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Surgical treatment of foregut disease is a complex field that demands advanced expertise to ensure favorable outcomes for patients. To address the growing need for foregut surgeons, leaders within several national societies have become interested in developing a foregut fellowship. The aim of this study was to develop data-driven benchmarks that will aid in defining appropriate accreditation criteria for these fellowships.We obtained case log data for Fellowship Council fellows trained from 2009-2019. We identified 78 complex foregut (non-bariatric) case codes and divided them into 5 index case categories including (1) hiatal/paraoesophageal hernia repair, (2) fundoplication, (3) esophageal myotomy, (4) major organ resection, and (5) minor organ resection. Median volumes in each index category were compared over time using Kruskall-Wallis tests. The share of cases done using open, laparoscopic, or robotic approaches were analyzed using linear regression analysis.For the 10 years analyzed, 1362 fellows logged 82,889 operations and 111,799 endoscopies. Median foregut cases per fellow grew significantly from 42 (IQR = 24-74) cases in 2010 to 69 (IQR = 33-106) cases in 2019. Median endoscopy volumes also grew significantly from 42 (IQR = 7-88) in 2010 to 69 (IQR 32-123) in 2019.The volume of hiatal/paraoesophageal hernia repairs increased significantly over time while volumes in the remaining 4 index categories remained stable. The share of robotic cases exhibited near perfect linear growth from 2.2% of all foregut cases in 2010 to 14.4% in 2019 (R = 0.99, p 0.0001). Open cases exhibited linear decay from 7.2% of cases in 2010 to 4.7% of cases in 2019 (R = 0.92, p = 0.0001). Laparoscopic/thoracoscopic cases also exhibited linear decay from 90.6% of cases in 2010 to 80.9% of cases in 2019 (R = 0.98, p 0.00001).FC fellows are exposed to robust volumes of foregut cases. This rich data set provides an evidence-based guide for establishing criteria for potential foregut fellowships.

Supplementary Figure from Lack of Telopeptides in Fibrillar Collagen I Promotes the Invasion of a Metastatic Breast Tumor Cell Line

Supplementary Movie 2 from Lack of Telopeptides in Fibrillar Collagen I Promotes the Invasion of a Metastatic Breast Tumor Cell Line

Supplementary Movie 1 from Lack of Telopeptides in Fibrillar Collagen I Promotes the Invasion of a Metastatic Breast Tumor Cell Line

Defective fibrillar collagen polymerization in primary tumors has been correlated with increased metastasis. However, it is unclear how collagen organization influences tumor invasion. In this study, we show that collagen I polymerized without telopeptides (the flanking regions of collagen molecules) can differentially affect the three-dimensional migration of mammary carcinoma cells. MDA-MB-231 cells capable of proteolytic degradation and mesenchymal motion, invaded telopeptide-intact and telopeptide-free collagen gels to the same extent. In contrast, MDA-MB-435S cells, with typical features of amoeboid cells (poor collagenolytic activity, rounded cell morphology), were 5-fold more invasive in telopeptide-free than telopeptide-intact collagen. A fraction of the MDA-MB-435S cells that invaded telopeptide-intact or telopeptide-free collagen had a rounded morphology; however, in telopeptide-free collagen, a significant fraction of the cells switched from a rounded to elongated morphology (protrusion formation). The dynamic changes in cellular shape facilitated MDA-MB-435S locomotion through the narrow interfiber gaps, which were smaller than cell diameters. Based on the spherical morphology of MDA-MB-435S cells, we tested if the changes in cell shape and invasion were related to RhoA-ROCK activity; GTP-bound RhoA was measured in pull-down assays. RhoA activity was 1.8-fold higher for MDA-MB-435S cells seeded on telopeptide-free than telopeptide-intact collagen. Y27632 inhibition of ROCK, a Rho effector, significantly reduced the changes in cellular morphodynamics and the invasion of MDA-MB-435S cells but did not alter the invasion of MDA-MB-231 cells. Thus, the higher RhoA activity of MDA-MB-435S cells in telopeptide-free collagen enhances the changes in cellular morphodynamics associated with motility and invasion.

Adult basic education (ABE) programs in the United States serve millions of students annually to help them achieve high school equivalency, English proficiency, and other skills. These skills are necessary for upward mobility and competitiveness in the labor market, which is important for ABE students who are disproportionately affected by racial/ethnic disparities and poverty. Among learners who are not in ABE programs, substance use and trauma affect student outcomes. Similar research is limited among ABE students. Understanding the influence of these factors among ABE students can better inform interventions. The current study, grounded in Stress and Coping Theory, examined rates, risk factors, and gender differences for substance use and trauma among 286 ABE students. Results indicated that trauma is prevalent and associated with substance use, substance use suggests a need for brief counseling, and there were gender differences in substance use behaviors. Recommendations for interventions among ABE programs are discussed.

This article focuses on the role of skeletal surgery within the modified Stanford protocol with particular attention focused on the evolved role of MMA. First, surgery in patients presenting with congenital dentofacial deformity or characteristic drug-induced sleep endoscopy findings, then the growing role of maxillary expansion in a newly identified patient phenotype, and finally genioglossus advancement, are discussed. Less commonly used and validated techniques, such as isolated mandibular advancement and maxillomandibular expansion are not discussed in this article.

Background: Rate of corrective nasal surgery after maxillomandibular advancement (MMA) for obstructive sleep apnea (OSA) has been reported to be 18.7% for functional and aesthetic indications. Obje...

Maxillomandibular advancement (MMA) for the treatment of obstructive sleep apnea (OSA) has remained a reliable and highly effective surgical intervention since its introduction in 1989. Modifications have been made to maximize skeletal movement and upper airway stability without compromising facial balance. Contemporary indications of recommending MMA prior to other soft tissue surgery are described. MMA poses unique challenges to surgeons. There are patient-related factors, including OSA, a chronic inflammatory condition with associated cardiovascular and metabolic comorbidity. Perioperative management is more complex than routine orthognathic patients. Key details are shared from a 3-decade experience at Stanford.

OBJECTIVES/HYPOTHESIS Examine trends in clinical research and levels of evidence related to obstructive sleep apnea (OSA) in the medical literature. Describe the features and trends of OSA research within otolaryngology journals. STUDY DESIGN Retrospective analysis. METHODS Review of OSA research articles from 2006, 2011, and 2016 in four leading medical sleep and otolaryngology journals. Level of evidence was graded, and study characteristics were measured. RESULTS Seven hundred eight total articles were reviewed. OSA articles significantly increased in both number and proportion of total articles in the medical sleep (P

Objective Efficacy of maxillomandibular advancement (MMA) in the treatment of obstructive sleep apnea (OSA) is associated with degree of maxillary advancement. Large maxillary advancement leads to profound changes of the nasolabial region. We present the incidence and indications of post-MMA corrective nasal surgery in a large cohort. Study Design Case series with chart review. Setting University medical center. Subjects and Methods A total of 379 subjects with OSA underwent MMA at Stanford Hospital (surgeons: S.Y.L., R.W.R.) from August 1992 to December 2015. Data were collected on age, sex, American Society of Anesthesiologists score, polysomnography parameters, and history of nasal surgery. Primary outcome parameters were the incidence and indications of post-MMA corrective nasal surgery. Results Of 379 subjects, the surgical success rate was 76.3% based on the change in respiratory disturbance index. Seventy-one subjects (18.7%) underwent corrective nasal surgery after MMA, whereas 48 underwent functional nasal surgery and 23 underwent both functional and aesthetic nasal surgery. Lower oxygen saturation nadir and higher baseline respiratory disturbance index were associated with increased likelihood of post-MMA corrective nasal surgery. Conclusion MMA surgical success is associated with degree of maxillary advancement, which is especially significant in patients with severe OSA. Patients must be counseled on its impact in nasal function and aesthetics. Our series, the largest to date to address this question, suggests that the incidence of post-MMA corrective nasal surgery is at least 18.7%. Prospectively, refinement in MMA techniques is needed to minimize postoperative compromise in nasal form and function.

OBJECTIVE To determine if a modified tissue-preserving palatopharyngoplasty could convert retropalatal concentric collapse to anteroposterior or lateral patterns of collapse on drug-induced sleep endoscopy (DISE) in patients who are not candidates for upper airway stimulation due to complete circumferential collapse at the velum. METHODS A prospective, nonconsecutive, single-blinded cohort study was performed by two sleep surgeons at a tertiary care center from 2015 to 2018. Inclusion criteria included adults > 18 years of age with a diagnosis of obstructive sleep apnea with an Apnea-Hypopnea Index (AHI) > 15, a body mass index (BMI)

Maxillomandibular advancement (MMA) for the treatment of obstructive sleep apnea (OSA) has remained a reliable and highly effective surgical intervention since its introduction in 1989. Modifications have been made to maximize skeletal movement and upper airway stability without compromising facial balance. Contemporary indications of recommending MMA prior to other soft tissue surgery are described. MMA poses unique challenges to surgeons. There are patient-related factors, including OSA, a chronic inflammatory condition with associated cardiovascular and metabolic comorbidity. Perioperative management is more complex than routine orthognathic patients. Key details are shared from a 3-decade experience at Stanford.

Whereas the original Stanford protocol relied on a tiered approach to care to avoid unnecessary surgery, it did not address the issue of surgical relapse, a common concern among sleep medicine specialists. With 3 decades of experience since the original 2-tiered Powell-Riley protocol was introduced and the role of evolving skeletal techniques and upper airway stimulation, we are pleased to present our current protocol. This update includes emphasis on the facial skeletal development with impact on function including nasal breathing, and the incorporation of upper airway stimulation. The increased versatility of palatopharyngoplasty as an adjunctive procedure is also discussed.

Objectives/Hypothesis The objective of this study was to systematically review the English literature for articles that have described skeletal surgeries in the treatment of obstructive sleep apnea in both adults and children. From these articles trends and patterns in the treatment of OSA with skeletal procedures are described. Study design Three databases including MEDLINE, Google Scholar and the Cochrane Library were searched through May 1, 2018. Methods The systematic and independent literature reviews were performed and the determination of included studies was made by consensus. Relevant studies were examined based on six categories of skeletal surgery: 1) Hyoid Advancement 2) Genioplasty/Genioglossus Advancement 3) Maxillary Expansion 4) Maxillomandibular Advancement 5) Mandibular Distraction and 6) Maxillomandibular Expansion. Results 1875 studies were analyzed for inclusion of which 414 were ultimately included in our analysis. A steady increase in the publication of articles pertaining to maxillary expansion and maxillomandibular advancement was identified. Research interest in hyoid advancement and genioplasty/genioglossus advancement has declined in the past decade. Conclusions Changing trends in skeletal surgery for OSA offer exciting and efficacious therapeutic surgical modalities. MMA is the most widely studied and efficacious multi-level surgery for OSA today. Newer modalities such as adult maxillary expansion offer encouraging early results with minimal complication rates, and further study should be directed in this area.

Objective To evaluate the clinical outcomes and complications rate among idiopathic intracranial hypertension (IIH) patients who underwent lumboperitoneal (LP) shunt insertion with a programmable Strata valve. Methods We retrospectively evaluated patients who underwent LP shunt with a programmable Strata valve insertion at the University of Ottawa Civic Hospital from November 2012 to June 2013. The demographic data, clinical symptoms, opening pressure, pre-operative and post-operative visual fields, neuroimaging, visual acuity, disc status, and complications were recorded and analyzed. Results Seven female patients with IIH underwent insertion of an LP shunt with a programmable Strata valve. The mean opening pressure was 35.8 cm H2O. The initial valve setting was 1.5, and four patients required post-operative valve pressure adjustment. All patients showed significant improvement in objective visual testing at follow-up as well as less frequent headaches. None of the patients developed intra- or post-operative complications. Conclusion LP shunts with programmable Strata valve systems are a potential alternative to conventional LP and programmable ventriculoperitoneal shunt systems as well as optic nerve sheath fenestration, due to their potential in avoiding brain injury, lower failure and complication rates, lower intracranial hypotension incidence, and flexibility in adjusting valve pressure settings post-operatively evading under- and overdrainage complications. They should be considered for the management of IIH instead of early design LP systems and VP shunts. A randomized multi-center trial should be conducted to compare the efficacy of these surgical techniques.

Examine trends in clinical research and levels of evidence related to obstructive sleep apnea (OSA) in the medical literature. Describe the features and trends of OSA research within otolaryngology journals.Retrospective analysis.Review of OSA research articles from 2006, 2011, and 2016 in four leading medical sleep and otolaryngology journals. Level of evidence was graded, and study characteristics were measured.Seven hundred eight total articles were reviewed. OSA articles significantly increased in both number and proportion of total articles in the medical sleep (P .001) and otolaryngology (P = .004) journals. Surgically focused articles did not significantly increase in either literature. There was no significant difference between medical sleep and otolaryngology literature levels of evidence regarding OSA, and no trend toward higher levels of evidence over time. Medical sleep publications had significantly higher proportions of grant-funded (P .001) and National Institutes of Health (NIH)-funded (P .001) publications versus otolaryngology journals. Over time, otolaryngology journals had decreasing numbers of grant-funded and NIH-funded projects.OSA research is increasingly present in medical sleep and otolaryngology literature. Levels of evidence are modest for the two specialties, and have shown no trend toward increasing over time. Concurrently, otolaryngologists are less likely to be grant funded than their medical colleagues, and sleep surgery has stagnated in the studied journals. This study encourages continued efforts to publish high-quality research on OSA. It may also help guide our specialty when setting priorities regarding research funding and support for sleep surgeons.NA Laryngoscope, 128:2193-2199, 2018.

Aim: To compare two bladder draining methods during labor on time to delivery, cost and nursing preference. Material and Methods: This trial randomized 139 women with singleton pregnancies in active labor or undergoing induction of labor. Eligibility required an anticipated vaginal delivery with a clinical indication for bladder catheterization (epidural). Participants were randomly assigned to either indwelling or intermittent catheterization. The primary outcome was time to delivery; secondary outcomes were nurse preference, cost and route of delivery. A sample size of 138 women would be needed for 80% power to detect a 30 min difference in the time to delivery interval with a 0.05 alpha error. Results: Outcome data was available for 138 patients (72 indwelling and 66 intermittent). The time to delivery was similar among the two groups (13.8 h for indwelling and 14.4 h for intermittent). Route of delivery and cost estimate was similar in both groups; however, nurses preferred the indwelling method. Conclusion: Indwelling catheterization is recommended as the standard method for bladder drainage in laboring women with epidural.

Background. Thermal ablative techniques have gained increasing popularity in recent years as safe and effective options for patients with unresectable solid malignancies. Microwave ablation has emerged as a relatively new technique with the promise of larger and faster burns without some of the limitations of radiofrequency ablation (RFA). Here we study a new microwave ablation device in a living porcine model using gross, histologic, and radiographic analysis. Materials and methods. The size and shape of ablated lesions were assessed using six pigs in a non-survival study. Liver tissue was ablated using 2, 4, and 8min burns, in both peripheral and central locations, with and without vascular inflow occlusion. To characterize the post-ablation appearance, three additional pigs underwent several 4min ablations each followed by serial computed tomography (CT) imaging at 7, 14, and 28 days postoperatively. Results. The 2 and 4min ablations resulted in lesions that were similar in size, 33.5cm3 and 37.5cm3, respectively. Ablations lasting 8min produced lesions that were significantly larger, 92.0cm3 on average. Proximity to hepatic vasculature and inflow occlusion did not significantly change lesion size or shape. In follow-up studies, CT imaging showed a gradual reduction in lesion volume over 28 days to 25–50% of the original volume. Discussion. Microwave ablation with a novel device results in consistently sized and shaped lesions. Importantly, we did not observe any significant heat-sink effect using this device, a major difference from RFA techniques. This system offers a viable alternative for creating fast, large ablation volumes for treatment in liver cancer.

Reforming graduate medical, nursing and health administrators' education to include the core competencies of interdisciplinary teamwork and quality improvement (QI) techniques is a key strategy to improve quality in hospital settings. Practicing clinicians are best positioned in these settings to understand systems issues and craft potential solutions. The authors describe how, in ten months during 2004 and 2005 the school of medicine, the school of nursing, and an administrative residency program, all at Johns Hopkins University, implemented and evaluated the Achieving Competency Today II Program (ACT II), a structured and interdisciplinary approach to learning QI that was piloted at various sites around the United States. Six teams of learners participated, each consisting of a medical, nursing, and administrative resident. The importance of interdisciplinary participation in planning QI projects, the value of the patient's perspective on systems issues, and the value of a system's perspective in crafting solutions to issues all proved to be valuable lessons. Challenges were encountered throughout the program, such as (1) participants' difficulties in balancing competing academic, personal and clinical responsibilities, (2) difficulties in achieving the intended goals of a broad curriculum, (3) barriers to openly discussing interdisciplinary team process and dynamics, and (4) the need to develop faculty expertise in systems thinking and QI. In spite of these challenges steps have been identified to further enhance and develop interdisciplinary education within this academic setting.

Defective fibrillar collagen polymerization in primary tumors has been correlated with increased metastasis. However, it is unclear how collagen organization influences tumor invasion. In this study, we show that collagen I polymerized without telopeptides (the flanking regions of collagen molecules) can differentially affect the three-dimensional migration of mammary carcinoma cells. MDA-MB-231 cells capable of proteolytic degradation and mesenchymal motion, invaded telopeptide-intact and telopeptide-free collagen gels to the same extent. In contrast, MDA-MB-435S cells, with typical features of amoeboid cells (poor collagenolytic activity, rounded cell morphology), were 5-fold more invasive in telopeptide-free than telopeptide-intact collagen. A fraction of the MDA-MB-435S cells that invaded telopeptide-intact or telopeptide-free collagen had a rounded morphology; however, in telopeptide-free collagen, a significant fraction of the cells switched from a rounded to elongated morphology (protrusion formation). The dynamic changes in cellular shape facilitated MDA-MB-435S locomotion through the narrow interfiber gaps, which were smaller than cell diameters. Based on the spherical morphology of MDA-MB-435S cells, we tested if the changes in cell shape and invasion were related to RhoA-ROCK activity; GTP-bound RhoA was measured in pull-down assays. RhoA activity was 1.8-fold higher for MDA-MB-435S cells seeded on telopeptide-free than telopeptide-intact collagen. Y27632 inhibition of ROCK, a Rho effector, significantly reduced the changes in cellular morphodynamics and the invasion of MDA-MB-435S cells but did not alter the invasion of MDA-MB-231 cells. Thus, the higher RhoA activity of MDA-MB-435S cells in telopeptide-free collagen enhances the changes in cellular morphodynamics associated with motility and invasion.

During normal development in the rat, hepatocytes undergo marked changes in the rate of proliferation. We have previously observed transient G(1) growth arrest at term, re-activation of proliferation immediately after birth, and a gradual transition to the quiescent adult hepatocyte phenotype after postnatal day 4. We hypothesized that these changes in proliferation are due in part to growth inhibitory effects mediated by the p38 mitogen-activated protein kinase pathway. p38 kinase activity measurements showed an inverse relationship with hepatocyte proliferation during the perinatal and postnatal transitions, whereas p38 content remained constant. Anisomycin activated the p38 pathway in fetal hepatocyte cultures while inducing growth inhibition that was sensitive to the p38 inhibitor, SB203580. Activation of p38 in these cultures, via transient transfection with a constitutively active form of its upstream kinase MKK6, also inhibited DNA synthesis as well as reducing cyclin D1 content. Transfection with inactive MKK6 did neither. Furthermore, MKK6-induced growth arrest was sensitive to SB203580. Finally, administration of SB203580 to near-term fetal rats in utero abrogated the transient hepatocyte growth arrest that occurs at term. These findings indicate a role for the p38 mitogen-activated protein kinase pathway in the physiological regulation of hepatocyte proliferation during normal development in the rat.

Late gestation fetal rat hepatocytes can proliferate under defined in vitro conditions in the absence of added mitogens. However, this capacity declines with advancing gestational age of the fetus from which the hepatocytes are derived. The present studies were undertaken to investigate this change in fetal hepatocyte growth regulation. Examination of E19 fetal hepatocyte primary cultures using immunocytochemistry for 5-bromo-2'-deoxyuridine (BrdU) incorporation showed that approximately 80% of these cells traverse S-phase of the cell cycle over the first 48 h in culture. Similarly, 65% of E19 hepatocytes maintained in culture under defined mitogen-free conditions for 24 h showed nuclear expression of proliferating cell nuclear antigen (PCNA). These in vitro findings correlated with a high level of immunoreactive PCNA in immunofluorescent analyses of E19 liver. In contrast, E21 (term) liver showed little immunoreactive PCNA. The in vivo finding was recapitulated by in vitro studies showing that E21 hepatocytes had low levels of BrdU incorporation during the first day in culture and were PCNA negative shortly after isolation. However, within 12 h of plating, E21 hepatocytes showed cytoplasmic staining for PCNA. Although maintained under mitogen-free conditions, PCNA expression progressed synchronously to a nucleolar staining pattern at 24 to 48 h in culture followed by intense, diffuse nuclear staining at 60 h which disappeared by 72 h. This apparently synchronous cell cycle progression was confirmed by studies showing peak BrdU incorporation on the third day in culture. Whereas DNA synthesis by both E19 and E21 hepatocytes was potentiated by transforming growth factor alpha (TGF alpha), considerable mitogen-independent DNA synthesis was seen in hepatocytes from both gestational ages. These results may indicate that fetal hepatocytes come under the influence of an exogenous, in vivo growth inhibitory factor as term approaches and that this effect is relieved when term fetal hepatocytes are cultured.

To estimate whether specific ambulation goals affect the adequacy or perceived barriers to ambulation in hospitalized surgical patients after major gynecologic surgery.One hundred forty-six surgical inpatients were randomized to specific ambulation goals or routine care. We assessed the number of pedometer-recorded steps in the 24 hours preceding discharge as well as patient-identified barriers to ambulation. Groups were compared using the Mann-Whitney U test.Of the 129 participants with outcome data, 12% were discharged without any pedometer-recorded steps. We did not detect an effect of specific ambulation goals by group (routine care: 87 compared with ambulation goals: 80, P=.7). The three main barriers to ambulation from a patient perspective were indwelling catheters (38.5%), intravenous poles (28%), and pain (12.5%) The median number of postoperative steps was higher after minimally invasive surgery (143) compared with laparotomy (27) (P=.035).Approximately 12% of gynecologic surgical patients do not walk while hospitalized despite formal encouragement to ambulate. Ambulation is easily quantified and may improve with attention to modifiable barriers, potentially improving postoperative recovery.

To compare two bladder draining methods during labor on time to delivery, cost and nursing preference.This trial randomized 139 women with singleton pregnancies in active labor or undergoing induction of labor. Eligibility required an anticipated vaginal delivery with a clinical indication for bladder catheterization (epidural). Participants were randomly assigned to either indwelling or intermittent catheterization. The primary outcome was time to delivery; secondary outcomes were nurse preference, cost and route of delivery. A sample size of 138 women would be needed for 80% power to detect a 30 min difference in the time to delivery interval with a 0.05 alpha error.Outcome data was available for 138 patients (72 indwelling and 66 intermittent). The time to delivery was similar among the two groups (13.8 h for indwelling and 14.4 h for intermittent). Route of delivery and cost estimate was similar in both groups; however, nurses preferred the indwelling method.Indwelling catheterization is recommended as the standard method for bladder drainage in laboring women with epidural.

We have compared the photoisomerization properties of two cyanine analogs, 3,3'-diethyloxadicarbocyanine iodide (DODCI) and 3,3'-diethylthiadicarbocyanine iodide (DTDCI). These two molecules are structurally similar, differing only in the presence of oxygen or sulfur at two heteroatom sites. Measurement of the radiative and nonradiative population relaxation kinetics of these molecules reveals a difference in their equilibrium geometries despite their outward similarities. We relate this difference to the steric constraints imposed by the oxygen and sulfur heteroatoms and to the occurrence of an excited state barrier predicted by semiempirical calculations of the ground- and excited-state isomerization surfaces for these molecules

We have compared the photoisomerization properties of two cyanine analogs, 3,3'-diethyloxadicarbocyanine iodide (DODCI) and 3,3'-diethylthiadicarbocyanine iodide (DTDCI). These two molecules are structurally similar, differing only in the presence of oxygen or sulfur at two heteroatom sites. Measurement of the radiative and nonradiative population relaxation kinetics of these molecules reveals a difference in their equilibrium geometries despite their outward similarities. We relate this difference to the steric constraints imposed by the oxygen and sulfur heteroatoms and to the occurrence of an excited state barrier predicted by semiempirical calculations of the ground- and excited-state isomerization surfaces for these molecules

Unresectable malignant tumors of the liver (e.g., hepatocellular carcinoma, colorectal metastases, neuroendocrine tumors, selected other types of metastases) Tumors

For ultrasound elastography there currently existsno large animal model of liver lesions for testing. In this study, we modeled liver lesions using agarose gel, characterizing thephantoms' elastic and echogenic properties. An equation wasderived to express a phantom's Young's modulus as a functionof its agarose concentration. Moreover, we altered phantoms'echogenicities by adding various amounts of graphite, and foundthat its inclusion up to 2% does not significantly affectelasticity. These findings can help to systematically createdesired liver tumor phantoms for numerous studies.

To assess the potential for interference of Hb with the normal coagulation mechanism, we performed in-vitro hemodilution tests. Platelet rich plasma (PRP) was prepared from citrated blood samples of 5 normal volunteers diluted 3:1, 1:1, and 1:3 volume ratio with human stroma-free hemoglobin solution (SFH) or human albumin (HSA). Coagulation kinetics and clot strength were assessed with a thrombelastograph (TEG). Extrinsic and intrinsic coagulation factors were assessed measuring prothrombin time (PT) and activated partial thromboplastin time (aPTT) with an optical coagulation timer. Statistical significance was assessed using ANOVA and Neuman-Keuls tests at p < 0.05. At all dilutions, SFH diluted plasma showed significantly prolonged initial rate of clot formation compared to undiluted control or HSA (p < 0.05). However, there was no difference in formed clot strength between SFH and HSA. At high Hb concentrations Hb seems to interfere with the optical measurements of coagulation times (particularly aPTT). SFH appears to interfere with the initial phase coagulation mechanism in human plasma in-vitro; further study is needed to clarify the cause. In measuring coagulation times of plasma containing Hb a non-optical instrument should be considered.

Our prior studies on liver growth during late gestation in the rat have shown that hepatocyte proliferation is developmentally modulated; it declines as term approaches, resumes in the immediate postnatal period, and declines during the latter part of the first postnatal week as hepatocytes attain an adult phenotype. The present studies were designed to elucidate mechanisms accounting for both temporary perinatal hepatocyte growth arrest and subsequent progression to the low level of cell growth seen in adult liver. Our studies focused on the family of MAP kinase signaling pathways as well as downstream cell cycle regulation. Key signaling kinases were examined for the ontogeny of their activity during late gestation and early postnatal liver development in the rat. Prior studies had shown that the prototypical MAP kinase pathway, which includes the 42 and 44 kDa MAP kinases (Erk1 and Erk2), is inactive in developing hepatocytes in vivo. We now report that the second MAP kinase pathway, involving the family of Jun N-terminal kinases(JNKs), is constitutively active in fetal liver and inactive in adult liver. However, JNK activity did not correlate with cell growth; activities in preterm and term liver were similar. The profile of JNK activity was recapitulated in gel shift assays for DNA binding activity to an AP-1 site in the liver collagenase gene promoter; nuclear extract AP-1 binding activity was high in both preterm and term fetuses, and declined after the first postnatal week. The third MAP kinase pathway, for which p38/HOG1 is the terminal kinase, was found to be inactive in livers obtained on days 17 and 19 of gestation. However, p38 was active in term (21 day) liver. It was again inactive in the immediate postnatal period, but activity increased during the first two postnatal weeks to the high level seen in adult rat hepatocytes. This activity pattern was inversely related to liver nuclear extract content of cyclin D1(determined by Western immunoblotting). Of note, p38 has been shown to regulate cyclin D1 expression in other systems. In addition, p38 is known to be regulated by cellular stresses such as change in redox state, osmolar stress and heat shock. We conclude from these studies that perinatal“stress” may result in hepatocyte growth arrest, and that this temporary period of quiescence is mediated by stimulation of p38 (but not JNK) activity which, in turn, suppresses expression of a key G1-phase cyclin.

We have found that late gestation rat FHs can proliferate in vitro in the absence of added mitogens or serum. However, this capacity varies with the gestational age at which the FHs are isolated: A gradual decline occurs as term approaches such that term FHs are non-proliferative in culture under these mitogen-free conditions. The present studies were undertaken to characterize the FH growth arrest which occurs at term. Primary cultures of FHs from day 19 of gestation (E19) showed a gradual decline in DNA synthesis (3H-thymidine incorporation) from very high levels during the first 24 hr in culture to low levels by 72 hr. In contrast, term (E21) FHs synthesized little DNA over the first 24 hr and showed a marked increase by 48 to 72 hr. In addition, E21 FH DNA synthesis was potentiated by Transforming Growth Factor α (TGFα) whereas E19 FH DNA synthesis was not. These findings correlated with immunocytochemical staining for Proliferating Cell Nuclear Antigen (PCNA). E19 FHs were PCNA positive immediately after plating and this persisted over 48 hr. E21 FHs showed a synchronized pattern of PCNA staining which was cytoplasmic at 12 hr and nucleolar at 24 to 48 hr. Intense, diffuse nuclear expression appeared for a brief period at 60 hr. Additional studies showed that: (a) E21 fetal liver has a high level of c-myc expression even though the cells are not proliferating; (b) The mitogenic Jun kinase signaling pathway is equally active at E19 and E21; (c) The cell cycle kinase, cdc2, is expressed at term but its inactive forms predominate. These results indicate that E21 FHs are growth arrested in vivo and that culturing releases them from inhibitory influences, resulting in synchronized proliferation in vitro.

Integration of blind and sighted students at the high school level is becoming a common practice. Section 504 of the Higher Education Act, which became law in June 1972, provides that no student may be denied admission to an educational institution because of visual impairment. The educational community thus has both a legal and a moral obligation to provide education for the blind.