York University Medical Center Research Articles

Antibiotic Resistance Genes Unexpectedly, Reversibly Subject to Silencing

Antibiotic resistance genes can be reversibly silenced without disrupting the genes themselves or their promoters, according to Virve I. Enne and Peter M. Bennett of the University of Bristol, United Kingdom, and their collaborators. The research, published in the September Antimicrobial Agents and Chemotherapy (50:3003–3010), has profound implications. “Once the mechanism is revealed, it might be possible to apply this phenomenon for therapeutic purposes in order to extend the usefulness of antibiotics,” says Philip M. Tierno, Jr. of New York University Medical Center in New York, N.Y.

Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

The role of members of the insulin-like superfamily in human thyroid carcinoma is primarily unknown. Here we demonstrate the presence of RLN2 relaxin and relaxin receptor LGR7 in human papillary, follicular, and undifferentiated anaplastic thyroid carcinoma suggesting a specific involvement of relaxin-LGR7 signaling in thyroid carcinoma. Stable transfectants of the LGR7-positive human follicular thyroid carcinoma cell lines FTC-133 and FTC-238 that secrete bioactive proRLN2 revealed this hormone to act as a multifunctional endocrine factor in thyroid carcinoma cells. Although RLN2 did not act as a mitogen, it acted as an autocrine/paracrine factor and significantly increased anchorage-independent growth and thyroid carcinoma cell motility and invasiveness through elastin matrices. Suppression of LGR7 expression by LGR7-siRNA abolished the RLN2-mediated accelerated tumor cell motility. The increased elastinolytic activity correlated with enhanced production and secretion of the lysosomal proteinases cathepsin-D (cath-D) and cath-L forms hereby identified as new RLN2 target molecules in human neoplastic thyrocytes. We found the intracellular distribution of procath-L specifically altered in RLN2 transfectants, providing first evidence for selective actions of relaxin on the powerful elastinolytic cath-L production, storage, and secretion in thyroid carcinoma cells. Thus, relaxin enhances the oncogenic potential and acts as novel endocrine modulator of invasiveness in human thyroid carcinoma cells.

Hotchkiss and MacLeod: An Historical Perspective

Hotchkiss and MacLeod: An Historical Perspective

Routine Use of Microvascular Coupling Device for Arterial Anastomosis in Breast Reconstruction

Although microvascular coupling devices are used routinely and successfully for venous anastomosis, there are few published reports demonstrating their efficacy for performing arterial anastomosis. It has been the senior author's (C.Y.A.) preference to perform arterial anastomosis using the microvascular coupling device when feasible. All microsurgical breast reconstructions performed by the senior author at the New York University Medical Center between 1998 and 2004 were retrospectively reviewed. A total of 60 patients underwent microsurgical breast reconstruction, of which 20 were bilateral, for a total of 80 flaps. Of the 80 flaps performed, there were 47 muscle-sparing TRAM and 22 deep inferior epigastric perforator (DIEP) flaps, and 11 were superior gluteal flaps. Arterial coupling was successfully performed in 60 of 69 flaps based on the deep inferior epigastric artery (87%) and 2 of 11 gluteal flaps (18%); arterial coupling was performed successfully 62 of 74 times (83.9%) when the thoracodorsal artery was the recipient vessel and never performed when the internal mammary artery was the recipient vessel. The overall flap success rate was 100%. In our large series, we were able to perform a coupled arterial anastomosis in nearly 80% of the cases, without the loss of any flaps. With proper vessel selection and sufficient experience using the microvascular coupler, arterial coupling may be performed in an expeditious, safe, and reliable fashion with minimal morbidity. Though not commonly practiced, use of the coupling device for arterial anastomosis can provide significant time savings, especially in bilateral breast reconstructions.

Dexmedetomidine Facilitates Withdrawal of Ventilatory Support

We appreciate Drs. Stemp and Karras’ close reading of our case report.1We would like to clarify that our inclusion of the acute physiology and chronic health evaluation (APACHE) II score in the case report was an attempt to provide a widely used risk stratification score for the benefit of readers of the report, rather than an explication of how we arrived at the decision to transition to palliative care. The decision to provide this patient with palliative care and how this was communicated to the patient’s family closely followed what they described as their practice, with the goal of optimizing patient comfort and functional quality of life. The APACHE II score was calculated post hoc at the time of writing the case report, and we agree with Drs. Stemp and Karras that it did not seem to correspond with our experiential-based assessment of this patient’s risk of death from this episode of illness.*New York University Medical Center, New York, New York. cjmjskent@worldnet.att.net

Spirituality and the Healthy Mind: Science, Therapy and the Need for Personal Meaning

Marc Galanter has turned professional experience, clinical acumen and erudite scholarship into a fine and timely book. Director of Alcoholism and Substance Abuse at New York University Medical Center, Professor Galanter's research interests have also included the extensive study of cultic groups. Regretting that mainstream psychiatrists have so far been reluctant to consider spirituality-oriented healing for their patients, his cautious but well-researched thesis is that, although biomedically-based psychiatry and spirituality involve two different perspectives, they might not be incompatible. He begins with the question, `What is spirituality?' We are first told, `There is no definition. It is a way of life'. Nevertheless, the word consistently evokes deep-seated personal experiences with universal relevance and appeal. Spirituality is described as central to psychological well being, providing both energy and direction. Spiritual awareness can therefore help a person discover not only a sense of meaning and purpose in life, but also a healthy sense of belonging, orientating us when seeking to define and adhere to our values. Another theme is that, `Spirituality can be experienced from either a secular or religious standpoint'. This shortcircuits another factor inhibiting many from engaging with the subject. Secular spirituality is no oxymoron. It is a reality for a high percentage of patients, surveys of whom reveal its central role in preventing and healing disease, also in enduring both distress and disability. All doctors should know about this, and Galanter has done us a service in providing such a sane and sensible guide. We are treated to a critical discussion of cults, including problem areas, also of Alcoholics Anonymous and the spirituality of the 12-step method of recovery from addiction. There is thought-provoking material on Christian psychiatry, spirituality in Indian faith traditions and in Islam, on hospital chaplaincy, on alternative (complementary) medicine and on meditation. This is a rich feast, not always entirely digestible due to its transatlantic bias, but readable enough to be satisfying. Galanter respects the intelligence of his readers. The most preachy he gets is to suggest in his final chapter that, `Mental health professionals would do well to attend to individual people as wholes over a lifetime... to see if they can be helped to an adaptation that carries meaning and value for them'. This echoes advice I received as a trainee in the eighties, and earlier as a medical student. The personcentred, holistic approach he advocates has always served me well. Psychological healing involves more than the relief of symptoms. It fosters improved emotional resilience and equanimity, thereby resulting in personal growth. John Swinton refers to spirituality as `the forgotten dimension' of mental health care. Like him, Marc Galanter has reminded us that we must not neglect this aspect in aiming towards healthy minds: both for our patients and, arguably, for ourselves. Their books both offer us reasoned and reasonable guidance for our effort. They provide cause, at personal and collective levels, to renew our search for sanity... and to do so with hope.

Hyphema Occurring During Selective Laser Trabeculoplasty

The first case of hyphema occurring during selective laser trabeculoplasty in an eye without neovascularization is described. A 77-year-old man with uncontrolled open-angle glaucoma received selective laser trabeculoplasty in both eyes for high intraocular pressure with maximally tolerated medical treatment. Hyphema occurred during selective laser trabeculoplasty in the left eye. This resolved spontaneously without sequelae. Successful intraocular pressure control was achieved. Hyphema and bleeding can happen during selective laser trabeculoplasty. Although this was transient and uneventful in one patient, careful monitoring of intraocular pressure and anterior chamber reaction is advised.

Discussion: medical illness and depression

Division of Behavioral Medicine and Consultation Psychiatry, Mount Sinai/New York University Medical Center Recebido 28-02-06 Aprovado 01-03-06 The comorbidity of medical and psychiatric illness presents many dilemmas for psychiatric diagnosis that have not been sufficiently taken into account in either the Diagnostic and Statistical Manu al of Mental Disorders IV – Text Revision (DSM-IV-TR) or the Tenth Revision of International Classification of Diseases (ICD-10) psychiatric section. These lexicons have not considered the confounds that arise with medical and psychiatric comorbidity. For example, vegetative signs of fatigue, change in appetite (increased or decreased), diminished libido, and sleep disturbances (either hypo or hypersomnia) can accompany medical illness, e.g., cardiac disease, or major affective disorders (MAD). DSM states that if a symptom can be attributable to a medical disease it cannot be enlisted to support a psychiatric diagnosis. Because it is so difficult to ascertain symptom attribution, the diagnosis of depression in the medically ill is significantly compromised with comorbidity. Symptom origin can be psychological, medical – somatic, pharmacological, mixed – or indeterminate. Comorbidity then means that there are two systems of diagnoses, two genres of medications to be considered, two disciplines of medical doctors, and two systems of patient care. Since depression is associated with making many medical illnesses worse it is essential that an attempt be made to diagnose this protean disease in the medical setting. For example, it has been shown that depressed patients with a Discussion: medical illness and depression

SERUM LEVELS OF SHED HER2/NEU PROTEIN IN MEN WITH PROSTATE CANCER CORRELATE WITH DISEASE PROGRESSION

We determined the association between serum levels of shed Her-2/neu protein and disease progression in men with prostate cancer. Serum from 279 patients enrolled in a prospective serum bank and database at New York University Medical Center was analyzed using the Food and Drug Administration approved Immuno-1 Her-2/neu assay. Patients were classified by the Prostate-Specific Antigen Working Group model into 5 groups, namely group 1-no evidence of cancer in 60, group 2-clinically localized disease in 67, group 3-prostate specific antigen increasing after therapy and no clinical metastases in 77, group 4-clinical metastases and castration sensitivity in 42, and group 5-clinical metastases and castration resistance in 33. A cutoff of 14 ng/ml for normal serum Her-2/neu was established based on the 95th order statistic in group 1. Of 279 patients 37 (13.3%) had increased serum Her-2/neu, that is 5%, 11.9%, 10.4%, 16.7% and 33.3% in groups 1 to 5, respectively. There was a significant difference between patients with (groups 4 and 5) and without (groups 2 and 3) clinical metastases (p = 0.006). In group 5 patients serum Her-2/neu was significantly higher than in group 2 patients (p <0.02). The risk of cause specific death increased significantly with each unit increase in serum Her-2/neu (p <0.001). Increased serum Her-2/neu correlates with the presence of metastatic disease and it may indicate an increased risk of death in patients with castrate, metastatic prostate cancer. The detection of serum Her-2/neu is a minimally invasive alternative to tumor sampling for identifying potential candidates for anti-Her-2/neu treatment strategies. Further studies are needed to optimize this assay for application in the clinical setting.

Fiber to the brain [brain surgery

This paper describes a promising new procedure developed by researchers from the New York University Medical Center, the Massachussets Institute of Technology, and the University of Tokyo to perform brain surgery via nanotechnology. The procedure involves attaching electrodes to small clusters of brain cells using the cardiovascular system as the conduit through which wires are threaded. This procedure does not require surgeons to break through the skull, which could damage healthy brain tissues and expose patients to infection.

Quality of life and behavioral follow-up study of pediatric survivors of craniopharyngioma

The authors set out to evaluate the quality of life (QOL), social-emotional functioning, and behavioral functioning of children treated surgically for craniopharyngiomas. Twelve girls and 17 boys with a mean age at diagnosis of 8 +/- 3.8 years were surgically treated between 1985 and 1998 at the New York University Medical Center. After a mean follow-up period of 6.8 +/- 3.5 years, these 29 patients were administered either the 36-item Short Form Health Survey version 2 or the Child Health Questionnaire-Parent Form to assess QOL, as well as the Achenbach Child Behavior Checklist or Young Adult Checklist to measure social-emotional and behavioral functioning. Patients older than 19 years of age and parents of patients younger than 19 years of age reported low average overall physical QOL, with overall psychosocial QOL in the average range. Behavioral difficulties were noted, including internalizing, attention, somatic, and social difficulties. Further analyses indicated that retrochiasmatic tumor location, recurrence, and additional surgery were associated with poorer outcomes. In contrast, hydrocephalus, tumor size, and sex were not prognostic variables, and patients significantly improved as post-operative time increased. Attention toward late effects arising after the treatment of pediatric craniopharyngioma, including decreased postoperative physical health and behavioral functioning, is warranted. Future approaches to treatment should consider the documented effects of either gross-total resection or limited surgery followed by cranial irradiation on QOL, with specific evaluation for those with retrochiasmatic tumors, a recurrent tumor, or the need for additional surgery. Psychosocial QOL and social-emotional functioning should be maintained through ongoing counseling and education.

Obstacles to the Early Detection of Endocervical Adenocarcinoma

We observed that the ratio of in situ to invasive carcinomas of the cervix is significantly greater for squamous than for glandular lesions. We wondered whether Pap smears were less effective for the identification of in situ glandular lesions. The purpose of this study was to determine if the location, extent of disease, and growth patterns of endocervical adenocarcinomas influence the ability to detect malignant cells by Pap smears. Medical records, doctor's office records, and all pathology materials (reports and slides) including Pap smears, biopsies, LEEP/cone biopsies, and hysterectomy specimens from 53 consecutive patients diagnosed with endocervical adenocarcinomas were examined at New York University Medical Center (a total of 654 pathology slides and 51 Pap smears were reviewed). Findings were correlated for each patient using gross descriptions and histopathology and stratified by location/extent of disease and growth pattern (exophytic or endophytic or both). Ten patients had in situ disease, seven (70%) of which involved the transformation zone (TZ); all seven of these were identified by Pap smears. In contrast, of the other three cases that did not involve the TZ but were confined to the endocervix, only one was identified by Pap smear. Forty-three patients had invasive disease. Twenty involved the TZ, and 23 involved the endocervix but spared the TZ. Of the 20 tumors involving the TZ, 11 (55%) were identified by Pap smears, whereas of the 23 sparing the TZ, 11 (47.8%) were diagnosed by Pap smear. Among the 23 patients with invasive disease that spared the TZ, 6 (26%) had a documented history of negative Pap smears at New York University within 3 years of diagnosis. Conversely only 1 of the 20 patients with TZ involvement had a history of negative Pap smears, and 3 patients in this group denied having had Pap smears for several years. Including all 53 patients, a significantly higher proportion were not detectable by Pap smear if the TZ was spared (54% versus 25%, p = 0.036). Of the 23 invasive cancers that spared the TZ, 6 (14%) had verified negative Pap smears. These lesions did not shed malignant cells onto Pap smears. Noteworthy was the finding that two of these six lesions extended from the endocervix upward, through the stroma, and into the endomyometrium of the lower uterine segment. Four extended downward into the exocervix through the stroma, sparing the surface mucosa; one reached the upper vagina. All six displayed an endophytic growth pattern.

SEVEN MORE TIPS FOR THE OPERATING ROOM

Department of Surgery (Plastic Surgery), New York University Medical Center, 420 East 55th Street, New York, N.Y. 10022, [email protected] Correspondence and brief communications are welcomed and need not concern only what has been published this journal. We shall print items of interest to our readers, such as experimental, clinical, and philosophical observations; reports of work in progress; educational notes; and travel accounts relevant to plastic surgery. We reserve the right to edit communications to meet requirements of space and format. Any financial interest relevant to the content of the correspondence must be disclosed. Submission of a letter constitutes permission for the American Society of Plastic Surgeons and its licensees and assignees to publish it in the journal and in any other form or medium. The views, opinions, and conclusions expressed in the Letters to the Editor represent the personal opinions of the individual writers and not those of the publisher, the Editorial Board, or the sponsors of the journal. Any stated views, opinions, and conclusions do not reflect the policy of any of the sponsoring organizations or of the institutions with which the writer is affiliated, and the publisher, the Editorial Board, and the sponsoring organizations assume no responsibility for the content of such letters.

40 kDa peginterferon alfa-2A (PEGASYS®) as a prophylaxis against hepatitis C infection recurrence after liver transplantation (LT): preliminary results of a randomized multicenter trial: Cosme Manzarbeitia, Albert Einstein Medical Center, Philadelphia, PA; Lewis Tepermann, New York University Medical Center, New York, NY; Naga Chalasani, Indiana University Medical Center, Indianapolis, IN; Patricia Sheiner, Mount Sinai Medical Center, New York, NY; Russel

40 kDa peginterferon alfa-2A (PEGASYS®) as a prophylaxis against hepatitis C infection recurrence after liver transplantation (LT): preliminary results of a randomized multicenter trial: Cosme Manzarbeitia, Albert Einstein Medical Center, Philadelphia, PA; Lewis Tepermann, New York University Medical Center, New York, NY; Naga Chalasani, Indiana University Medical Center, Indianapolis, IN; Patricia Sheiner, Mount Sinai Medical Center, New York, NY; Russel

Mandatory submission of microarray data to public repositories: how is it working?

one of the underlying principles of scientific research and publication in peer-reviewed journals is the concept of reproducibility, within studies and between laboratories. Since January 1, 2003, Physiological Genomics and the American Physiological Society have adopted the microarray data standard

Myc Antagonizes Ras-mediated Growth Arrest in Leukemia Cells through the Inhibition of the Ras-ERK-p21Cip1 Pathway

Even though RAS usually acts as a dominant transforming oncogene, in primary fibroblasts and some established cell lines Ras inhibits proliferation. This can explain the virtual absence of RAS mutations in some types of tumors, such as chronic myeloid leukemia (CML). We report that in the CML cell line K562 Ras induces p21Cip1 expression through the Raf-MEK-ERK pathway. Because K562 cells are deficient for p15INK4b, p16INK4a, p14ARF, and p53, this would be the main mechanism whereby Ras up-regulates p21 expression in these cells. Accordingly, we also found that Ras suppresses K562 growth by signaling through the Raf-ERK pathway. Because c-Myc and Ras cooperate in cell transformation and c-Myc is up-regulated in CML, we investigated the effect of c-Myc on Ras activity in K562 cells. c-Myc antagonized the induction of p21Cip1 mediated by oncogenic H-, K-, and N-Ras and by constitutively activated Raf and ERK2. Activation of the p21Cip1 promoter by Ras was dependent on Sp1/3 binding sites in K562. However, mutational analysis of the p21 promoter and the use of a Gal4-Sp1 chimeric protein strongly suggest that c-Myc affects Sp1 transcriptional activity but not the binding of Sp1 to the p21 promoter. c-Myc-mediated impairment of Ras activity on p21 expression required a transactivation domain, a DNA binding region, and a Max binding region. Moreover, the effect was independent of Miz1 binding to c-Myc. Consistent with its effect on p21Cip1 expression, c-Myc rescued cell growth inhibition induced by Ras. The data suggest that in particular tumor types, such as those associated with CML, c-Myc contributes to tumorigenesis by inhibiting Ras antiproliferative activity.

New York University Medical Center's Pilot “Epo-Depot” Program: A Win-Win for Patients and Health Care

Therapy associated with treatment-related anemia continues to be of great concern for health care providers. Patient satisfaction, patient adherence, and growing insurance reimbursement concerns related to Epoetin alpha therapy for anemia initiated the development of a nursing-led process improvement team at New York University (NYU) Medical Center. Multiple patient groups were identified and treated for anemia with Epoetin alpha through the guide of a standardized pathway providing a convenient and effective treatment plan. The treatment delivery had to be consistent with institutional reimbursement requirements while avoiding significant cost to the patient. Patient populations diagnosed with HIV anemia, HIV oncology, presurgical anemia, and medically complex anemia can now receive appropriate ambulatory treatment. This article describes the formation of the "Epo-Depot" and the logistics involved to service these patients with anemia.

Point of View

From the Department of Neurosurgery, New York University Medical Center, New York, NY. The manuscript submitted does not contain information about medical device(s)/drug(s). No funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. Address correspondence to Paul R. Cooper, MD, Department of Neurosurgery, New York University Medical Center, 550 1st Avenue, New York, NY 10016; E-mail: [email protected]

Psychoanalysis and Trauma: September 11 Revisited

One year later, a few miles from Ground Zero, at the invitation of two psychoanalytic colleagues from New York, I took up the role of discussant for a panel of three presentations reflecting on clinical work after September 11. I felt both honored and surprised by this request, since I work in a small psychiatric hospital (the Austen Riggs Center), three hours north of the city by car. After I read the presentations, I felt admiring, even in awe of the presenters’ work, but I also felt like those people, mentioned in the presentations, who had not come to work that day. I began my assignment feeling the shame and guilt of the survivor. From my insulated spot in the Berkshire mountains of Western Massachusetts, I hesitated to discuss this work. Not having been there, I felt inclined to de-authorize myself from speaking.

Cranial Nerve Preservation in Surgery for Large Acoustic Neuromas

Facial nerve outcomes and surgical complication rates for other cranial nerves were evaluated retrospectively after the resection of large acoustic neuromas. The charts of all patients who underwent surgical removal of an acoustic neuroma between 1992 and 2001 at New York University Medical Center were reviewed. Fifty-four patients with tumors measuring 3 cm or larger were included in the study. Four patients had neurofibromatosis type 2, two of whom underwent bilateral removal of acoustic neuromas. Translabyrinthine microsurgical removal of tumor was performed in 47 of 56 cases (84%). In all cases, EMG monitoring, improved sharp microdissection, and ultrasonic aspiration were employed. Facial nerve function was assessed using the House-Brackmann facial nerve grading system immediately after surgery and at follow-up visits. A House-Brackmann grade III or better was achieved in 90% of patients, and a grade II or better was achieved in 84% of patients. Ultimate facial nerve outcome was excellent after the surgical resection of large acoustic neuromas. Preoperative cranial nerve palsies also improved after surgery. The translabyrinthine approach for tumor removal is our treatment of choice for acoustic neuromas 3 cm or larger.