Neil Gesundheit

All Publications

• Vasopressin deficiency: a hypothesized driver of both social impairment and fluid imbalance in autism spectrum disorder. Molecular psychiatry Clarke, L., Gesundheit, N., Sherr, E. H., Hardan, A. Y., Parker, K. J. 2024

  View details for DOI 10.1038/s41380-024-02497-6

  View details for PubMedID 38454082

• Maturing through awareness: An exploratory study into the development of educational competencies, identity, and mission of medical educators. Medical teacher Ottenhoff-de Jonge, M. W., van der Hoeven, I., Gesundheit, N., Kramer, A. W., van der Rijst, R. M. 2023: 1-9

  Abstract

  PURPOSE: Faculty development in learning-centred medical education aims to help faculty mature into facilitators of student learning, but it is often ineffective. It is unclear how to support educators' maturation sustainably. We explored how and why medical educators working in learning-centred education, more commonly referred to as student-centred education, mature over time.METHODS: We performed a qualitative follow-up study and interviewed 21 senior physician-educators at two times, ten years apart. A hierarchical model, distinguishing four educator phenotypes, was employed to deductively examine educators' awareness of the workplace context, their educational competencies, identity, and 'mission,' i.e. their source of personal inspiration. Those educators who grew in awareness, as measured by advancing in educator phenotype, were re-interviewed to inductively explore factors they perceived to have guided their maturation.RESULTS: A minority of the medical educators grew in awareness of their educational qualities over the 10-year study period. Regression in awareness did not occur. Maturation as an educator was perceived to be linked to maturation as a physician and to engaging in primarily informal learning opportunities.CONCLUSIONS: Maturation of medical educators can take place, but is not guaranteed, and appears to proceed through a growth in awareness of, successively, educational competencies, identity, and mission. At all stages, maturation is motivated by the task, identity, and mission as a physician.

  View details for DOI 10.1080/0142159X.2023.2239442

  View details for PubMedID 37544887

• Use of the Community of Inquiry Framework to Measure Student and Facilitator Perceptions of Online Flipped Classroom Compared with Online Lecture Learning in Undergraduate Medical Education. Advances in medical education and practice Chang, J. J., Hain, A., Dosiou, C., Gesundheit, N. 2023; 14: 963-972

  Abstract

  Background: The COVID-19 pandemic and a movement away from traditional lecture-based learning have increased the use of online flipped classroom (FC) and active learning models in medical education. The Community of Inquiry (CoI) framework for online learning may be used to evaluate the effectiveness and strengths of the online FC model compared with other learning formats.Methods: An observational survey study was conducted to measure medical student and facilitator perceptions of an online FC endocrinology tutorial compared with online lecture experiences. For the tutorial, students were instructed to watch short, pre-recorded lecture videos on thyroid pathophysiology prior to class. During class, small groups of students were paired with a faculty facilitator in online Zoom rooms for case discussion. Students were surveyed using the CoI framework to assess elements of cognitive, social, and teaching presence between the two online learning modalities. Facilitators were also surveyed. Survey questions were rated on a 5-point Likert scale.Results: Fifty-three out of 92 students (58% response rate) and seven out of eight facilitators (88% response rate) completed surveys. In general, students felt that online FC learning improved cognitive, teaching, and social presence compared with online lecture. Areas of cognitive presence (mean score 3.9 ± 1.0 SD), such as stimulating curiosity and applying concepts, were highly rated. Certain elements of social presence (3.6 ± 0.9) and teaching presence (3.7 ± 0.9), such as expression of emotion and communication of expectations, garnered lower ratings. All surveyed facilitators felt that online FC was more effective and enjoyable to teach than online lectures but did not feel it was superior to in-person instruction.Conclusion: Medical students and facilitators viewed an online FC tutorial in endocrinology positively. Most, but not all, areas of the CoI framework were enhanced with the online FC tutorial compared with online lecture-based learning.

  View details for DOI 10.2147/AMEP.S413201

  View details for PubMedID 37701423

• The Student Guidance Program: Applying an Executive Coaching Model to Medical Student Remediation. Academic medicine : journal of the Association of American Medical Colleges Ariel, D., Lau, J., Osterberg, L., Gesundheit, N., Brar, K., Merrell, S. B. 2022; 97 (11S): S117

  View details for DOI 10.1097/ACM.0000000000004886

  View details for PubMedID 36287648

• The Student Guidance Program: Applying an Executive Coaching Model to Medical Student Remediation. Academic medicine : journal of the Association of American Medical Colleges Ariel, D., Lau, J., Osterberg, L., Gesundheit, N., Brar, K., Merrell, S. B. 2022; 97 (11S): S117

  View details for DOI 10.1097/ACM.0000000000004886

  View details for PubMedID 37838851

• The Student Guidance Program: Applying an Executive Coaching Model to Medical Student Remediation. Academic medicine : journal of the Association of American Medical Colleges Ariel, D., Lau, J., Osterberg, L., Gesundheit, N., Brar, K., Merrell, S. B. 2022; 97 (11S): S117

  View details for DOI 10.1097/ACM.0000000000004886

  View details for PubMedID 36734742

• Medical educators' beliefs about teaching, learning, and knowledge: development of a new framework. BMC medical education Ottenhoff-de Jonge, M. W., van der Hoeven, I., Gesundheit, N., van der Rijst, R. M., Kramer, A. W. 2021; 21 (1): 176

  Abstract

  BACKGROUND: The educational beliefs of medical educators influence their teaching practices. Insight into these beliefs is important for medical schools to improve the quality of education they provide students and to guide faculty development. Several studies in the field of higher education have explored the educational beliefs of educators, resulting in classifications that provide a structural basis for diverse beliefs. However, few classification studies have been conducted in the field of medical education. We propose a framework that describes faculty beliefs about teaching, learning, and knowledge which is specifically adapted to the medical education context. The proposed framework describes a matrix in which educational beliefs are organised two dimensionally into belief orientations and belief dimensions. The belief orientations range from teaching-centred to learning-centred; the belief dimensions represent qualitatively distinct aspects of beliefs, such as 'desired learning outcomes' and 'students' motivation'.METHODS: We conducted in-depth semi-structured interviews with 26 faculty members, all of whom were deeply involved in teaching, from two prominent medical schools. We used the original framework of Samuelowicz and Bain as a starting point for context-specific adaptation. The qualitative analysis consisted of relating relevant interview fragments to the Samuelowicz and Bain framework, while remaining open to potentially new beliefs identified during the interviews. A range of strategies were employed to ensure the quality of the results.RESULTS: We identified a new belief dimension and adapted or refined other dimensions to apply in the context of medical education. The belief orientations that have counterparts in the original Samuelowicz and Bain framework are described more precisely in the new framework. The new framework sharpens the boundary between teaching-centred and learning-centred belief orientations.CONCLUSIONS: Our findings confirm the relevance of the structure of the original Samuelowicz and Bain beliefs framework. However, multiple adaptations and refinements were necessary to align the framework to the context of medical education. The refined belief dimensions and belief orientations enable a comprehensive description of the educational beliefs of medical educators. With these adaptations, the new framework provides a contemporary instrument to improve medical education and potentially assist in faculty development of medical educators.

  View details for DOI 10.1186/s12909-021-02587-x

  View details for PubMedID 33745444

• The National Board of Medical Examiners on Potential Conflicts of Interest Reply ACADEMIC MEDICINE Gesundheit, N. 2020; 95 (9): 1291

  View details for Web of Science ID 000566861500036

• In Reply to Tallia et al. Academic medicine : journal of the Association of American Medical Colleges Gesundheit, N. 2020; 95 (9): 1291

  View details for DOI 10.1097/ACM.0000000000003545

  View details for PubMedID 32841994

• Stanford University School of Medicine ACADEMIC MEDICINE Bernstein, D., Irvine, C. A., Basaviah, P., Lau, J. N., Austin, B., Utz, P. J., Gesundheit, N. 2020; 95 (9): S50–S53

  View details for DOI 10.1097/ACM.0000000000003493

  View details for Web of Science ID 000619186200013

  View details for PubMedID 33626643

• A Crisis of Trust Between U.S. Medical Education and the National Board of Medical Examiners. Academic medicine : journal of the Association of American Medical Colleges Gesundheit, N. 2019

  Abstract

  This Invited Commentary is an independent opinion piece and companion to the Perspective by Carmody and Rajasekaran that appears in this issue of Academic Medicine. The National Board of Medical Examiners (NBME), a 501(c)(3) nonprofit, is a powerful gatekeeper to the medical profession in the United States. According to publicly available tax data, the NBME, which has increased its number of income-enhancing products, had revenues of $153.9 million (M) and net assets of $177.6M in 2017, earnings (revenue less expenses) of $39.7M in 2013-17, and a highly compensated management team. Medical students are ultimately the source of nearly all the NBME's revenue, and the NBME has contributed to the growth of medical student debt. The NBME has operated as a monopoly since its agreement in the early 1990s with the Federation of State Medical Boards to co-sponsor the United States Medical Licensing Examination (USMLE). Although the NBME has developed valuable products and is ostensibly governed by a capable board, the NBME has inherent financial conflicts of interest and may be benefiting from the current "Step 1 mania" undermining undergraduate medical education. Here, the author makes 4 recommendations to reestablish the trust of the U.S. medical education community in the NBME: (1) the NBME should recuse itself from current discussions and policy-making decisions related to changes in the score reporting of the USMLE Step 1 exam; (2) the NBME should disclose and be transparent about all aspects of its finances; (3) new NBME products, changes in pricing, and changes to pass thresholds should be approved by an oversight committee, independent of the NBME; and (4) the NBME (and USMLE) should not charge students or residents for re-taking any of its licensing examinations.

  View details for DOI 10.1097/ACM.0000000000003131

  View details for PubMedID 31850949

• From critic to inspirer: four profiles reveal the belief system and commitment to educational mission of medical academics. BMC medical education Ottenhoff-de Jonge, M. W., van der Rijst, R. M., Gesundheit, N. n., van Staveren, L. N., Assendelft, W. J., Dekker, F. W., Scherpbier, A. J., Kramer, A. W. 2019; 19 (1): 268

  Abstract

  The educational beliefs of medical academics influence how they act in class and thus influence student learning. One component of these are beliefs academics hold about the qualities of teachers themselves. These teacher qualities range from behaviours and competencies to more personal attributes such as the teacher's identity and mission. However, it is unclear what medical academics believe to be key teacher qualities. Therefore, this study explored the variety of medical academics' beliefs about 'teacher qualities', aiming to identify and characterise profiles of academics with similar beliefs.We interviewed 26 expert academics from two medical schools to explore their beliefs about teacher qualities. A concentric onion-model focusing on teacher qualities was used to analyse and categorise the data deductively. Within each theme we developed subthemes inductively. To gain insight into the variety of beliefs we then clustered the participants into teacher profiles according to the themes. To better understand each of the profiles we carried out a quantitative study of the differences between profiles regarding subthemes, contextual and personal factors, and analysed statistical significance using Fisher's exact- and Student's t-tests for categorical and continuous data, respectively.Four profiles of medical academics were identified, corresponding to the most central theme that each participant had reflected on: the 'Inspirer', 'Role-model', 'Practitioner', and 'Critic'. The focus of the profiles varied from external constraining factors within the 'Critic' profile to affective personal qualities within the 'Role-model' and 'Inspirer' profiles. The profiles could be regarded as hierarchically ordered by inclusiveness. Educational institute was the only significant factor related to the profiles.Besides the relevance of affective teacher qualities, the 'Inspirer' profile demonstrates the importance of developing a clear mission as a teaching academic, centred around student learning and professional development. In our view, academics who inspire their students continue to be inspired themselves. The practical implications are described for faculty development programmes, and for the potential value of using these profiles within medical schools. In the discourse on educational beliefs, the authors argue that more attention should be paid to affective qualities, in particular to explicating the educational mission of academics.

  View details for DOI 10.1186/s12909-019-1665-0

  View details for PubMedID 31319835

• Promoting student case creation to enhance instruction of clinical reasoning skills: a pilot feasibility study Advances in Medical Education and Practice Chandrasekar, H., Gesundheit, N., Nevins, A. B., Pompei, P., Bruce, J., Bereknyei Merrell, S. 2018; 2018 (9): 249-257

  Abstract

  It is a common educational practice for medical students to engage in case-based learning (CBL) exercises by working through clinical cases that have been developed by faculty. While such faculty-developed exercises have educational strengths, there are at least two major drawbacks to learning by this method: the number and diversity of cases is often limited; and students decrease their engagement with CBL cases as they grow accustomed to the teaching method. We sought to explore whether student case creation can address both of these limitations. We also compared student case creation to traditional clinical reasoning sessions in regard to tutorial group effectiveness, perceived gains in clinical reasoning, and quality of student-faculty interaction.Ten first-year medical students participated in a feasibility study wherein they worked in small groups to develop their own patient case around a preassigned diagnosis. Faculty provided feedback on case quality afterwards. Students completed pre- and post-self-assessment surveys. Students and faculty also participated in separate focus groups to compare their case creation experience to traditional CBL sessions.Students reported high levels of team engagement and peer learning, as well as increased ownership over case content and understanding of clinical reasoning nuances. However, students also reported decreases in student-faculty interaction and the use of visual aids (P < 0.05).The results of our feasibility study suggest that student-generated cases can be a valuable adjunct to traditional clinical reasoning instruction by increasing content ownership, encouraging student-directed learning, and providing opportunities to explore clinical nuances. However, these gains may reduce student-faculty interaction. Future studies may be able to identify an improved model of faculty participation, the ideal timing for incorporation of this method in a medical curriculum, and a more rigorous assessment of the impact of student case creation on the development of clinical reasoning skills.

  View details for DOI 10.2147/AMEP.S155481

  View details for PubMedCentralID PMC5903478

• Is a career in medicine the right choice? The impact of a physician shadowing program on undergraduate premedical students ACADEMIC MEDICINE Wang, J. Y., Lin, H., Lewis, P. Y., Fetterman, D. M., Gesundheit, N. 2015; 90 (5): 629-33
• Filling the treatment gap in the weight management of overweight and obese patients INTERNATIONAL JOURNAL OF OBESITY SUPPL. Gesundheit, N. 2012; 2: S39-S42
• Does the Duration of a Scholarly Concentration Affect Medical Students' Productivity? ACADEMIC MEDICINE Laskowitz, D. T., Drucker, R. P., Gesundheit, N. 2011; 86 (1): 3
• Impact of student ethnicity and patient-centredness on communication skills performance MEDICAL EDUCATION Hauer, K. E., Boscardin, C., Gesundheit, N., Nevins, A., Srinivasan, M., Fernandez, A. 2010; 44 (7): 653-661

  Abstract

  The development of patient-centred attitudes by health care providers is critical to improving health care quality. A prior study showed that medical students with more patient-centred attitudes scored higher in communication skills as judged by standardised patients (SPs) than students with less patient-centred attitudes. We designed this multicentre study to examine the relationships among students' demographic characteristics, patient-centredness and communication scores on an SP examination.Early Year 4 medical students at three US schools completed a 12-item survey during an SP examination. Survey items addressed demographics (gender, ethnicity, primary childhood language) and patient-centredness. Factor analysis on the patient-centredness items defined specific patient-centred attitudes. We used multiple regression analysis incorporating demographic characteristics, school and patient-centredness items and examined the effect of these variables on the outcome variable of communication score.A total of 351 students took the SP examination and 329 (94%) completed the patient-centredness questionnaire. Responses indicated generally high patient-centredness. Student ethnicity and medical school were significantly associated with communication scores; gender and primary childhood language were not. Two attitudinal factors were identified: patient perspective and impersonal attitude. Multiple regression analysis revealed that school and scores on the impersonal factor were associated with communication scores. The effect size was modest.In a medical student SP examination, modest differences in communication scores based on ethnicity were observed and can be partially explained by student attitudes regarding patient-centredness. Curricular interventions to enhance clinical experiences, teaching and feedback are needed to address key elements of a patient-centred approach to care.

  View details for DOI 10.1111/j.1365-2923.2010.03632.x

  View details for Web of Science ID 000278928700005

  View details for PubMedID 20636584

• Empowerment Evaluation: A Collaborative Approach to Evaluating and Transforming a Medical School Curriculum ACADEMIC MEDICINE Fetterman, D. M., Deitz, J., Gesundheit, N. 2010; 85 (5): 813-820

  Abstract

  Medical schools continually evolve their curricula to keep students abreast of advances in basic, translational, and clinical sciences. To provide feedback to educators, critical evaluation of the effectiveness of these curricular changes is necessary. This article describes a method of curriculum evaluation, called "empowerment evaluation," that is new to medical education. It mirrors the increasingly collaborative culture of medical education and offers tools to enhance the faculty's teaching experience and students' learning environments. Empowerment evaluation provides a method for gathering, analyzing, and sharing data about a program and its outcomes and encourages faculty, students, and support personnel to actively participate in system changes. It assumes that the more closely stakeholders are involved in reflecting on evaluation findings, the more likely they are to take ownership of the results and to guide curricular decision making and reform. The steps of empowerment evaluation include collecting evaluation data, designating a "critical friend" to communicate areas of potential improvement, establishing a culture of evidence, encouraging a cycle of reflection and action, cultivating a community of learners, and developing reflective educational practitioners. This article illustrates how stakeholders used the principles of empowerment evaluation to facilitate yearly cycles of improvement at the Stanford University School of Medicine, which implemented a major curriculum reform in 2003-2004. The use of empowerment evaluation concepts and tools fostered greater institutional self-reflection, led to an evidence-based model of decision making, and expanded opportunities for students, faculty, and support staff to work collaboratively to improve and refine the medical school's curriculum.

  View details for DOI 10.1097/ACM.0b013e3181d74269

  View details for Web of Science ID 000279375600025

  View details for PubMedID 20520033

• Engaging Students in Dedicated Research and Scholarship During Medical School: The Long-Term Experiences at Duke and Stanford ACADEMIC MEDICINE Laskowitz, D. T., Drucker, R. P., Parsonnet, J., Cross, P. C., Gesundheit, N. 2010; 85 (3): 419-428

  Abstract

  For more than 40 years, the faculties of Duke University School of Medicine (SOM) and Stanford University SOM have encouraged or required students to engage in scholarship as a way to broaden their education and attract them to careers in academic medicine. A dedicated period of research was first integrated into the Duke curriculum in 1959 to provide an opportunity for students to develop into physician leaders through a rigorous scholarly experience in biomedically related research. Originally designed to foster experience in laboratory-based basic research, the third-year program has evolved in response to the changing landscape of medicine and shifting needs and career interests of the medical student population. Stanford University SOM also has a long-standing commitment to biomedical research and currently requires each student to complete an in-depth, mentored "scholarly concentration." In contrast to Duke, where most of the scholarly research experiences take place in an immersive third year, the Stanford program encourages a longitudinal, multiyear exposure over all four (or five) years of medical school. Although the enduring effects of embedding a rigorous research program are not yet fully known, preliminary data suggest that these experiences instill an appreciation for research, impart research rigor and methodologies, and may motivate students to pursue careers in academic medicine. The authors discuss the histories, evolution, logistics, and ongoing challenges of the research programs at Duke University SOM and Stanford University SOM.

  View details for DOI 10.1097/ACM.0b013e3181ccc77a

  View details for Web of Science ID 000276132100015

  View details for PubMedID 20182114

• Medical Education for a Healthier Population: Reflections on the Flexner Report From a Public Health Perspective ACADEMIC MEDICINE Maeshiro, R., Johnson, I., Koo, D., Parboosingh, J., Carney, J. K., Gesundheit, N., Ho, E. T., Butler-Jones, D., Donovan, D., Finkelstein, J. A., Bennett, N. M., Shore, B., McCurdy, S. A., Novick, L. F., Velarde, L. D., Dent, M. M., Banchoff, A., Cohen, L. 2010; 85 (2): 211-219

  Abstract

  Abraham Flexner's 1910 report is credited with promoting critical reforms in medical education. Because Flexner advocated scientific rigor and standardization in medical education, his report has been perceived to place little emphasis on the importance of public health in clinical education and training. However, a review of the report reveals that Flexner presciently identified at least three public-health-oriented principles that contributed to his arguments for medical education reform: (1) The training, quality, and quantity of physicians should meet the health needs of the public, (2) physicians have societal obligations to prevent disease and promote health, and medical training should include the breadth of knowledge necessary to meet these obligations, and (3) collaborations between the academic medicine and public health communities result in benefits to both parties. In this article, commemorating the Flexner Centenary, the authors review the progress of U.S. and Canadian medical schools in addressing these principles in the context of contemporary societal health needs, provide an update on recent efforts to address what has long been perceived as a deficit in medical education (inadequate grounding of medical students in public health), and provide new recommendations on how to create important linkages between medical education and public health. Contemporary health challenges that require a public health approach in addition to one-on-one clinical skills include containing epidemics of preventable chronic diseases, reforming the health care system to provide equitable high-quality care to populations, and responding to potential disasters in an increasingly interconnected world. The quantitative skills and contextual knowledge that will prepare physicians to address these and other population health problems constitute the basics of public health and should be included throughout the continuum of medical education.

  View details for DOI 10.1097/ACM.0b013e3181c885d8

  View details for Web of Science ID 000276131700017

  View details for PubMedID 20107345

• The use of virtual patients to assess the clinical skills and reasoning of medical students: initial insights on student acceptance. Medical Teacher Gesundheit N, Brutlag P, Youngblood P, Gunning WT, Zary N, Fors U 2009; 31 (8): 739-42
• Integrating Collaborative Population Health Projects into a Medical Student Curriculum at Stanford ACADEMIC MEDICINE Chamberlain, L. J., Wang, N. E., Ho, E. T., Banchoff, A. W., Braddock, C. H., Gesundheit, N. 2008; 83 (4): 338-344

  Abstract

  The authors describe the population health curriculum at the Stanford University School of Medicine from 2003 to 2007 that includes a requirement for first-year medical students to engage in community-based population health projects. The new curriculum in population health comprises classroom and experiential teaching methods. Population health projects, a key component of the curriculum, are described and classified by topic and topic area (e.g., health education; health services) and the intended outcome of the intervention (e.g., establishing new policies; advocacy). During the past four years, 344 students have entered the curriculum and have participated in 68 population health projects. The projects were determined both by students' interests and community needs, and they represented diverse topics: 51% of the 68 projects addressed topics in the area of disease prevention and health promotion; 28% addressed health care access; 15% addressed health services; 4% addressed emergency preparedness; and 1% addressed ethical issues in health. Each project had one of three targets for intervention: community capacity building, establishing policies and engaging in advocacy, and bringing about change or improvement in an aspect of the health care system. Projects represented diverse stages in the evolution of a community-campus partnership, from needs assessment to planning, implementation, and evaluation of project outcomes. Experience to date shows that classroom-based sessions and experiential learning in the area of population health can be successfully integrated in a medical school curriculum. When contextualized in a population health curriculum, population health projects can provide future physicians with an experiential counterpart to their classroom learning.

  View details for Web of Science ID 000267654000005

  View details for PubMedID 18367891

• Acute hepatitis associated with the use of an herbal supplement (Polygonum multiflorum) mimicking iron-overload syndrome. J Clin Gastroenterol. Laird AR, Ramchandani N, deGoma EM, Avula B, Khan IA, Gesundheit N 2008; 42 ((7)): 861-2
• Does feedback matter? Practice-based learning for medical students after a multi-institutional clinical performance examination MEDICAL EDUCATION Srinivasan, M., Hauer, K. E., Der-Martirosian, C., Wilkes, M., Gesundheit, N. 2007; 41 (9): 857-865

  Abstract

  Achieving competence in 'practice-based learning' implies that doctors can accurately self- assess their clinical skills to identify behaviours that need improvement. This study examines the impact of receiving feedback via performance benchmarks on medical students' self-assessment after a clinical performance examination (CPX).The authors developed a practice-based learning exercise at 3 institutions following a required 8-station CPX for medical students at the end of Year 3. Standardised patients (SPs) scored students after each station using checklists developed by experts. Students assessed their own performance immediately after the CPX (Phase 1). One month later, students watched their videotaped performance and reassessed (Phase 2). Some students received performance benchmarks (their scores, plus normative class data) before the video review. Pearson's correlations between self-ratings and SP ratings were calculated for overall performance and specific skill areas (history taking, physical examination, doctor-patient communication) for Phase 1 and Phase 2. The 2 correlations were then compared for each student group (i.e. those who received and those who did not receive feedback).A total of 280 students completed both study phases. Mean CPX scores ranged from 51% to 71% of items correct overall and for each skill area. Phase 1 self-assessment correlated weakly with SP ratings of student performance (r = 0.01-0.16). Without feedback, Phase 2 correlations remained weak (r = 0.13-0.18; n = 109). With feedback, Phase 2 correlations improved significantly (r = 0.26-0.47; n = 171). Low-performing students showed the greatest improvement after receiving feedback.The accuracy of student self-assessment was poor after a CPX, but improved significantly with performance feedback (scores and benchmarks). Videotape review alone (without feedback) did not improve self-assessment accuracy. Practice-based learning exercises that incorporate feedback to medical students hold promise to improve self-assessment skills.

  View details for DOI 10.1111/j.1365-2923.2007.02818.x

  View details for Web of Science ID 000249185000004

  View details for PubMedID 17727526

• The effect of transurethral alprostadil on the quality of life of men with erectile dysfunction, and their partners BRITISH JOURNAL OF UROLOGY Williams, G., Abbou, C. C., Amar, E. T., Desvaux, P., Flam, T. A., Nijeholt, G. A., Lynch, S. F., Morgan, R. J., Muller, S. C., Porst, H., Pryor, J. P., Ryan, P., Witzsch, U. K., Hall, M. M., Place, V. A., Spivack, A. P., Todd, L. K., Gesundheit, N. 1998; 82 (6): 847-854

  Abstract

  To evaluate the impact of treatment for erectile dysfunction on the quality of life of men and their partners.The study included 249 men with organic erectile dysfunction of more than 3 months' duration who self-administered transurethral alprostadil in an open-label, dose-escalating manner in an outpatient medical setting. Patients with a sufficient response (159) were randomly assigned in a double-blind protocol to either active medication or placebo for 3 months at home. Patients and partners each completed quality-of-life questionnaires before and after treatment.In the clinic 159 of the 249 men (64%) had an erection sufficient for intercourse when using transurethral alprostadil. At home, 46 of 67 men (69%) reported intercourse at least once on transurethral alprostadil, compared with eight of 73 (11%) on placebo (P < 0.001). Patients on alprostadil showed a 34% improvement in their 'relationship with partner', a 5% improvement in 'personal wellness', and a 71% improvement in 'quality of erection' domains, compared with a decline of 11%, 8% and 1%, respectively, in patients on placebo (P < 0.005 for each comparison). Partners of patients on alprostadil showed a 35% improvement in the 'relationship with partner' domain, compared with a 12% improvement in the placebo group (P = 0.028). There was a trend toward improvement in other partner domains. Urogenital pain was reported by 14% of patients during home treatment.The resumption of sexual intercourse with the use of transurethral alprostadil was accompanied by an improvement in several important quality-of-life domains in patients and their partners.

  View details for Web of Science ID 000077810000014

  View details for PubMedID 9883223

• Efficacy and safety of transurethral alprostadil in patients with erectile dysfunction following radical prostatectomy 92nd Annual Meeting of the American-Urological-Association Costabile, R. A., Spevak, M., Fishman, I. J., Govier, F. E., Hellstrom, W. J., Shabsigh, R., Nemo, K. J., Rapport, J. L., Tam, P. Y., Weldon, K. L., Gesundheit, N. ELSEVIER SCIENCE INC. 1998: 1325–28

  Abstract

  A retrospective analysis of the MUSE clinical trial was performed to evaluate the efficacy and safety of transurethral alprostadil in patients with erectile dysfunction after radical prostatectomy.Patients received doses of transurethral alprostadil in the clinic and those for whom a suitable dose was determined were treated at home with active drug or placebo for 3 months. Patients had undergone radical prostatectomy no less than 3 months before study entry.Of the 384 patients in whom radical prostatectomy was identified as a cause of erectile dysfunction 70.3% had an erection believed sufficient for intercourse in the clinic and 57.1% on active medication had sexual intercourse at least once at home. The product of clinic and home success rates (70.3 x 57.1%) was an overall success rate (the likelihood of active treatment to lead to intercourse at home) of 40.1%. The frequency of most adverse effects of radical prostatectomy was comparable to that of other organic etiologies of erectile dysfunction (1,127 patients). The percentage of patients with hypotension in the clinic was lower after radical prostatectomy compared to other erectile dysfunction etiologies (0.8 versus 4.2%, p < 0.001) but the percentage of patients with urethral pain/burning was higher (18.3 versus 10.4%, p = 0.027). No urinary tract infection, fibrosis or priapism occurred in the post-radical prostatectomy patients.Transurethral alprostadil is a well tolerated and efficacious method of treating erectile dysfunction after radical prostatectomy, although psychological changes associated with cancer and surgery may limit home response. The severe neurovascular deficit associated with prostatectomy neither limits the efficacy of transurethral alprostadil nor increases the risks.

  View details for Web of Science ID 000075986600028

  View details for PubMedID 9751346

• Changes in thyroid hormone levels during growth hormone therapy in initially euthyroid patients: Lack of need for thyroxine supplementation JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Wyatt, D. T., Gesundheit, N., Sherman, B. 1998; 83 (10): 3493-3497

  Abstract

  The occurrence of central hypothyroidism in previously euthyroid children during GH therapy has been reported with widely varying incidence. We monitored the acute effects on the hypothalamic-pituitary-thyroid axis in 15 euthyroid children with classic GH deficiency during the first year of GH therapy. All were initially euthyroid, as assessed by normal baseline TSH, T4, free T4, and T3 levels and negative antithyroid antibodies. A thyroid profile (T4, free T4 index, T3, rT3, and TSH) was performed at baseline and 1, 3, 6, 9, and 12-15 months after GH therapy began; a TRH stimulation test was performed at baseline and after 1, 3, and 9 months of therapy. By 1 month, there were significant decreases in T4, free T4 index, and rT3, and significant increases in T3 and the T3/T4 ratio. The changes from baseline values were greatest at 1 month, were almost universal for all thyroid values, and showed a gradual return to baseline from 3-12 months. There were no clinical signs of hypothyroidism and no change in baseline or TRH-stimulated TSH levels or in cholesterol levels, and all patients grew at velocities expected for the treatment schedule. There is little evidence for the development of clinically significant hypothyroidism in the great majority of initially euthyroid patients after GH therapy is begun. T4 supplementation is seldom needed in such patients.

  View details for Web of Science ID 000076275500018

  View details for PubMedID 9768652

• Hemodynamic effects of transurethral alprostadil measured by color duplex ultrasonography in men with erectile dysfunction Annual Meeting of American-Urological-Association Tam, P. Y., Keller, T., Poppiti, R., Gesundheit, N., Padma-Nathan, H. ELSEVIER SCIENCE INC. 1998: 1321–24

  Abstract

  We evaluated the hemodynamic effects of transurethral alprostadil in 21 patients with erectile dysfunction using color duplex ultrasonography.Penile arterial diameter, peak flow velocity and end diastolic velocity were compared following intraurethral administration of 500 microg. alprostadil and intracavernosal injection of 10 microg. alprostadil.A dose of 500 microg. transurethral alprostadil resulted in significant increases in corporeal blood flow comparable to those achieved with intracavernosal injection of 10 microg. alprostadil as measured by duplex ultrasonography in men with erectile dysfunction. Transurethral alprostadil resulted in statistically significant increases in arterial diameter and peak flow velocity comparable to those achieved with intracavernosal injection. End diastolic velocities were higher after transurethral alprostadil than intracavernosal injections. Color ultrasonography following transurethral alprostadil showed arterial and venous hyperemia of the corpus spongiosum and corpora cavernosa. Furthermore, color ultrasonography revealed communicating vessels between the corpus spongiosum and corpora cavernosa following administration of transurethral alprostadil.The visualization of communicating vessels between the corpus spongiosum and corpora cavernosa after transurethral alprostadil suggests local mechanisms of drug transfer from one to the other. In addition to potential clinical benefits, transurethral alprostadil may be useful to visualize the vascular anatomy of the penis and to test for patient responsiveness to local vasoactive agents.

  View details for Web of Science ID 000075986600027

  View details for PubMedID 9751345

• Efficacy and safety of transurethral alprostadil therapy in men with erectile dysfunction BRITISH JOURNAL OF UROLOGY Williams, G., Abbou, C. C., Amar, E. T., Desvaux, P., Flam, T. A., Lycklama a Nijeholt, G. A., Lynch, S. F., Morgan, R. J., Muller, S. C., Porst, H., Pryor, J. P., Ryan, P., Witzsch, U. K., Hall, M. M., Place, V. A., Spivack, A. P., Gesundheit, N. 1998; 81 (6): 889-894

  Abstract

  To examine the safety and efficacy of transurethral pharmacotherapy for erectile dysfunction, involving the use of a novel therapeutic system to administer alprostadil (prostaglandin E1) to the urethral mucosa in a double-blind, randomized, parallel, placebo-controlled study conducted in five countries in Europe.In an outpatient setting, patients with primarily organic erectile dysfunction of at least 3 months' duration were treated with transurethral alprostadil, in an open-label, dose-escalating study. Testing stopped when the dose provided an erection sufficient for intercourse, as assessed by the patient and the investigator. Patients who achieved a sufficient response were then randomized to either active medication at the selected dose or to placebo for use at home for 3 months. After each home administration, patients recorded in diaries whether or not sexual intercourse occurred and any adverse reactions to the drug.A total of 249 patients were treated in an outpatient setting; of these patients, 159 (64%) achieved an erection sufficient for intercourse and were randomized (1:1) to either active medication or placebo for home treatment. Of the patients randomized to alprostadil for home treatment, 69% reported intercourse at least once, compared with 11% of patients randomized to placebo (P < 0.001). The most common adverse reaction, urethral pain/burning, was reported by 7% of patients in the clinic. Most patients (83%) graded transurethral alprostadil as causing minimal or no discomfort in the clinic. No patient reported priapism or developed penile fibrosis.Alprostadil delivered transurethrally by this system was well tolerated and effective in treating erectile dysfunction.

  View details for Web of Science ID 000074529200019

  View details for PubMedID 9666777

• Effects of alprostadil and prazosin on motility, viability and membrane integrity of human sperm JOURNAL OF UROLOGY Hellstrom, W. J., Wang, R., Peterson, C. A., Varady, J. C., Gesundheit, N., Sikka, S. C. 1998; 159 (5): 1559-1562

  Abstract

  We evaluated the effects of alprostadil, prazosin hydrochloride, and alprostadil/prazosin hydrochloride, agents used in the clinical treatment of male erectile dysfunction, on the motility, viability and membrane integrity of human sperm.Ten healthy volunteers provided semen samples that were incubated with 0.4 mg./ml. alprostadil, 0.1 and 0.2 mg./ml. prazosin hydrochloride and 0.4 mg./ml. alprostadil plus 0.1 mg./ml. prazosin hydrochloride for 2 hours. Control incubations included polyethylene glycol 1450, the formulation vehicle for the clinical use of alprostadil and prazosin, and Ham's F-10 buffer. Serial evaluations of percent sperm motility, percent viability, membrane function (by hypo-osmotic swelling test) and several computer generated measurements of sperm motion, including straight line velocity, curvilinear velocity, linearity and amplitude of lateral head displacement, were made.None of the agents had a significant impact on the percentage of motile or viable sperm or on sperm membrane function. Incubation with 0.2 mg./ml. prazosin reduced straight line velocity and curvilinear velocity significantly compared with the other agents. These changes were most likely a direct result of the viscosity of the 0.2 mg./ml. prazosin solution and not a cellular or metabolic effect on the sperm.Alprostadil and prazosin hydrochloride at doses used in transurethral therapy for erectile dysfunction have no effect on the motility, viability and membrane integrity of human sperm.

  View details for Web of Science ID 000073045200040

  View details for PubMedID 9554354

• Erectile response to transurethral alprostadil, prazosin and alprostadil-prazosin combinations Annual Meeting of American-Urological-Association Peterson, C. A., Bennett, A. H., Hellstrom, W. J., Kaiser, F. E., Morley, J. E., Nemo, K. J., Padma-Nathan, H., Place, V. A., Prendergast, J. J., Tam, P. Y., Tanagho, E. A., Todd, L. K., Varady, J. C., Gesundheit, N. ELSEVIER SCIENCE INC. 1998: 1523–27

  Abstract

  Transurethral alprostadil has been shown to be efficacious in many men with erectile dysfunction. We compared transurethral alprostadil and prazosin alone, and in combination to treat this disorder.In this double-blind, placebo controlled study the erectile responses to transurethral alprostadil, prazosin and alprostadil-prazosin combinations were assessed in 234 men 26.8 to 81.5 years old with complete organic erectile dysfunction. Patients self-administered a random sequence of 7 doses in the clinic in 4 weeks. The erectile response was assessed using categorical and visual analog scales.Full penile enlargement or rigidity was achieved by 165 of the 234 men (70.5%) after at least 1 active dose of medication. The most effective alprostadil dose (500 microg.) resulted in full penile enlargement or rigidity in 51.8% of administrations, whereas the most effective prazosin dose (2,000 microg.) and placebo resulted in a similar response in 12.7 and 2.7%, respectively (p <0.001). The 500/2,000 microg. alprostadil/prazosin combination, which resulted in full enlargement or rigidity in 58.9% of doses, was only slightly better than the most effective dose of alprostadil alone (500 microg.). However, combinations of 125/500 and 250/500 microg. alprostadil/prazosin were more effective (p <0.01) than 125 and 250 microg. alprostadil given alone, respectively. The most common side effect of therapy was penile pain, which rarely led to study discontinuation. Hypotension most commonly developed at the higher alprostadil-prazosin combination.Transurethral alprostadil and alprostadil-prazosin combinations produced erections in men with complete organic erectile dysfunction. This combination therapy may be an option in patients who do not respond to transurethral alprostadil alone.

  View details for Web of Science ID 000073045200029

  View details for PubMedID 9554347

• Body composition of HIV/AIDS males: Effects of treatment with insulin-like growth factor (IGF-I) and growth hormone (GH) International Symposium on In Vivo Body Composition Studies Ellis, K. J., Lee, P. D., Pivarnik, J. M., Bukar, J. G., Gesundheit, N. PERGAMON-ELSEVIER SCIENCE LTD. 1998: 653–55

  View details for Web of Science ID 000072752700069

  View details for PubMedID 9569569

• Pilot study of the immunologic effects of recombinant human growth hormone and recombinant insulin-like growth factor in HIV-infected patients 1995 Annual Meeting of the Laboratory-of-Tumor-Cell-Biology Nguyen, B. Y., CLERICI, M., VENZON, D. J., Bauza, S., Murphy, W. J., Longo, D. L., Baseler, M., Gesundheit, N., Broder, S., Shearer, G., Yarchoan, R. LIPPINCOTT WILLIAMS & WILKINS. 1998: 895–904

  Abstract

  To study the immunologic effects of recombinant human growth hormone (rhGH), recombinant human insulin-like growth factor type 1 (rhIGF-1), or the combination, in patients with moderately advanced HIV infection.Randomized but not blinded trial.Government medical research center.Twenty-four HIV-infected patients with CD4 cell counts of 100-400 x 10(6)/l who were receiving nucleoside antiretroviral therapy.Either rhGH, rhIGF-1, or the combination was administered subcutaneously for 12 weeks.Immunologic parameters, including T-cell subsets and assays of in vitro interleukin (IL)-2 production in response to antigens and mitogens, and safety profile.Plasma IGF-1 levels were low or low-normal prior to treatment and increased with all three therapies. There were no significant changes in CD4 cell counts, RA/RO CD4 cell subsets, natural killer cell function, immunoglobulin levels, or in vitro IL-2 production in response to mitogen or alloantigens. However, there was an upward trend (and for p18IIIB a statistically significant increase) in the in vitro IL-2 production in response to each of five HIV envelope peptides. Potential toxic effects included fatigue, arthralgia, edema, myalgia, and headache. Patients also were noted to have weight gain averaging 4 kg early in the course of treatment.These results suggest that treatment with rhGH/rhIGF-1 was reasonably well tolerated and that modest improvement in HIV-specific immune function was attained. Further studies will help clarify the therapeutic potential of rhGH/rhIGF-1 as an immunostimulator in the setting of HIV infection.

  View details for Web of Science ID 000073688000012

  View details for PubMedID 9631143

• Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: a Phase II safety and efficacy trial. Neurosurgical focus Hatton, J., Rapp, R. P., Kudsk, K. A., Brown, R. O., Luer, M. S., Bukar, J. G., Chen, S. A., McClain, C. J., Gesundheit, N., Dempsey, R. J., Young, B. 1997; 2 (5): ECP1-?

  Abstract

  The purpose of this study was to determine the effect of insulin-like growth factor-I (IGF-I) on the catabolic state and clinical outcome of head-injured patients. Thirty-three patients between the ages of 18 and 59 years with isolated traumatic head injury and Glasgow Coma Scale (GCS) scores of 4 to 10 were randomized to one of two groups. All patients received standard neurosurgical intensive care plus aggressive nutritional support; the patients in the treatment group also received intravenous therapy with continuous IGF-I (0.01 mg/kg/hour). During the 14-day dosing period, the control patients lost weight, whereas treated patients gained weight despite a significantly higher measured energy expenditure and lower caloric intake (p = 0.02). Daily glucose concentrations and nitrogen outputs were greater in control patients (p = 0.03) throughout the study period. During Week 1, only treated patients achieved positive nitrogen balance. Fifteen of 17 treated and 13 of 16 control patients survived the 1st week. No deaths occurred in patients whose serum IGF-I concentrations were higher than 350 ng/ml. Dichotomized Glasgow Outcome Scale scores for patients with baseline GCS scores of 5 to 7 improved from poor to good for eight of 12 treated patients but for only three of 11 control patients (p = 0.06). Eight of 11 treated patients with serum IGF-I concentrations that were at least 350 ng/ml achieved moderate-to-good outcome scores at 6 months, compared to only one of five patients with lower concentrations (p < 0.05). These findings indicate that pharmacological concentrations of IGF-I may improve clinical outcome and nitrogen utilization in patients with moderate-to-severe head injury.

  View details for PubMedID 15096005

• Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: A Phase II safety and efficacy trial JOURNAL OF NEUROSURGERY Hatton, J., Rapp, R. P., Kudsk, K. A., Brown, R. O., Luer, M. S., Bukar, J. G., Chen, S. A., McClain, C. J., Gesundheit, N., Dempsey, R. J., Young, B. 1997; 86 (5): 779-786

  Abstract

  The purpose of this study was to determine the effect of insulin-like growth factor-I (IGF-I) on the catabolic state and clinical outcome of head-injured patients. Thirty-three patients between the ages of 18 and 59 years with isolated traumatic head injury and Glasgow Coma Scale (GCS) scores of 4 to 10 were randomized to one of two groups. All patients received standard neurosurgical intensive care plus aggressive nutritional support; the patients in the treatment group also received intravenous therapy with continuous IGF-I (0.01 mg/kg/hour). During the 14-day dosing period, the control patients lost weight, whereas treated patients gained weight despite a significantly higher measured energy expenditure and lower caloric intake (p = 0.02). Daily glucose concentrations and nitrogen outputs were greater in control patients (p = 0.03) throughout the study period. During Week 1, only treated patients achieved positive nitrogen balance. Fifteen of 17 treated and 13 of 16 control patients survived the 1st week. No deaths occurred in patients whose serum IGF-I concentrations were higher than 350 ng/ml. Dichotomized Glasgow Outcome Scale scores for patients with baseline GCS scores of 5 to 7 improved from poor to good for eight of 12 treated patients but for only three of 11 control patients (p = 0.06). Eight of 11 treated patients with serum IGF-I concentrations that were at least 350 ng/ml achieved moderate-to-good outcome scores at 6 months, compared to only one of five patients with lower concentrations (p < 0.05). These findings indicate that pharmacological concentrations of IGF-I may improve clinical outcome and nitrogen utilization in patients with moderate-to-severe head injury.

  View details for Web of Science ID A1997WV75600006

  View details for PubMedID 9126892

• Adjunctive growth hormone during ovarian hyperstimulation increases levels of insulin-like growth factor binding proteins in follicular fluid: A randomized, placebo-controlled, cross-over study JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Rabinovici, J., Cataldo, N. A., Dandekar, P., Rosenthal, S. M., Gargosky, S. E., Gesundheit, N., Martin, M. C. 1997; 82 (4): 1171-1176

  Abstract

  GH increases circulating insulin-like growth factor I (IGF-I), which can promote the growth and differentiated function of ovarian granulosa and theca cells. Reported studies of GH as an adjunct to menotropin stimulation in women, largely those with ovarian dysfunction, have not consistently shown a benefit of GH, despite increases in serum and follicular fluid IGF-I. We hypothesized that changes in intrafollicular IGF-binding proteins (IGFBPs), which can antagonize IGF actions on granulosa cells, may underlie the inconsistent effects of GH. In the present study of GH, administered in double-blind, placebo-controlled, cross-over fashion to regularly cycling women undergoing in vitro fertilization, we found that follicular fluid levels of IGFBP-1, -3, and -4 and serum levels of IGFBP-3, as well as follicular fluid and serum IGF-I, were significantly increased in the GH-treated cycles, when compared with the placebo cycle of the same patient. We suggest that the net increase in intrafollicular IGFBPs in GH cycles may mitigate the potential beneficial effect of increased IGF-I.

  View details for Web of Science ID A1997WT03400033

  View details for PubMedID 9100591

• Dual hormonal replacement therapy with insulin and recombinant human insulin-like growth factor (IGF)-I in insulin-dependent diabetes mellitus: Effects on the growth hormone IGF IGF-binding protein system JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Thrailkill, K., Quattrin, T., Baker, L., Litton, J., Dwigun, K., Rearson, M., POPPENHEIMER, M., KOTLOVKER, D., Giltinan, D., Gesundheit, N., Martha, P. 1997; 82 (4): 1181-1187

  Abstract

  Patients with insulin-dependent diabetes mellitus (IDDM) exhibit abnormalities in the GH/insulin-like growth factor (IGF) axis, including GH hypersecretion, low serum IGF-I and IGF-binding protein-3 (IGFBP-3) levels, and elevated IGFBP-1 levels. We recently demonstrated that in IDDM, dual hormonal replacement therapy with insulin plus recombinant human IGF-I (rhIGF-I) improves glycemic control better than insulin alone. To determine whether the addition of rhIGF-I therapy to insulin therapy also corrects GH/IGF/ IGFBP abnormalities, we examined the effects of chronic combined rhIGF-I/insulin therapy on key components of the somatotropin axis. Forty-three pediatric IDDM patients were randomly assigned to groups receiving daily, fasting subcutaneous injections of placebo or rhIGF-I (80 micrograms.kg.day) for 28 days, while continuing to receive splitmix insulin therapy and intensive outpatient management. rhIGF-I therapy corrected IGF-I deficiency, suppressed IGFBP-1 levels (P < 0.01), and induced a trend toward lower circulating GH levels throughout the study. rhIGF-I therapy also induced an approximate 50% decrease in IGF-II levels (P < 0.001) and an approximate 70% increase in IGFBP-2 levels (P < 0.05). Serum IGFBP-3 levels, normal before treatment, remained normal during rhIGF-I administration. All effects were apparent during the first week of rhIGF-I therapy and persisted throughout treatment. Because improvements in the GH/ IGF axis abnormalities and in glycemic control were greater in subjects receiving combined rhIGF-I and insulin, these data strongly support the concept that dual hormonal replacement in IDDM may offer distinct therapeutic advantages over insulin monotherapy.

  View details for Web of Science ID A1997WT03400035

  View details for PubMedID 9100593

• Dual hormonal replacement with insulin and recombinant human insulin-like growth factor I in IDDM - Effects on glycemic control, IGF-I levels, and safety profile DIABETES CARE Quattrin, T., Thrailkill, K., Baker, L., Litton, J., Dwigun, K., Rearson, M., POPPENHEIMER, M., Giltinan, D., Gesundheit, N., Martha, P. 1997; 20 (3): 374-380

  Abstract

  To examine if dual replacement with insulin and rhIGF-I, recombinant human insulin-like growth factor I (rhIGF-I) may be safe and result in improved metabolic control and reduced insulin usage.Forty-three patients with IDDM were randomized to receive a daily injection of rhIGF-I (80 mcg/kg s.c.) or placebo while on conventional insulin therapy for 4 weeks. Insulin was adjusted in the attempt to achieve predetermined goal glycemic values. Free and total IGF-I, four daily blood glucoses, and HbA1c were measured.Before randomization, placebo and rhIGF-I groups exhibited low plasma levels of free and total IGF-I, which increased toward normal levels during the treatment period only in the rhIGF group. The regression curve obtained from the average of daily blood glucose measurements indicated that the glycemic profile, overlapping in the lead-in period, exhibited a downward trend in the rhIGF-I group during the treatment period. Mean blood glucose level during the last 10 days of treatment was lower in the rhIGF-I groups (174 +/- 37 vs. 194 +/- 32 mg/dl). HbA1c level was reduced by more than one-half percent more in the rhIGF-I group (-1.85%) than in the control group (-1.3%). The dose of regular insulin was significantly lower in the rhIGF-I group (0.2 +/- 0.1 vs. 0.28 +/- 0.1 U. kg-1. 10 days-1 in the placebo group; P < 0.05).rhIGF-I in combination with conventional insulin treatment ameliorated the low plasma total and free IGF-I levels and was well tolerated in IDDM. There was a trend toward improved glycemic control, while the regular insulin dose was significantly decreased.

  View details for Web of Science ID A1997WJ36600028

  View details for PubMedID 9051390

• Treatment of men with erectile dysfunction with transurethral alprostadil 53rd Annual Meeting of the American-Geriatrics-Society PADMANATHAN, H., Hellstrom, W. J., Kaiser, F. E., Labasky, R. F., Lue, T. F., Nolten, W. E., NORWOOD, P. C., Peterson, C. A., Shabsigh, R., Tam, P. Y., Place, V. A., Gesundheit, N. MASS MEDICAL SOC. 1997: 1–7

  Abstract

  Erectile dysfunction in men is common. We evaluated a system by which alprostadil (prostaglandin E1) is delivered transurethrally to treat this disorder.Alprostadil was delivered transurethrally in a double-blind, placebo-controlled study of 1511 men, 27 to 88 years of age, who had chronic erectile dysfunction from various organic causes. The men were first tested in the clinic with up to four doses of the drug (125, 250, 500, and 1000 microg); those who had sufficient responses were randomly assigned to treatment with either the effective dose of alprostadil or placebo for three months at home.During in-clinic testing, 996 men (65.9 percent) had erections sufficient for intercourse. Of these men, 961 reported the results of at least one home treatment; 299 of the 461 treated with alprostadil (64.9 percent) had intercourse successfully at least once, as compared with 93 of the 500 who received placebo (18.6 percent, P<0.001). On average, 7 of 10 alprostadil administrations were followed by intercourse in men responsive to treatment. The efficacy of alprostadil was similar regardless of age or the cause of erectile dysfunction, including vascular disease, diabetes, surgery, and trauma (P<0.001 for all comparisons with placebo). The most common side effect was mild penile pain, which occurred after 10.8 percent of alprostadil treatments, but the pain rarely resulted in refusal to continue in the study. Hypotension occurred in the clinic in 3.3 percent of men receiving alprostadil. Hypotension-related symptoms were uncommon at home. No men had priapism or penile fibrosis.In men with erectile dysfunction, transurethral alprostadil therapy resulted in erections in the clinic and in intercourse at home.

  View details for Web of Science ID A1997WA49600001

  View details for PubMedID 8970933

• Recombinant human growth hormone, insulin-like growth factor 1, and combination therapy in AIDS-associated wasting - A randomized, double-blind, placebo-controlled trial ANNALS OF INTERNAL MEDICINE Waters, D., Danska, J., Hardy, K., Koster, F., Qualls, C., Nickell, D., Nightingale, S., Gesundheit, N., Watson, D., Schade, D. 1996; 125 (11): 865-?

  Abstract

  To increase lean body mass and improve health status in patients with wasting associated with the acquired immunodeficiency syndrome (AIDS) by treatment with recombinant human growth hormone (rhGH), recombinant human insulin-like growth factor 1 (rhIGF-1), or both.Randomized, double-blind, placebo-controlled clinical trial.University of New Mexico Clinical Research Center and University of Texas Southwestern Medical Center.60 patients with AIDS and wasting as defined by the Centers for Disease Control and Prevention. Patients were divided into four groups of 15 patients each.Group 1 received 1.4 mg of rhGH once daily plus placebo twice daily; group 2 received 5 mg of rhIGF-1 twice daily plus placebo once daily; group 3 received 5 mg of rhIGF-1 twice daily plus 1.4 mg of rhGH once daily; and group 4 received placebo three times daily.Body weight, body composition, muscle strength, protein catabolism, quality of life, and immune status were assessed at baseline, and changes in these variables were measured at 6 and 12 weeks.At 6 weeks, lean body mass had increased and total fat mass had decreased in the groups receiving rhGH, rhIGF-1, or both. Group 3 had the greatest changes in lean body mass (mean +/- SE, 3.2 +/- 0.59 kg; P < 0.001); only in this group were changes in body mass maintained at 12 weeks. Only patients in group 1 had improvement in muscular strength of the knees and upper body (P = 0.04) and quality of life (P = 0.01). Immunologic function did not improve in any group.Growth factor therapy had significantly increased lean body mass and decreased fat mass by 6 weeks, but these improvements persisted for 12 weeks only in group 3. Growth factor therapy at the dosages used in this study is not recommended because the magnitude of weight gain was modest and improvements in quality-of-life measures varied.

  View details for Web of Science ID A1996VV54100001

  View details for PubMedID 8967666

• A double-blind, placebo-controlled evaluation of the erectile response to transurethral alprostadil 55th Annual Meeting and Scientific Sessions of the American-Diabetes-Association Hellstrom, W. J., Bennett, A. H., Gesundheit, N., Kaiser, F. E., Lue, T. F., PADMANATHAN, H., Peterson, C. A., Tam, P. Y., Todd, L. K., Varady, J. C., Place, V. A. ELSEVIER SCIENCE INC. 1996: 851–56

  Abstract

  Previous studies have indicated that the urethra may provide an effective route for administering vasoactive medication for the treatment of erectile dysfunction. We evaluated the safety and efficacy of alprostadil administered intraurethrally at home for the treatment of this disorder.This prospective, multicenter, double-blind, placebo-controlled study evaluated the erectile response to randomly assigned doses of transurethral alprostadil at home in 68 men with long-standing (mean 41 months) erectile dysfunction of primarily organic etiology. Patients completing the study each administered a random sequence of four different doses (125, 250, 500, and 1000 micrograms) and placebo over a 2 to 4-week period. Assessments included the couples' ability to have intercourse, patient ratings of erectile response by both categorical and visual analogue scales, penile volume measurements, and overall assessments of comfort and ease of administration.Overall, 75.4% (49 of 65) of study patients achieved full enlargement of the penis and 49.2% (32 of 65) achieved an erection judged by the patient to be sufficient for intercourse. In addition, 63.6% (42 of 66) of patients reported intercourse. Efficacy was similar across etiologies. The most common side effect was penile pain, which occurred in association with 9.1% to 18.3% of alprostadil administrations, depending on dose. Mean comfort ratings ranged from 79 to 87, depending on dose, where 0 = severe discomfort and 100 = comfortable; ease of administration scores were above 90 for each dose, where 0 = difficult and 100 = easy. There were no episodes of priapism in this study.Short-term treatment with transurethral alprostadil produced erections resulting in sexual intercourse in most patients with chronic erectile dysfunction. This therapy may be a useful treatment option for patients with erectile dysfunction.

  View details for Web of Science ID A1996VZ28000005

  View details for PubMedID 8973666

• Changes in body composition of human immunodeficiency virus-infected males receiving insulin-like growth factor I and growth hormone JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Ellis, K. J., Lee, P. D., Pivarnik, J. M., Bukar, J. G., Gesundheit, N. 1996; 81 (8): 3033-3038

  Abstract

  Weight loss is a common, persistent characteristic of long term human immunodeficiency virus (HIV-1) infection; its full etiology remains unknown. Because treatment with GH has induced nitrogen retention in various catabolic conditions, we designed this study to determine whether a moderate dose of insulin-like growth factor I (IGF-I) combined with a low GH dose could impede the catabolic response seen in HIV-1 infection. A double blind, placebo-controlled study design was used. Subjects in the GH/IGF-I treatment group (n = 44) and control group (n = 22) continued to receive their routine stable antiretroviral therapy. No patient had a recent history of opportunistic infection, malignancy, or Kaposi's sarcoma and had dietary intakes of at least 25 Cal/kg weight.day at study entry. During the 12-week study period, dietary instruction was given, and subjects were encouraged to maintain an intake of 35 Cal/kg and 1 g protein/kg. All subjects had a body mass index of 19.8 kg/m2 or less at the time of study entry or a weight loss of 10% or more of their premorbid weight and a body mass index below 26.1 kg/m2. The treatment group received 0.34 mg (0.68 mg/day) GH, twice daily, and 5.0 mg (10 mg/day) IGF-I, twice daily. Changes in body composition of total body potassium (TBK), total body nitrogen (TBN), fat-free mass (FFM), and body fat (Fat) were examined at 6 and 12 weeks during the treatment period. TBK, TBN, FFM, and Fat for the treatment and placebo groups were, on the average, below normal at study entry. At 6 weeks, the GH/IGF-I group showed a significant increase in FFM (P < 0.0001), a minimal increase in TBK (P < 0.05), and a substantial decrease in Fat (P < 0.01) compared with baseline values. The loss of body fat continued to be significant (P < 0.01) in the GH/IGF-I group treatment at 12 weeks, whereas the increase in FFM was minimal (P < 0.05). No significant changes in the mean body composition occurred at 6 or 12 weeks in the placebo group. By 12 weeks, neither TBK (body cell mass) nor TBN (total protein mass) had significantly increased relative to the values at baseline, although the FFM remained elevated. Thus, the combined GH and IGF-I doses used in this study in adult males with HIV-associated weight loss were ineffective in producing a sustained anabolic response and, in fact, resulted primarily in a significant loss of body fat.

  View details for Web of Science ID A1996VC90100049

  View details for PubMedID 8768870

• A randomized, placebo-controlled trial of combined insulin-like growth factor I and low dose growth hormone therapy for wasting associated with human immunodeficiency virus infection JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Lee, P. D., Pivarnik, J. M., Bukar, J. G., Muurahainen, N., Berry, P. S., Skolnik, P. R., Nerad, J. L., Kudsk, K. A., Jackson, L., Ellis, K. J., Gesundheit, N. 1996; 81 (8): 2968-2975

  Abstract

  Loss of body mass, or wasting, is a major cause of morbidity and a contributor to mortality in human immunodeficiency virus-1 (HIV-1) infection. Dietary supplements and appetite adjuvants have had limited effectiveness in treating this condition. GH and insulin-like growth factor I (IGF-I) have been shown to be anabolic in many catabolic conditions, and limited data suggest similar efficacy in HIV wasting. In addition, it appears that GH and IGF-I may have complementary anabolic effects with opposing glucoregulatory effects. We report results from a 12-week randomized, placebo-controlled trial of combination recombinant human GH (rhGH; Nutropin; 0.34 mg, sc, twice daily) and rhIGF-I (5.0 mg, sc, twice daily) in individuals with HIV wasting and without active opportunistic infection, cancer, or gastrointestinal disease. A total of 142 subjects (140 males and 2 females) were randomized using a 2:1, double blind treatment scheme and assigned to receive either active treatment or placebo injections. Eighty subjects completed the 12-week protocol. Nutritional intake and demographic and clinical characteristics did not differ between the groups at any study time point. At 3 weeks, the treatment group had a significantly larger weight increase (P = 0.0003), but this difference was not observed at any later time point. Similarly, fat-free mass, calculated from skinfold measurements, increased transiently in the treatment group at 6 weeks (P = 0.002). No significant differences in isokinetic muscle strength or endurance testing or in quality of life were observed between the groups. Resting heart rate was significantly higher in the treatment group at each time point post-baseline. GH and IGF-binding protein-3 levels did not change; however, IGF-I levels were higher in the treatment group at 6 and 12 weeks. There were no significant between-group differences in any of the measured biochemical or immunological parameters. rhGH plus rhIGF-I treatment was associated with an increased incidence of peripheral edema and other side-effects, possibly related to fluid retention. We conclude that the combination of rhIGF-I and low dose rhGH used in this study had no significant anabolic effect in HIV wasting.

  View details for Web of Science ID A1996VC90100039

  View details for PubMedID 8768860

• Pharmacokinetics of insulin-like growth factor-1 in advanced chronic renal failure KIDNEY INTERNATIONAL Rabkin, R., Fervenza, F. C., Maidment, H., Ike, J., Hintz, R., Liu, F., Bloedow, D. C., Hoffman, A. R., Gesundheit, N. 1996; 49 (4): 1134-1140

  Abstract

  Information regarding the impact of chronic renal failure (CRF) on IGF-1 serum clearance is limited. Thus we evaluated the pharmacokinetics of insulin-like growth factor-1 (IGF-1) in six normal adults and six adults with advanced CRF (serum creatinine 7 +/- 0.8 mg/dl). All subjects were given 80 micrograms/kg recombinant human IGF-1 s.c. and blood was sampled over 48 hours. Baseline total serum IGF-1 levels were similar in both groups, but peak levels were elevated significantly in CRF; this was apparently related to the reduced distribution volume in CRF subjects. CRF did not affect the metabolic clearance rate (MCR) of total serum IGF-1. Immunoreactive IGF binding protein-3 (IGFBP-3) levels were greater in CRF. Western immunoblots revealed that the apparent increase in IGFBP-3 was largely due to an increase in immunoreactive fragments. IGFBP-3 protease activity was not increased. Thus IGFBP fragment accumulation likely reflects reduced fragment clearance. Western ligand blots revealed elevated 30 and 34 kDa IGFBP levels and IGFBP products in CRF serum. Serum acid labile subunit levels were unchanged in CRF. Peak free IGF-1 levels and the MCR of free IGF-1 did not differ between groups. In both groups the MCR of free IGF-1 exceeded the MCR of total IGF-1 by approximately 30-fold. These data suggest that in CRF patients receiving s.c. IGF-1: (a) total serum IGF-1 levels are increased as a result of elevated circulating IGFBPs that may restrict the distribution of IGF-1 beyond plasma; (b) serum free IGF-1 levels are not altered; and (c) the IGF-1 MCR is unchanged in CRF. Thus, in advanced CRF, apart from a reduction in the total IGF-1 volume of distribution the pharmacokinetics of IGF-1 are largely unaltered.

  View details for Web of Science ID A1996UB11200035

  View details for PubMedID 8691735

• MUTATIONS OF THE GROWTH-HORMONE RECEPTOR IN CHILDREN WITH IDIOPATHIC SHORT STATURE NEW ENGLAND JOURNAL OF MEDICINE Goddard, A. D., Covello, R., Luoh, S. M., Clackson, T., Attie, K. M., Gesundheit, N., Rundle, A. C., Wells, J. A., Carlsson, L. M. 1995; 333 (17): 1093-1098

  Abstract

  Short stature in children who are not deficient in growth hormone (GH) is probably caused by a variety of defects. Some children with idiopathic short stature have low serum concentrations of GH-binding protein, which is derived from the GH receptor. The possibility that low serum concentrations of GH-binding protein might indicate partial insensitivity to GH led us to investigate possible defects in the gene for the GH receptor in children with idiopathic short stature and low serum concentrations of GH-binding protein.We studied 14 children with idiopathic short stature who were selected on the basis of normal GH secretion and low serum concentrations of GH-binding protein. Analysis of single-strand conformation polymorphisms and DNA sequencing were both used to identify mutations in the GH-receptor gene.Mutations in the region of the GH-receptor gene that codes for the extracellular domain of the receptor were found in 4 of the 14 children, but in none of 24 normal subjects. One of the four children with mutations was a compound heterozygote, with one mutation that reduced the affinity of the receptor for GH and a second mutation that may affect a function other than ligand binding. The remaining three children had single mutations in one allele of the gene. One mutation introduced a premature termination codon, and two caused substitutions of single amino acids in a structurally conserved domain of the receptor.Some children with idiopathic short stature may have partial insensitivity to GH due to mutations in the GH-receptor gene.

  View details for Web of Science ID A1995TA37200001

  View details for PubMedID 7565946

• DYNAMIC CHANGES OF GROWTH HORMONE-BINDING PROTEIN CONCENTRATIONS IN NORMAL MEN AND PATIENTS WITH ACROMEGALY - EFFECTS OF SHORT-TERM FASTING METABOLISM-CLINICAL AND EXPERIMENTAL Ho, P. J., Gesundheit, N., Wong, W. L., Huang, S. H., FRIBERG, R. D., Barkan, A. L. 1995; 44 (5): 667-672

  Abstract

  Plasma concentrations of growth hormone (GH) and GH-binding protein (GHBP) were measured at hourly intervals in five healthy men and five patients with acromegaly during the fed state and after a 5-day fast. GHBP concentrations (both total and complexed with endogenous GH) were analyzed by the ligand-mediated immunofunctional assay (LIFA). Total GHBP was similar in both groups during the fed state (104.4 +/- 5.2 and 101.6 +/- 10.3 pmol/L), did not exhibit a diurnal rhythm, and was unchanged by fasting (91.9 +/- 5.4 and 109.9 +/- 10.5 pmol/L, respectively). However, the GHBP/GH complex concentration was significantly higher in acromegalics than in controls (41.0 +/- 2.8 v 18.0 +/- 2.2 pmol/L, respectively; P < .05), closely followed diurnal GH rhythm in normals, and was significantly correlated with mean 24-hour GH concentrations (r = .86, P < .01). We conclude that plasma concentrations of GHBP are stable throughout the day and are unchanged either by short-term calorie deprivation or by chronic exposure to high levels of endogenous GH. In contrast, GHBP/GH complex concentrations are altered both acutely and chronically by ambient GH.

  View details for Web of Science ID A1995QW97900017

  View details for PubMedID 7752917

• EFFECTS OF RECOMBINANT HUMAN GROWTH-HORMONE ON METABOLIC INDEXES, BODY-COMPOSITION, AND BONE TURNOVER IN HEALTHY ELDERLY WOMEN JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Holloway, L., Butterfield, G., Hintz, R. L., Gesundheit, N., Marcus, R. 1994; 79 (2): 470-479

  Abstract

  We conducted a controlled trial of recombinant human GH (rhGH) in 27 healthy elderly women (66.7 +/- 3.0 yr), of whom 8 took a stable dose of replacement estrogen throughout the study (plus estrogen group). Hormone or placebo was given as a single daily injection. A total of 19 women were assigned to receive rhGH at an initial daily dose of 0.043 mg/kg BW. After several weeks, 50% dose reductions were necessitated by side-effects. The last 7 subjects to be enrolled began treatment at this reduced level. A total of 13 women assigned to rhGH and 14 women assigned to placebo completed 6 months of drug treatment. In the rhGH group, 6 women took estrogen; thus, the effects of rhGH were assessed separately by estrogen status. Circulating insulin-like growth factor-I (IGF-I) levels were similar at baseline (rhGH, 133 +/- 40.4 micrograms/L; placebo, 128 +/- 13). rhGH increased IGF-I and IGF-I-binding protein-3 (IGFBP-3) in all subjects [6 month IGF-I in plus estrogen women, 230 +/- 25.4 micrograms/L; in those not receiving estrogen (minus estrogen), 308 +/- 21.3]. No changes in IGF-I or IGFBP-3 occurred with placebo (IGF-I, 144 +/- 21.3 micrograms/L). Skinfold thickness measurements showed an 11% decrease in fat mass (P < 0.005) and a 9% decrease in percent fat after 6 months of rhGH treatment. No significant difference in nitrogen balance was seen in either group at 6 months, but rhGH increased creatinine clearance by 9.2% (P < 0.05). rhGH dramatically increased markers of bone turnover, with more pronounced effects in minus estrogen women. Hydroxyproline excretion increased by 20% and 80%, and pyridinoline excretion increased by 44% and 75% in plus and minus estrogen subgroups, respectively. Osteocalcin concentrations increased by more than 60% in minus estrogen women (P < 0.05), but did not change in the plus estrogen group. No changes were observed in circulating type I procollagen extension peptide in either group, and no change in any turnover marker was seen in the placebo group. rhGH did not alter blood pressure or circulating L-T4 levels, but a transient increase in serum T3 was observed in the minus estrogen group at 3 months. rhGH decreased low density lipoprotein cholesterol in the minus estrogen group, but otherwise no significant changes in circulating lipoproteins or fibrinogen were observed. Eight women assigned to rhGH and 14 placebo-treated women remained on blinded treatment through 12 months.(ABSTRACT TRUNCATED AT 400 WORDS)

  View details for Web of Science ID A1994PB50500026

  View details for PubMedID 7519191

• COMPARISON OF THE METABOLIC EFFECTS OF RECOMBINANT HUMAN INSULIN-LIKE GROWTH-FACTOR-I AND INSULIN - DOSE-RESPONSE RELATIONSHIPS IN HEALTHY-YOUNG AND MIDDLE-AGED ADULTS JOURNAL OF CLINICAL INVESTIGATION BOULWARE, S. D., Tamborlane, W. V., Rennert, N. J., Gesundheit, N., Sherwin, R. S. 1994; 93 (3): 1131-1139

  Abstract

  The actions of recombinant human insulin-like growth factor-I (rhIGF-I) and insulin were compared in 21 healthy young (24 +/- 1 yr) and 14 healthy middle-aged (48 +/- 2 yr) subjects during 3-h paired euglycemic clamp studies using one of three doses (rhIGF-I 0.2, 0.4, and 0.8 micrograms/kg.min and insulin 0.2, 0.4, and 0.8 mU/kg.min, doses chosen to produce equivalent increases in glucose uptake). In younger subjects, rhIGF-I infusions suppressed insulin by 19-33%, C-peptide by 47-59% and glucagon by 33-47% (all, P < 0.02). The suppression of C-peptide was less pronounced with insulin than with rhIGF-I (P < 0.007). The metabolic responses to rhIGF-I and insulin were remarkably similar: not only did both hormones increase glucose uptake and oxidation in a nearly identical fashion, but they also produced similar suppression of glucose production, free fatty acid levels, and fat oxidation rates. In contrast, rhIGF-I had a more pronounced amino acid-lowering effect than did insulin (P < 0.004). In middle-aged subjects, basal IGF-I levels were 44% lower (P < 0.0001) whereas basal insulin and C-peptide were 20-25% higher than in younger subjects. Age did not alter the response to rhIGF-I. However, insulin-induced stimulation of glucose uptake was blunted in older subjects (P = 0.05). Our data suggest that absolute IGF-I and relative insulin deficiency contribute to adverse metabolic changes seen in middle age.

  View details for Web of Science ID A1994NB19500032

  View details for PubMedID 8132753

• A LONGITUDINAL ASSESSMENT OF HORMONAL AND PHYSICAL ALTERATIONS DURING NORMAL PUBERTY IN BOYS .1. SERUM GROWTH HORMONE-BINDING PROTEIN JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Martha, P. M., Rogol, A. D., Carlsson, L. M., Gesundheit, N., Blizzard, R. M. 1993; 77 (2): 452-457

  Abstract

  Previous studies have provided compelling evidence that GH secretion increases transiently during midpuberty in normally growing children. Although it is likely that the increase in GH production serves a primary role in generating the pubertal growth spurt, such a conclusion necessarily assumes that other essential "down-stream" components of the GH axis responsible for mediating the effects of GH remain unchanged. To investigate this concept, we assessed longitudinally another important component of the endogenous GH axis, the serum GH-binding protein (GHBP)/receptor system, in a cohort of 11 normal boys as they matured through normal puberty. At 4-month intervals over 4.0-5.1 yr, 24-h serum GH concentration profiles and serum GHBP activity were evaluated. Serum GHBP levels varied over a more than 12-fold range (40-504 pmol/L) among all subjects. However, the values for individual subjects consistently varied within more narrow limits. The coefficient of variation for values from all subjects was 51% compared to the mean intrasubject coefficient of variation of only 30% (P < 0.05). Although the highest GHBP level (all subjects) was 12.6-fold greater than the lowest, the mean intrasubject range was only 3.1 +/- 0.5-fold (P < 0.05). The overall mean serum GHBP level correlated directly with the overall mean body mass index (r = 0.69; P = 0.018), but correlated inversely with the mean 24-h GH concentration (r = -0.61; P < 0.05). There was no significant increase in the GHBP level during puberty. However, because mean 24-h GH concentrations did increase during midpuberty, the data suggest that an increase in the relative amounts of free vs. bound GH develops during the period of the pubertal growth spurt. These data indicate that serum GHBP levels are regulated in individual children within much more narrow limits than those present in the larger population and do not undergo the dramatic changes during puberty typical of GH secretion and linear growth velocity. As a consequence, alterations may develop in the relative amounts of free vs. bound GH present in serum during the midpubertal years compared to those present during either the prepubertal or postpubertal periods. The majority of the known age-related increase in serum GHBP levels probably occurs before the period of active pubertal development. These findings strengthen further the concept that the midpubertal changes in GH secretion serve a primary role in generating the growth spurt.(ABSTRACT TRUNCATED AT 400 WORDS)

  View details for Web of Science ID A1993LR71900031

  View details for PubMedID 8345051

• LIGAND-MEDIATED IMMUNOFUNCTIONAL ASSAY FOR QUANTITATION OF GROWTH HORMONE-BINDING PROTEIN IN HUMAN BLOOD JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Carlsson, L. M., Rowland, A. M., Clark, R. G., Gesundheit, N., Wong, W. L. 1991; 73 (6): 1216-1223

  Abstract

  Human serum contains a high affinity GH-binding protein (GHBP) whose amino-terminal sequence is identical to the extracellular domain of the GH receptor. Current methods that measure GHBP are laborious, require size or charcoal separation of the GH/GHBP complex, and may be influenced by ambient GH concentrations. We have developed a novel assay method that allows quantitation of the total amount of functional GHBP in serum or plasma. The assay can also be used to measure the concentration of the circulating GH/GHBP complex. An anti-GHBP monoclonal antibody, which recognizes both free GHBP and GH-bound GHBP, is used to capture the GHBP on a microtiter plate. Recombinant human GH is added to saturate all binding sites, and an anti-GH antibody conjugated with horseradish peroxidase is used to detect the amount of GH (endogenous and exogenous) bound to the GHBP. The same procedure, but without incubation with GH, allows measurement of the endogenous GH/GHBP complex. The assay is sensitive (detection range, 31-2000 pmol/L), with average inter- and intraassay precisions of 11.3% and 7.3%, respectively. Measurements in random blood samples from 16 healthy adults showed that all subjects had clearly detectable GHBP concentrations (range, 65.8-305.6 pmol/L). In contrast, GHBP levels were undetectable in samples from 2 patients with Laron-type dwarfism. We believe that this ligand-mediated immunofunctional assay, which combines the simplicity and specificity of an enzyme-linked immunosorbent assay with the ability to detect only biochemically active binding protein, will be useful for studies of the role of the GHBP in health and disease.

  View details for Web of Science ID A1991GW87900011

  View details for PubMedID 1955503

• CHANGES IN THE SIALYLATION AND SULFATION OF SECRETED THYROTROPIN IN CONGENITAL HYPOTHYROIDISM PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA GYVES, P. W., Gesundheit, N., Thotakura, N. R., Stannard, B. S., DeCherney, G. S., Weintraub, B. D. 1990; 87 (10): 3792-3796

  Abstract

  We have examined the oligosaccharide structure of secreted thyrotropin (TSH) in perinatal and mature rats with congenital primary hypothyroidism. Rat pituitaries from euthyroid control animals and those rendered hypothyroid by methimazole treatment were incubated with [3H]glucosamine in vitro. Secreted TSH was purified, and oligosaccharides were enzymatically released and characterized by anion-exchange HPLC. In perinatal hypothyroid animals compared with control animals, oligosaccharides from TSH alpha and beta subunits contained more species with three or more negative charges. Moreover, perinatal hypothyroid animals demonstrated a dramatic increase in the ratio of sialylated to sulfated species within oligosaccharides of the same negative charge (2.9- to 7.4-fold increase for TSH-alpha; 15.1- to 25.5-fold increase for TSH-beta). In mature hypothyroid 9-week-old animals compared with control animals, changes were less pronounced, suggesting that endocrine regulation of oligosaccharide structure is dependent upon the maturational state of the animal. These changes were specific for TSH because glycosylation of free alpha subunit (synthesized by the thyrotroph and gonadotroph) and of total glycoproteins was minimally altered by hypothyroidism. Together, these data provide direct evidence and characterization of specific changes in the structure of a secreted pituitary glycoprotein hormone occurring as a result of in vivo endocrine alterations during early development. Moreover, they provide a potential structural basis to explain the delayed clearance of both TSH and the gonadotropins with end-organ deficiency, which may have important implications for the in vivo biological activities of these hormones. Specifically, such posttranslational changes may be an important adaptive response to prevent the consequences of endocrine deficiency during early development.

  View details for Web of Science ID A1990DD87300033

  View details for PubMedID 1692623

• PRETRANSLATIONAL AND POSTTRANSLATIONAL REGULATION OF TSH - RELATIONSHIP TO BIOACTIVITY INTERNATIONAL SYMP ON PHYSIOLOGICAL REGULATION AND BIOLOGICAL FUNCTION OF THYREOTROPIN Weintraub, B. D., Wondisford, F. E., FARR, E. A., Steinfelder, H. J., Radovick, S., Gesundheit, N., GYVES, P. W., Taylor, T., DeCherney, G. S. GEORG THIEME VERLAG KG. 1990: 9–11

  Abstract

  We are interested in the mechanisms by which endocrine and developmental factors regulate TSH synthesis at both pre-translational and post-translational levels. Thyroid hormone profoundly decreases transcription of the TSH beta gene, while TRH and agents modifying cyclic AMP increase transcription. To elucidate the molecular mechanisms underlying these effects, human embryonal kidney cells were transfected with constructs of the human TSH-beta gene fused to the chloramphenicol acetyl transferase gene. The first exon of human TSH-beta contains an element that increases basal expression and mediates T3-induced gene repression, probably through a direct interaction with c-erbA beta. In contrast, TRH and agents modifying cyclic AMP mediate increased transcription of TSH-beta through interacting with upstream regulatory elements. Thyroid hormone, TRH and developmental factors also regulate the branching pattern and relative sialylation of TSH carbohydrate chains, which may affect TSH action in vitro and in vivo.

  View details for Web of Science ID A1990EC34300003

  View details for PubMedID 2120122

• A BASE MUTATION OF THE C-ERBA-BETA THYROID-HORMONE RECEPTOR IN A KINDRED WITH GENERALIZED THYROID-HORMONE RESISTANCE - MOLECULAR HETEROGENEITY IN 2 OTHER KINDREDS JOURNAL OF CLINICAL INVESTIGATION Usala, S. J., Tennyson, G. E., Bale, A. E., Lash, R. W., Gesundheit, N., Wondisford, F. E., Accili, D., Hauser, P., Weintraub, B. D. 1990; 85 (1): 93-100

  Abstract

  Generalized thyroid hormone resistance (GTHR) is a disorder of thyroid hormone action that we have previously shown to be tightly linked to one of the two thyroid hormone receptor genes, c-erbA beta, in a single kindred, A. We now show that in two other kindreds, B and D, with differing phenotypes, there is also linkage between c-erbA beta and GTHR. The combined maximum logarithm of the odds score for all three kindreds at a recombination fraction of 0 was 5.77. In vivo studies had shown a triiodothyronine (T3)-binding affinity abnormality in nuclear receptors of kindred A, and we therefore investigated the defect in c-erbA beta in this kindred by sequencing a major portion of the T3-binding domain in the 3'-region of fibroblast c-erbA beta cDNA and leukocyte c-erbA beta genomic DNA. A base substitution, cytosine to adenine, was found at cDNA position 1643 which altered the proline codon at position 448 to a histidine. By allelic-specific hybridization, this base substitution was found in only one allele of seven affected members, and not found in 10 unaffected members of kindred A, as expected for a dominant disease. Also, this altered base was not found in kindreds B or D, or in 92 random c-erbA beta alleles. These results and the fact that the mutation is predicted to alter the secondary structure of the crucial T3-binding domain of the c-erbA beta receptor suggest this mutation is an excellent candidate for the genetic cause of GTHR in kindred A. Different mutations in the c-erbA beta gene are likely responsible for the variant phenotypes of thyroid hormone resistance in kindreds B and D.

  View details for Web of Science ID A1990CH52200014

  View details for PubMedID 2153155

• DIFFERENTIAL EFFECT OF INHIBITORS OF OLIGOSACCHARIDE PROCESSING ON THE SECRETION OF THYROTROPIN FROM DISPERSED RODENT PITUITARY-CELLS BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Stannard, B. S., Gesundheit, N., Thotakura, N. R., GYVES, P. W., Ronin, C., Weintraub, B. D. 1989; 165 (2): 788-794

  Abstract

  We examined the effect of various inhibitors of oligosaccharide processing on the content and secretion of newly synthesized thyroid-stimulating hormone (TSH) from dispersed hypothyroid rodent pituitary cells. 1-deoxynojirimycin and N-methyl-1-deoxynojirimycin, both inhibitors of glucosidases I and II, decreased intracellular TSH (to 60-76% of control) and secreted TSH (to 60-63% of control) after a 1-hour incubation (pulse) with [35S]methionine and an 8-hour incubation (chase) in isotope-free media. In contrast, deoxymannojirimycin and swainsonine, inhibitors of mannosidase I and II, respectively, increased both intracellular TSH (to 267-309% of control) and secreted TSH (to 192% of control) at 8 hours. TSH oligosaccharides synthesized in the presence of these glucosidase and mannosidase inhibitors were largely sensitive to endo-beta-N-acetylglucosaminidase H (endo H), confirming inhibition of processing. Despite differences in oligosaccharide structure, the in vitro bioactivities of these secreted TSH isoforms were nearly identical. These data confirm and extend previous work performed with 1-deoxynojirimycin suggesting that glucosylated high mannose forms of TSH are more susceptible to intracellular degradation. The novel finding that deoxymannojirimycin and swainsonine increase secreted and total TSH above control levels suggests that non-glucosylated high mannose forms as well as hybrid-type oligosaccharides may facilitate secretion and direct TSH away from a natural degradation pathway.

  View details for Web of Science ID A1989CD84400035

  View details for PubMedID 2532008

• PREOPERATIVE LATERALIZATION OF PITUITARY MICROADENOMAS BY PETROSAL SINUS SAMPLING - UTILITY IN 2 PATIENTS WITH NON-ACTH SECRETING TUMORS AMERICAN JOURNAL OF MEDICINE Frank, S. J., Gesundheit, N., DOPPMAN, J. L., MILLER, D. L., Merriam, G. R., Oldfield, E. H., Weintraub, B. D. 1989; 87 (6): 679-682

  View details for Web of Science ID A1989CC93400015

  View details for PubMedID 2556029

• THYROTROPIN-SECRETING PITUITARY-ADENOMAS - CLINICAL AND BIOCHEMICAL HETEROGENEITY - CASE-REPORTS AND FOLLOW-UP OF 9 PATIENTS ANNALS OF INTERNAL MEDICINE Gesundheit, N., PETRICK, P. A., Nissim, M., DAHLBERG, P. A., DOPPMAN, J. L., Emerson, C. H., Braverman, L. E., Oldfield, E. H., Weintraub, B. D. 1989; 111 (10): 827-835

  Abstract

  To evaluate the clinical and biochemical features of patients with TSH (thyroid-stimulating hormone, thyrotropin)-secreting pituitary tumors; to measure the biologic activity in vitro of circulating TSH from selected patients before and after pituitary surgery.Case series.Patients in an endocrinology unit.Nine patients with TSH-secreting pituitary tumors.All patients had hyperthyroidism, elevated free thyroxine and triiodothyronine levels, and detected levels of TSH. The free alpha subunit, a tumor marker for neoplasms of gonadotropic or thyrotropic cell origin, was elevated in all nine patients. Seven of the nine patients had been treated with thionamides, radioactive iodine, or thyroidectomy for presumed primary hyperthyroidism. The delay from the initial treatment of hyperthyroidism to the correct diagnosis of a pituitary neoplasm was 6.2 +/- 4.8 (mean +/- SD) years. Two of the seven patients with macroadenomas died in the perioperative period (one at NIH, one at a referring hospital). Of the remaining five patients with macroadenomas, four have residual tumor and inappropriate TSH secretion, despite surgery and radiation therapy, at follow-up from 3.5 to 6 years. In contrast, the two patients with microadenomas are clinically cured 2.5 and 4 years after transsphenoidal adenomectomy. The biologic to immunologic (B/I) ratio of serum TSH, determined preoperatively in five patients with TSH-secreting tumors, was elevated compared with euthyroid subjects. In three patients the B/I ratio of serum TSH was also measured after pituitary surgery; in two the elevated B/I ratio returned to normal after successful pituitary adenomectomy, while in the third this ratio remained elevated after incomplete adenoma resection.With the routine availability of ultrasensitive TSH assays and their increasing use to confirm thyrotoxicosis from all causes, we expect that TSH-secreting pituitary tumors will be diagnosed earlier, before inappropriate antithyroid therapy, permitting an improved outcome.

  View details for Web of Science ID A1989CA10100010

  View details for PubMedID 2479309

• PRE-TRANSLATIONAL AND POSTTRANSLATIONAL REGULATION OF TSH SYNTHESIS IN NORMAL AND NEOPLASTIC THYROTROPHS HORMONE RESEARCH Weintraub, B. D., Wondisford, F. E., FARR, E. A., Steinfelder, H. J., Radovick, S., Gesundheit, N., GYVES, P. W., Taylor, T., DeCherney, G. S. 1989; 32 (1-3): 22-24

  Abstract

  We are interested in the mechanisms by which endocrine and developmental factors regulate TSH synthesis at both pre-translational and post-translational levels. Thyroid hormone profoundly decreases transcription of the TSH-beta gene, while TRH and agents modifying cyclic AMP increase transcription. To elucidate the molecular mechanisms underlying these effects, human embryonal kidney cells were transfected with constructs of the human TSH-beta gene fused to the chloramphenicol acetyltransferase gene. The first exon of human TSH-beta, contains an element that increases basal expression and mediates T3-induced gene repression, probably through a direct interaction with c-erbA beta. This transcriptional repression by T3 appears aberrant in thyrotropic tumors. In contrast, TRH and agents modifying cyclic AMP mediate increased transcription of TSH-beta through interacting with upstream regulatory elements. Thyroid hormone, TRH and developmental factors also regulate the branching pattern and relative sialylation of TSH carbohydrate chains, which may affect TSH action in vitro and in vivo. Certain thyrotropic tumors produce TSH with more complex carbohydrate branching patterns, which may increase its biologic activity.

  View details for Web of Science ID A1989CJ23300005

  View details for PubMedID 2693312

• CHARACTERIZATION AND CHARGE-DISTRIBUTION OF THE ASPARAGINE-LINKED OLIGOSACCHARIDES ON SECRETED MOUSE THYROTROPIN AND FREE ALPHA-SUBUNITS ENDOCRINOLOGY Gesundheit, N., GYVES, P. W., DeCherney, G. S., Stannard, B. S., Winston, R. L., Weintraub, B. D. 1989; 124 (6): 2967-2977

  Abstract

  Mouse hemipituitaries in vitro secrete TSH, composed of an alpha-beta heterodimer, as well as excess (free) alpha-subunits. By dual metabolic labeling with [35S]sulfate and [3H]mannose, we have characterized oligosaccharides from secreted TSH alpha, TSH beta, and free alpha-subunits released from the apoprotein by enzymatic deglycosylation. Oligosaccharides from each subunit displayed a distinct anion exchange HPLC profile due to a specific pattern of sialylation and sulfation. Six species were obtained from TSH alpha (with two glycosylation sites), including neutral oligosaccharides as well as those with one or two negative charges. For TSH beta (with one glycosylation site) at least eight oligosaccharide species were noted, representing nearly every permutation of sialylation and sulfation; approximately 30% contained three or more negative charges. Analysis of [3H]mannose-labeled oligosaccharides on Concanavalin-A-agarose showed 85% binding for those from TSH alpha, 70% for free alpha, and 50% for those from TSH beta. These data demonstrate that oligosaccharides from secreted TSH beta were more sialylated and sulfated, consistent with a more complex branching pattern, than those from TSH alpha. Oligosaccharides from free alpha-subunit were more sialylated than those from TSH alpha, and the net negative charge was intermediate between those of TSH alpha and TSH beta. Although great microheterogeneity is present even at the single glycosylation site on the beta-subunit of secreted TSH, a pattern of sialylation and sulfation could be discerned. If one assigns probabilities of sialylation [p(N)] and sulfation [p(S)] based on the observed distribution within monoacidic (charge -1) species, the proportion of diacidic (charge -2) oligosaccharides could be predicted for each subunit by [p(N)]2, 2[p(N)] [p(S)], [p(S)]2, corresponding to species containing two sialic acid, one sialic acid and one sulfate, and two sulfate residues, respectively. This suggests that the probability of sialylation or sulfation at a second site on these oligosaccharides is similar to that at the first and that anionic oligosaccharides in secreted TSH and free alpha are distributed binomially with regard to sialic acid and sulfate residues.

  View details for Web of Science ID A1989U851800042

  View details for PubMedID 2721453

• EFFECT OF TRH ON TSH GLYCOSYLATION AND BIOLOGICAL ACTION ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Weintraub, B. D., Gesundheit, N., Taylor, T., GYVES, P. W. 1989; 553: 205-213

  View details for Web of Science ID A1989AU05700017

  View details for PubMedID 2497672

• ALTERATIONS IN THE GLYCOSYLATION OF SECRETED THYROTROPIN DURING ONTOGENESIS - ANALYSIS OF SIALYLATED AND SULFATED OLIGOSACCHARIDES JOURNAL OF BIOLOGICAL CHEMISTRY GYVES, P. W., Gesundheit, N., Stannard, B. S., DeCherney, G. S., Weintraub, B. D. 1989; 264 (11): 6104-6110

  Abstract

  We have examined the carbohydrate structure of thyrotropin (TSH) secreted in vitro by pituitaries from prenatal, perinatal, and mature rats using concanavalin A (ConA)-agarose chromatography and anion-exchange high performance liquid chromatography (HPLC). [3H]Glucosamine-labeled TSH was immuno-precipitated and treated with either Pronase to generate glycopeptides or a mixture of endo-beta-N-acetyl-glucosaminidase F and peptide:N-glycosidase F to release oligosaccharides. The percentage of secreted TSH glycopeptides not bound to ConA was greater in mature animals (47 +/- 3%) than in either prenatal (29 +/- 3%) or perinatal animals (29 +/- 6%), suggesting more multiantennary oligosaccharides in the older animals. These structural changes were characterized further by performing anion-exchange HPLC on released oligosaccharides. Secreted TSH from prenatal rats predominantly contained oligosaccharides with 1 and 2 negative charges, while TSH from mature rats contained these structures as well as 15% with 3 negative charges. In addition, the ratio of sialylated to sulfated oligosaccharides was greater in mature compared to prenatal animals for species with 1 negative charge (1.9-fold) as well as for species with 2 negative charges (4.3-fold). We also correlated the structural alterations noted by ConA analysis with anion-exchange HPLC. Oligosaccharides that bound to ConA and were eluted with alpha-methylglucoside, when analyzed by anion-exchange HPLC, consisted of species with 1 and 2 negative charges, whereas oligosaccharides that were unbound to ConA were predominantly species with three negative charges. Together, these data suggest that with maturation of the hypothalamic-pituitary-thyroid axis secreted TSH contains more negatively charged multiantennary oligosaccharides with increased sialylation and decreased sulfation.

  View details for Web of Science ID A1989U112700020

  View details for PubMedID 2703481

• ALTERATIONS IN THE SIALYLATION AND SULFATION OF SECRETED MOUSE THYROTROPIN IN PRIMARY HYPOTHYROIDISM BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS DeCherney, G. S., Gesundheit, N., GYVES, P. W., Showalter, C. R., Weintraub, B. D. 1989; 159 (2): 755-762

  Abstract

  We investigated the effect of in vivo hypothyroidism on the sialylation and sulfation of thyroid-stimulating hormone (TSH) secreted by mouse pituitary explants. Oligosaccharides from secreted thyroid-stimulating hormone from hypothyroid animals contained greater sialic acid relative to sulfate in both alpha and beta subunits. Aging per se had little effect on thyroid-stimulating hormone sialylation or sulfation. Variable sialylation and sulfation demonstrates a mechanism for charge microheterogeneity of thyroid-stimulating hormone, and the increasing sialylation observed with hypothyroidism may functionally mediate the prolonged metabolic clearance that has been noted previously.

  View details for Web of Science ID A1989T659600059

  View details for PubMedID 2930540

• TIGHT LINKAGE BETWEEN THE SYNDROME OF GENERALIZED THYROID-HORMONE RESISTANCE AND THE HUMAN C-ERBA-BETA GENE MOLECULAR ENDOCRINOLOGY Usala, S. J., Bale, A. E., Gesundheit, N., Weinberger, C., Lash, R. W., Wondisford, F. E., MCBRIDE, O. W., Weintraub, B. D. 1988; 2 (12): 1217-1220

  Abstract

  Multiple cDNAs belonging to the c-erbA gene family encode proteins that bind T3 with high affinity. However, the biological functions of these multiple thyroid hormone receptors have not yet been clarified. Generalized thyroid hormone resistance (GTHR) refers to a human syndrome characterized by tissue refractoriness to the action of thyroid hormones; several studies have suggested quantitative or qualitative defects in T3 binding to nuclear receptors in certain kindreds. To investigate the biological functions of the c-erbA genes, c-erbA alpha and c-erbA beta, we tested the hypothesis that an abnormal c-erbA gene product is present in GTHR by examining these genes in members of one kindred. Restriction enzyme analysis failed to identify an abnormal pattern in affected individuals suggesting no rearrangements or large deletions. However, we demonstrated that the gene conferring the GTHR phenotype is tightly linked to the c-erbA beta locus on chromosome 3. This linkage strongly suggests that the c-erbA beta gene is important in man as a thyroid hormone receptor and identifies a putative c-erbA beta mutant phenotype with central nervous system, pituitary, liver, metabolic, and growth abnormalities.

  View details for Web of Science ID A1988R146400010

  View details for PubMedID 2905763

• DIFFERENTIAL CARBOHYDRATE PROCESSING AND SECRETION OF THYROTROPIN AND FREE ALPHA-SUBUNIT - EFFECTS OF 1-DEOXYNOJIRIMYCIN JOURNAL OF BIOLOGICAL CHEMISTRY Stannard, B. S., Gesundheit, N., Ronin, C., Burnside, J., Weintraub, B. D. 1988; 263 (17): 8309-8317

  Abstract

  In pulse-chase experiments we compared the kinetics of early carbohydrate processing and subsequent secretion of thyroid-stimulating hormone (TSH) and free alpha subunit under control conditions and after treatment with 1-deoxynojirimycin, an inhibitor of glucosidases I and II. Under control conditions TSH achieved resistance to endo-beta-N-acetylglucosaminidase H (endo H) more rapidly than free alpha (t1/2 0.3 h versus 0.9 h); however, free alpha was secreted more rapidly than TSH (t1/2 2.2 h versus 3.4 h). With 1-deoxynojirimycin, oligosaccharides co-migrating with G3Man9GlcNAc and G2Man9GlcNAc were demonstrated on TSH for the first time, suggesting that previous pulse-chase studies did not disclose these intermediates due to rapid removal of glucose residues from the common G3Man9GlcNAc2 precursor. 1-Deoxynojirimycin delayed the rate of attainment of endo H resistance for both TSH and free alpha, but there was no effect on subunit combination. With 5 mM 1-deoxynojirimycin the amount of secreted free alpha was reduced to 65% of control; secreted TSH was reduced markedly to 17% of control without intracellular accumulation, suggesting increased intracellular degradation. There was no significant toxicity from these doses of 1-deoxynojirimycin on the production or secretion of the two major nonglycosylated pituitary proteins, growth hormone and prolactin, or on at least 10 other secretory proteins. Basal differences in the relative rates of TSH and free alpha processing and secretion as well as differential sensitivity to 1-deoxynojirimycin suggest separate secretory pathways for these two closely related proteins.

  View details for Web of Science ID A1988N776600062

  View details for PubMedID 2453512

• HYPOTHALAMIC HYPOTHYROIDISM CAUSED BY LESIONS IN RAT PARAVENTRICULAR NUCLEI ALTERS THE CARBOHYDRATE STRUCTURE OF SECRETED THYROTROPIN ENDOCRINOLOGY Taylor, T., Gesundheit, N., GYVES, P. W., Jacobowitz, D. M., Weintraub, B. D. 1988; 122 (1): 283-290

  Abstract

  The effects of hypothalamic hypothyroidism vs. primary hypothyroidism on TSH carbohydrate structure were studied in the rat. Adult male rats with bilateral paraventricular nuclear lesions (n = 10), sham lesions (n = 10), and thyroidectomies (n = 6) were studied 2 weeks postoperatively and compared to normal animals without surgery (n = 6). Pituitaries were incubated in medium containing [3H]glucosamine for 24 h. TSH was immunoprecipitated from medium and pituitary sonicates using anti-TSH beta serum, digested with pronase to obtain TSH glycopeptides, desalted, then analyzed by Concanavalin-A (Con-A) chromatography. Compared to sham controls, hypothalamus-lesioned animals contained a greater proportion of secreted TSH glycopeptides that bound weakly to Con-A, indicating a shift from bisecting and/or multiantennary structures in control animals to biantennary and/or truncated hybrid forms in hypothalamus-lesioned animals. In contrast, thyroidectomized animals, compared to normal and lesioned animals, contained a greater proportion of secreted TSH glycopeptides that did not bind to Con-A, indicating a shift from biantennary and/or truncated hybrid forms to bisecting and/or multiantennary forms. The characteristics of the carbohydrate chains on secreted TSH differed markedly in hypothalamic vs. primary hypothyroidism despite equally low thyroid hormone levels in vivo. Thus, in addition to regulating TSH secretion, hypothalamic hormones alter TSH carbohydrate structure, which may affect its bioactivity and MCR.

  View details for Web of Science ID A1988L548900038

  View details for PubMedID 3335209

• ENDOCRINE AND DEVELOPMENTAL REGULATION OF THYROTROPIN (TSH) CARBOHYDRATE SYNTHESIS INTERNATIONAL THYROID SYMP Weintraub, B. D., Gesundheit, N., GYVES, P. W., Taylor, T., DeCherney, G. S. ELSEVIER SCIENCE PUBL B V. 1988: 13–18

  View details for Web of Science ID A1988BR09C00003

• THYROID-HORMONE RESISTANCE SYNDROME 8TH INTERNATIONAL CONGRESS OF ENDOCRINOLOGY Weintraub, B. D., Usala, S. J., Bale, A. E., Gesundheit, N., Weinberger, C., Lash, R. W., Wondisford, F. E., MCBRIDE, O. W., MENEZESFERREIRA, M. M. ELSEVIER SCIENCE PUBL B V. 1988: 797–802

  View details for Web of Science ID A1988BR45V00110

• RESPONSE OF THYROTROPIN-SECRETING PITUITARY-ADENOMAS TO A LONG-ACTING SOMATOSTATIN ANALOG NEW ENGLAND JOURNAL OF MEDICINE Comi, R. J., Gesundheit, N., Murray, L., GORDEN, P., Weintraub, B. D. 1987; 317 (1): 12-17

  Abstract

  Thyrotropin-secreting pituitary adenomas are aggressive, invasive tumors that respond poorly to available surgical and medical treatments. Inappropriate release of thyrotropin by these tumors can result in hyperthyroidism. We treated five patients who had thyrotropin-secreting pituitary adenomas with the long-acting somatostatin analogue SMS 201-995, which was administered by subcutaneous injection in doses of 50 to 100 micrograms every 8 to 12 hours. Serum levels of thyrotropin were dramatically reduced by treatment in four of the five patients, and levels of another tumor marker, the alpha-subunit of thyrotropin, were reduced in all five. In two patients with hyperthyroidism due to production of excess thyrotropin by the tumor, treatment with the somatostatin analogue resulted in a sustained euthyroid state. One patient who was treated for more than 16 months had a persistent reduction in serum levels of thyrotropin and iodothyronines. We conclude that SMS 201-995 is an effective means of controlling hypersecretion of thyrotropin and the associated hyperthyroidism due to thyrotropin-secreting pituitary tumors.

  View details for Web of Science ID A1987H949200003

  View details for PubMedID 2884564

• CHANGES IN THYROTROPIN (TSH) CARBOHYDRATE STRUCTURE AND RESPONSE TO TSH-RELEASING HORMONE DURING POSTNATAL ONTOGENY - ANALYSIS BY CONCANAVALIN-A CHROMATOGRAPHY ENDOCRINOLOGY GYVES, P. W., Gesundheit, N., Taylor, T., Butler, J. B., Weintraub, B. D. 1987; 121 (1): 133-140

  Abstract

  We have studied the carbohydrate structure of TSH as well as its response to TRH during postnatal ontogenesis in the rat using Concanavalin-A (Con A)-Sepharose chromatography of labeled glycopeptides. Pituitaries from neonatal (5-day-old) rats with low levels of endogenous TRH and mature (56-day-old) rats were incubated for 24 h in medium containing [3H] glucosamine in the presence or absence of 10(-7) M TRH. Both intracellular and secreted TSH were immunoprecipitated, treated with Pronase to generate glycopeptides, and analyzed by chromatography on Con A-Sepharose. The total amount of [3H]glucosamine-labeled TSH was greater per pituitary in mature rats compared to that in neonatal rats (P less than 0.05), while there was no significant difference between the groups in the concentration of total labeled TSH per microgram pituitary DNA. RIA determination of total TSH was greater in the older animals than in the younger animals when normalized both per pituitary and per microgram pituitary DNA (P less than 0.01 and P less than 0.02, respectively). However, for both labeled and unlabeled TSH the percentage of TSH secreted was greater in mature rats than in neonatal rats (P less than 0.02 and P less than 0.01, respectively), indicating a less active hormonal secretory process in the younger animals. In control animals, the proportion of labeled TSH glycopeptides that did not bind to Con A was greater in 56- than in 5-day-old animals for both intrapituitary and secreted forms (P less than 0.01), reflecting a shift toward more multiantennary and/or bisected biantennary complex carbohydrate structures in the older animals. In response to TRH in vitro, the total amount of labeled secreted TSH was increased more than 2-fold in both 5-day-old (P less than 0.05) and 56-day-old (P = NS) animals. However, there was a marked difference in the glycopeptide distribution between these two ages. Five-day-old animals showed a small but not significant decrease in the percentage of secreted TSH glycopeptides that bound to Con A-Sepharose, while 56-day-old animals had a specific increase in the glycopeptide fractions that bound and corresponded to biantennary complex and/or unusual hybrid forms (P less than 0.01). These studies in the rat suggest differences in TSH carbohydrate structure and secretion as well as a differential response to TRH during postnatal ontogenesis.

  View details for Web of Science ID A1987H881200020

  View details for PubMedID 3109878

• EFFECT OF THYROTROPIN-RELEASING-HORMONE ON THE CARBOHYDRATE STRUCTURE OF SECRETED MOUSE THYROTROPIN - ANALYSIS BY LECTIN AFFINITY-CHROMATOGRAPHY JOURNAL OF BIOLOGICAL CHEMISTRY Gesundheit, N., Fink, D. L., SILVERMAN, L. A., Weintraub, B. D. 1987; 262 (11): 5197-5203

  Abstract

  Thyrotropin (TSH) is a glycoprotein hormone whose secretion from the anterior pituitary is regulated, in part, by the hypothalamic tripeptide thyrotropin-releasing hormone (TRH). We have used serial lectin affinity analysis to explore whether TRH, in addition to promoting TSH secretion, alters the carbohydrate structure of secreted TSH. Hypothyroid mouse hemipituitaries were incubated in medium containing [3H] mannose, [3H]glucosamine, or [3H]fucose either with or without 10(-7) M TRH. TSH was immunoprecipitated, proteolytically digested into glycopeptides, and chromatographed on serial lectin-Sepharose columns. Under basal conditions, 37% of secreted [3H]mannose-labeled TSH glycopeptides failed to bind to concanavalin A (ConA)-Sepharose, 55% bound and eluted with 10 mM alpha-methylglucoside, and 8% bound and eluted with 500 mM alpha-methylmannoside. Approximately 35% of glycopeptides not binding to ConA-Sepharose were bound by pea lectin-Sepharose, suggesting the presence of certain core fucosylated triantennary complex oligosaccharides. TRH caused a 2-fold increase in secretion of [3H]mannose-labeled TSH glycopeptides due almost exclusively to a specific increase in structures that bound to ConA-Sepharose and eluted with 10mM alpha-methylglucoside, corresponding to biantennary complex or unusual hybrid species. There was no change in the distribution of intrapituitary TSH glycopeptides with TRH. Acid hydrolysis of secreted proteins showed little metabolism of the tritiated sugar precursors, except for a 20% conversion of [3H]mannose to [3H]fucose. Moreover, ConA-Sepharose chromatography of secreted [3H]glucosamine- and [3H]fucose-labeled TSH glycopeptides showed similar increases in ConA-Sepharose binding with TRH as noted with [3H]mannose labeling. Subsequent lectin analysis of secreted [3H] mannose-labeled TSH glycopeptides on erythroagglutinating phytohemagglutinin-Sepharose and leukoagglutinating phytohemagglutinin-Sepharose disclosed no significant differences in TRH-treated versus control samples. These data suggest that secreted mouse TSH has greater carbohydrate heterogeneity than has been recognized previously. In addition, TRH in vitro promotes the secretion of specific TSH molecules apparently enriched in biantennary complex or unusual hybrid oligosaccharides.

  View details for Web of Science ID A1987G882300042

  View details for PubMedID 3104329

• DIFFERENTIAL SULFATION AND SIALYLATION OF SECRETED MOUSE THYROTROPIN (TSH) SUBUNITS - REGULATION BY TSH-RELEASING HORMONE ENDOCRINOLOGY Gesundheit, N., Magner, J. A., Chen, T., Weintraub, B. D. 1986; 119 (2): 455-463

  Abstract

  To determine whether sulfate and/or sialic acid are present on secreted mouse TSH, thyrotropic tumor minces and hypothyroid pituitaries were incubated with [3H]methionine and [35S]sulfate, or [35S]methionine and [3H]N-acetylmannosamine. The metabolically labeled TSH and free alpha-subunits were then analyzed by gel electrophoresis. [3H]N-Acetylmannosamine was a specific precursor (greater than 80%) for the sialic acid [3H]N-acetylneuraminic acid, as established by HPLC characterization of tritium label released by acid hydrolysis. Each of the three secreted subunits (TSH alpha, TSH beta, and free alpha) incorporated both sulfate and sialic acid. The incorporation of these labels was confirmed by the release of [35S]sulfate by endoglycosidase F and of [3H]N-acetylneuraminic acid by neuraminidase. Differential labeling of newly synthesized secreted TSH subunits was observed. In secreted TSH dimer, TSH beta incorporated 1.3 times more [35S]sulfate (P less than 0.05) and 2.5 times more [3H] N-acetylmannosamine (P less than 0.02) per carbohydrate chain than did TSH alpha. Secreted free alpha-subunit incorporated more [3H]N-acetylmannosamine, but less [35S]sulfate, then did secreted TSH alpha. To investigate the effect of TRH on TSH sulfation and sialylation, thyrotropic tumor minces and hypothyroid pituitaries were incubated with [35S]sulfate or [3H]N-acetylmannosamine, with or without 10(-7) M TRH; labeling was then normalized in each case to incorporation of [3H]mannose, a marker of the inner core sugars. TSH secreted in the presence of TRH had a lower sulfate to mannose ratio [28 +/- (+/- SE) 4% of control; P less than 0.05] and a lower sialic acid to mannose ratio (63 +/- 8% of control; P less than 0.05). TSH alpha and TSH beta were affected equally. No change was seen in the labeling of non-TSH secretory proteins. Differential glycoprotein sulfation and sialylation may, in part, explain the previously observed variability in isoelectric point, bioactivity, and MCR of TSH in different physiological states and may represent a point of regulation by TRH.

  View details for Web of Science ID A1986D342700001

  View details for PubMedID 2426082

• EFFECTS OF INVIVO BOLUS VERSUS CONTINUOUS TRH ADMINISTRATION ON TSH SECRETION, BIOSYNTHESIS, AND GLYCOSYLATION IN NORMAL AND HYPOTHYROID RATS MOLECULAR AND CELLULAR ENDOCRINOLOGY Taylor, T., Gesundheit, N., Weintraub, B. D. 1986; 46 (3): 253-261

  Abstract

  The effects of in vivo TRH administered either as bolus or continuous doses on TSH secretion, synthesis, and glycosylation were studied in normal and hypothyroid rats. Nine-week-old normal or 3-week postthyroidectomy rats were administered bolus doses of saline or TRH (0.5 mg/kg) twice daily or continuous saline or TRH (1 mg/kg/day) via an osmotic pump. After 5 days, pituitaries were removed and incubated with [35S]methionine (MET) and [3H]glucosamine (GLCN), with or without 10(-8) M TRH, for 6 and 24 h. Samples were precipitated with anti-TSH beta sera and then analyzed by gel electrophoresis. In normal rats, plasma TSH, T4 and T3 increased with continuous in vivo TRH but not with bolus TRH; in hypothyroid rats, plasma TSH, T4 and T3 were not altered by continuous or bolus doses of TRH. Additionally, in normal rats, continuous in vivo TRH increased incorporation of MET in secreted TSH (477 vs. 212 X 10(3) dpm/mg DNA; P less than 0.05) and intrapituitary TSH (5035 vs. 2124 X 10(3) dpm/mg DNA; P less than 0.05), and GLCN in secreted TSH (148 vs. 50 dpm/mg DNA; P less than 0.05) and intrapituitary TSH (2344 vs. 744 X 10(3) dpm/mg DNA; P less than 0.05). In contrast, in hypothyroid animals, continuous in vivo TRH did not alter MET or GLCN incorporation in TSH. Bolus TRH did not alter secreted or intrapituitary MET or GLCN incorporation into TSH in the normal rat. However, bolus TRH in the intrapituitary MET or GLCN incorporation into TSH in the normal rat.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1986D468000007

  View details for PubMedID 3091425

• ENZYMATIC DEGLYCOSYLATION OF THYROID-STIMULATING HORMONE WITH PEPTIDE N-GLYCOSIDASE-F AND "ENDO-BETA-N-ACETYLGLUCOSAMINIDASE-F BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Lee, K. O., Gesundheit, N., Chen, H. C., Weintraub, B. D. 1986; 138 (1): 230-237

  Abstract

  We investigated the ability of two enzymes, peptide N-glycosidase F (PNGase F) and endo-beta-N-acetylglucosaminidase F (Endo F), to deglycosylate microgram quantities of bovine TSH and its subunits under nondenaturing conditions. One oligosaccharide chain could be selectively removed from the alpha subunit by PNGase F, and all the oligosaccharide chains from both subunits could be removed by Endo F. These methods of enzymatic deglycosylation should permit study of the functional role of each N-linked carbohydrate chain of various glycoprotein hormones.

  View details for Web of Science ID A1986D241700033

  View details for PubMedID 3091014

• Mechanisms and regulation of TSH glycosylation. Advances in experimental medicine and biology Gesundheit, N., Weintraub, B. D. 1986; 205: 87-105

  Abstract

  Thyroid-stimulating hormone provides an interesting model to study the glycosylation and carbohydrate processing of a heterodimeric glycoprotein with a clear physiological function. The carbohydrate moiety on TSH is required for subunit combination, protection from intracellular proteolysis and aggregation, and for attainment of full biological activity. Recent work, summarized herein, has studied mechanisms and kinetics of TSH carbohydrate maturation and has contrasted processing rates and composition of free and combined subunits. Neuroendocrine factors, such as thyrotropin-releasing hormone, appear to modulate the carbohydrate structure of secreted TSH, which results in a change in the relative bioactivity of the circulating hormone. The biochemical mechanisms by which these carbohydrate alterations occur and how they affect hormone-receptor interaction are currently under investigation.

  View details for PubMedID 3788719

• Glycosylation and posttranslational processing of thyroid-stimulating hormone: clinical implications. Recent progress in hormone research Weintraub, B. D., Stannard, B. S., Magner, J. A., Ronin, C., Taylor, T., Joshi, L., CONSTANT, R. B., Menezes-Ferreira, M. M., PETRICK, P., Gesundheit, N. 1985; 41: 577-606

  View details for PubMedID 3931191

• INFECTED LIVER CYST IN A PATIENT WITH POLYCYSTIC KIDNEY-DISEASE WESTERN JOURNAL OF MEDICINE Gesundheit, N., Kent, D. L., Fawcett, H. D., EFFRON, M. K., MAFFLY, R. H. 1982; 136 (3): 246-249

  View details for Web of Science ID A1982NG84700018

  View details for PubMedID 7046254