Teaching Note-Supporting Homebound Older Adults and Caregivers Through Integrative Service Learning.

The Supporting Older Adults & Caregivers: Integrative Service Learning (SOCIAL) partnership trains undergraduate social work students to provide practical home-based support for older adults with chronic illness and their family caregivers, serving as a pipeline for future leaders in older adult care. More than 2 million older adults are homebound, and 5 million need help leaving their homes due to physical limitations from chronic conditions or cognitive impairments. Family members often assume daily caregiving tasks to assist their loved ones, navigate health care systems, and provide much needed emotional support. The challenges of caregiving are further compounded by the problems associated with insufficient health care professionals who are trained to work with older adults. Integrative service learning models can provide home-based support to older adults while offering valuable, hands-on learning experiences for students. In this teaching note, we acknowledge a need for developing an educational pipeline that can provide training opportunities for students to work with older adults and their caregivers at home. We provide an example of an integrative service-learning model which offers valuable pedagogical experiences to baccalaureate students along with strategies for curriculum building, community engagement, research and evaluation, and program sustainability.

Intravenous supplementation type and volume are associated with 1-year outcome and major complications in patients with chronic intestinal failure.

BACKGROUND AND AIM: No marker to categorise the severity of chronic intestinal failure (CIF) has been developed. A 1-year international survey was carried out to investigate whether the European Society for Clinical Nutrition and Metabolism clinical classification of CIF, based on the type and volume of the intravenous supplementation (IVS), could be an indicator of CIF severity. METHODS: At baseline, participating home parenteral nutrition (HPN) centres enrolled all adults with ongoing CIF due to non-malignant disease; demographic data, body mass index, CIF mechanism, underlying disease, HPN duration and IVS category were recorded for each patient. The type of IVS was classified as fluid and electrolyte alone (FE) or parenteral nutrition admixture (PN). The mean daily IVS volume, calculated on a weekly basis, was categorised as <1, 1-2, 2-3 and >3 L/day. The severity of CIF was determined by patient outcome (still on HPN, weaned from HPN, deceased) and the occurrence of major HPN/CIF-related complications: intestinal failure-associated liver disease (IFALD), catheter-related venous thrombosis and catheter-related bloodstream infection (CRBSI). RESULTS: Fifty-one HPN centres included 2194 patients. The analysis showed that both IVS type and volume were independently associated with the odds of weaning from HPN (significantly higher for PN <1 L/day than for FE and all PN >1 L/day), patients' death (lower for FE, p=0.079), presence of IFALD cholestasis/liver failure and occurrence of CRBSI (significantly higher for PN 2-3 and PN >3 L/day). CONCLUSIONS: The type and volume of IVS required by patients with CIF could be indicators to categorise the severity of CIF in both clinical practice and research protocols.

A framework to support quality of care for patients with chronic intestinal failure requiring home parenteral nutrition.

BACKGROUND AND AIM: Chronic intestinal failure requiring home parenteral nutrition (HPN) is a disabling condition that is best facilitated by a multidisciplinary approach to care. Variation in care has been identified as a key barrier to achieving quality of care for patients on HPN and requires appropriate strategies to help standardize management. METHOD: The Australasian Society for Parenteral and Enteral Nutrition (AuSPEN) assembled a multidisciplinary working group of 15 clinicians to develop a quality framework to assist with the standardization of HPN care in Australia. Obstacles to quality care specific to Australia were identified by consensus. Drafts of the framework documents were based on the available literature and refined by two Delphi rounds with the clinician work group, followed by a further two involving HPN consumers. The Oxford Centre for Evidence-Based Medicine Levels of Evidence was used to assess the strength of evidence underpinning each concept within the framework documents. RESULTS: Quality indicators, standards of care, and position statements have been developed to progress the delivery of quality care to HPN patients. CONCLUSION: The quality framework proposed by AuSPEN is intended to provide a practical structure for clinical and organizational aspects of HPN service delivery to reduce variation in care and improve quality of care and represents the initial step towards development of a national model of care for HPN patients in Australia. While developed for implementation in Australia, the evidence-based framework also has relevance to the international HPN community.

Development of consensus on models of care in adults with intestinal failure using a modified Delphi approach.

BACKGROUND AND AIM: The aims of this study were to establish consensus on service delivery models for management of Type III intestinal failure (IF) and home parenteral nutrition (HPN) within the Australian health-care system and to identify barriers and enablers in moving towards this ideal model. METHODS: A modified Delphi methodology was utilized to survey experts working in Type III IF HPN. The panel comprised physicians, dietitians, nurses, and pharmacists from 18 of the 20 adult Type III IF HPN centres across Australia. The study consisted of two rounds of email administered questionnaires developed around four key areas of health service delivery: access to services, clinical care, service guidance, and models of care. Open-ended responses were evaluated via an inductive thematic approach to identify areas of consensus. Experts reviewed the final report to consolidate consensus and validity. RESULTS: There was >80% consensus that an ideal team should consist of a physician, nurse, dietitian, pharmacist, and access to psychological support. Consensus supported the need for updated guidelines (75%) and a hub and spoke model of care (82%). However, further consultation is required in order to establish consensus around the use of HPN in the palliative oncology setting (69%). CONCLUSIONS: This consensus provides a framework within which health professionals, managers, policy-makers, and consumer groups can move towards optimal management for Type III IF HPN patients. Advocacy and a review of service delivery across Australia are now required to facilitate the ideal model of care identified.

Bridging the gap between conventional and standardized competency to stand trial (CST) assessments: An examination of defendant answers to conventional CST questions.

Despite research suggesting that use of forensic assessment instruments of competency to stand trial (CST) can improve the integrity of forensic conceptualizations (Rogers & Johansson-Love, 2009), the majority of evaluators do not use these measures in CST evaluations (Nicholson & Norwood, 2000). The purpose of this study is to bridge the gap between competency evaluations based on a conventional interview and those conducted with the aid of a standardized forensic assessment instrument. To this end, we utilized an archival sample of 704 criminal defendants (543 males, 161 females) ordered to undergo evaluations of CST. In the overall sample, as well as in 2 comparison groups comprised of individuals with psychotic disorders and mental retardation, we coded evaluee responses to 45 conventional competency questions relating to factual understanding, rational understanding, and ability to cooperate with counsel. We present accuracy rates to these questions across competent and incompetent groups in an effort to provide information that can make conventional interviews more evidence-based. Using relative risk ratios, we also sought to identify the questions most associated with evaluator opinions of incompetency. Overall, the results indicated fairly consistent trends that questions relating to rational understanding and ability to cooperate with counsel were the most associated with competence. We discuss how the relative risk ratio findings and descriptive information can be used to make conventional competency interviews more objective and empirically based by providing evaluators with a normative reference point for commonly asked competency questions. (PsycINFO Database Record

Investigating the Self-Protective Potential of Immobility in Victims of Rape.

Using a nationwide sample of reported rape cases collected by the Federal Bureau of Investigation (FBI; 389 victims; 89% stranger rapes), this study investigates assumptions about self-protective behaviors for rape victims. Past research on victim resistance strategies often specifies active resistance as self-protective, inadvertently underestimating the potential for biologically based reactions, such as tonic immobility, to be self-protective as well. Results confirm that rape victims who were verbally and physically immobile during the attack were less likely to be injured and have force used against them. In addition, victims who were verbally immobile suffered a less severe attack. The results indicate that immobility may protect the victim from increased injury, force, and severity of the attack. Implications for the legal and public definition of consent are discussed.

Tonic Immobility as a Defensive Trauma Response to Rape: Bridging Public Health and Law.

There is widespread scientific evidence that validates tonic immobility (TI) as part of the trauma response in victims of rape, and criminal justice practitioners are increasingly trained in trauma-informed approaches. Yet, legal and policy definitions of consent do not fully recognize TI during the incident as evidence of nonconsent. Using a systematic review of U.S. law and policy regarding sexual violence and consent, this paper analyzes the substantial legal reform of rape law and definitions of consent, suggesting ways to further integrate TI into existing law and legal practices to improve public health approaches and justice responses for victims.

Acuity-Based Staffing in Labor and Delivery Using Electronic Health Record Data.

BACKGROUND: Planning safe and effective nurse staffing can be challenging for nurse leaders of labor and delivery units due to the dynamic nature of birth and unpredictable fluctuations in census and acuity. The electronic health record (EHR) has a vast source of patient data that can be used to retrospectively review patient needs and nurse staffing gaps that can serve as a basis for prospective planning for nurse staffing. PURPOSE: This quality improvement project was initiated with the goal of developing real-time and longitudinal reports to quantify hourly nurse staffing needs based on patient census, acuity, and required clinical interventions from data that are contained with the EHR. The plan was to determine trends and nurse staffing needs for each 24-hour period every day of the week and identify ongoing staffing patterns to meet the Association of Women's Health, Obstetric, and Neonatal Nurses' (AWHONN) staffing guidelines. METHODS: The obstetric nursing leadership team worked with the information technology specialists and developed an algorithm that identifies patient acuity level, indicated clinical interventions, and outlines necessary staffing requirements to provide safe high-quality care. Various reports were built in the EHR to inform the nursing leadership team about nurse staffing on a real-time and historical basis. RESULTS: The reports provided quantitative data that supported a budgetary increase in nurse staffing and a more flexible nurse staffing scheduling system to meet the needs of the patients. The project was successfully implemented in all four of the hospital system maternity units. CLINICAL IMPLICATIONS: Use of EHR in labor and delivery units is nearly universal. Working with the information technology specialists to integrate nurse staffing data into the EHR is one way to align nurse staffing with the AWHONN nurse staffing standards in real-time and for projections of nurse staffing needs based on unit historical patient data.

Detailed analysis of in-hospital costs for adult patients with type III intestinal failure: A single-center study with global implications.

BACKGROUND: Home parenteral nutrition (HPN) is the recommended treatment for patients with type III intestinal failure (IF). However, owing to IF's rarity, the economic cost of managing these patients is not well understood. These patients often develop complications resulting in readmissions, which in turn contribute to ongoing costs. This study aims to document the costs of type III IF within the hospital, from initial admission, including readmissions, and to compare incurred costs with current government reimbursement. METHODS: A retrospective study design reviewed costs and reimbursement for 25 consecutive patients commencing HPN at a quaternary hospital (October 2011 to September 2017). Hospital admissions were separated into the initial admission and readmission(s) period. Healthcare use and cost data were collected using electronic medical records. Hospital reimbursement costs were retrieved from Sydney Local Health District's Targeted Activity and Reporting Systems. Patient demographics were tabulated, and healthcare use and cost data were compared using Wilcoxon signed rank tests. RESULTS: The median cost of the initial hospital admission was substantially higher than the median reimbursement ($36,675; interquartile range [IQR], $23,196-$67,439 vs $19,247; IQR, $7485-$41,090; P < .001). Similar results were observed in the readmissions period, with median incurred costs of $13,898; (IQR, $11,151-$32,130) vs reimbursement of $8469 (IQR, $5625-$13,078) (P = .001). CONCLUSION: Results indicate that type III IF patients have high inpatient costs, which substantially outweigh current reimbursement. Improved funding models are needed to ensure hospitals that accept the management challenge of type III IF patients are not unduly penalized.

Characteristics of adult patients with chronic intestinal failure due to short bowel syndrome: An international multicenter survey.

BACKGROUND AND AIMS: The case-mix of patients with intestinal failure due to short bowel syndrome (SBS-IF) can differ among centres and may also be affected by the timeframe of data collection. Therefore, the ESPEN international multicenter cross-sectional survey was analyzed to compare the characteristics of SBS-IF cohorts collected within the same timeframe in different countries. METHODS: The study included 1880 adult SBS-IF patients collected in 2015 by 65 centres from 22 countries. The demographic, nutritional, SBS type (end jejunostomy, SBS-J; jejuno-colic anastomosis, SBS-JC; jejunoileal anastomosis with an intact colon and ileocecal valve, SBS-JIC), underlying disease and intravenous supplementation (IVS) characteristics were analyzed. IVS was classified as fluid and electrolyte alone (FE) or parenteral nutrition admixture (PN). The mean daily IVS volume, calculated on a weekly basis, was categorized as <1, 1-2, 2-3 and >3 L/day. RESULTS: In the entire group: 60.7% were females and SBS-J comprised 60% of cases, while mesenteric ischaemia (MI) and Crohn' disease (CD) were the main underlying diseases. IVS dependency was longer than 3 years in around 50% of cases; IVS was infused ≥5 days/week in 75% and FE in 10% of cases. Within the SBS-IF cohort: CD was twice and thrice more frequent in SBS-J than SBS-JC and SBS-JIC, respectively, while MI was more frequent in SBS-JC and SBS-JIC. Within countries: SBS-J represented 75% or more of patients in UK and Denmark and 50-60% in the other countries, except Poland where SBS-JC prevailed. CD was the main underlying disease in UK, USA, Denmark and The Netherlands, while MI prevailed in France, Italy and Poland. CONCLUSIONS: SBS-IF type is primarily determined by the underlying disease, with significant variation between countries. These novel data will be useful for planning and managing both clinical activity and research studies on SBS.

NEW RECORDS OF PHLEBOTOMINE SAND FLIES (DIPTERA: PSYCHODIDAE) FROM ECUADOR.

The number of recorded phlebotomine sand fly species in Ecuador has nearly doubled during the past 20 years as a result of surveys. In 2005, a sand fly survey of two localities, Tiputini in the Amazon rain forest and Paraiso Escondido in the Pacific coastal lowland forest, resulted in the capture of 25 species. New records for Ecuador consisted of five species from the Amazonian region and one from Paraiso Escondido. The Amazonian species were Nyssomyia richardwardi (Ready and Fraiha), Psathyromyia dreisbachi (Causey and Damasceno), Psathyromyia runoides (Fairchild and Hertig), Trichophoromyia pabloi (Barretto, Burbano and Young), and Trichopygomyia witoto (Young and Morales). The Pacific coastal lowland species was Psathyromyia punctigeniculata (Floch and Abonnenc).

Home parenteral nutrition provision modalities for chronic intestinal failure in adult patients: An international survey.

BACKGROUND & AIMS: The safety and effectiveness of a home parenteral nutrition (HPN) program depends both on the expertise and the management approach of the HPN center. We aimed to evaluate both the approaches of different international HPN-centers in their provision of HPN and the types of intravenous supplementation (IVS)-admixtures prescribed to patients with chronic intestinal failure (CIF). METHODS: In March 2015, 65 centers from 22 countries enrolled 3239 patients (benign disease 90.1%, malignant disease 9.9%), recording the patient, CIF and HPN characteristics in a structured database. The HPN-provider was categorized as health care system local pharmacy (LP) or independent home care company (HCC). The IVS-admixture was categorized as fluids and electrolytes alone (FE) or parenteral nutrition, either commercially premixed (PA) or customized to the individual patient (CA), alone or plus extra FE (PAFE or CAFE). Doctors of HPN centers were responsible for the IVS prescriptions. RESULTS: HCC (66%) was the most common HPN provider, with no difference noted between benign-CIF and malignant-CIF. LP was the main modality in 11 countries; HCC prevailed in 4 European countries: Israel, USA, South America and Oceania (p < 0.001). IVS-admixture comprised: FE 10%, PA 17%, PAFE 17%, CA 38%, CAFE 18%. PA and PAFE prevailed in malignant-CIF while CA and CAFE use was greater in benign-CIF (p < 0.001). PA + PAFE prevailed in those countries where LP was the main HPN-provider and CA + CAFE prevailed where the main HPN-provider was HCC (p < 0.001). CONCLUSIONS: This is the first study to demonstrate that HPN provision and the IVS-admixture differ greatly among countries, among HPN centers and between benign-CIF and cancer-CIF. As both HPN provider and IVS-admixture types may play a role in the safety and effectiveness of HPN therapy, criteria to homogenize HPN programs are needed so that patients can have equal access to optimal CIF care.

Assessing Patient Preferences for Intestinal Failure Management Using the Time Trade-Off Methodology.

BACKGROUND: There are limited management options available for people with Type III intestinal failure (IF), with home parenteral nutrition (HPN) being the main treatment option. The aim of this research is to compare patient preferences in managing Type III IF using time trade-off (TTO) methodology and to determine which factors have the greatest impact on health-related quality of life (HRQoL). METHODS: An interviewer-administered telephone survey was conducted on a cross-sectional cohort of 19 HPN participants. The survey was designed to measure HRQoL using a TTO methodology. Four different treatment options were presented, and participants decided how many years of life they would trade to have access to the treatment and hence a different health state. The 4 scenarios included reduction in line infections, optimization of care, small bowel growth (teduglutide), and intestinal transplantation. Health state utility scores were calculated. RESULTS: The median health utility score for optimization of care and small bowel growth (teduglutide) were lowest (0.5; range 0-1) meaning a greater desire for this treatment. Intestinal transplant had the highest median utility score (1.0; range 0-1) indicating less willingness for this treatment option. CONCLUSIONS: This is the first known study to use TTO methodology assessing treatment options in people with IF requiring HPN. Results indicate people requiring HPN make careful decisions when considering treatment options. Facilities providing HPN services should focus on optimization of current care, which is highly valued by their patients.

Clinical classification of adult patients with chronic intestinal failure due to benign disease: An international multicenter cross-sectional survey.

BACKGROUND & AIMS: The aim of the study was to evaluate the applicability of the ESPEN 16-category clinical classification of chronic intestinal failure, based on patients' intravenous supplementation (IVS) requirements for energy and fluids, and to evaluate factors associated with those requirements. METHODS: ESPEN members were invited to participate through ESPEN Council representatives. Participating centers enrolled adult patients requiring home parenteral nutrition for chronic intestinal failure on March 1st 2015. The following patient data were recorded though a structured database: sex, age, body weight and height, intestinal failure mechanism, underlying disease, IVS volume and energy need. RESULTS: Sixty-five centers from 22 countries enrolled 2919 patients with benign disease. One half of the patients were distributed in 3 categories of the ESPEN clinical classification. 9% of patients required only fluid and electrolyte supplementation. IVS requirement varied considerably according to the pathophysiological mechanism of intestinal failure. Notably, IVS volume requirement represented loss of intestinal function better than IVS energy requirement. A simplified 8 category classification of chronic intestinal failure was devised, based on two types of IVS (either fluid and electrolyte alone or parenteral nutrition admixture containing energy) and four categories of volume. CONCLUSIONS: Patients' IVS requirements varied widely, supporting the need for a tool to homogenize patient categorization. This study has devised a novel, simplified eight category IVS classification for chronic intestinal failure that will prove useful in both the clinical and research setting when applied together with the underlying pathophysiological mechanism of the patient's intestinal failure.

Control of DNA replication and chromosome ploidy by geminin and cyclin A.

Alteration of the control of DNA replication and mitosis is considered to be a major cause of genome instability. To investigate the mechanism that controls DNA replication and genome stability, we used the RNA silencing-interference technique (RNAi) to eliminate the Drosophila geminin homologue from Schneider D2 (SD2) cells. Silencing of geminin by RNAi in SD2 cells leads to the cessation of mitosis and asynchronous overreplication of the genome, with cells containing single giant nuclei and partial ploidy between 4N and 8N DNA content. The effect of geminin deficiency is completely suppressed by cosilencing of Double parked (Dup), the Drosophila homologue of Cdt1, a replication factor to which geminin binds. The geminin deficiency-induced phenotype is also partially suppressed by coablation of Chk1/Grapes, indicating the involvement of Chk1/Grapes in the checkpoint control in response to overreplication. We found that the silencing of cyclin A, but not of cyclin B, also promotes the formation of a giant nucleus and overreplication. However, in contrast to the effect of geminin knockout, cyclin A deficiency leads to the complete duplication of the genome from 4N to 8N. We observed that the silencing of geminin causes rapid downregulation of Cdt1/Dup, which may contribute to the observed partial overreplication in geminin-deficient cells. Analysis of cyclin A and geminin double knockout suggests that the effect of cyclin A deficiency is dominant over that of geminin deficiency for cell cycle arrest and overreplication. Together, our studies indicate that both cyclin A and geminin are required for the suppression of overreplication and for genome stability in Drosophila cells.

Plasma membrane KATP channel-mediated cardioprotection involves posthypoxic reductions in calcium overload and contractile dysfunction: mechanistic insights into cardioplegia.

Our recent data demonstrate that activation of pmKATP channels polarizes the membrane of cardiomyocytes and reduces Na+/Ca2+ exchange-mediated Ca2+ overload. However, it is important that these findings be extended into contractile models of hypoxia/reoxygenation injury to further test the notion that pmKATP channel activation affords protection against contractile dysfunction and calcium overload. Single rat heart right ventricular myocytes were enzymatically isolated, and cell contractility and Ca2+ transients in field-stimulated myocytes were measured in a cellular model of metabolic inhibition and reoxygenation. Activation of pmKATP with P-1075 (5 microM) or inhibition of the Na+/Ca2+ exchanger with KB-R7943 (5 microM)reduced reoxygenation-induced diastolic Ca2+ overload and improved the rate and magnitude of posthypoxic contractile recovery during the first few minutes of reoxygenation. Moreover,diastolic Ca2+ overload and posthypoxic contractile dysfunction were aggravated in ventricular myocytes either subjected to specific blockade of pmKATP with HMR1098 (20 microM) or expressing the dominant-negative pmKATP construct Kir6.2(AAA) in the presence of P-1075. Our results suggest that a common mechanism, involving resting membrane potential-modulated increases in diastolic [Ca2+]i, is responsible for the development of contractile dysfunction during reoxygenation following metabolic inhibition. This novel and highly plausible cellular mechanism for pmKATP-mediated cardioprotection may have direct clinical relevance as evidenced by the following findings: a hypokalemic polarizing cardioplegia solution supplemented with the pmKATP opener P-1075 improved Ca2+ homeostasis and recovery of function compared with hyperkalemic depolarizing St. Thomas' cardioplegia following contractile arrest in single ventricular myocytes and working rat hearts. We therefore propose that activation of pmKATP channels improves posthypoxic cardiac function via reductions in abnormal diastolic Ca2+ homeostasis mediated by reverse-mode Na+/Ca2+ exchange.

African Americans' knowledge of cancer genetic counseling: an examination of information delivery.

Two groups totaling 44 African Americans from two community churches were examined to determine the impact of two presentations on the uptake of genetic counseling educational material. Both presentations were developed with adult learning theory principles and offered information about cancer genetic risk assessment. The second presentation was enhanced to include a description, with pictures, of a culturally relevant fictitious family's course through risk assessment. Hypotheses were: a) knowledge would increase for each group and b) culturally relevant pictures and a family description would increase satisfaction with the presentation. A pre- and post-assessment was conducted with pre-assessment including demographic information and a knowledge questionnaire. Post-assessment included the knowledge questionnaire and a presentation satisfaction questionnaire. Independent t tests were used to analyze the gain scores between pre- and post-knowledge questionnaires and the satisfaction scores between groups. These results are discussed in terms of decreasing disparities in African Americans' participation in risk assessment through community outreach educational programs.

Pleural effusion: An uncommon manifestation of nitrofurantoin-induced pulmonary injury.

Nitrofurantoin has been documented as a cause of acute, sub-acute, and chronic pulmonary injury. This is a case of an 82 year-old female who presented with multiple episodes of respiratory symptoms due to recurrent pleural effusions after beginning nitrofurantoin therapy for urinary tract infection prophylaxis. Due to the rarity of pleural effusion as an adverse reaction to nitrofurantoin, the diagnosis was overlooked at first. This led to the patient undergoing multiple invasive procedures and accruing unnecessary healthcare cost before the diagnosis was made. This case demonstrates the need for physicians to remain mindful of rare adverse reactions from medications and maintain a high index of clinical suspicion with any patient presenting with a respiratory complaint while taking nitrofurantoin.

Functional interaction between mouse erbB3 and wild-type rat c-neu in transgenic mouse mammary tumor cells.

INTRODUCTION: Co-expression of several receptor tyrosine kinases (RTKs), including erbB2 and erbB3, is frequently identified in breast cancers. A member of the RTK family, the kinase-deficient erbB3 can activate downstream signaling via heterodimer formation with erbB2. We studied the expression of RTK receptors in mammary tumors from the wild-type (wt) rat c-neu transgenic model. We hypothesized that physical and functional interactions between the wt rat neu/ErbB2 transgene and mouse ErbB3-encoded proteins could occur, activating downstream signaling and promoting mammary oncogenesis. METHODS: Immunohistochemical and Western blot analyses were performed to study the expression of rat c-neu/ErbB2 and mouse erbB3 in mammary tumors and tumor-derived cell lines from the wt rat c-neu transgenic mice. Co-immunoprecipitation methods were employed to quantitate heterodimerization between the transgene-encoded protein erbB2 and the endogenous mouse erbB3. Tumor cell growth in response to growth factors, such as Heregulin (HRG), epidermal growth factor (EGF), or insulin-like growth factor-1 (IGF-1), was also studied. Post-HRG stimulation, activation of the RTK downstream signaling was determined by Western blot analyses using antibodies against phosphorylated Akt and mitogen-activated protein kinase (MAPK), respectively. Specific inhibitors were then used with cell proliferation assays to study the phosphoinositide-3 kinase (PI-3K)/Akt and MAPK kinase (MEK)/MAPK pathways as possible mechanisms of HRG-induced tumor cell proliferation. RESULTS: Mammary tumors and tumor-derived cell lines frequently exhibited elevated co-expression of erbB2 and erbB3. The transgene-encoded protein erbB2 formed a stable heterodimer complex with endogenous mouse erbB3. HRG stimulation promoted physical and functional erbB2/erbB3 interactions and tumor cell growth, whereas no response to EGF or IGF-1 was observed. HRG treatment activated both the Akt and MAPK pathways in a dose- and time-dependent manner. Both the PI-3K inhibitor LY 294002 and MEK inhibitor PD 98059 significantly decreased the stimulatory effect of HRG on tumor cell proliferation. CONCLUSION: The co-expression of wt rat neu/ErbB2 transgene and mouse ErbB3, with physical and functional interactions between these two species of RTK receptors, was demonstrated. These data strongly suggest a role for erbB3 in c-neu (ErbB2)-associated mammary tumorigenesis, as has been reported in human breast cancers.