Search

Homicidality rates have been shown to be more prominent among persons diagnosed with mental disorders as compared to the general population. However, the role that anxiety plays in homicidal ideation and intent is poorly understood. This study investigated predictors of homicidal intent, thought, or plan in an adult population of psychiatric inpatients diagnosed with anxiety disorders. Results suggest that the factors most strongly associated with homicidality include male gender, substance abuse, mania, and current legal problems. Multiple regression analyses showed that only male gender predicted homicidality when other variables were taken into account. [ABSTRACT FROM AUTHOR]

Concern exists that heading the ball in soccer may cause brain injury. Studies using EEG, CT, neurologic exams, and neuropsychological testing have not clearly established that the practice is hazardous. Studies generally have shown no neuropsychological differences between soccer players and other athletes, but some have revealed differences between soccer players and nonathletes. Because of the uncertainties, the authors advocate use of correct heading technique, enforcement of game rules, and increased awareness of the potential for injury from heading the ball. [ABSTRACT FROM AUTHOR]

Benzophenone-3 (also referred to as oxybenzone) is a putative endocrine disrupting chemical and common ingredient in sunscreens and other personal care products. We previously showed that benzophenone-3 was promotional for epithelial tumorigenesis in mice fed adult high-fat diet, while protective against the incidence of more aggressive spindle cell tumors in the same treatment group. In this study, we show that benzophenone-3 reduces epithelial to mesenchymal transition in the epithelial tumors of these mice. This reduction in epithelial to mesenchymal transition is associated with altered expression of several genes involved in regulation of angiogenesis and epithelial to mesenchymal transition. Among the genes altered in expression, Timp1 is of particular interest because benzophenone-3 suppressed both migration and Timp1 expression in a mammary tumor cell line that displays epithelial to mesenchymal transition characteristics. These alterations in gene expression plausibly stabilize the vasculature of epithelial carcinomas and contribute to benzophenone-3 promotion of epithelial tumors, while at the same time suppress epithelial to mesenchymal transition and suppress incidence of spindle cell tumors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Richard C. Schwartz reports financial support was provided by National Institute of Environmental Health Sciences., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We describe Richard Schwartz's development of the Internal Family Systems model (IFS) from his position as a Structural/Strategic family therapist. Four decades ago, Schwartz struggled to help clients who exhibited serious risk of harm to self and others. Through a process of inquiry, he began to work with the positive intentions behind his most challenging clients' harmful thoughts and behaviors. He applied foundational ideas from family systems thinking to patterns of internal experiences. As he experimented with ways of applying these ideas, he created an approach to healing. We summarize the IFS model delineating ways a range of family systems theory and practice inform its development and contribute to its best practice. Our purposes are to inform IFS practitioners who are not trained in foundational family systems models as well as to acknowledge the significant contributions family therapy theories made in the development and best practice of the IFS model., (© 2023 Family Process Institute.)

Environmental chemicals are a persistent and pervasive part of everyday life. A subset of environmental chemicals are xenoestrogens, compounds that bind to the estrogen receptor (ER) and drive estrogen-related processes. One such chemical, benzophenone-3 (BP3), is a common chemical in sunscreen. It is a potent UV protectant but also is quickly absorbed through the skin. While it has been approved by the FDA, there is a renewed interest in the safety of BP3, particularly in relation to breast cancer. The focus of this study was to examine the impact that BP3 has on triple negative breast cancer (TNBC) through alterations to cells in the immune microenvironment. In this study, we exposed female mice to one of two doses of BP3 before injecting them with a TNBC cell line. Several immune endpoints were examined both in the primary tissues and from in vitro studies of T cell behavior. Our studies revealed that in the lung tumor microenvironment, exposure to BP3 not only increased the number of metastases, but also the total area of tumor coverage. We also found that BP3 caused alterations in immune populations in a tissue-dependent manner, particularly in T cells. Taken together, our data suggest that while BP3 may not directly affect the proliferation of TNBC, growth and metastasis of TNBC-derived tumors can be altered by BP3 exposures via the alterations in the immune populations of the tumor microenvironment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Virus infection affects cellular proteostasis and provides an opportunity to study this cellular process under perturbation. The proteostasis network in the endoplasmic reticulum (ER) is composed of the calnexin cycle, and the two protein degradation pathways ER-associated protein degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD/ER-phagy/reticulophagy). Here we show that calnexin and calreticulin trigger Zaire Ebolavirus (EBOV) glycoprotein GP 1,2 misfolding. Misfolded EBOV-GP 1,2 is targeted by ERAD machinery, but this results in lysosomal instead of proteasomal degradation. Moreover, the ER Ub ligase RNF185, usually associated with ERAD, polyubiquitinates EBOV-GP 1,2 on lysine 673 via ubiquitin K27-linkage. Polyubiquinated GP 1,2 is subsequently recruited into autophagosomes by the soluble autophagy receptor sequestosome 1 (SQSTM1/p62), in an ATG3- and ATG5-dependent manner. We conclude that EBOV hijacks all three proteostasis mechanisms in the ER to downregulate GP 1,2 via polyubiquitination and show that this increases viral fitness. This study identifies linkages among proteostasis network components previously thought to function independently., (© 2022. The Author(s).)

Zaire ebolavirus (EBOV) causes a severe hemorrhagic fever in humans and non-human primates with high morbidity and mortality. EBOV infection is dependent on its structural glycoprotein (GP), but high levels of GP expression also trigger cell rounding, detachment, and downregulation of many surface molecules that is thought to contribute to its high pathogenicity. Thus, EBOV has evolved an RNA editing mechanism to reduce its GP expression and increase its fitness. We now report that the GP expression is also suppressed at the protein level in cells by protein disulfide isomerases (PDIs). Although PDIs promote oxidative protein folding by catalyzing correct disulfide formation in the endoplasmic reticulum (ER), PDIA3/ERp57 adversely triggered the GP misfolding by targeting GP cysteine residues and activated the unfolded protein response (UPR). Abnormally folded GP was targeted by ER-associated protein degradation (ERAD) machinery and, unexpectedly, was degraded via the macroautophagy/autophagy-lysosomal pathway, but not the proteasomal pathway. PDIA3 also decreased the GP expression from other ebolavirus species but increased the GP expression from Marburg virus (MARV), which is consistent with the observation that MARV-GP does not cause cell rounding and detachment, and MARV does not regulate its GP expression via RNA editing during infection. Furthermore, five other PDIs also had a similar inhibitory activity to EBOV-GP. Thus, PDIs negatively regulate ebolavirus glycoprotein expression, which balances the viral life cycle by maximizing their infection but minimizing their cellular effect. We suggest that ebolaviruses hijack the host protein folding and ERAD machinery to increase their fitness via reticulophagy during infection. Abbreviations: 3-MA: 3-methyladenine; 4-PBA: 4-phenylbutyrate; ACTB: β-actin; ATF: activating transcription factor; ATG: autophagy-related; BafA1: bafilomycin A 1 ; BDBV: Bundibugyo ebolavirus; CALR: calreticulin; CANX: calnexin; CHX: cycloheximide; CMA: chaperone-mediated autophagy; ConA: concanamycin A; CRISPR: clusters of regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9; dsRNA: double-stranded RNA; EBOV: Zaire ebolavirus; EDEM: ER degradation enhancing alpha-mannosidase like protein; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; Env: envelope glycoprotein; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GP: glycoprotein; HA: hemagglutinin; HDAC6: histone deacetylase 6; HMM: high-molecular-mass; HIV-1: human immunodeficiency virus type 1; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; IAV: influenza A virus; IP: immunoprecipitation; KIF: kifenesine; Lac: lactacystin; LAMP: lysosomal associated membrane protein; MAN1B1/ERManI: mannosidase alpha class 1B member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARV: Marburg virus; MLD: mucin-like domain; NHK/SERPINA1: alpha1-antitrypsin variant null (Hong Kong); NTZ: nitazoxanide; PDI: protein disulfide isomerase; RAVV: Ravn virus; RESTV: Reston ebolavirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SBOV: Sudan ebolavirus; sGP: soluble GP; SQSTM1/p62: sequestosome 1; ssGP: small soluble GP; TAFV: Taï Forest ebolavirus; TIZ: tizoxanide; TGN: thapsigargin; TLD: TXN (thioredoxin)-like domain; Ub: ubiquitin; UPR: unfolded protein response; VLP: virus-like particle; VSV: vesicular stomatitis virus; WB: Western blotting; WT: wild-type; XBP1: X-box binding protein 1.

Experimental studies have suggested benzophenone-3 (BP-3), a sunscreen ingredient, may have endocrine-disrupting properties. A cohort of girls were recruited at ages 6-7 years and returned semi-annually for pubertal maturation staging, provided blood for serum hormone analyses [estradiol, estrone, testosterone, dehydroepiandrosterone-sulfate (DHEA-S)], and urine to measure BP-3 concentrations. We found a significant negative linear association between amount of reported sunscreen use and testosterone levels at the onset of puberty (N = 157, adjusted β = -0.0163, 97.5% CI:-0.0300,-0.0026). The 2nd quartile of the BP-3 biomarker had earlier thelarche compared to the 1st quartile (N = 282, adjusted HR = 1.584, 97.5% CI:1.038,2.415). Results suggest that higher report of sunscreen use may be associated with lower testosterone levels at thelarche and a non-linear relationship between the BP-3 urinary biomarker and onset of puberty, although the clinical significance of the finding is limited and may be a random effect. Improved methods of BP-3 exposure characterization are needed.

While mammographic breast density is associated with breast cancer risk in humans, there is no comparable surrogate risk measure in mouse and rat mammary glands following various environmental exposures. In the current study, mammary glands from mice and rats subjected to reproductive factors and exposures to environmental chemicals that have been shown to influence mammary gland development and/or susceptibility to mammary tumors were evaluated for histologic density by manual and automated digital methods. Digital histological density detected changes due to hormonal stimuli/reproductive factors (parity), dietary fat, and exposure to environmental chemicals, such as benzophenone-3 and a combination of perfluorooctanoic acid and zeranol. Thus, digital analysis of mammary gland density offers a high throughput method that can provide a highly reproducible means of comparing a measure of histological density across independent experiments, experimental systems, and laboratories. This methodology holds promise for the detection of environmental impacts on mammary gland structure in mice and rats that may be comparable to human breast density, thus potentially allowing comparisons between rodent models and human breast cancer studies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Benzophenone-3 is a putative endocrine disrupting chemical and common ingredient in sunscreens. The potential of endocrine disrupting chemicals to act as agonists or antagonists in critical hormonally regulated processes, such as mammary gland development and mammary tumorigenesis, demands evaluation of its potential in promoting breast cancer. This study identifies the effects of BP-3 on mammary tumorigenesis with high-fat diet during puberty versus adulthood in Trp53 - null transplant BALB/c mice. Benzophenone-3 exposure yielded levels in urine similar to humans subjected to heavy topical sunscreen exposure. Benzophenone-3 was protective for epithelial tumorigenesis in mice fed lifelong low-fat diet, while promotional for epithelial tumorigenesis in mice fed adult high-fat diet. Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology. Even in instances of an ostensibly protective effect, other parameters suggest greater risk. Although benzophenone-3 seemed protective on low-fat diet, spindle cell tumors arising in these mice showed increased proliferation and decreased apoptosis. This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2020 Kariagina et al.)

Serine incorporator 5 (SERINC5) is a recently identified restriction factor that strongly blocks HIV-1 entry but is counteracted by Nef. Notably, tier 1 HIV-1 Env proteins are sensitive to SERINC5, whereas the majority of tier 2/3 Env proteins are resistant to SERINC5, when viruses are produced from CD4-negative cells and tested by a single-round replication assay. Here, we investigated the Env-dependent SERINC5 antiviral mechanism by comparing tier 1 NL Env with tier 3 AD8 Env proteins. We found that when NL and AD8 viruses were inoculated into CD4 + T cells and human peripheral blood mononuclear cells (PBMCs), the propagation of the two viruses was restricted to a similar level when Nef was not expressed. Using a bimolecular fluorescence complementation (BiFC) assay, we detected Env-Env association and Env-SERINC5 interactions. A much greater level of NL Env-SERINC5 interactions was detected than was AD8 Env-SERINC5 interactions, which was further validated by immunoprecipitation assays. In addition, SERINC5 dissociated the NL Env trimeric complex more effectively than the AD8 Env trimeric complex when CD4 was not expressed. However, when CD4 was expressed, SERINC5 became more capable of interacting with AD8 Env and dissociating its trimeric complex. Moreover, AD8 and several other tier 2/3 viruses produced in the presence of CD4 became sensitive to SERINC5 when measured by the single-round replication assay. Because tier 1 and tier 2/3 Env trimers have open and closed conformations, respectively, and CD4 opens the closed conformation, we conclude that SERINC5 selectively dissociates Env trimers with an open conformation to restrict HIV-1 replication. IMPORTANCE Restriction factors provide the first line of defense against retrovirus infection by posing several blocks to the viral replication cycle. SERINC5 is a novel restriction factor that strongly blocks HIV-1 entry, although it is counteracted by Nef. Currently, it is still unclear how HIV-1 entry is blocked by SERINC5. Notably, this entry block is dependent on viral Env proteins. Laboratory-adapted HIV-1 strains are sensitive, whereas primary isolates are highly resistant to SERINC5. Env proteins mediate virus entry via extensive conformational rearrangements from a closed ground state to a CD4-bound open state. We detected Env-Env associations and Env-SERINC5 interactions in live cells by a novel bimolecular fluorescence assay. We demonstrate that CD4 expression increases the Env sensitivity to SERINC5 and allows SERINC5 to dissociate the Env complex, suggesting that SERINC5 restriction is dependent on Env conformation. Our results provide new insights into the poorly defined Env-dependent SERINC5 antiviral mechanism., (Copyright © 2019 American Society for Microbiology.)

CCAAT/enhancer binding protein β (C/EBPβ) is required for murine mammary ductal morphogenesis and alveologenesis. Progesterone is critical for proliferation and alveologenesis in adult mammary glands, and there is a similar requirement for progesterone receptor isoform B (PRB) in alveologenesis. We examined C/EBPβ regulation of PR expression. All three C/EBPβ isoforms, including typically inhibitory LIP, transactivated the PR promoter. LIP, particularly, strongly synergized with c-Jun to drive PR transcription. Endogenous C/EBPβ and c-Jun stimulated a PR promoter-reporter and these two factors showed promoter occupancy on the endogenous PR gene. Additionally, LIP overexpression elevated endogenous PR protein expression. In pregnancy, both PRB and the relative abundance of LIP among C/EBPβ isoforms increase. Consistent with a role in PRB expression, in vivo C/EBPβ and PR isoform A expression showed mutually exclusive localization in mammary epithelium, while C/EBPβ and PRB largely co-localized. We suggest a critical role for C/EBPβ, particularly LIP, in PRB expression., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

First responders are psychosocially burdened with work-related stressors that occur frequently during required duties. Related mental health difficulties, such as direct and vicarious trauma, depression, and interpersonal problems often affect first responders' ability to perform effectively, and their personal lives may be disrupted. Mindfulness-based interventions have been shown to directly promote first responders' mental and physical health while providing increased resilience when facing work-related stressors. This article summarizes mindfulness-based benefits and empirical research related to first responders, using law enforcement officers as one specific example. Two specific mindfulness-based psychotherapies are introduced, as are generalizable mindfulness techniques useful for first responders. Psychotherapists can use these empirically supported treatment approaches to help first responders understand and incorporate awareness-based, nonjudgmental, and present-centered mindfulness techniques during critical incidents and while off duty as resilience-building mechanisms.

Increased proliferation and breast cancer risk has been observed in postmenopausal women receiving estrogen (E) + progestin hormone replacement therapy (HRT). Progestin action is mediated through two progesterone receptor (PR) isoforms, PRA and PRB, with unique transcriptional activity and function. The current study examines hormonal regulation of PR isoforms in the normal postmenopausal human breast and the mechanism by which progestins increase proliferation and breast cancer risk. Archival benign breast biopsies from postmenopausal and premenopausal women, and luminal breast tumor biopsies from postmenopausal women, were analyzed for regulation of PRA and PRB expression by E and E+medroxyprogesterone acetate (MPA). In the postmenopausal breast without HRT, PRA and PRB expression was decreased compared to the premenopausal breast. Both E (n = 12) and E+MPA (n = 13) HRT in the postmenopausal breast were associated with increased PRA and PRB expression, increased nuclear cyclin E expression, and decreased nuclear p27 expression compared to no HRT (n = 16). With E+MPA HRT, there was a further decrease in nuclear p27 and increased Receptor Activator of NF-kappa B Ligand (RANKL) expression compared to E-alone HRT. In luminal breast cancers, E+MPA HRT (n = 6) was also associated with decreased nuclear expression of the cell cycle inhibitor p27 compared to E HRT (n = 6), but was not associated with increased proliferation. These results suggest that p27 mediates progestin-induced proliferation in the normal human breast and that regulation of this proliferative response by E+MPA is lost in breast tumors., (Copyright © 2018. Published by Elsevier Inc.)

Innate immunity provides an immediate defense against infection after host cells sense danger signals from microbes. Endoplasmic reticulum (ER) stress arises from accumulation of misfolded/unfolded proteins when protein load overwhelms the ER folding capacity, which activates the unfolded protein response (UPR) to restore ER homeostasis. Here, we show that a mechanism for antiviral innate immunity is triggered after the ER stress pathway senses viral glycoproteins. When hemagglutinin (HA) glycoproteins from influenza A virus (IAV) are expressed in cells, ER stress is induced, resulting in rapid HA degradation via proteasomes. The ER-associated protein degradation (ERAD) pathway, an important UPR function for destruction of aberrant proteins, mediates HA degradation. Three class I α-mannosidases were identified to play a critical role in the degradation process, including EDEM1, EDEM2, and ERManI. HA degradation requires either ERManI enzymatic activity or EDEM1/EDEM2 enzymatic activity when ERManI is not expressed, indicating that demannosylation is a critical step for HA degradation. Silencing of EDEM1, EDEM2, and ERManI strongly increases HA expression and promotes IAV replication. Thus, the ER stress pathway senses influenza HA as "nonself" or misfolded protein and sorts HA to ERAD for degradation, resulting in inhibition of IAV replication. IMPORTANCE Viral nucleic acids are recognized as important inducers of innate antiviral immune responses that are sensed by multiple classes of sensors, but other inducers and sensors of viral innate immunity need to be identified and characterized. Here, we used IAV to investigate how host innate immunity is activated. We found that IAV HA glycoproteins induce ER stress, resulting in HA degradation via ERAD and consequent inhibition of IAV replication. In addition, we have identified three class I α-mannosidases, EDEM1, EDEM2, and ERManI, which play a critical role in initiating HA degradation. Knockdown of these proteins substantially increases HA expression and IAV replication. The enzymatic activities and joint actions of these mannosidases are required for this antiviral activity. Our results suggest that viral glycoproteins induce a strong innate antiviral response through activating the ER stress pathway during viral infection., (Copyright © 2017 American Society for Microbiology.)

Premenopausal breast cancer is associated with increased animal fat consumption among normal-weight but not overweight women. Our previous findings in obesity-resistant BALB/c mice showed that a diet high in saturated animal fat (HFD) promotes mammary tumorigenesis in both DMBA carcinogenesis and Trp53-null transplant models. Having made these observations in BALB/c mice, which have very modest HFD weight gain, we determined the effects of HFD in FVB mice, which gain significant weight on HFD. Three-week-old FVB mice fed a low-fat diet or HFD were subjected to 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. Like BALB/c mice, HFD promoted mammary tumorigenesis. Development of tumors largely occurred prior to mice becoming obese, indicating the role of animal-derived HFD rather than resulting obesity in tumor promotion. Also similar to BALB/c mice, early-occurring adenosquamous mammary tumors were abundant among HFD-fed FVB mice. Tumors from HFD mice also had increased intra-tumor M2 macrophages. Prior to tumor development, HFD accelerated normal mammary gland development and increased mammary M2 macrophages, similarly to BALB/c mice. The promotional effects of puberty-initiated HFD on carcinogen-induced mammary cancer are thus largely weight gain-independent. Like BALB/c mice, HFD promoted adenosquamous tumors, suggesting a role for early age HFD in promoting this subtype of triple negative mammary cancer. M2 macrophage recruitment was common to both mouse strains. We speculate that a similar effect of HFD on immune function may contribute to epidemiological findings of increased breast cancer risk in young, premenopausal, normal-weight women who consume a diet high in saturated animal fat., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Objective: Amphiregulin is a member of the epidermal growth factor family. In breast tissue, amphiregulin is a mediator of estrogen and progesterone signaling. The objectives were to examine the relationship of amphiregulin levels during peripuberty with estrogen levels. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: The participants in this analysis were a subset from a longitudinal study of pubertal maturation, the Breast Cancer and the Environment Research Program. They were recruited between ages 3 and 7 years. Blood specimens were selected for hormone analysis between 24 months before and 6 months after breast development. Serum amphiregulin levels were analyzed using enzyme-linked immunosorbent assay., Results: Amphiregulin levels were measured in 188 girls; 8.5% had a maternal history of breast cancer, and 30.9% of samples were below the limit of detection. Amphiregulin levels were greatest at 18 months before the onset of breast development (P < .006), and the rise in estrone levels between -24 and -18 months was correlated with the increase in amphiregulin levels in the same time period (P = .0002). After adjustment for time relative to breast development, amphiregulin levels were associated with maternal breast cancer (P = .024). Tracking of amphiregulin levels was highly significant (P < .0001) within a given individual., Conclusion: Amphiregulin levels peaked at 18 months before the onset of breast development, were temporally related to the rise in serum estrone, and were significantly associated with maternal history of breast cancer. Elevated amphiregulin levels at puberty might be a predictor of increased breast cancer risk., (Copyright © 2017 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Premenopausal breast cancer is associated with increased animal fat consumption among normal weight, but not overweight women (Farvid et al., 2014). Our previous findings in obesity-resistant BALB/c mice similarly showed promotion of carcinogen-induced mammary tumorigenesis by a diet high in saturated animal fat (HFD). This effect was specific to pubertal versus adult HFD. This study identifies the effects of HFD during puberty versus adulthood in Trp53-null transplant BALB/c mice and investigates its mechanism of enhancing tumorigenesis. Either pubertal or adult HFD is sufficient to increase incidence of Trp53-null mammary tumors. Puberty-restricted HFD exposure promoted tumor cell proliferation, increased angiogenesis, and increased recruitment of total and M2 macrophages in epithelial tumors. Adult-restricted exposure to HFD similarly increased proliferation, angiogenesis, recruitment of total and M2 macrophages, and additionally reduced apoptosis. Adult HFD also increased incidence of spindle cell carcinomas resembling claudin-low breast cancer, and thus adult HFD in the Trp53-null transplantation system may be a useful model for human claudin low breast cancer. Importantly, these results on Trp53-null and our prior studies on DMBA-induced mammary tumorigenesis demonstrate a pubertal window of susceptibility to the promotional effects of HFD, indicating the potential of early life dietary intervention to reduce breast cancer risk.

Introduction: Increased animal fat consumption is associated with increased premenopausal breast cancer risk in normal weight, but not overweight, women. This agrees with our previous findings in obesity-resistant BALB/c mice, in which exposure to a high saturated animal fat diet (HFD) from peripuberty through adulthood promoted mammary tumorigenesis. Epidemiologic and animal studies support the importance of puberty as a life stage when diet and environmental exposures affect adult breast cancer risk. In this study, we identified the effects of peripubertal exposure to HFD and investigated its mechanism of enhancing tumorigenesis., Methods: Three-week-old BALB/c mice fed a low-fat diet (LFD) or HFD were subjected to 7,12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis. At 9 weeks of age, half the mice on LFD were switched to HFD (LFD-HFD group) and half the mice on HFD were switched to LFD (HFD-LFD group). Tumor gene expression was evaluated in association with diet and tumor latency., Results: The peripubertal HFD reduced the latency of DMBA-induced mammary tumors and was associated with tumor characteristics similar to those in mice fed a continuous HFD. Notably, short-latency tumors in both groups shared gene expression characteristics and were more likely to have adenosquamous histology. Both HFD-LFD and continuous HFD tumors showed similar gene expression patterns and early latency. Adult switch from HFD to LFD did not reverse peripubertal HFD tumor promotion. Increased proliferation, hyperplasia, and macrophages were present in mammary glands before tumor development, implicating these as possible effectors of tumor promotion. Despite a significant interaction between pubertal diet and carcinogens in tumor promotion, peripubertal HFD by itself produced persistent macrophage recruitment to mammary glands., Conclusions: In obesity-resistant mice, peripubertal HFD is sufficient to irreversibly promote carcinogen-induced tumorigenesis. Increased macrophage recruitment is likely a contributing factor. These results underscore the importance of early life exposures to increased adult cancer risk and are consistent with findings that an HFD in normal weight premenopausal women leads to increased breast cancer risk. Notably, short-latency tumors occurring after peripubertal HFD had characteristics similar to human basal-like breast cancers that predominantly develop in younger women.

Psychotic disorder diagnoses are common in the United States and internationally. However, racial disparities in rates of psychotic disorder diagnoses have been reported across time and mental health professions. This literature review provides an updated and comprehensive summary of empirical research on race and diagnosis of psychotic disorders spanning a 24-year period. Findings reveal a clear and pervasive pattern wherein African American/Black consumers show a rate of on average three to four higher than Euro-American/White consumers. Latino American/Hispanic consumers were also disproportionately diagnosed with psychotic disorders on average approximately three times higher compared to Euro-American/White consumers. In addition, a trend among international studies suggests that immigrant racial minority consumers receiving mental health services may be assigned a psychotic disorder diagnosis more frequently than native consumers sharing a majority racial background. Potential explanations for this phenomenon are discussed, including possible clinical bias and sociological causes such as differential access to healthcare and willingness to participate in mental health services. Directions for future research should include the exploration of disproportionate diagnoses according to race through qualitative interviewing as well as empirical investigation.

It is well documented that macrophages and eosinophils play important roles in normal murine pubertal mammary gland development. Although it is accepted that estrogen (E) and progesterone (P) are key players in mammary gland development, the roles these hormones might play in regulating the actions of leukocytes in that process is an understudied area. We show here that P and E, respectively, induce unique, but overlapping, sets of proinflammatory and angiogenic cytokines and chemokines, in the pubertal female BALB/c mammary gland, as well as induce infiltration of macrophages and eosinophils to the mammary periepithelium. This extends earlier studies showing P induction of proinflammatory products in pubertal and adult mammary epithelial organoids and P-induced in vivo infiltration of leukocytes to the adult mammary periepithelium. Importantly, epidermal growth factor receptor-signaling, which is likely mediated by amphiregulin (Areg), a downstream mediator of E and P, is both necessary and sufficient for both E- and P-induced recruitment of macrophages and eosinophils to the pubertal mammary periepithelium. We further show that receptor activator of nuclear factor κB ligand (RANKL), although not sufficient of itself to cause macrophage and eosinophil recruitment, contributes to an optimal response to P. The potency of Areg is highlighted by the fact that it is sufficient to induce macrophage and eosinophil recruitment at levels equivalent to that induced by either E or P. Our finding of a dominant role for Areg in hormonally induced leukocyte recruitment to the pubertal mammary gland parallels its dominance in regulating ductal outgrowth and its role in P-induced proliferation in the pubertal gland.

Objective: To conduct a proof-of-concept randomized trial of an Internal Family Systems (IFS) psychotherapeutic intervention on rheumatoid arthritis (RA) disease activity and psychological status., Methods: Patients with RA were randomized to either an IFS group for 9 months (n = 39) or an education (control) group (n = 40) that received mailed materials on RA symptoms and management. The groups were evaluated every 3 months until intervention end and 1 year later. Self-assessed joint pain (RA Disease Activity Index joint score), Short Form-12 physical function score, visual analog scale for overall pain and mental health status (Beck Depression Inventory, and State Trait Anxiety Inventory) were assessed. The 28-joint Disease Activity Score-C-reactive Protein 4 was determined by rheumatologists blinded to group assignment. Treatment effects were estimated by between-group differences, and mixed model repeated measures compared trends between study arms at 9 months and 1 year after intervention end., Results: Of 79 participants randomized, 68 completed the study assessments and 82% of the IFS group completed the protocol. Posttreatment improvements favoring the IFS group occurred in overall pain [mean treatment effects -14.9 (29.1 SD); p = 0.04], and physical function [14.6 (25.3); p = 0.04]. Posttreatment improvements were sustained 1 year later in self-assessed joint pain [-0.6 (1.1); p = 0.04], self-compassion [1.8 (2.8); p = 0.01], and depressive symptoms [-3.2 (5.0); p =0.01]. There were no sustained improvements in anxiety, self-efficacy, or disease activity., Conclusion: An IFS-based intervention is feasible and acceptable to patients with RA and may complement medical management of the disease. Future efficacy trials are warranted. ClinicalTrials.gov identifier: NCT00869349.

Clients come to psychotherapy intent on changing, rather than accepting, their unwanted behaviors, emotions, or thoughts. The problem often is, however, that their lack of self-acceptance is the primary obstacle to change. This article describes how one approach, the Internal Family Systems (IFS) model, fosters clients' acceptance of all parts of themselves no matter how destructive, and how that acceptance can lead to the transformation of those parts and, in turn, of other people., (© 2013 Wiley Periodicals, Inc.)

Introduction: Puberty is a period of increased susceptibility to factors that cause increased breast cancer risk in adulthood. Mammary end buds (EBs) that develop during puberty are believed to be the targets of breast cancer initiation. Whereas the role of estrogen (E) has been extensively studied in pubertal mammary gland development, the role of progesterone (P) during puberty is less defined., Methods: Pubertal and prepubertal ovariectomized mice were treated with vehicle control (C), E, P, or E+P. Mammary glands from these mice were analyzed for changes in morphology, proliferation, and expression of the downstream targets amphiregulin (AREG) and receptor activator of NF-κB ligand (RANKL)., Results: P, acting specifically through the progesterone receptor, induced increases in mammary gland proliferation and EB formation that were associated with increased AREG expression in ducts and EBs. E, acting specifically through the estrogen receptor, produced similar responses also mediated by AREG. Blocking AREG action by treatment with an EGFR inhibitor completely abrogated the effect of P on EB formation and proliferation and significantly reduced proliferation within ducts. P also increased expression of RANKL, primarily in ducts. Treatment with RANK-Fc, an inhibitor of RANKL, reduced P-dependent proliferation in ducts and to a lesser extent in EB, but did not cause EB regression., Conclusions: These results demonstrate a novel P-specific effect through AREG to cause EB formation and proliferation in the developing mammary gland both before and during puberty. Thus, hormones and/or factors in addition to E that upregulate AREG can promote mammary gland development and have the potential to affect breast cancer risk associated with pubertal mammary gland development.

Introduction: Epidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of these can promote mammary tumorigenesis. To test the effect of HFD initiated during puberty on tumorigenesis, we utilized BALB/c mice, for which HFD neither induces obesity nor metabolic syndrome, allowing dissociation of HFD effects from other conditions associated with HFD., Methods: Pubertal BALB/c mice were fed a low fat diet (12% kcal fat) or a HFD (60% kcal fat), and subjected to carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis., Results: HFD elevated mammary gland expression of inflammatory and growth factor genes at 3 and 4 weeks of diet. Receptor activator of nuclear factor kappa-B ligand (RANKL), robustly induced at 4 weeks, has direct mitogenic activity in mammary epithelial cells and, as a potent inducer of NF-κB activity, may induce inflammatory genes. Three weeks of HFD induced a transient influx of eosinophils into the mammary gland, consistent with elevated inflammatory factors. At 10 weeks, prior to the appearance of palpable tumors, there were increased numbers of abnormal mammary epithelial lesions, enhanced cellular proliferation, increased growth factors, chemokines associated with immune-suppressive regulatory T cells, increased vascularization, and elevated M2 macrophages. HFD dramatically reduced tumor latency. Early developing tumors were more proliferative and were associated with increased levels of tumor-related growth factors, including increased plasma levels of HGF in tumor-bearing animals. Early HFD tumors also had increased vascularization, and more intra-tumor and stromal M2 macrophages., Conclusions: Taken together in this non-obesogenic context, HFD promotion of inflammatory processes, as well as local and systemically increased growth factor expression, are likely responsible for the enhanced tumorigenesis. It is noteworthy that although DMBA mutagenesis is virtually random in its targeting of genes in tumorigenesis, the short latency tumors arising in animals on HFD showed a unique gene expression profile, highlighting the potent overarching influence of HFD.

There is a need for low-cost, high-accuracy measurement of water content in various materials. This study assesses the performance of a new microwave swept frequency domain instrument (SFI) that has promise to provide a low-cost, high-accuracy alternative to the traditional and more expensive time domain reflectometry (TDR). The technique obtains permittivity measurements of soils in the frequency domain utilizing a through transmission configuration, transmissometry, which provides a frequency domain transmissometry measurement (FDT). The measurement is comparable to time domain transmissometry (TDT) with the added advantage of also being able to separately quantify the real and imaginary portions of the complex permittivity so that the measured bulk permittivity is more accurate that the measurement TDR provides where the apparent permittivity is impacted by the signal loss, which can be significant in heavier soils. The experimental SFI was compared with a high-end 12 GHz TDR/TDT system across a range of soils at varying soil water contents and densities. As propagation delay is the fundamental measurement of interest to the well-established TDR or TDT technique; the first set of tests utilized precision propagation delay lines to test the accuracy of the SFI instrument's ability to resolve propagation delays across the expected range of delays that a soil probe would present when subjected to the expected range of soil types and soil moisture typical to an agronomic cropping system. The results of the precision-delay line testing suggests the instrument is capable of predicting propagation delays with a RMSE of +/-105 ps across the range of delays ranging from 0 to 12,000 ps with a coefficient of determination of r(2) = 0.998. The second phase of tests noted the rich history of TDR for prediction of soil moisture and leveraged this history by utilizing TDT measured with a high-end Hewlett Packard TDR/TDT instrument to directly benchmark the SFI instrument over a range of soil types, at varying levels of moisture. This testing protocol was developed to provide the best possible comparison between SFI to TDT than would otherwise be possible by using soil moisture as the bench mark, due to variations in soil density between soil water content levels which are known to impact the calibration between TDR's estimate of soil water content from the measured propagation delay which is converted to an apparent permittivity measurement. This experimental decision, to compare propagation delay of TDT to FDT, effectively removes the errors due to variations in packing density from the evaluation and provides a direct comparison between the SFI instrument and the time domain technique of TDT. The tests utilized three soils (a sand, an Acuff loam and an Olton clay-loam) that were packed to varying bulk densities and prepared to provide a range of water contents and electrical conductivities by which to compare the performance of the SFI technology to TDT measurements of propagation delay. For each sample tested, the SFI instrument and the TDT both performed the measurements on the exact same probe, thereby both instruments were measuring the exact same soil/soil-probe response to ensure the most accurate means to compare the SFI instrument to a high-end TDT instrument. Test results provided an estimated instrumental accuracy for the SFI of +/-0.98% of full scale, RMSE basis, for the precision delay lines and +/-1.32% when the SFI was evaluated on loam and clay loam soils, in comparison to TDT as the bench-mark. Results from both experiments provide evidence that the low-cost SFI approach is a viable alternative to conventional TDR/TDT for high accuracy applications.

Bone loss in type 1 diabetes is accompanied by increased marrow fat, which could directly reduce osteoblast activity or result from altered bone marrow mesenchymal cell lineage selection (adipocyte vs. osteoblast). CCAAT/enhancer binding protein beta (C/EBPβ) is an important regulator of both adipocyte and osteoblast differentiation. C/EBPβ-null mice have delayed bone formation and defective lipid accumulation in brown adipose tissue. To examine the balance of C/EBPβ functions in the diabetic context, we induced type 1 diabetes in C/EBPβ-null (knockout, KO) mice. We found that C/EBPβ deficiency actually enhanced the diabetic bone phenotype. While KO mice had reduced peripheral fat mass compared with wild-type mice, they had 5-fold more marrow adipocytes than diabetic wild-type mice. The enhanced marrow adiposity may be attributed to compensation by C/EBPδ, peroxisome proliferator-activated receptor-γ2, and C/EBPα. Concurrently, we observed reduced bone density. Relative to genotype controls, trabecular bone volume fraction loss was escalated in diabetic KO mice (-48%) compared with changes in diabetic wild-type mice (-22%). Despite greater bone loss, osteoblast markers were not further suppressed in diabetic KO mice. Instead, osteoclast markers were increased in the KO diabetic mice. Thus, C/EBPβ deficiency increases diabetes-induced bone marrow (not peripheral) adipose depot mass, and promotes additional bone loss through stimulating bone resorption. C/EBPβ-deficiency also reduced bone stiffness and diabetes exacerbated this (two-way ANOVA P < 0.02). We conclude that C/EBPβ alone is not responsible for the bone vs. fat phenotype switch observed in T1 diabetes and that suppression of CEBPβ levels may further bone loss and decrease bone stiffness by increasing bone resorption.

Accurate measurement of moisture content is a prime requirement in hydrological, geophysical and biogeochemical research as well as for material characterization and process control. Within these areas, accurate measurements of the surface area and bound water content is becoming increasingly important for providing answers to many fundamental questions ranging from characterization of cotton fiber maturity, to accurate characterization of soil water content in soil water conservation research to bio-plant water utilization to chemical reactions and diffusions of ionic species across membranes in cells as well as in the dense suspensions that occur in surface films. In these bound water materials, the errors in the traditional time-domain-reflectometer, "TDR", exceed the range of the full span of the material's permittivity that is being measured. Thus, there is a critical need to re-examine the TDR system and identify where the errors are to direct future research. One promising technique to address the increasing demands for higher accuracy water content measurements is utilization of electrical permittivity characterization of materials. This technique has enjoyed a strong following in the soil-science and geological community through measurements of apparent permittivity via time-domain-reflectometery as well in many process control applications. Recent research however, is indicating a need to increase the accuracy beyond that available from traditional TDR. The most logical pathway then becomes a transition from TDR based measurements to network analyzer measurements of absolute permittivity that will remove the adverse effects that high surface area soils and conductivity impart onto the measurements of apparent permittivity in traditional TDR applications. This research examines the theoretical basis behind the coaxial probe, from which the modern TDR probe originated from, to provide a basis on which to perform absolute permittivity measurements. The research reveals currently utilized formulations in accepted techniques for permittivity measurements which violate the underlying assumptions inherent in the basic models due to the TDR acting as an antenna by radiating energy off the end of the probe, rather than returning it back to the source as is the current assumption. To remove the effects of radiation from the experimental results obtain herein, this research utilized custom designed coaxial probes of various diameters and probe lengths by which to test the coaxial cell measurement technique for accuracy in determination of absolute permittivity. In doing so, the research reveals that the basic models available in the literature all omitted a key correction factor that is hypothesized by this research as being most likely due to fringe capacitance. To test this theory, a Poisson model of a coaxial cell was formulated to calculate the effective extra length provided by the fringe capacitance which is then used to correct the experimental results such that experimental measurements utilizing differing coaxial cell diameters and probe lengths, upon correction with the Poisson model derived correction factor, all produce the same results thereby lending support for the use of an augmented measurement technique, described herein, for measurement of absolute permittivity, as opposed to the traditional TDR measurement of apparent permittivity.

Clinical reaction related to client socioeconomic status has not been adequately researched, yet socioeconomic status can profoundly affect psychotherapist perceptions of a client's presenting concerns, symptom severity, and prognosis. Using an online national survey, this study examined the influence of client socioeconomic status on psychotherapist cognitive attributions and countertransference reactions (N = 141). Results revealed no significant differences in cognitive attributions based on socioeconomic status. However, significantly stronger countertransference reactions of being dominated by the client with a higher socioeconomic status were found. In addition, the clients with higher socioeconomic status were ascribed with mild problems compared with the client of lower socioeconomic status. Psychotherapeutic implications are discussed.

Accurate measurement of moisture content is a prime requirement in hydrological, geophysical and biogeochemical research as well as for material characterization and process control. Within these areas, accurate measurements of the surface area and bound water content is becoming increasingly important for providing answers to many fundamental questions ranging from characterization of cotton fiber maturity, to accurate characterization of soil water content in soil water conservation research to bio-plant water utilization to chemical reactions and diffusions of ionic species across membranes in cells as well as in the dense suspensions that occur in surface films. One promising technique to address the increasing demands for higher accuracy water content measurements is utilization of electrical permittivity characterization of materials. This technique has enjoyed a strong following in the soil-science and geological community through measurements of apparent permittivity via time-domain-reflectometry (TDR) as well in many process control applications. Recent research however, is indicating a need to increase the accuracy beyond that available from traditional TDR. The most logical pathway then becomes a transition from TDR based measurements to network analyzer measurements of absolute permittivity that will remove the adverse effects that high surface area soils and conductivity impart onto the measurements of apparent permittivity in traditional TDR applications.This research examines an observed experimental error for the coaxial probe, from which the modern TDR probe originated, which is hypothesized to be due to fringe capacitance. The research provides an experimental and theoretical basis for the cause of the error and provides a technique by which to correct the system to remove this source of error. To test this theory, a Poisson model of a coaxial cell was formulated to calculate the effective theoretical extra length caused by the fringe capacitance which is then used to correct the experimental results such that experimental measurements utilizing differing coaxial cell diameters and probe lengths, upon correction with the Poisson model derived correction factor, all produce the same results thereby lending support and for an augmented measurement technique for measurement of absolute permittivity.

The mechanism by which the platelet-endothelial cell adhesion molecule PECAM-1 regulates leukodiapedesis, vascular endothelial integrity, and proinflammatory cytokine expression in vivo is not known. We recently identified PECAM-1 as a negative regulator of Kv11.1, a specific voltage-gated potassium channel that functioned in human macrophages to reset a resting membrane potential following depolarization. We demonstrate here that dofetilide (DOF), a selective inhibitor of the Kv11.1 current, had a profound inhibitory effect on neutrophil recruitment in mice following TLR/IL-1R-elicited peritonitis or intrascrotal injection of IL-1 Beta, but had no effect on responses seen with TNF alpha. Furthermore, inhibitors of Kv11.1 (DOF, E4031, and astemizole), but not Kv1.3 (margatoxin), suppressed the expression of IL-6 and MCP-1 cytokines by murine resident peritoneal macrophages, while again having no effect on TNF alpha. In contrast, IL-6 expression by peritoneal mesothelial cells was unaffected. Using murine P388 cells, which lack endogenous C/EBP Beta expression and are unresponsive to LPS for the expression of both IL-6 and MCP-1, we observed that DOF inhibited LPS-induced expression of IL-6 mRNA following ectopic expression of wild-type C/EBP Beta, but not a serine-64 point mutant. Finally, DOF inhibited the constitutive activation of cdk2 in murine peritoneal macrophages; cdk2 is known to phosphorylate C/EBP Beta at serine-64. Taken together, our results implicate a potential role for Kv11.1 in regulating cdk2 and C/EBP Beta activity, where robust transactivation of both IL-6 and MCP-1 transcription is known to be dependent on serine-64 of C/EBP Beta. Our data might also explain the altered phenotypes displayed by PECAM-1 knockout mice in several disease models.

Unlabelled: Advances in genetics have prompted recommendations that all healthcare providers perform genetic counseling and testing. Some experts are concerned about potential negative outcomes from cancer genetic testing performed without genetic counseling by certified genetics professionals. We report a national series of cases illustrating negative outcomes of cancer genetic testing performed without counseling by a qualified provider. Three major patterns emerged from analysis of these cases: 1) Wrong genetic test ordered, 2) Genetic test results misinterpreted, and 3) Inadequate genetic counseling. Negative outcomes included unnecessary prophylactic surgeries, unnecessary testing, psychosocial distress, and false reassurance resulting in inappropriate medical management., Conclusion: With the complexities of cancer genetic counseling and testing, it may be unrealistic to expect all clinicians to provide these services. A more realistic approach is better provider education and a framework in which healthcare providers identify patients who would benefit from a referral to a certified genetic counselor or experienced cancer genetics professional.

Phosphorus (P) in animal manure can be an important nutrient for crops or an environmental contaminant if in excess. Organic P in dairy manure may add to the environmentally bioactive P pools upon mineralization. A 353d incubation study of manures containing C:P between 83 and 130:1 was conducted to determine linkages between C and P transformations and the effects of C:P on the immobilization-mineralization of manure P. As C:P widened from 83:1 to 130:1, P mineralization increased and phosphate accumulated at rates between 0.013 and 0.021mgkg(-1) d(-1). Water-extractable C was positively correlated with N:P, particularly at narrow C:P (P<0.001). Absence of a negative feedback by phosphate suggested that P mineralization occurred with degradation of organic P-containing C substrates and appeared incidental to microbial P needs. Carbon content in manure may be managed to lower risks of elevated soluble P and C losses under non-limiting N conditions., (Published by Elsevier Ltd.)

C/EBPzeta was originally identified as a gene induced upon DNA damage and growth arrest. It has been shown to be involved in the cellular response to endoplasmic reticulum stress. Because of sequence divergence from other C/EBP family members in its DNA-binding domain and its consequent inability to bind the C/EBP consensus-binding motif, C/EBPzeta can act as a dominant negative inhibitor of other C/EBPs. C/EBP transactivators are essential to the expression of many proinflammatory cytokines and acute phase proteins, but a role for C/EBPzeta in regulating their expression has not been described. We found that expression of C/EBPzeta is induced in response to LPS treatment of B cells at both the mRNA and protein levels. Correlating with the highest levels of C/EBPzeta expression at 48 h after LPS treatment, there is an increased association of C/EBPzeta with C/EBPbeta, and both the abundance of C/EBP DNA-binding species and IL-6 expression are downregulated. Furthermore, ectopic expression of C/EBPzeta inhibited C/EBPbeta-dependent IL-6 expression from both the endogenous IL-6 gene and an IL-6 promoter-reporter. These results suggest that C/EBPzeta functions as negative regulator of IL-6 expression in B cells and that it contributes to the transitory expression of IL-6 that is observed after LPS treatment.

Progesterone, through the progesterone receptor (PR), promotes development of the normal mammary gland and is implicated in the etiology of breast cancer. We identified PRA-regulated genes by microarray analysis of cultured epithelial organoids derived from pubertal and adult mouse mammary glands, developmental stages with differing progesterone responsiveness. Microarray analysis showed significant progestin (R5020)-regulation of 162 genes in pubertal organoids and 104 genes in adult organoids, with 68 genes regulated at both developmental stages. Greater induction of receptor activator of NFkappaB ligand and calcitonin expression was observed in adult organoids, suggesting possible roles in the differential progesterone responsiveness of the adult and pubertal mammary glands. Analysis of the R5020-responsive transcriptome revealed several enriched biological processes including cell adhesion, immune response, and survival. R5020 both induced Agtr1 and potentiated angiotensin II-stimulated proliferation, highlighting the functional significance of the latter process. Striking up-regulation of genes involved in innate immunity processes included the leukocyte chemoattractants serum amyloid A1, 2 and 3 (Saa1, 2, 3). In vivo analysis revealed that progesterone treatment increased SAA1 protein expression and leukocyte density in mammary gland regions undergoing epithelial expansion. These studies reveal novel targets of PRA in mammary epithelial cells and novel linkages of progesterone action during mammary gland development.

Progesterone (P) is required for normal mammary gland development, and is implicated in the etiology of mammary cancer in rodents and humans. We analyzed mammary gland developmental responses to P and estrogen (E) in two strains of mice (BALB/c and C57BL/6) that exhibit differences in ductal development at sexual maturity and alveologenesis during pregnancy. C57BL/6 mice exhibited reduced proliferative and morphological responses to P. Analysis of known mediators of sidebranching and alveologenesis revealed that reduced P-induced expression of P receptor isoform B and receptor activator of nuclear factor-kappaB ligand (RANKL), as well as altered expression and regulation of cyclin D1, CCAAT/enhancer binding protein beta, and the downstream effectors of RANKL, nuclear Id2 and p21, contribute significantly to the reduced P responsiveness of the C57BL/6 mammary gland. In contrast, E responsiveness was greater in C57BL/6 than in BALB/c glands. E may play a compensatory role in C57BL/6 alveologenesis through its effect on the induction and activation of signal transducer and activator of transcription 5a, a known regulator of RANKL. These observations suggest that in human populations with heterogeneous genetic backgrounds, individuals may respond differentially to the same hormone. Thus, genetic diversity may have a role in determining the effects of P in normal mammary development and tumorigenesis.

Type I diabetes is associated with bone loss and marrow adiposity. To identify early events involved in the etiology of diabetic bone loss, diabetes was induced in mice by multiple low dose streptozotocin injections. Serum markers of bone metabolism and inflammation as well as tibial gene expression were examined between 1 and 17 days post-injection (dpi). At 3 dpi, when blood glucose levels were significantly elevated, body, fat pad and muscle mass were decreased. Serum markers of bone resorption and formation significantly decreased at 5 dpi in diabetic mice and remained suppressed throughout the time course. An osteoclast gene, TRAP5 mRNA, was suppressed at early and late time points. Suppression of osteogenic genes (runx2 and osteocalcin) and induction of adipogenic genes (PPARgamma2 and aP2) were evident as early as 5 dpi. These changes were associated with an elevation of serum cytokines, but more importantly we observed an increase in the expression of cytokines in bone, supporting the idea that bone, itself, exhibits an inflammatory response during diabetes induction. This inflammation could in turn contribute to diabetic bone pathology. IFN-gamma (one of the key cytokines elevated in bone and known to be involved in bone regulation) deficiency did not prevent diabetic bone pathology. Taken together, our findings indicate that bone becomes inflamed with the onset of T1-diabetes and during this time bone phenotype markers become altered. However, inhibition of one cytokine, IFN-gamma was not sufficient to prevent the rapid bone phenotype changes.

Screening for genetic abnormalities is a relatively complex task requiring detailed training and knowledge. Analysis of a person's genetic makeup has implications not only for that individual but also for their progenitors, offspring, siblings, and spouses. There are potential insurance, employment, and other risks regarding disclosure of this information. With proper training, surgeons or nurses with advanced skills can be qualified to conduct this type of initial analysis. Geneticists may be the ideal professionals to counsel patients. In this article, we explore these and other issues. The goal is to provide the surgeon with the information needed to identify patients at risk for carrying identifiable mutations that might lead to the development of breast cancer.

Substance abuse is one of the most common comorbid conditions among clients with schizophrenia. This study assessed correlates of current substance abuse severity not evaluated in past research (e.g., manic symptoms, traumatic stress, self-care deficits, interpersonal relationship problems), as well as factors previously shown to be associated with substance abuse among clients with schizophrenia (e.g., age, gender, depressive symptoms, psychotic symptoms, work/school problems, legal problems). Multiple regression analyses revealed that more severe self-care deficits and less extreme psychotic symptomatology were related to exacerbated symptoms of substance abuse. Implications of these findings for future research are discussed.

Although the Global Assessment of Functioning (GAF) scale is a widely utilized instrument, little data on construct validity is available about its use with clients having schizophrenia. This study compared point-specific GAF scores with concurrent ratings of symptomatology and social and occupational impairments using the Functional Assessment Rating Scale (Ward & Dow, 1994). A linear multiple regression analysis of empirical data from investigations of clients' global functioning showed that increased work and school-related problems, danger to others, and psychotic symptoms predicted lower GAF scores. In general, GAF scores seem to reflect the construct of global psychological, social, and occupational functioning that the scale was designed to measure.

C/EBPbeta is a member of the CCAAT/enhancer binding protein family of transcription factors and has been shown to be a critical transcriptional regulator of various proinflammatory genes, including IL-6 and MCP-1. Serine 64 in the transactivation domain of C/EBPbeta has recently been identified as a Ras-induced phosphoacceptor site. The integrity of serine 64 along with threonine 189 is important for the Ha-ras(V12)-induced transformation of NIH3T3 cells, however no target genes dependent upon serine 64 for their expression have been reported. In order to evaluate a potential role of serine 64 in C/EBPbeta-regulated cytokine expression, we expressed a form of C/EBPbeta with an alanine substitution at serine 64 (C/EBPbeta(S64A)) in P388 murine B lymphoblasts, which lack endogenous C/EBPbeta expression and are normally unresponsive to LPS for expression of IL-6 and MCP-1. In comparison to wild type C/EBPbeta, which robustly supports the LPS-induced expression of IL-6 and MCP-1, C/EBPbeta(S64A) was severely impaired in its ability to support the LPS-induced transcription of IL-6 and MCP-1. Furthermore, LPS stimulation increased the level of phosphorylation detected at serine 64. Thus, serine 64, probably through its phosphorylation, is a critical determinant of C/EBPbeta activity in the transcription of IL-6 and MCP-1.

C/EBPbeta is a member of the CCAAT/enhancer binding protein family of transcription factors and has been shown to be a critical transcriptional regulator of various proinflammatory genes, including IL-6 and MCP-1. To examine the roles of the C/EBPbeta transactivation and regulatory domains in LPS-induced MCP-1 and IL-6 expression, we expressed various N-terminal truncations and deletions of C/EBPbeta in P388 murine B lymphoblasts, which lack endogenous C/EBPbeta expression and are normally unresponsive to LPS for expression of IL-6 and MCP-1. Unexpectedly, a region between amino acids 105 and 212 of C/EBPbeta that includes regulatory domains 1 and 2 facilitates C/EBPbeta activation of IL-6 expression, while having an inhibitory effect on MCP-1 expression. Thus, this region can mediate promoter-specific effects on cytokine and chemokine gene transcription. LIP, the naturally occurring truncated form of C/EBPbeta, largely retains these regulatory domains and stimulates IL-6 but not MCP-1 transcription.

Contemporary theoretical and clinical literature asserts that countertransference reactions are common and may be specific to clients' presenting concerns and interpersonal styles. Although this phenomenon has broad implications for psychotherapy training and practice, little empirical research is available to support these claims. This study investigated the phenomenon of client-induced countertransference toward two client populations that may evoke strong reactions in psychotherapists--persons with Antisocial Personality Disorder and Schizophrenia. Results of a MANOVA and follow-up ANOVAs indicate that psychotherapists displayed significantly stronger feelings of being dominated (i.e., exploited, manipulated, talked down to) by clients with Antisocial Personality Disorders. Counselors manifested significantly stronger positive feelings (i.e., being liked and welcomed and being in charge, that is, being put in a decision-making role) when working with clients having Schizophrenia. We discuss research and clinical implications of these findings.

Managing fertilizer applications to maintain soil P below environmentally unacceptable levels should consider the contribution of manure and synthetic fertilizer sources to soluble and extractable forms of P. Our objective was to evaluate soil and manure characteristics and application rates on P extractability in recently amended soils. Five soils of the U.S. southern High Plains were amended with beef cattle manures, composted beef manure, and inorganic fertilizers [Ca(H(2)PO(4))(2) or KH(2)PO(4)] at five rates and incubated under controlled conditions. Mehlich 3-, Olsen (NaHCO(3))-, Texas A&M extractant (TAM)-, and water-extractable P were determined for the soils after selected incubation periods. Except for TAM and some water extractions, P extractability as a function of total P applied was linear (P < 0.001) for a wide range of application rates. Mehlich-3, NaHCO(3), and water P extraction efficiencies of KH(2)PO(4)-amended soils averaged 22, 34, and 115% greater (P < or = 0.036), respectively, than efficiencies of soils amended with manures except for the Texline (calcareous) loam and Pullman clay loam soils. Phosphorus extraction efficiencies decreased with time for KH(2)PO(4)-amended soils (P < 0.05) but remained stable or increased for manure-amended soils during the 8-wk incubation period. Across all soils and manure sources, changes in water-extractable P per unit increase in Mehlich 3-, NaHCO(3)-, and TAM-extractable P averaged 100, 85, and 125% greater, respectively, for inorganic as compared with manure-amended soils. These source-dependent relationships limit the use of agronomic soil extractants to make correct inferences about water-extractable P and dissolved P in runoff.

The purpose of the present Perspectives is to present a synopsis of the literature on bacterial "quorum sensing" as a background for the proposal that interference with this communication system offers potential targets for the design of novel antibiotic drugs. Quorum sensing is the recently discovered chemical communication system among bacteria (both Gram-positive and -negative). It is vital for intra- and interbacterial gene regulation and for keeping bacterial colonies ("biofilms") intact, allowing resident bacteria to assume specialized roles that contribute to enhanced survival of the group. There are several processes involved in quorum sensing that are familiar to pharmacologists; i.e., specific signaling molecules bind to and activate receptors that transduce the quorum-sensing signal into intracellular second messenger responses. We highlight herein the similarity between quorum-sensing communication to ligand-receptor interactions, suggesting that inhibitor drugs could be designed using current standard pharmacologic principles. Such drugs would have novel mechanisms of action and might therefore be more effective against antibiotic-resistant strains of bacteria.

This study investigated the convergent validity of the Beck Depression Inventory for Youth in a sample of 34 children (22 boys, 12 girls) who ranged in age from 7 to 14 years (M= 11.3, SD=2.3) by comparing scores with simultaneous ratings on the Children's Depression Inventory. Analysis indicated that the sets of scores correlated very strongly regardless of age or sex. Given that this Beck Depression Inventory has fewer items and is guided by a strong theoretical premise, this scale may be a valuable tool for use with youth by clinicians in various mental health disciplines.