-0.98]; P=0.040). CONCLUSIONS: CST improved QoL in patients with HF. Monitoring and improving QoL is emerging as an important aspect of the clinical management of HF that can reduce disease burden and may help improve clinical outcomes in this vulnerable patient population. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00873418.

Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue.

Sphingosine kinase 1 (SK1) is a key enzyme critical to the sphingolipid metabolic pathway responsible for catalyzing the formation of the bioactive lipid sphingosine-1-phosphate. SK1-mediated production of sphingosine-1-phosphate has been shown to stimulate such biological processes as cell growth, differentiation, migration, angiogenesis, and inhibition of apoptosis. In this study, cell type-specific immunolocalization of SK1 was examined in the bronchus/terminal bronchiole of the lung. Strong immunopositive staining was evident at the apical surface of pseudostratified epithelial cells of the bronchus and underlying smooth muscle cells, submucosal serous glands, immature chondrocytes, type II alveolar cells, foamy macrophages, endothelial cells of blood vessels, and neural bundles. Immunohistochemical screening for SK1 expression was performed in 25 samples of normal/tumor patient matched non-small-cell lung cancer tissue and found that 25 of 25 tumor samples (carcinoid [5 samples], squamous [10 samples], and adenocarcinoma tumors [10 samples]), exhibited overwhelmingly positive immunostaining for SK1 as compared with patient-matched normal tissue. In addition, an approximately 2-fold elevation of SK1 mRNA expression was observed in lung cancer tissue versus normal tissue, as well as in several other solid tumors. Taken together, these findings define the localization of SK1 in lung and provide clues as to how SK1 may play a role in normal lung physiology and the pathophysiology of lung cancer.

Minimal FLAG sequence useful in the functional epitope tagging of H-Ras.

Epitope tagging can interfere with normal protein function, indicating the need for an unobtrusive epitope tag. The FLAG epitope (DYKDDDDK) was examined for a minimal epitope useful in the tagging of H-Ras. The heptapeptide tag, F7 (MDYKDDD), was found to retain reactivity with M2 and M5 monoclonal antibodies in immunoprecipitation, Western blotting, and immunofluorescence microscopy. The F7 tag did not interfere with Ras stability, EGF stimulation of Ras activation, and downstream phosphorylation of MAPK Erk1/2. Unlike the full FLAG sequence, the F7 tag had minimal effect on the growth properties of H-Ras in a colony-forming assay. The F7 tag may be useful when minimizing the effect of tagging on protein function is an important criterion in the selection of an N-terminal epitope tag.

Changes in hemodynamics and left ventricular structure after menopause.

To evaluate the cardiovascular changes associated with menopause, we studied hemodynamics at rest, ambulatory blood pressure, and left ventricular structure in a biracial cohort of pre- and postmenopausal women of similar age, race, weight, and blood pressure. Despite similar levels of blood pressure, postmenopausal women had a higher indexed peripheral resistance (2,722 +/- 757 vs 2,262 +/- 661 dynes.s.m(2)/cm(5), p <0.01) and a lower cardiac index (2.64 +/- 0.73 vs 3.10 +/- 0.71 L/min.m(2), p <0.01) than premenopausal women. Postmenopausal women also had less nocturnal decreases in both systolic (15 +/- 8 vs 19 +/- 8 mm Hg, p <0.01) and diastolic (12 +/- 6 vs 15 +/- 6 mm Hg, p = 0.05) pressures during ambulatory monitoring and higher levels of hematocrit (40 +/- 2% vs 38 +/- 3%, p <0.01). In association with this greater hemodynamic load, postmenopausal women had evidence of early concentric left ventricular remodeling, manifested by a greater relative wall thickness (0.38 +/- 0.06 vs 0.35 +/- 0.06, p <0.01) than that observed in premenopausal women. Differences between pre- and postmenopausal women in hemodynamics, diurnal blood pressure variation, and left ventricular structure were observed in white and African-American subjects. These results suggest that menopause is associated with hemodynamic changes and left ventricular remodeling, which may contribute to the enhanced cardiovascular risk observed in postmenopausal women.

Worsening depressive symptoms are associated with adverse clinical outcomes in patients with heart failure.

OBJECTIVES: The purpose of this study was to assess the impact of changes in symptoms of depression over a 1-year period on subsequent clinical outcomes in heart failure (HF) patients. BACKGROUND: Emerging evidence shows that clinical depression, which is prevalent among patients with HF, is associated with a poor prognosis. However, it is uncertain how changes in depression symptoms over time may relate to clinical outcomes. METHODS: One-hundred forty-seven HF outpatients with ejection fraction of less than 40% were assessed for depressive symptoms using the Beck Depression Inventory (BDI) at baseline and again 1 year later. Cox proportional hazards regression analyses, controlling for established risk factors, were used to evaluate how changes in depressive symptoms were related to a combined primary end point of death or cardiovascular hospitalization over a median follow-up period of 5 years (with a range of 4 to 7 years and no losses to follow-up). RESULTS: The 1-year change in symptoms of depression, as indicated by higher BDI scores over a 1-year interval (1-point BDI change hazard ratio [HR]: 1.07, 95% confidence interval [CI]: 1.02 to 1.12, p = 0.007), was associated with death or cardiovascular hospitalization after controlling for baseline depression (baseline BDI HR: 1.1, 95% CI: 1.06 to 1.14, p < 0.001) and established risk factors, including HF cause, age, ejection fraction, plasma N-terminal pro-B-type natriuretic peptide level, and prior hospitalizations. CONCLUSIONS: Worsening symptoms of depression are associated with a poorer prognosis in HF patients. Routine assessment of symptoms of depression in HF patients may help to guide appropriate medical management of these patients who are at increased risk for adverse clinical outcomes.

Kinematics of level terrestrial and underwater walking in the California newt, Taricha torosa.

Salamanders are acknowledged to be the closest postural model of early tetrapods and are capable of walking both in a terrestrial environment and while submerged under water. Nonetheless, locomotion in this group is poorly understood, as is underwater pedestrian locomotion in general. We, therefore, quantified the movements of the body axis and limbs of the California newt, Taricha torosa, during steady-speed walking in two environments, both of which presented a level surface: a treadmill and a trackway that was submerged in an aquarium. For treadmill walking at a relative speed of 0.63 snout-vent lengths (SVL)/sec, newts used a diagonal couplets lateral sequence walk with a duty factor of 77%. In contrast, submerged speeds were nearly twice as fast, with a mean of 1.19 SVL/sec. The submerged gait pattern was closer to a trot, with a duty factor of only 41%, including periods of suspension. Environment appears to play a critical role in determining gait differences, with reduction of drag being one of the most important determinants in increasing duration of the swing phase. Quantitative analysis of limb kinematics showed that underwater strides were more variable than terrestrial ones, but overall were strikingly similar between the two environments, with joint movement reversals occurring at similar points in the step cycle. It is suggested that the fundamental walking pattern appears to function well under multiple conditions, with only minor changes in motor control necessary.