Evaluation of Two Clinical Stem-Fit Philosophies Within the Femoral Canal Using a Preoperative Planning Tool: Could a Hybrid Approach Be Best?

BACKGROUND: Total hip arthroplasty (THA) has transformed patient lives, yet evolving expectations and the number of postoperative foot angle changes have underscored the need for precise component positioning. The objective of this study was to use 3-dimensional (3D) preoperative planning to evaluate stem alignment and orientation for three THA systems using two different stem-fit algorithms. It was hypothesized that the different stem alignments would yield similar changes in stem orientation and placement within the canal for all 3 systems. METHODS: This study introduced a novel 3D preoperative planning tool, comparing two different surgical stem-fit philosophies within the canal: "canal fit" (CF) and "anatomical fit" (AF). We virtually implanted 10 subjects with three different THA implant systems using both philosophies, evaluating 60 total fits within the canals. The CF philosophy aimed to minimize cortical bone removal. In contrast, the AF philosophy prioritized aligning the implanted head with the anatomical head center. RESULTS: Detailed analyses revealed that AF led to fixation occurring mainly on the medial aspect of the stem, while CF exhibited a more even distribution between medial and lateral sides. The AF philosophy achieved significantly closer placement of the implanted head to the anatomical center (2.0 to 2.1 mm) compared to the CF philosophy (3.0 to 6.0 mm) (P < 0.01). The AF resulted in neutral stem orientation (0°) across all stems, whereas the CF exhibited greater malrotation (2.0 to 7.0°) (P < 0.02). The AF required more bone removal (0.13 to 0.46 cm³) than the CF (0.02 to 0.06 cm³) (P < 0.01). CONCLUSIONS: The findings underscore the importance of 3D planning, emphasizing its potential to improve stem version alignment in THA. The results from this study may advocate 3D preoperative planning with robotic surgery to plan stem placement within the canal while maintaining anatomical femoral head restoration.

Mass Measurements of Neutron-Deficient Yb Isotopes and Nuclear Structure at the Extreme Proton-Rich Side of the N=82 Shell.

High-accuracy mass measurements of neutron-deficient Yb isotopes have been performed at TRIUMF using TITAN's multiple-reflection time-of-flight mass spectrometer (MR-TOF-MS). For the first time, an MR-TOF-MS was used on line simultaneously as an isobar separator and as a mass spectrometer, extending the measurements to two isotopes further away from stability than otherwise possible. The ground state masses of ^{150,153}Yb and the excitation energy of ^{151}Yb^{m} were measured for the first time. As a result, the persistence of the N=82 shell with almost unmodified shell gap energies is established up to the proton drip line. Furthermore, the puzzling systematics of the h_{11/2}-excited isomeric states of the N=81 isotones are unraveled using state-of-the-art mean field calculations.

Birth delivery mode alters perinatal cell death in the mouse brain.

Labor and a vaginal delivery trigger changes in peripheral organs that prepare the mammalian fetus to survive ex utero. Surprisingly little attention has been given to whether birth also influences the brain, and to how alterations in birth mode affect neonatal brain development. These are important questions, given the high rates of cesarean section (C-section) delivery worldwide, many of which are elective. We examined the effect of birth mode on neuronal cell death, a widespread developmental process that occurs primarily during the first postnatal week in mice. Timed-pregnant dams were randomly assigned to C-section deliveries that were yoked to vaginal births to carefully match gestation length and circadian time of parturition. Compared with rates of cell death just before birth, vaginally-born offspring had an abrupt, transient decrease in cell death in many brain regions, suggesting that a vaginal delivery is neuroprotective. In contrast, cell death was either unchanged or increased in C-section-born mice. Effects of delivery mode on cell death were greatest for the paraventricular nucleus of the hypothalamus (PVN), which is central to the stress response and brain-immune interactions. The greater cell death in the PVN of C-section-delivered newborns was associated with a reduction in the number of PVN neurons expressing vasopressin at weaning. C-section-delivered mice also showed altered vocalizations in a maternal separation test and greater body mass at weaning. Our results suggest that vaginal birth acutely impacts brain development, and that alterations in birth mode may have lasting consequences.

The microbiota influences cell death and microglial colonization in the perinatal mouse brain.

The mammalian fetus develops in a largely sterile environment, and direct exposure to a complex microbiota does not occur until birth. We took advantage of this to examine the effect of the microbiota on brain development during the first few days of life. The expression of anti- and pro-inflammatory cytokines, developmental cell death, and microglial colonization in the brain were compared between newborn conventionally colonized mice and mice born in sterile, germ-free (GF) conditions. Expression of the pro-inflammatory cytokines interleukin 1ß and tumor necrosis factor α was markedly suppressed in GF newborns. GF mice also had altered cell death, with some regions exhibiting higher rates (paraventricular nucleus of the hypothalamus and the CA1 oriens layer of the hippocampus) and other regions exhibiting no change or lower rates (arcuate nucleus of the hypothalamus) of cell death. Microglial labeling was elevated in GF mice, due to an increase in both microglial cell size and number. The changes in cytokine expression, cell death and microglial labeling were evident on the day of birth, but were absent on embryonic day 18.5, approximately one-half day prior to expected delivery. Taken together, our results suggest that direct exposure to the microbiota at birth influences key neurodevelopmental events and does so within hours. These findings may help to explain some of the behavioral and neurochemical alterations previously seen in adult GF mice.

Effects of sex and prenatal androgen manipulations on Onuf's nucleus of rhesus macaques.

The role of gonadal steroids in sexual differentiation of the central nervous system (CNS) is well established in rodents, but no study to date has manipulated androgens prenatally and examined their effects on any CNS structure in a primate. Onuf's nucleus is a column of motoneurons in the sacral spinal cord that innervates the striated perineal muscles. This cell group is larger in males than in females of many species, due to androgens acting during a sensitive perinatal period. Here, we examined Onuf's nucleus in 21 adult rhesus monkeys, including control males and females, as well as males whose mothers had been treated with an anti-androgen or testosterone during gestation. We found a robust sex difference, with more motoneurons in control males than in females. The soma size of Onuf's nucleus motoneurons was also marginally larger in males. Treatment with the anti-androgen flutamide for 35-40 days during early gestation partially blocked masculinization of Onuf's nucleus: motoneuron number in flutamide-treated males was decreased relative to control and testosterone-treated males, but remained greater than in females, with no effect on cell size. A control motor nucleus that innervates foot muscles (Pes9) showed no difference in motoneuron number or size between control males and females. Prenatal testosterone treatment of males did not alter Onuf's nucleus motoneuron number, but did increase the size of both Onuf's and Pes9 motoneurons. Thus, prenatal androgen manipulations cause cellular-level changes in the primate CNS, which may underlie previously observed effects of these manipulations on behavior.

Synovial Sarcoma Is Not Associated With a Higher Risk of Lymph Node Metastasis Compared With Other Soft Tissue Sarcomas.

BACKGROUND: Reported rates of the incidence of lymph node metastasis in soft tissue sarcoma vary considerably. Many are based on single-institution series and small patient populations. Certain sarcoma subtypes, including synovial sarcoma, have been associated with a higher risk of lymph node involvement. Most single centers have insufficient numbers of patients to assess lymph node metastasis accurately, but larger national databases may allow a more accurate estimation. QUESTIONS/PURPOSES: We queried a large national database and asked the following questions: (1) What proportion of patients with soft tissue sarcoma have lymph node metastasis and distant metastasis? (2) What histologic subtypes are associated with increased risk of nodal metastasis? (3) What is the impact of lymph node metastases and histologic subtype on survival? (4) Does lymph node excision improve survival of patients with soft tissue sarcoma? METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program is a national database that covers a geographic cross-section representing approximately 28% of the US population across demographic groups. Using the SEER database, we identified 15,525 adults diagnosed with histologically confirmed soft tissue sarcoma from 2004 to 2013. Proportions of patients with lymph node or distant metastases were calculated using descriptive statistics. Overall survival was computed using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazard regression to calculate the association of lymph node metastasis with overall survival while controlling for patient age, sex, race, tumor size, and tumor location. RESULTS: A total of 820 of 15,525 patients had lymph node metastasis at the time of diagnosis, yielding an overall proportion of 5.3% (95% confidence interval [CI], 4.9%-5.6%). Histologic subtypes that most frequently developed nodal metastasis were rhabdomyosarcoma, clear cell sarcoma, epithelioid sarcoma, and myxoid/round cell liposarcoma. Despite frequent reports regarding its association with lymph node metastasis, the proportion of patients with lymph node metastasis among 885 patients with synovial sarcoma (4.2%) was not different from the proportion with nodal metastasis in the overall soft tissue sarcoma population. For all soft tissue sarcomas, distant metastatic disease was present at diagnosis in 1869 (12%) patients (95% CI, 11.5%-12.6%). After controlling for relevant covariates, lymph node metastasis was associated with poorer overall survival (hazard ratio [HR], 1.34; 95% CI, 1.22-1.48; p < 0.001) as was distant metastasis (HR, 2.87; 95% CI, 2.66-3.09; p < 0.001). When comparing the subgroup of patients with positive lymph nodes, lymphadenectomy in conjunction with local excision/limb salvage was associated with the highest overall 5-year survival (HR, 0.46; 95% CI, 0.31-0.67; p < 0.001). CONCLUSIONS: In clarifying the overall proportion of patients with soft tissue sarcoma with nodal metastases, the current study indicates that lymph node metastases occur at a higher proportion than previous studies have suggested and that synovial sarcoma is not associated with a higher risk of lymphatic spread compared with soft tissue sarcoma overall. Patients with lymph node metastases are associated with poorer survival than those without metastases. Further investigation is needed to clarify the apparent improved overall survival after lymphadenectomy in the setting of nodal metastasis from soft tissue sarcoma. LEVEL OF EVIDENCE: Level II, prognostic study.

The sinus venosus contributes to coronary vasculature through VEGFC-stimulated angiogenesis.

Identifying coronary artery progenitors and their developmental pathways could inspire novel regenerative treatments for heart disease. Multiple sources of coronary vessels have been proposed, including the sinus venosus (SV), endocardium and proepicardium, but their relative contributions to the coronary circulation and the molecular mechanisms regulating their development are poorly understood. We created an ApjCreER mouse line as a lineage-tracing tool to map SV-derived vessels onto the heart and compared the resulting lineage pattern with endocardial and proepicardial contributions to the coronary circulation. The data showed a striking compartmentalization to coronary development. ApjCreER-traced vessels contributed to a large number of arteries, capillaries and veins on the dorsal and lateral sides of the heart. By contrast, untraced vessels predominated in the midline of the ventral aspect and ventricular septum, which are vessel populations primarily derived from the endocardium. The proepicardium gave rise to a smaller fraction of vessels spaced relatively uniformly throughout the ventricular walls. Dorsal (SV-derived) and ventral (endocardial-derived) coronary vessels developed in response to different growth signals. The absence of VEGFC, which is expressed in the epicardium, dramatically inhibited dorsal and lateral coronary growth but left vessels on the ventral side unaffected. We propose that complementary SV-derived and endocardial-derived migratory routes unite to form the coronary vasculature and that the former requires VEGFC, revealing its role as a tissue-specific mediator of blood endothelial development.

Racial and ethnic disparities in treatment and survival of pediatric sarcoma.

BACKGROUND: Childhood sarcomas are rare and require complex interdisciplinary care including surgery, chemotherapy, and radiation. The goal of this study was to determine if racial or ethnic disparities exist for pediatric sarcoma patients in the United States. METHODS: The United States' National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to identify patients aged 0-21 diagnosed with primary sarcomas from 1973 to 2012. Patients were considered by race and ethnicity. Survival curves were computed using the Kaplan-Meier method and the log-rank test. RESULTS: A total of 11,502 patients were included in this study. When stratified by race, non-Hispanic black and Hispanic patients were significantly more likely to present with advanced stage disease than white patients. White patients were more likely to receive radiation therapy than black and Hispanic patients (P = 0.01). There was no significant difference between patients who underwent surgery (P = 0.21). Overall survival was better for white patients than black or Hispanic ones. Despite the overall 5-year survival improvement during the study period (56.2%-70.3%), survival disparities between race and ethnicity have grown. CONCLUSIONS: Racial and ethnic disparities do exist with respect to stage, treatment, and survival of these rare tumors. Black and Hispanic patients are presenting at more advanced stage and have overall worse survival. This survival disparity has widened over the past 4 decades.

Down-regulation of the glucan synthase-like 6 gene (HvGsl6) in barley leads to decreased callose accumulation and increased cell wall penetration by Blumeria graminis f. sp. hordei.

The recent characterization of the polysaccharide composition of papillae deposited at the barley cell wall during infection by the powdery mildew pathogen, Blumeria graminis f. sp. hordei (Bgh), has provided new targets for the generation of enhanced disease resistance. The role of callose in papilla-based penetration resistance of crop species is largely unknown because the genes involved in the observed callose accumulation have not been identified unequivocally. We have employed both comparative and functional genomics approaches to identify the functional orthologue of AtGsl5 in the barley genome. HvGsl6 (the barley glucan synthase-like 6 gene), which has the highest sequence identity to AtGsl5, is the only Bgh-induced gene among the HvGsls examined in this study. Through double-stranded RNA interference (dsRNAi)-mediated silencing of HvGsl6, we have shown that the down-regulation of HvGsl6 is associated with a lower accumulation of papillary and wound callose and a higher susceptibility to penetration of the papillae by Bgh, compared with control lines. The results indicate that the HvGsl6 gene is a functional orthologue of AtGsl5 and is involved in papillary callose accumulation in barley. The increased susceptibility of HvGsl6 dsRNAi transgenic lines to infection indicates that callose positively contributes to the barley fungal penetration resistance mechanism.

Chest wall Ewing sarcoma: a population-based analysis.

BACKGROUND: The globally low incidence of pediatric chest wall Ewing sarcoma (CWES) has limited prior studies of this disease to mostly small, single-institution reviews. Our objective was to assess incidence, demographics, treatment patterns, and long-term survival of this disease through a population-based analysis. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database was used to identify patients aged 0-21 y diagnosed with CWES from 1973 to 2011. Patients were grouped by decade to assess changes in treatment patterns and outcomes. The effects of clinical, demographic, and treatment variables on overall survival (OS) were assessed by the computation of Kaplan-Meier curves and the log-rank test, with Cox proportional hazard regression used for multivariable analysis. RESULTS: A total of 193 pediatric patients with histologically confirmed CWES were identified. The disease was more common in men (61%), whites (92%), and 11- to 17-y olds (49%). It was metastatic at presentation in 37% of patients. When grouped approximately by decade, 10-y OS improved progressively from 38% in 1973-1979 to 65% in 2000-2011 (P = 0.033). The use of radiation decreased from 84% in the earliest period to 40% in the most recent, whereas the proportion of patients receiving surgery increased from 75% to 85%. When controlling for covariates in multivariable analysis, male patients were found to have a higher mortality than female patients (hazard ratio: 2.4; confidence interval: 1.4, 4.4; P = 0.0028). CONCLUSIONS: This population-based analysis of CWES demonstrated an impressive trend of improving OS, with increasing use of surgery and decreasing use of radiation therapy. Our study demonstrated a gender difference in survival of CWES, with females having a better prognosis. The presence of metastatic disease is a very important prognostic factor for this illness.

The Na(+) transporter, TaHKT1;5-D, limits shoot Na(+) accumulation in bread wheat.

Bread wheat (Triticum aestivum L.) has a major salt tolerance locus, Kna1, responsible for the maintenance of a high cytosolic K(+) /Na(+) ratio in the leaves of salt stressed plants. The Kna1 locus encompasses a large DNA fragment, the distal 14% of chromosome 4DL. Limited recombination has been observed at this locus making it difficult to map genetically and identify the causal gene. Here, we decipher the function of TaHKT1;5-D, a candidate gene underlying the Kna1 locus. Transport studies using the heterologous expression systems Saccharomyces cerevisiae and Xenopus laevis oocytes indicated that TaHKT1;5-D is a Na(+) -selective transporter. Transient expression in Arabidopsis thaliana mesophyll protoplasts and in situ polymerase chain reaction indicated that TaHKT1;5-D is localised on the plasma membrane in the wheat root stele. RNA interference-induced silencing decreased the expression of TaHKT1;5-D in transgenic bread wheat lines which led to an increase in the Na(+) concentration in the leaves. This indicates that TaHKT1;5-D retrieves Na(+) from the xylem vessels in the root and has an important role in restricting the transport of Na(+) from the root to the leaves in bread wheat. Thus, TaHKT1;5-D confers the essential salinity tolerance mechanism in bread wheat associated with the Kna1 locus via shoot Na(+) exclusion and is critical in maintaining a high K(+) /Na(+) ratio in the leaves. These findings show there is potential to increase the salinity tolerance of bread wheat by manipulation of HKT1;5 genes.

Hv-CBF2A overexpression in barley accelerates COR gene transcript accumulation and acquisition of freezing tolerance during cold acclimation.

C-Repeat Binding Factors (CBFs) are DNA-binding transcriptional activators of gene pathways imparting freezing tolerance. Poaceae contain three CBF subfamilies, two of which, HvCBF3/CBFIII and HvCBF4/CBFIV, are unique to this taxon. To gain mechanistic insight into HvCBF4/CBFIV CBFs we overexpressed Hv-CBF2A in spring barley (Hordeum vulgare) cultivar 'Golden Promise'. The Hv-CBF2A overexpressing lines exhibited stunted growth, poor yield, and greater freezing tolerance compared to non-transformed 'Golden Promise'. Differences in freezing tolerance were apparent only upon cold acclimation. During cold acclimation freezing tolerance of the Hv-CBF2A overexpressing lines increased more rapidly than that of 'Golden Promise' and paralleled the freezing tolerance of the winter hardy barley 'Dicktoo'. Transcript levels of candidate CBF target genes, COR14B and DHN5 were increased in the overexpressor lines at warm temperatures, and at cold temperatures they accumulated to much higher levels in the Hv-CBF2A overexpressors than in 'Golden Promise'. Hv-CBF2A overexpression also increased transcript levels of other CBF genes at FROST RESISTANCE-H2-H2 (FR-H2) possessing CRT/DRE sites in their upstream regions, the most notable of which was CBF12. CBF12 transcript levels exhibited a relatively constant incremental increase above levels in 'Golden Promise' both at warm and cold. These data indicate that Hv-CBF2A activates target genes at warm temperatures and that transcript accumulation for some of these targets is greatly enhanced by cold temperatures.

3D preoperative predictions of in vivo hip stability and edge loading for neutral and lipped liners.

Hip dislocation is one of the leading causes of failure and revision surgery for total hip arthroplasty. To reduce dislocation rates, lipped liners have been designed with an elevated portion of the rim, to increase jump distance and maintain greater contact area. While it has been documented that lipped liners help reduce dislocation, the objective of this study is to investigate whether lipped liners also help reduce smaller instances of hip micromotion, separation, and edge loading. This study uses an advanced three-dimensional preoperative planning tool to analyze 10 patients, each implanted with both a neutral and lipped liner. Patients within the simulation performed stance phase of gait, and each cup was implanted with the rotation center aligned with the preoperative acetabulum center as well as shifted medially by 2, 4, 6, 8, and 10 mm, yielding 120 total simulations. Specific postoperative outcomes-of-interest included specified component offset, resultant in vivo hip forces, hip separation, and contact area to evaluate edge loading. The planner predicted a reduction in hip separation and an increase in articulating contact area for when using a lipped liner compared to a neutral liner. Additionally, regardless of liner type, increases in hip separation corresponded to decreases in contact area, therefore resulting in edge loading of the liner. Together, this indicates that improper component alignment and offsets may lead to an increase in hip separation and edge loading, but the use of a lipped liner may provide improved stability and resistance to this micromotion.

Progressive Improvement in 5-Year Survival Rates for Extremity Soft Tissue Sarcomas from 1999 to 2019.

Background: Extremity soft-tissue sarcoma (ESTS) is a group of rare, heterogeneous malignancies. Previous studies have demonstrated a progressive improvement in 5-year survival rate over time, but recent trends are unknown. Therefore, this study aimed to provide an update on the clinical characteristics and 5-year survival rate of ESTS from 1999 to 2019. Methods: This retrospective cohort study used the Surveillance, Epidemiology, and End Results (SEER) database. Overall, 5,654 patients over the age of 15 years with primary ESTS diagnosed between 1999 and 2019 were included. Data on patient demographics, clinical characteristics, and survival were extracted. Patients were grouped by year of diagnosis: 1999-2005, 2006-2012, and 2013-2019. Kaplan-Meier and Cox proportional hazards regression analyses were performed. Results: ESTS occurred primarily in the lower extremity (76.1%) and was frequently grade III (58.3%), >5 cm in size (69.9%), and without metastasis (77.9%) at diagnosis. Furthermore, there was a significant increase in the proportion of patients over age 60 (p < 0.001) and without metastasis (p < 0.001) over the study period. The 5-year survival rate successively improved, from 47% in 1999-2005, to 61% in 2006-2012, to 78% in 2013-2019. Similarly, in multivariate analysis, the mortality rate progressively declined from a hazard ratio (HR) of 3.4 in 1999-2005 to an HR of 2.1 in 2006-2012, with the 2013-2019 group having the best overall survival (p < 0.001). Age, tumor size, grade, and metastasis were negative prognostic factors for survival; radiation and surgery were positive prognostic factors. Conclusions: The 5-year overall survival rate for ESTS progressively improved over the 20-year study period, perhaps due to an increasing proportion of older patients diagnosed with local disease. These findings may also be related to earlier detection or more effective treatment over the study period.

A compact ion source combining electron-impact and thermal ionization for multiple-reflection time-of-flight mass spectrometry.

A compact ion source combining electron impact and thermal ionization has been developed and commissioned in two Multiple-Reflection Time-Of-Flight Mass Spectrometer (MR-TOF-MS) setups at the Fragment Separator Ion Catcher at the GSI Helmholtz Centre for Heavy Ion Research, Darmstadt, Germany, and at TRIUMF's Ion Trap for Atomic and Nuclear science at TRIUMF Canada's particle accelerator center, Vancouver, Canada. The ion source is notable for its compact dimensions of 50 mm in height and 68 mm in diameter. The ion source is currently in daily operation at both facilities. Design, simulations, and results of combining ions from thermal and electron-impact ionization of different gases (perfluoropropane and sulfur hexafluoride) are presented in this work. The systematic effects of heating power on the thermal source were studied in detail. The source has demonstrated stable and long-term production of reference ions over a wide mass range for the MR-TOF-MS. This versatile ion source has also been used to optimize and investigate the transport of ions with different chemical reactivity and ionization potentials.

Structural and functional analyses of PpENA1 provide insights into cation binding by type IID P-type ATPases in lower plants and fungi.

PpENA1 is a membrane-spanning transporter from the moss Physcomitrella patens, and is the first type IID P-type ATPase to be reported in the plant kingdom. In Physcomitrella, PpENA1 is essential for normal growth under moderate salt stress, while in yeast, type IID ATPases provide a vital efflux mechanism for cells under high salt conditions by selectively transporting Na+ or K+ across the plasma membrane. To investigate the structural basis for cation-binding within the type IID ATPase subfamily, we used homology modeling to identify a highly conserved cation-binding pocket between membrane helix (MH) 4 and MH 6 of the membrane-spanning pore of PpENA1. Mutation of specific charged and polar residues on MHs 4-6 resulted in a decrease or loss of protein activity as measured by complementation assays in yeast. The E298S mutation on MH 4 of PpENA1 had the most significant effect on activity despite the presence of a serine at this position in fungal type IID ATPases. Activity was partially restored in an inactivated PpENA1 mutant by the insertion of two additional serine residues on MH 4 and one on MH 6 based on the presence of these residues in fungal type IID ATPases. Our results suggest that the residues responsible for cation-binding in PpENA1 are distinct from those in fungal type IID ATPases, and that a fungal-type cation binding site can be successfully engineered into the moss protein.

A randomized, controlled, double-blinded clinical trial of gabapentin 300 versus 900 mg versus placebo for anxiety symptoms in breast cancer survivors.

Gabapentin is used for the treatment of hot flashes and neuropathic pain in breast cancer survivors, and is commonly used off-label for the treatment of anxiety. Yet, clinical trial evidence to support the use of gabapentin for anxiety symptoms is lacking. In a randomized, double-blinded controlled trial we compared 300 mg gabapentin versus 900 mg gabapentin versus placebo. Subjects were 420 breast cancer patients who had completed all chemotherapy cycles. Anxiety traits and current (state) anxiety were measured using the Speilberger Strait-Trait Anxiety Inventory at baseline, 4 and 8 weeks. Pain was measured at baseline using a 10-point scale. Analyses included analysis of covariance and ordinary least squares regression. At 4 weeks, state anxiety change scores were significantly better for gabapentin 300 and 900 mg (p = 0.005) compared to placebo. The magnitude of improvement was proportional to baseline state anxiety. At 8 weeks, the anxiolytic effects of gabapentin compared to placebo persisted (p < 0.005). We found no significant interactions. The lower dose (300 mg) was associated with the best treatment outcomes for all patients except those with the highest baseline anxiety. Given its similar pharmacology, efficacy in the treatment of hot flashes, and low cost, gabapentin may provide a low cost and parsimonious alternative treatment choice for breast cancer survivors presenting in primary care practices with anxiety symptoms. Gabapentin is effective for hot flashes, and, therefore, may provide therapeutic benefit for both anxiety and hot flashes at a generic drug price. For patients reluctant to take a controlled substance, such as a benzodiazepine, gabapentin may offer an alternative therapy. Similarly, patients with a history of substance use may benefit from gabapentin without risk of addiction or abuse. For cancer survivors experiencing both hot flashes and anxiety, gabapentin may provide a single effective treatment for both and is an alternative therapy for anxiety for patients unwilling to take a benzodiazepine or those with a history of substance use.

Genomic studies with preselected markers reveal dominance effects influencing growth traits in Eucalyptus nitens.

Genomic selection (GS) is being increasingly adopted by the tree breeding community. Most of the GS studies in trees are focused on estimating additive genetic effects. Exploiting the dominance effects offers additional opportunities to improve genetic gain. To detect dominance effects, trait-relevant markers may be important compared to nonselected markers. Here, we used preselected markers to study the dominance effects in a Eucalyptus nitens (E. nitens) breeding population consisting of open-pollinated (OP) and controlled-pollinated (CP) families. We used 8221 trees from six progeny trials in this study. Of these, 868 progeny and 255 parents were genotyped with the E. nitens marker panel. Three traits; diameter at breast height (DBH), wood basic density (DEN), and kraft pulp yield (KPY) were analyzed. Two types of genomic relationship matrices based on identity-by-state (IBS) and identity-by-descent (IBD) were tested. Performance of the genomic best linear unbiased prediction (GBLUP) models with IBS and IBD matrices were compared with pedigree-based additive best linear unbiased prediction (ABLUP) models with and without the pedigree reconstruction. Similarly, the performance of the single-step GBLUP (ssGBLUP) with IBS and IBD matrices were compared with ABLUP models using all 8221 trees. Significant dominance effects were observed with the GBLUP-AD model for DBH. The predictive ability of DBH is higher with the GBLUP-AD model compared to other models. Similarly, the prediction accuracy of genotypic values is higher with GBLUP-AD compared to the GBLUP-A model. Among the two GBLUP models (IBS and IBD), no differences were observed in predictive abilities and prediction accuracies. While the estimates of predictive ability with additive effects were similar among all four models, prediction accuracies of ABLUP were lower than the GBLUP models. The prediction accuracy of ssGBLUP-IBD is higher than the other three models while the theoretical accuracy of ssGBLUP-IBS is consistently higher than the other three models across all three groups tested (parents, genotyped, and nongenotyped). Significant inbreeding depression was observed for DBH and KPY. While there is a linear relationship between inbreeding and DBH, the relationship between inbreeding and KPY is nonlinear and quadratic. These results indicate that the inbreeding depression of DBH is mainly due to directional dominance while in KPY it may be due to epistasis. Inbreeding depression may be the main source of the observed dominance effects in DBH. The significant dominance effect observed for DBH may be used to select complementary parents to improve the genetic merit of the progeny in E. nitens.

Rice plants expressing the moss sodium pumping ATPase PpENA1 maintain greater biomass production under salt stress.

High cytosolic concentrations of Na+ inhibit plant growth and development. To maintain low cytosolic concentrations of Na+ , higher plants use membrane-bound transporters that drive the efflux of Na+ or partition Na+ ions from the cytosol, either to the extracellular compartment or into the vacuole. Bryophytes also use an energy-dependent Na+ pumping ATPase, not found in higher plants, to efflux Na+ . To investigate whether this transporter can increase the salt tolerance of crop plants, Oryza sativa has been transformed with the Physcomitrella patens Na+ pumping ATPase (PpENA1). When grown in solutions containing 50 mm NaCl, plants constitutively expressing the PpENA1 gene are more salt tolerant and produce greater biomass than controls. Transgenics and controls accumulate similar amounts of Na+ in leaf and root tissues under stress, which indicates that the observed tolerance is not because of Na+ exclusion. Moreover, inductively coupled plasma analysis reveals that the concentration of other ions in the transformants and the controls is similar. The transgenic lines are developmentally normal and fertile, and the transgene expression levels remain stable in subsequent generations. GFP reporter fusions, which do not alter the ability of PpENA1 to complement a salt-sensitive yeast mutant, indicate that when it is expressed in plant tissues, the PpENA1 protein is located in the plasma membrane. PpENA1 peptides are found in plasma membrane fractions supporting the plasma membrane targeting. The results of this study demonstrate the utility of PpENA1 as a potential tool for engineering salinity tolerance in important crop species.

Birth elicits a conserved neuroendocrine response with implications for perinatal osmoregulation and neuronal cell death.

Long-standing clinical findings report a dramatic surge of vasopressin in umbilical cord blood of the human neonate, but the neural underpinnings and function(s) of this phenomenon remain obscure. We studied neural activation in perinatal mice and rats, and found that birth triggers activation of the suprachiasmatic, supraoptic, and paraventricular nuclei of the hypothalamus. This was seen whether mice were born vaginally or via Cesarean section (C-section), and when birth timing was experimentally manipulated. Neuronal phenotyping showed that the activated neurons were predominantly vasopressinergic, and vasopressin mRNA increased fivefold in the hypothalamus during the 2-3 days before birth. Copeptin, a surrogate marker of vasopressin, was elevated 30-to 50-fold in plasma of perinatal mice, with higher levels after a vaginal than a C-section birth. We also found an acute decrease in plasma osmolality after a vaginal, but not C-section birth, suggesting that the difference in vasopressin release between birth modes is functionally meaningful. When vasopressin was administered centrally to newborns, we found an ~ 50% reduction in neuronal cell death in specific brain areas. Collectively, our results identify a conserved neuroendocrine response to birth that is sensitive to birth mode, and influences peripheral physiology and neurodevelopment.