Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

Research in pediatric surgery

Pediatric surgical research continues to expand along technical avenues while addressing issues of basic science. Splenic salvage is an established goal which can ordinarily be achieved without surgical intervention. Operative approaches, when indicated, can be done with minimal moribidity. Although the spleen acts as a bacterial monitor under normal circumstances by direct phagocytosis, opsonization, and modulation of macrophage function, our understanding of how the injured spleen resumes these activities remains fragmentary. Extracorporeal membrane oxygenation shows increasing promise for newborns with refractory respiratory failure. New applications of pulmonary vasoactive meidators will yield a better understanding of how this radical therapy affects cardiopulmonary homeostasis. The lungs either synthesize, modify, or pass on a number of substances including eicosanoids, vasoactive amines, and carboxypeptidases which form a resonating feedback network that controls pulmonary vascular tone. Disturbed homeostasis results in the various disease states that have pulmonary hypertension and lung injury as common features. Developments in fetal surgery have permitted creation of improved models of in utero conditions. These models variably mimic the human condition, particularly obstructive uropathy, congenital diaphragmatic hernia, and neural tube defects. Complex problems remain for patient/fetus selection and timing of surgical intervention.

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Resumen La investigación en cirugía pediátrica continúa progresando en el campo técnico al tiempo que se ocupa de temas de ciencias básicas.La preservatión del bazo es un objetivo ya bien establecido, el cual generalmente puede ser logrado sin intervention quirúrgica. Los aproches operatorios, cuando existe la correspondiente indicación, pueden ser realizados con mínima morbilidad. Aún cuando se sabe que el bazo actúa como un monitor bacteriano en circunstancias normales mediante fagocitosis directa, opsonización y modulation de la función macrófaga, nuestro conocimiento sobre cómo el bazo lesionado reasume estas funciones es todavía fragmentario.La oxigenación extracorpórea de membrana aparece crecientemente promisoria en recién nacidos con falla respiratoria refractaria. Nuevas aplicaciones de los agentes mediadores vasoactivos pulmonares permit en una mejor comprensión de cómo esta modalidad radical de terapia afecta la homeostasis cardiopulmonar. Los pulmones sintetizan, modifican o circulan un número de sustancias, incluyendo los eicosanoides, las aminas vasoactivas y las carboxipeptidasas, las cuales forman una resonante red de retroalimentación, red que controla el tono vascular pulmonar. Una homeostasis alterada resulta en los diversos estados patológicos que se acompañan de hipertensión pulmonar y de lesion pulmonar como denominador común.Avances en el campo de la cirugía fetal han permitido el desarrollo de mejores modelos de condiciones intrauterinas. Estos modelos simulan en forma variable la condition humana, particularmente la uropatía obstructiva, la hernia diafragmática congénita y los defectos del tubo neural. Quedan por resolver complejos problemas relativos a la selection del paciente/feto y a la oportunidad de la intervention quirúrgica.

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Résumé La recherche chirurgicale pédiatrique continue à s'épanouir en fonction des progrès des sciences fondamentales.La conservation de la rate est un but à atteindre en dehors de toute tentative d'intervention chirurgicale. Celle-ci quand elle est indiquée se doit d'être conservatrice au prix d'un faible taux de morbidité. Alors que la rate agit comme un agent de contrôle bactérien dans les conditions normales par phagocytose directe, opsonisation et modulation de la fonction macrophagique notre compréhension de la reprise de ces fonctions reste incomplète lorsque la rate a été victime de lésions traumatiques.L'oxygénation extracorporelle sur un tout autre plan est pleine de promesses chez le nouveau né atteint de déficience respiratoire réfractaire. L'emploi de médiateurs vasoactifs pulmonaires permettra de mieux comprendre comment ce traitement radical agit sur l'homéostasie cardiopulmonaire. Les poumons exercent une action de synthèse modifiant ou transmettant un grand nombre de substances comme les eicosanoïdes, les amines vaso-actives et les carboxypeptidases qui forment un réseau de résonance par processus de feed-back, réseau qui contrôle le tonus vasculaire du poumon. Les troubles de l'homéostasie entrainent des états pathologiques variés qui se manifestent par de l'hypertension pulmonaire ou des lésions du parenchyme pulmonaire. Les progrès de la chirurgie foetale ont permis la création de modèles améliorées des conditions de la vie in utéro. Ces modèles simulent ceux de la vie foetale in utero chez l'être humain et concernent particulièrement l'uropathie obstructive, la hernie diaphragmatique congénitale et les défauts du tube neural. Cependant de nombreux problèmes complexes restent à résoudre concernant les indications et le moment de l'intervention chirurgicale chez le foetus.

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Supported in part by a grant from the Charles Edison Foundation     

Physicians at the roadside: Pre-hospital emergency care in the United Kingdom

In some parts of the United Kingdom (UK), family doctors (or "general practitioners" as they are called in the UK) are routinely called upon by the emergency medical services (EMS) system to attend road accidents. The doctors are volunteers and travel to the scene of the accident in their own cars. Members of one such general practitioner accident service operating in Mid-Anglia complete an accident report form after attending each incident. In 1983, the Mid-Anglia General Practitioner Accident Service (MAGPAS) received 1,715 calls for medical assistance, and in 95% of these a doctor was sent immediately. Of these calls, 57% were passed to the doctor within one minute of the receipt of the call in the MAGPAS control room, and 78% were relayed within two minutes. This rapid call-out, combined with the close proximity of the local doctor to the accident site, resulted in the doctors arriving ahead of the ambulance in 42% of the calls. A total of 54 patients with airway obstruction were treated by the doctors prior to the arrival of the ambulance. Ninety-nine patients required immediate intravenous fluid replacement in the pre-hospital phase of their medical care. This report suggests that general practitioners in rural areas can play a vital role in the early management of trauma patients, especially in the absence of ambulance personnel trained in advanced life support skills.     

Chlorophyll catabolism in senescing plant tissues: In vivo breakdown intermediates suggest different degradative pathways for Citrus fruit and parsley leaves

High-pressure liquid chromatography was used to separate chlorophyll derivatives in acetone extracts from senescing Citrus fruit peel, autumnal Melia azedarach L. leaves, and dark-held detached parsley (Petroselinum sativum L.) leaves. Chlorophyllide a and another polar, dephytylated derivative accumulated in large amounts in senescing Citrus peel, particularly in fruit treated with ethylene. Ethylene also induced a 4-fold increase in the specific activity of Citrus chlorophyllase (chlorophyll chlorophyllidohydrolase, EC 3.1.1.14). Detailed kinetics based on a hexane/acetone solvent partition system showed that the in vivo increase in dephytylated derivatives coincided with the decrease in total chlorophyll. Polar, dephytylated derivatives accumulated also in senescing Melia leaves. Senescing parsley leaves revealed a very different picture. The gradual disappearance of chlorophyll a was accompanied by an increase in pheophytin a and by the transient appearance of several phytylated derivatives. Only pheophytin a and an adjacent peak were left when all the chlorophyll a had disappeared. The pathways for breakdown of chlorophyll in the Citrus and parsley senescence systems are discussed.     

Relevance of spontaneous activity to urinary bladder function: an in vitro and in vivo study

The presence and functional significance (if any) of spontaneous activity in the normal urinary bladder during filling is a controversial subject. One model used by many investigators to study spontaneous activity has been isolated urinary bladder smooth muscle strips. Although spontaneous activity is a property commonly observed in isolated urinary bladder strip preparations, the in vitro whole bladder preparation (rabbit) is devoid of spontaneous activity. Additionally, under normal conditions the in vivo rabbit bladder does not display spontaneous activity during the filling phases of micturition. The present study compares the spontaneous activity of isolated smooth muscle strips, the whole bladder preparation, and the catheterized in vivo bladder (rabbit). The results are as follows: The spontaneous activity (frequency and amplitude) of isolated strips is extremely variable among strips of the same bladder. Spontaneous activity is not affected by the following specific inhibitory compounds: tetrodotoxin, atropine, phentolamine, propranolol and hexamethonium. This indicates that spontaneous activity observed in isolated strips is myogenic in nature and not dependent on the activation of specific autonomic receptors. The in vitro whole bladder preparation shows no spontaneous activity at any volume or pressure unless longitudinal tension is applied. The spontaneous activity of the whole bladder subjected to longitudinal tension is not affected by the same compounds mentioned above. Spontaneous activity of the in vivo bladder is absent at low intravesical volumes and pressures. Spontaneous activity develops upon reaching a critical pressure. However, this activity is completely inhibited by intravenous ganglionic blockade (hexamethonium). In the presence of hexamethonium, the in vivo bladder is devoid of spontaneous activity at any volume or pressure, thus the in vivo "spontaneous activity" is mediated through neuronal reflexes. It is concluded that under normal circumstances the rabbit bladder is devoid of myogenic spontaneous activity and that the spontaneous activity observed in isolated strips is directly related to longitudinal stretch. Since under normal conditions the bladder is not subjected to longitudinal stretch, the spontaneous activity observed in the isolated strip studies has little physiological significance under normal conditions, but could help explain the pathophysiology of certain dysfunctions during the filling stage of micturition.     

Breast cancer in young women: Imaging and clinical course

The purpose of this study was to characterize presenting imaging findings in women younger than 40 diagnosed with invasive breast cancer in the context of pathology and clinical course. Retrospective chart and imaging reviews were performed in patients under 40 diagnosed with breast cancer between July 1, 2004, and December 31, 2013. Patient demographic, imaging, pathology, and clinical data were collected. Overall and recurrence-free survival were estimated using the Kaplan-Meier method. Univariate Cox proportional hazards models were performed to identify factors associated with recurrence-free survival. Our study cohort consisted of 110 patients with invasive mammary carcinoma. One hundred one (91.8%) presented with a palpable mass. The mean size of all lesions on imaging was 3.5 cm ± 2.9 cm. Malignant calcifications were present in 54 (49.1%) cases. Imaging demonstrated multifocal or multicentric disease in 45 (40.9%) cases. Seventy four (67.3%) cancers were high grade. Luminal genomic subtypes were the most common (n = 61, 55.5%). At presentation, 4 (3.6%) patients had bilateral malignancy and 8 (7.3%) patients had distant metastatic disease. Ninety seven (88.2%) underwent neoadjuvant chemotherapy and 67 (60.9%) underwent radiation therapy. Seventy five (68.2%) of the patients underwent mastectomy. The restricted mean time to recurrence was 9.01 years (standard error 3.162 months). ER positivity was associated with compromised recurrence-free survival. The overall survival rate was 0.962 at 10 years. Young patients diagnosed with breast cancer typically present with advanced breast imaging findings and undergo aggressive treatment. Recurrence often occurs >5 years from diagnosis, and ER positive subtypes are at increased risk for recurrence.     

Functional and molecular characterization of a monoclonal antibody against human interleukin 2

Human recombinant interleukin 2 (r-IL2) was used as an immunizing antigen to yield a murine monoclonal antibody (mAb) termed BO-7. Although the antibody binds to r-IL2 more avidly, it also reacted strongly with IL2 from natural sources in an enzyme-linked immunosorbent assay (ELISA), allowing the detection of the purified lymphokine at sensitivity levels closely approaching those found with the IL2 biological assay. Binding to the antigen is specific, as deduced from the close correlation of ELISA immunoreactivity with IL2 biological activity and from immunoblot analysis of electrophoretically separated IL2 from various sources. Binding studies with synthetic IL2-derived peptides revealed the location of the epitope, which is recognized by mAb BO-7: A peptide representing amino acid residues 59-72 (peptide 84) is strongly reactive with the antibody, while an overlapping peptide (residues 48-69) is not. Peptide 84, moreover, can be applied for immunopurification of mAb BO-7 and competes for binding to the antibody with the intact IL2 molecule. In turn, another monoclonal anti-IL2 antibody (35H10), showing the same reactivity pattern with peptides, competes with mAb BO-7 for binding to IL2. The application of mAb BO-7 as a specific reagent for the quantitation of IL2 in a sandwich-type ELISA is demonstrated.     

Changes in gastrointestinal, pancreatic, biliary, and hepatic function with aging

The understanding of "normal" aging of the gastrointestinal tract, pancreas, and hepatobiliary system is confounded by the difficulty in identifying healthy elderly subjects for study. There appear to be predictable changes in gastric secretion and emptying, intestinal and pancreatic morphology, colorectal motility, and hepatic mass and blood flow with aging. However, the functional significance of these changes is variable. Further investigations will be necessary to resolve currently conflicting data, and validation of animal models of aging will enhance future research into these areas.     

Quality of Life Assessment,of Ileogastrostomy

Twenty of 26 (77%) consecutive patients undergoing ileogastrostomy, performed by the same surgeon (IGMC) between February 1989 and May 1992, responded to a mailed quality of life survey. Average present weight was reported as 50.9 kg less than a mean preoperative weight of 139.7 kg. Mean time of follow-up was 24.75 months. When comparing perceptions before and after surgery, several quality of life improvements were noted in the areas of vocation, relationships, emotional well-being and physical well-being. Post-surgery, jobs were rated more satisfying, eating habits improved, self-image and self-confidence increased and body disparagement declined. Satisfaction with sexual relations increased, as did frequency. In general, relations with partners, co-workers and friends seemed to improve. Exercise also increased significantly. In contrast, foul flatus, bloating, and bowel movements regularly hampered activities or caused embarassment when in public. Despite these physical side-effects, we observed that a large majority of persons undergoing ileogastrostomy noted significant improvements in quality of life.