Traumatic injuries to the pregnant patient: a critical literature review.

INTRODUCTION: Trauma during pregnancy is the leading non-obstetrical cause of maternal death and a significant public health burden. This study reviews the most common causes of trauma during pregnancy, morbidity, and mortality, and the impact upon perinatal outcomes associated with trauma, providing a management approach to pregnant trauma patients. MATERIALS AND METHODS: A systematic review of the current literature from January 2006 to July 2016 was performed. RESULTS: Fifty-one articles were identified, including a total of 95,949 patients. Motor vehicle crash was the most frequent cause of blunt trauma, followed by falls, assault both domestic and interpersonal violence, and penetrating injuries (gunshot and stab wounds). CONCLUSIONS: Trauma in pregnant women is associated with high rates of adverse maternal and neonatal outcomes. Knowledge of the mechanism of injury is important to identify the potential injuries and the complexity of the management of these patients. As in all traumatic events, prevention is of paramount importance.

Losing God.

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded the Kenneth B. Schwartz Center. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, support to caregivers, and sustenance to the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. Nebulous language, distrust, and dogma confound spiritual aspects of cancer care. However, existential well being is an important determinant of quality of life: finding meaning and purpose make suffering more tolerable. The case presented is of a patient who experienced "losing God" as a Hodgkin's disease survivor with metastatic prostate cancer and severe coronary artery disease. His caregivers were able to provide the sense of community in which he could re-establish his faith. Health care providers do not have to be religious in order to help patients to deal with a spiritual crisis. The clinical skills of compassion need to be deployed to diagnose and respond to spiritual suffering. Acknowledging and addressing anger or guilt, common sources of suffering, are essential to adjustment. Simply being there for the patient and being open to their hurt can help resolve their spiritual crisis, a responsibility that is shared by the whole health care team.

Hypersensitivity of circulating progenitor cells to megakaryocyte growth and development factor (PEG-rHu MGDF) in essential thrombocythemia.

Hematopoietic progenitor cells in 2 myeloproliferative disorders, juvenile chronic myelomonocytic leukemia and polycythemia vera, are known to be hypersensitive to cytokines that control normal progenitor cell proliferation, differentiation, and survival in their respective granulocyte/macrophage and erythroid lineages. Because thrombopoietin controls these functions in the normal megakaryocytic lineage, we asked the question: Are megakaryocytic progenitor cells in the myeloproliferative disorder essential thrombocythemia (ET) hypersensitive to thrombopoietin? Peripheral blood mononuclear cells from patients with ET, or secondary (reactive) thrombocytosis (2 degrees T), or healthy volunteers were grown in strictly serum-free agarose culture containing interleukin 3 (IL-3) and all-trans-retinoic acid, with various concentrations of PEG-rHu megakaryocyte growth and development factor (MGDF). The concentration of cytokine at half-maximum colony number served as a measure of progenitor cell sensitivity. Hypersensitivity to PEG-rHu MGDF was found in circulating progenitors from 18 of 20 (90%) informative patients with presumptive diagnosis ET, 1 of 8 (12.5%) 2 degrees T patients, and none of the 22 healthy volunteers. Median MGDF sensitivity ratio in ET patients was approximately 53 times greater than in the controls. This hypersensitivity, which was also directed to rHu thrombopoietin, was highly specific with respect to cytokine, disease, and cell lineage. We propose that, despite their single pluripotential cell origin, the different clinicopathologic phenotypes in different chronic myeloproliferative disorders are determined by lineage-restricted hypersensitivities of hematopoietic progenitor cells to endogenous cytokines. This work emphasizes the importance of stringent serum-free conditions for revealing true sensitivities to cytokines. The findings also offer a basis for evolving a positive test for ET, a diagnosis now made essentially by exclusion.

Insulin-like growth factor binding protein-1 is elevated in patients with polycythemia vera and stimulates erythroid burst formation in vitro.

Previously, we found that, in the myeloproliferative disorder polycythemia vera (PV), circulating erythroid progenitor cells were hypersensitive to insulin-like growth factor I (IGF-I), an effect shown to occur through the IGF-I receptor. Also, in cells of PV patients, the IGF-I receptor was hyperphosphorylated on tyrosine residues under basal conditions, and its tyrosine phosphorylation in response to exogenous IGF-I was strongly augmented. Thus, because IGF-I appeared to play a role in the pathogenesis of PV, we wished to assess its level in the circulation of these patients. Normally, most of the circulating IGF-I is bound to specific high-affinity IGF binding proteins that can regulate its activity. We determined the circulating levels of IGF-I and two of its key binding proteins, IGFBP-1 and IGFBP-3. In two separate experiments, plasma samples from a total of 23 PV patients age- and sex-matched with 41 normal individuals were compared by radioimmunoassay. The levels of IGFBP-1 in patients with PV (37.80 +/- 4.33 microg/L) were more than fourfold higher than in normals (9.34 +/- 1.34 microg/L) or patients with secondary erythrocytosis (9.47 +/- 1.96 microg/L), whereas the plasma concentrations of IGFBP-3 and IGF-I in these patients were similar to those of normal subjects. Because circulating IGFBP-1 levels may be influenced by insulin, we measured the concentrations of insulin in the same samples. Our data showed that the elevation of circulating IGFBP-1 in PV could not be attributed to low levels of insulin in these patients. The substantial increase in concentration of IGFBP-1 was confirmed on ligand blots performed with (125)I-IGF-I. IGFBP-1 can be either inhibitory or stimulatory to the action of IGF-I under different conditions. We reasoned that if IGFBP-1 were stimulatory for erythropoiesis, an elevated IGFBP-1 level could help to explain the increased sensitivity to IGF-I observed in PV. If IGFBP-1 were inhibitory, it might suggest a compensatory mechanism in which a hyperphosphorylated IGF-I receptor in PV might induce a negative modulator of IGF-I action, in this case IGFBP-1. To distinguish between these two hypotheses, we titrated the effect of IGFBP-1 in the presence of IGF-I with respect to erythroid burst formation and found that IGFBP-1 was strikingly stimulatory. The elevated level of IGFBP-1 coupled with its ability to stimulate erythroid burst formation provide an attractive mechanism to account for the increased sensitivity of erythroid progenitor cells to IGF-I and the consequent overproduction of red blood cells characteristic of PV.

Silicone-covered Wallstent prototypes for palliation of malignant esophageal obstruction and digestive-respiratory fistulas.

BACKGROUND: Endoscopic palliation of malignant esophageal obstruction with uncovered self-expanding metal stents has been shown to have fewer complications than with conventional plastic stents. The addition of a membrane might prevent tumor ingrowth and allow treatment of digestive-respiratory fistulas. We report the clinical experience with a prototype silicone membrane-covered self-expanding metal stent. METHODS: Twenty-three silicone membrane-covered Wallstent prototypes were used in 21 patients with dysphagia due to inoperable malignant tumors involving the esophagus and cardia. RESULTS: Stent implantation was technically successful in all patients. There were no procedure-related perforations or deaths. The prototype stent was successful in sealing seven of the eight (87.5%) digestive-respiratory fistulas. As a group, the mean dysphagia grade improved significantly after stent placement (4.8 +/- 0.9 vs 3.4 +/- 1.6, p < 0.0005). However, 9 of 21 (42.9%) patients experienced no improvement in their dysphagia. Complications occurred in 13 of 21 (61.9%) patients. Tumor ingrowth was not observed in any patient. CONCLUSIONS: The prototype covered self-expanding metal stent was effective in sealing digestive-respiratory fistulas and provided palliation of dysphagia in slightly more than one half of the patients studied. A great deal has been learned from the preliminary experience, which has led to design modifications. The utility of the commercially available device should be evaluated in further prospective clinical trials.

Prospective multicenter trial of esophageal Z-stent placement for malignant dysphagia and tracheoesophageal fistula.

BACKGROUND: Conventional esophageal prosthesis placement has been associated with a 6% to 8% perforation rate and numerous postplacement complications. Expandable esophageal stents have been developed to preclude the above but there are few studies that have prospectively defined clinical results and subsequent stent-related complications. METHODS: All patients who underwent esophageal Z-stent placement at nine university or referral hospitals were prospectively assessed. Data collected included patient demographics, acute and subacute placement problems, the ability to occlude airway fistulas, prestent and poststent dysphagia scores, and patient survival. RESULTS: Fifty-four of 56 patients (96%) with refractory dysphagia or malignant esophagoairway fistulae had 73 Z-stents successfully inserted. Initial distal deployment occurred in 13% of the patients and an additional 17% required balloon dilation to achieve maximal diameter. Acute placement complications occurred in 11% of patients and included severe pain (3), bleeding from necrotic tumor (2), and hiatal hernia intussusception (1). No perforations occurred. Eight of 11 patients (73%) had complete tracheoesophageal fistula occlusion and mean dysphagia score (+/- SD) improved from 2.6 (0.7) to 1.1 (1.2) (p < 0.01). Fifteen stents (27%) had delayed migration at a mean of 1 month and 3 required surgery for retrieval. Three patients had ultimate stent erosion resulting in bleeding in 2 (exsanguination 1) or fistula (treated with a conventional stent). CONCLUSIONS: The authors conclude that esophageal Z-stents can be placed safely and successfully in the majority of patients. The tendency of distal deployment during placement and subsequent migration problems at a time distant from placement in a patient subset deserve attention and are currently being addressed.

Video-laparoscopic reduction of an intrathoracic stomach.

A paraesophageal hiatal hernia is caused by a defect in the anterolateral aspect of the diaphragmatic esophageal hiatus. Most commonly, the stomach migrates into the hernia sac. Although most patients are asymptomatic, repair is advised at the time of the diagnosis because of the high morbidity and mortality associated with surgery for the complications of paraesophageal hiatal hernias. However, because of the morbidity associated with conventional surgical techniques, there has been great reluctance to subject an asymptomatic patient to surgical repair. We report a minimally invasive technique for the reduction of a paraesophageal hiatal hernia and repair of the diaphragmatic hiatal defect. Video laparoscopy, with its attendant low morbidity, may be the ideal technique for the repair of paraesophageal hiatal hernias.

High-resolution chromoendoscopy for the diagnosis of diminutive colon polyps: implications for colon cancer screening.

BACKGROUND & AIMS: A visual, nonbiopsy technique that could reliably determine the histology of diminutive colorectal polyps could greatly reduce the cost of colon cancer screening. This study was designed to report our experience using a high-resolution colonoscope combined with indigo carmine dye to diagnosis diminutive colorectal polyps. METHODS: Colonoscopy using a Fujinon EC-400 HM/HL was performed in 36 patients with polyps <10mm in diameter. Polyps from the first 12 patients (phase 1) were sprayed with 10 mL of 0.2% indigo carmine dye, and a biopsy was performed or a specimen removed and submitted for histological analysis. The morphological data were used to predict polyp histology in the subsequent 24 patients (phase 2). RESULTS: Hyperplastic polyps had a characteristic surface "pit pattern" of orderly arranged "dots" that resembled the surrounding, nonpolypoid mucosa. Adenomatous polyps had surface "grooves" or "sulci." Sensitivity and specificity of our techniques in distinguishing adenomatous from nonadenomatous colorectal polyps were 93% and 95% respectively. CONCLUSIONS: High-resolution chromoendoscopy provides morphological detail of diminutive colorectal polyps that correlates well with polyp histology. If incorporated into colon cancer screening, these techniques may limit the need for biopsy and/or subsequent colonoscopy and ultimately decrease costs.

Increased basal and induced tyrosine phosphorylation of the insulin-like growth factor I receptor beta subunit in circulating mononuclear cells of patients with polycythemia vera.

We have previously shown that circulating progenitor cells in patients with polycythemia vera (PV) are hypersensitive to insulin-like growth factor I (IGF-I) with respect to erythroid burst formation in serum-free medium, and that this effect occurs through the IGF-I receptor. To investigate the molecular basis of this IGF-I hypersensitivity phenomenon, we examined tyrosine phosphorylation of the IGF-I receptor beta subunit in peripheral blood mononuclear cells (PBMNC) from eight PV patients and six normals. Cells were exposed to IGF-I at concentrations of 10(-8) and 10(-10) mol/L for 0, 1, 3, and 10 minutes, and then lysed. The IGF-I receptor beta subunit was immunoprecipitated, and the protein was resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotted with antiphosphotyrosine antibody (4G10). We found that, in the absence of exogenous IGF-I, there was a basal level of tyrosine phosphorylation of the IGF-I receptor beta subunit, and it was substantially greater in PV than in normal. At 10(-10) mol/L IGF-I in normals, no evidence of increased tyrosine phosphorylation was detected; however in PV, a pronounced increase in tyrosine phosphorylation was observed at both 10(-10) and 10(-8) mol/L IGF-I, and it occurred earlier and attained a higher level than in normal. In contrast, in PBMNC from three patients with erythrocytosis, no significant increase above normal was seen in either basal or induced tyrosine phosphorylation of the IGF-I receptor beta subunit. Thus, our findings show two distinctive features of the PV phenotype in PBMNC: (1) an increased basal tyrosine phosphorylation of the IGF-I receptor beta subunit, and (2) a hypersensitive and hyperresponsive receptor with respect to tyrosine phosphorylation. These features may influence the ability of the receptor to transmit a proliferative signal; thus, they may play a role in the pathogenesis of PV.

Can ultrasound replace diagnostic peritoneal lavage in the assessment of blunt trauma?

Diagnostic peritoneal lavage (DPL) and computed tomography (CT) are the primary diagnostic modalities in the evaluation of patients with suspected blunt abdominal trauma (BAT). Diagnostic peritoneal lavage is fast and accurate but associated with complications. Computed tomography is also accurate, yet requires that patients be stable and transportable. A prospective study was designed to determine the utility of emergency ultrasound (US) studies in the initial assessment of BAT. Two hundred acutely injured patients with suspected BAT were evaluated with US. Patients were eligible for the study if they met trauma criteria and had suspected BAT. Subsequently, without knowledge of the US results, DPL or CT was performed. Ultrasound showed a sensitivity of 83%, a specificity of 100%, and an accuracy of 97% in detecting intra-abdominal injuries. Six injuries were missed but only one was felt to be significant. If US had been used in all 200 patients, 199 would have had appropriate care. We conclude US is reliable in the detection of free intraperitoneal fluid and may be used in place of DPL or CT.

Circulating erythroid progenitors in polycythemia vera are hypersensitive to insulin-like growth factor-1 in vitro: studies in an improved serum-free medium.

We have investigated the question of erythropoietin (Epo) hypersensitivity versus Epo independence as the basis for the endogenous erythroid bursts (EEBs) that develop in cultures without added Epo from hematopoietic cells of polycythemia vera (PV) patients. Using an improved serum-free (SF) medium containing interleukin (IL)-3, but no insulin-like growth factor-1 (IGF-1), and devoid of contaminants that influence erythropoiesis, we compared circulating normal and PV early erythroid progenitors (BFU-E) with respect to their responses in vitro to recombinant human (rHu) Epo. Cultures were seeded with Ficoll-Hypaque density-separated peripheral blood (PB) mononuclear cells (MNCs), and erythroid bursts, together with their component colonies of > or = 50 cells, were scored in situ at 13 to 16 days of culture. The Epo dose-response curve of BFU-E from PV patients was found to be statistically indistinguishable from that of normal subjects. This observation provides compelling evidence against the Epo-hypersensitivity hypothesis. In the complete SF medium minus Epo, the sensitivity of BFU-E to IGF-1 was much greater in PV than in normals, the dose-response curve being shifted to the left by at least 2 orders of magnitude. These data show that the erythroid progenitor cell response in PV is hypersensitive to IGF-1, and independent of Epo. The data also emphasize the importance of truly SF medium conditions for assessment of progenitor cell sensitivities to recombinant growth factors. Depletion of adherent cells totally prevented erythroid burst formation by normal circulating progenitors, but did not prevent the hypersensitive response to IGF-1 of such cells from PV patients. Hence, again unlike its normal counterpart, the progenitor cell response in PV appears to be independent of adherent cell control.

Autocrine and paracrine growth control by granulocyte-monocyte colony-stimulating factor of acute lymphoblastic leukemia cells.

Blast colony assays were performed on freshly obtained bone marrow samples from 19 newly diagnosed or relapsed children with acute lymphoblastic leukemia (ALL) of B lineage to determine the effect of added granulocyte-monocyte colony-stimulating factor (GM-CSF). Of the 19 marrow samples tested, 7 responded to GM-CSF with a mean increase in ALL blast colonies of 346%. Blast cells from one of the responders chosen for flow cytometric study showed expression of GM-CSF receptors on 38% of cells. These findings prompted us to establish five ALL cell lines of diverse phenotypes to examine the expression of GM-CSF and GM-CSF receptor genes in human leukemia, and to determine the role of GM-CSF in autocrine and paracrine growth control of ALL cells. One line, termed G2, manifested a GM-CSF-mediated autocrine pattern of cell growth with the following features: G2 blast colony growth in a serum-free system without added growth factor was density dependent; exogenous GM-CSF augmented G2 colony formation when the cells were seeded at low density; G2 cells constitutively expressed mRNA for GM-CSF and GM-CSF receptor; G2 cells also produced and secreted measurable amounts of GM-CSF into cell culture supernatant; and, monoclonal anti-GM-CSF antibodies abolished G2 colony growth when added to cultures with cells seeded at low density without growth factors. Of the other four ALL cell lines, three expressed mRNA for GM-CSF receptor and responded in vitro to added GM-CSF with increased blast colony growth; however, none of these four cell lines expressed mRNA for constitutive production of GM-CSF. A fifth ALL cell line lacked receptors for GM-CSF and did not respond in clonogenic assays to added GM-CSF. Thus, a bioregulator of normal hematopoiesis plays a central role in autocrine growth control of G2 ALL cells, and an important paracrine growth-promoting role in three of four other ALL cell lines.

Retinyl acetate and all-trans-retinoic acid enhance erythroid colony formation in vitro by circulating human progenitors in an improved serum-free medium.

Retinyl acetate (RA) dramatically increased the production of early (d16) erythroid colonies in vitro by circulating human progenitor cells growing in an improved serum-free (SF) medium. In the absence of either erythropoietin (Epo) or insulin-like growth factor I (IGF-I), RA alone was able to induce the hemoglobinization of cells in these erythroid colonies. RA synergized with Epo or with IGF-I to yield increased numbers of well-hemoglobinized early colonies. In the presence of defined burst promoting activity (BPA) provided by recombinant human interleukin 3 (rHuIL-3) and hemin, RA and all-trans-retinoic acid (ATRA) were identical with respect to their differentiation-inducing function for early erythroid colonies. ATRA increased the number of these colonies in a concentration-dependent manner, with maximal stimulation (3.5-fold) occurring at 30 nM in the presence of 5.5 ng/ml IL-3, 0.1 mM hemin, 3.0 U/ml Epo and 30 nM IGF-I. This appears to be the first demonstration of erythropoietic activity of two metabolic derivatives of vitamin A in SF medium.

Production of erythropoietic bursts by progenitor cells from adult human peripheral blood in an improved serum-free medium: role of insulinlike growth factor 1.

Several culture media for the growth of human circulating erythroid burst-forming units (BFU-E) that have been claimed to be "serum-free" ("SF") have actually included albumin preparations known to be contaminated with an undefined burst-promoting activity (BPA); a BPA has also been found in the preparations of other "SF" medium components. This has precluded reliable investigation of the growth factor (GF) requirements of these progenitors. Using a defatted, BPA-free bovine serum albumin (BSA) and the recombinant human growth factors (GFs) erythropoietin (rHu Epo), insulinlike growth factor 1 (rHu IGF-1), and interleukin-3 (rHu IL-3), we have developed an improved serum-free (SF) medium for the production of erythroid bursts from normal adult human peripheral blood mononuclear cells (PBMNC), which requires both hemin and retinyl acetate for its optimal performance. In the presence of BSA without IL-3 or Epo, no burst or colony formation was observed. With IL-3 and Epo alone, only a small number of day 14 erythroid colonies was obtained (12 +/- 1/10(5) PBMNC). Addition of hemin (0.1 mmol/L) allowed the direct scoring of day 14 hemoglobinized colonies and increased their number sevenfold (86 +/- 5). Inclusion of retinyl acetate at physiologic concentrations further augmented the number of colonies threefold to fourfold. Under these apparently optimal conditions, we found that IGF-I could entirely replace Epo. However, IGF-I required a 100-fold higher molar concentration than that of Epo to reach maximal stimulation. The combined effect of Epo and IGF-I was found to be less than the sum of their individual effects, suggesting an overlap in the sensitivities of erythroid progenitors to these GFs. The colony-forming efficiencies of erythroid progenitors in the improved SF medium was very high: 700 single, day 14 erythroid colonies/10(5) PB MNC (at 0.25 mmol/L hemin) distributed as 126 clusters (bursts), with a mean of 5.6 component colonies per burst. These findings show that IGF-I has an Epo-like activity that targets circulating early erythroid progenitors or their progeny, providing strong evidence for the existence of an Epo-independent pathway for normal human adult erythropoiesis, possibly operative when Epo levels are low.

Diamond-Blackfan anemia: heterogenous response of hematopoietic progenitor cells in vitro to the protein product of the steel locus.

Diamond-Blackfan anemia is a congenital disorder of erythropoiesis in humans, characterized by a macrocytic anemia often associated with physical anomalies. Mutations at either the W or Steel loci in the mouse also leads to a severe macrocytic anemia, as well as other developmental abnormalities. The W locus encodes the proto-oncogene c-kit, a member of the receptor tyrosine kinase family, while the Steel locus encodes a potent hematopoietic growth factor that is the ligand for c-kit. Growth of clonogenic marrow erythroid progenitor cells in vitro in the presence of the recombinant hematopoietic growth factors interleukin-3 (IL-3) and Steel was used to characterize this disease at the cellular level. Three patterns of in vitro marrow response to both recombinant IL-3 or Steel were observed among 10 Diamond-Blackfan patients: those that responded quantitatively and qualitatively almost as well as cells from normal marrow, those that responded at an intermediate level, and those that did not respond at all. These results provide evidence for cellular heterogeneity underlying the pathogenesis of this disorder and therefore raise the possibility that there may be more than one underlying molecular basis for the disease. No gross abnormalities in the structure of either the c-kit or Steel loci were observed in these patients. The normal response in culture of the progenitor cells from at least some patients to Steel with or without IL-3 raises the possibility of using this novel growth factor as a therapeutic agent in Diamond-Blackfan anemia.