Transforming growth factor-beta 3 alters intestinal smooth muscle function: implications for gastroschisis-related intestinal dysfunction.

BACKGROUND: Gastroschisis (GS) is a congenital abdominal wall defect that results in the development of GS-related intestinal dysfunction (GRID). Transforming growth factor-ß, a pro-inflammatory cytokine, has been shown to cause organ dysfunction through alterations in vascular and airway smooth muscle. The purpose of this study was to evaluate the effects of TGF-ß3 on intestinal smooth muscle function and contractile gene expression. METHODS: Archived human intestinal tissue was analyzed using immunohistochemistry and RT-PCR for TGF-ß isoforms and markers of smooth muscle gene and micro-RNA contractile phenotype. Intestinal motility was measured in neonatal rats ± TGF-ß3 (0.2 and 1 mg/kg). Human intestinal smooth muscle cells (hiSMCs) were incubated with fetal bovine serum ± 100 ng/ml of TGF-ß 3 isoforms for 6, 24 and 72 h. The effects of TGF-ß3 on motility, hiSMC contractility and hiSMC contractile phenotype gene and micro-RNA expression were measured using transit, collagen gel contraction assay and RT-PCR analysis. Data are expressed as mean ± SEM, ANOVA (n = 6-7/group). RESULTS: GS infants had increased immunostaining of TGF-ß3 and elevated levels of micro-RNA 143 & 145 in the intestinal smooth muscle. Rats had significantly decreased intestinal transit when exposed to TGF-ß3 in a dose-dependent manner compared with Sham animals. TGF-ß3 significantly increased hiSMC gel contraction and contractile protein gene and micro-RNA expression. CONCLUSION: TGF-ß3 contributed to intestinal dysfunction at the organ level, increased contraction at the cellular level and elevated contractile gene expression at the molecular level. A hyper-contractile response may play a role in the persistent intestinal dysfunction seen in GRID.

Regulation of endothelial nitric oxide synthase (eNOS) in myocardium subjected to cardioplegic arrest.

BACKGROUND: Nitric oxide (NO) production by both coronary endothelial cells and cardiomyocytes is thought to play a significant role in myocardial pathophysiology following ischemia/reperfusion (I/R). METHODS: In thirteen pigs subjected to 1 hour cardioplegic arrest (CA) on CPB, left ventricular (LV) biopsies were collected prior to CPB (baseline), at 60 min CPA, at 15 and 30 min reperfusion on CPB, and at 120 min post CPB. LV specimens were immunocytochemically stained against phospho-eNOS (Ser1177), phospho-eNOS (Thr495), phosphorylated ERK1/2, and AKT/PKB. Four additional pigs without CA served as controls. Cardiomyocytes were quantitatively investigated using TV densitometry (gray units: U). RESULTS: After 60 min CA phosphorylation of eNOS (Ser1177) increased significantly and remained elevated until 30 min of reperfusion. In contrast, eNOS (Thr495) phosphorylation remained unchanged during CA and throughout reperfusion. In control animals, eNOS phosphorylation remained unchanged. Akt/PKB activity significantly increased after 60 min CA and decreased thereafter. ERK1/2 activity remained unchanged during ischemia but increased during reperfusion. CONCLUSIONS: ENOS activation during ischemia occurs through phosphorylation at Ser1177 mediated by Akt/PKB. ERK1/2 does not seem to be involved in myocardial eNOS regulation especially not via phosphorylation at eNOS (Thr495).

Tissue Engineering to Repair Diaphragmatic Defect in a Rat Model.

Tissue engineering is an emerging strategy for repairing damaged tissues or organs. The current study explored using decellularized rat diaphragm scaffolds combined with human amniotic fluid-derived multipotent stromal cells (hAFMSC) to provide a scaffold, stem cell construct that would allow structural barrier function during tissue ingrowth/regeneration. We created an innovative cell infusion system that allowed hAFMSC to embed into scaffolds and then implanted the composite tissues into rats with surgically created left-sided diaphragmatic defects. Control rats received decellularized diaphragm scaffolds alone. We found that the composite tissues that combined hAFMSCs demonstrated improved physiological function as well as the muscular-tendon structure, compared with the native contralateral hemidiaphragm of the same rat. Our results indicate that the decellularized diaphragm scaffolds are a potential support material for diaphragmatic hernia repair and the composite grafts with hAFMSC are able to accelerate the functional recovery of diaphragmatic hernia.

International comparative analysis of injury mortality. Findings from the ICE on injury statistics. International Collaborative Effort on Injury Statistics.

OBJECTIVE: This report investigates international differences in injury mortality rates among 11 of the countries participating in the International Collaborative Effort on Injury Statistics. METHODS: The cause, intent, and age-specific injury mortality rates are calculated and presented from Australia, Canada, Denmark, England & Wales, France, Israel, New Zealand, The Netherlands, Norway, Scotland, and the United States. Data are presented by cause (or mechanism) and intent (or manner of death) according to the matrix framework for presenting injury mortality statistics published in August 1997. The benefits of this matrix approach to investigating injury mortality are explained with numerous examples. RESULTS: Injury death rates are higher in France and Denmark and lower in England & Wales, Israel, and The Netherlands than elsewhere. New Zealand, the United States, and Norway had similar average annual injury death rates of 56-57 per 100,000 population. As an example of the benefit of presenting data in the matrix framework, the total poisoning death rate in Denmark for all categories of intent (13 per 100,000) is about twice the rate in the United States. Unintentional poisoning death rates, however, are similar in the United States and Denmark (about 4 per 100,000) and are higher than elsewhere. However, the suicide poisoning death rate in Denmark is 3 times the rate in the United States. CONCLUSION: Using these results, the ICE on Injury will be investigating death registration practices in each of the countries to better understand international variation in injury mortality due to reporting or registration procedures.

Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1.

To address the controversy regarding the relationship between cognitive impairment (lowering of IQ) and magnetic resonance imaging (MRI) characteristics (T2-weighted hyperintensities or unidentified bright objects [UBOs]) in children with neurofibromatosis-1 (NF-1), we used a pairwise NF-1/ sibling design; we set out to predict the lowering of IQ in each child with NF-1 as a discrepancy from the IQ of an unaffected sibling (D-SIQ). Our multiple regression model included the age of the child with NF-1, familial or sporadic nature of the NF-1, number of locations in the child's brain occupied by T2-weighted hyperintensities (UBOs), and the volumetric percentage of brain tissue occupied by T2-weighted hyperintensities (UBOs). Only the number of locations occupied by UBOs accounted for IQ lowering (D-SIQ) in children with NF-1 (42% of the variance in D-SIQ). This is the first report to confirm that a continuum of lowered IQs in NF-1-affected children exists in relation to the distribution of UBOs (range 0-7), not just presence (vs. absence) of any UBOs.

A fluoxetine-induced frontal lobe syndrome in an obsessive compulsive patient.

The authors report the occurrence of apathy, indifference, inattention, and perseveration in an obsessive compulsive patient taking high doses of fluoxetine. These changes were associated with a decrease in cerebral blood flow in the frontal lobes and changes in neuropsychological tests generally associated with frontal lobe impairment. These clinical manifestations disappeared 4 weeks after discontinuation of fluoxetine.

Effects of selectin-sialyl Lewis blockade on mesenteric microvascular permeability associated with cardiopulmonary bypass.

OBJECTIVES: Cardiopulmonary bypass is associated with an inflammatory response that is associated with a neutrophil-mediated microvascular barrier injury. We studied the effects of blocking neutrophil-endothelial tethering on microvascular permeability and edema formation during cardiopulmonary bypass. Using a selectin antagonist that prevents interactions with their ligands, we hypothesized that there would be less neutrophil infiltration into the tissue and a reduction in microvascular permeability and edema formation. METHODS: A canine mesenteric lymphatic fistula was created to measure Starling forces and to determine microvascular permeability. Normothermic, atrial-femoral cardiopulmonary bypass was initiated (70-90 mL. kg(-1). min(-1)). Intestinal tissue water was determined with microgravimetry. Ileal tissue myeloperoxidase was measured as an index of neutrophil tissue infiltration. One experimental group received the selectin antagonist TBC 1269 before the initiation of bypass, and the control group received saline solution. RESULTS: There was a modest increase in microvascular permeability in both groups, as evidenced by significantly increased transvascular protein clearance and a trend toward a decrease in reflection coefficient. There were no differences in the experimental group compared with the control group. Ileal tissue myeloperoxidase levels were lower in the experimental group than in the control group. CONCLUSIONS: The selectin antagonist TBC 1269 reduces neutrophil infiltration into the ileum without altering ileal microvascular permeability or edema associated with cardiopulmonary bypass.

Complications of neonatal extracorporeal membrane oxygenation. Collective experience from the Extracorporeal Life Support Organization.

Since 1973, 7667 neonates have been treated with extracorporeal membrane oxygenation for severe respiratory failure and their cases reported to the Extracorporeal Life Support Organization Registry. The overall survival was 81% in these neonates, who were thought to have a survival of 20% without extracorporeal membrane oxygenation. A total of 4322 mechanical complications (0.56 +/- 0.84 per case) and 13,827 patient complications (1.80 +/- 2.12 per case) were reported overall. The most common mechanical complications included clots in the circuit (19%), cannula placement (9%), oxygenator failure (4%), and others (9%). Common patient complications included cardiopulmonary (43%), neurologic (35%), bleeding (35%), metabolic (32%), renal (25%), and renal (25%), and infectious (9%). From the initial experience to 1988 the average number of mechanical complications per case was 0.27 per case and this significantly increased during 1990 to 1992 to 0.75 per case (p < 0.05). Likewise, from 1973-1985 to 1988 the average patient complications per case were 1.44 per case and this significantly increased during 1990 to 1992 to 2.10 per case. During the same periods, patient survival significantly decreased from 84% (1973-1985 to 1988, n = 2463) to 80% (1990 to 1992, n = 4005). Venovenous double-lumen single cannula extracorporeal membrane oxygenation had a higher survival than venoarterial extracorporeal membrane oxygenation (91% versus 81%) and a lower rate of major neurologic complications. The incidence and survival with seizures (6% and 89% venovenous versus 13% and 61% venoarterial) or cerebral infarction (9% and 69% venovenous versus 14% and 46% venoarterial) was significantly lower with the venovenous method and appeared to have a substantial impact on overall survival. The correlation of patient complication rate and total complication rate with survival was highly significant, however, causality cannot be established. Explanations for the increase in complications, relative to a decrease in survival, despite a growing nationwide experience include (1) increased complexity of cases as many programs expand entry criteria (more premature infants, infants with grade 1 or 2 intracranial hemorrhage, and complex congenital diaphragmatic hernia), (2) a growing number of programs with fewer cases per program, yet greater accessibility, (3) less reluctance to report complications encountered during extracorporeal membrane oxygenation as group experience grows, and (4) changes in the Extracorporeal Life Support Organization data form to be more inclusive of more minor complications.

Pathophysiology of ovine smoke inhalation injury treated with extracorporeal membrane oxygenation.

An ovine model was used to study the pathophysiology of smoke inhalation injury treated with extracorporeal membrane oxygenation (ECMO). Smoke inhalation is characterized by leukocyte-oxygen free-radical mediated acute lung injury. Treatment with ECMO was by extracorporeal venoarterial or venovenous perfusion using a venous drainage reservoir, roller pump, heat exchanger, and membrane lung oxygenator capable of oxygen delivery to and carbon dioxide removal from a patient. Blood-foreign surface interactions are known to occur during ECMO. We examined the effects of ECMO on circulating leukocytes, oxygen free-radical activity, thromboxane release, and gas exchange after smoke inhalation injury. Animals treated with smoke and ECMO had significantly increased circulating thromboxane B2 levels and oxygen free-radical activity compared with sham-treated animals and animals treated with smoke and mechanical ventilation (MV). Likewise, there was a significant increase in lung wet-to-dry weight ratios in animals treated with smoke and ECMO compared with those treated with smoke and MV. These data may account for the initial deterioration in native lung function after the initiation of ECMO and imply that ECMO may potentiate the pathophysiology of smoke inhalation injury.

Impact of hetastarch on the intestinal microvascular barrier during ECLS.

The effects of hetastarch on microvascular fluid flux were determined in anesthetized dogs undergoing extracorporeal life support (ECLS) with a roller pump and membrane oxygenator. ECLS with a lactated Ringer priming solution resulted in a decrease in microvascular protein reflection coefficient and an increase in transvascular protein clearance. Use of a 6% hetastarch priming solution attenuated the decrease in microvascular protein reflection coefficient and blunted the increase in transvascular protein clearance. Ileal tissue water increased in the group treated with the lactated Ringer priming solution compared with the group treated with 6% hetastarch. The effective plasma-to-interstitial colloid osmotic pressure gradient was greater in the group treated with hetastarch than in the group treated with lactated Ringer solution. Hetastarch decreases the edema associated with ECLS. The reduction in edema is due to the maintenance of the plasma-to-interstitial colloid osmotic pressure gradient and the reduction in the microvascular permeability to protein.

Influence of detergent aerosol on lung microvascular permeability.

Noncardiogenic edema fluid often contains high levels of plasma proteins, which may inhibit the function of the lung surfactant complex and thus decrease interstitial hydrostatic pressures. We questioned whether, in the awake and standing animal, displacement of the alveolar surface lining would alter the permeability of the thin and sparsely supported pulmonary capillaries. Sheep prepared with lung lymph fistulae were given an aerosolized detergent (Det) to displace the lung surfactant complex. After the sheep were given Det, protein flux was significantly increased (P < 0.05). To validate the suggested permeability increase, pulmonary vein occluders were surgically implanted and experiments repeated with pulmonary arterial pressures elevated 10 mmHg above baseline. After 2 h of elevated pulmonary arterial pressure, lung lymph increased fivefold. At this time, lymph-to-plasma total protein concentration ratios for air and saline-plus-ethanol vehicle were significantly lower (P < 0.01) than baseline ratios (0.26 +/- 0.06 and 0.34 +/- 0.07, respectively). No significant difference could be shown in lymph-to-plasma ratios after the sheep were given Det. We conclude that disruption of the alveolar lining can cause a detectable increase in protein flux due, in part, to an increase in microvascular permeability.

Effects of manganese superoxide dismutase on lung fluid balance after smoke inhalation.

There is evidence of increased oxygen free radical activity after smoke inhalation with and without concomitant burn injury. We determined the effects of manganese superoxide dismutase (Mn SOD) on lung fluid balance as measured by lung microvascular permeability coefficient (sigma), filtration coefficient (Kf), and lymph flow. Merino breed ewes (n = 6/group) were surgically prepared. The SOD group (SOD) received Mn SOD (9,000 U/kg) as an intravenous bolus and was insufflated with smoke. The control group (CON) received saline and smoke. sigma and Kf were determined 24 h before and 24 h after smoke injury. Lymph flow, arterial O2-to-inspired O2 fraction ratio, systemic hemodynamics, and pulmonary arterial and capillary pressures were measured. The sigma was significantly (P < 0.05) higher after smoke insufflation in SOD compared with CON (0.71 +/- 0.03 vs. 0.53 +/- 0.05). Kf was significantly lower after smoke insufflation in SOD compared with CON (0.038 +/- 0.010 vs. 0.061 +/- 0.010). Lymph flows were significantly lower during the 24 h after smoke insufflation in SOD compared with CON (33 +/- 7 vs. 55 +/- 8 ml/h at 24 h). Arterial O2-to-inspired O2 fraction ratio was significantly improved at 6 and 12 h after smoke insufflation in SOD compared with CON at the same time points. Mn SOD meliorates the lung microvascular permeability changes associated with smoke inhalation injury.

Delayed diagnosis of blunt duodenal injury: an avoidable complication.

BACKGROUND: There is controversy about the impact on morbidity from delayed diagnoses of blunt hollow viscus injuries. A recent study suggested that the increased morbidity was primarily from delayed diagnosis of blunt duodenal injury (BDI). STUDY DESIGN: We studied the medical records from a 10-year period from June 1987 to June 1997 examining the data on 22,163 cases of blunt trauma. We assessed the incidence and consequences of delayed diagnoses of BDI, and identified preoperative factors associated with these delayed diagnoses. RESULTS: Thirty-five patients (0.2%) were identified in the retrospective study of the records from 22,163 blunt trauma patients to have sustained BDI. Of these, 25 patients (71%) were male. Ages ranged from 1 to 58 years (mean 18.8 years), and the predominant mechanism was motor vehicle accident in 18 patients (51%). Seven patients (20%) (group I) had a diagnostic delay of > 6 hours; 28 patients (80%) (group II) were diagnosed in < 6 hours. Six of the seven group I patients (86%) were evaluated initially with CT scans, and five (83%) showed findings suggestive of BDI. Among the 28 group II patients, 14 (50%) underwent initial diagnostic peritoneal lavage (DPL), and 14 (50%) had a CT scan. In seven of the group II patients (50%) who were initially evaluated by CT scan, there were findings suggestive of BDI. Diagnostic peritoneal lavage was initially equivocal (red blood cell count=5,000 to 100,000) in the remaining one group I patient compared with three of the group II patients who had DPL. Deterioration found on physical examinations prompted followup CT scans in 6 group I patients (86%), and the scans were diagnostic for BDI in all cases. CONCLUSIONS: Blunt duodenal injury is an uncommon entity. Despite the presence of suggestive CT and DPL findings, the diagnosis was delayed in 20% of the 35 patients whose records were examined in the study; this delayed diagnosis was associated with increased abdominal complications. Patients with persistent abdominal complaints and equivocal CT or DPL findings should undergo laparotomy or repeat CT scan evaluations.

Pulmonary contusion: are children different?

BACKGROUND: Pulmonary contusion (PC) is a common sequelae of blunt trauma in adults and children; previous reports suggest that children have more favorable outcomes because of differences in mechanisms of injury, associated injury, and physiologic response. Our objective was to determine whether children who sustain PC have different outcomes compared with similarly injured adults. STUDY DESIGN: Our Level I Trauma Registry was reviewed for a 4-year period and identified 251 consecutive patients who sustained PC. Their charts were reviewed retrospectively for demographics, injury mechanism, injury severity scores, associated injuries, and outcomes (measured by the need for intubation, ventilation days, pneumonia, acute respiratory distress syndrome, and death). Data are expressed as the mean +/- SEM. The Student's t-test was used to compare the groups. A p value less than 0.05 was considered significant. RESULTS: Of the study patients, 41 (16%) were children (ages 2-16, mean 10 years) and 210 (84%) were adults (ages 17-80, mean 34 years). The most common injury mechanisms in children were motor vehicle accidents (56%) and auto-pedestrian accidents (39%), but in adults, motor vehicle accidents (80%, p = 0.02) predominated. Injury severity score was not significantly different between groups (children, 26 +/- 2 and adults 25 +/- 1). Similarly, the incidence of associated injuries was not different between children and adults: head 78% versus 62%, abdomen 59% versus 43%, and skeletal fractures 41% versus 29%, respectively. Neither need for intubation, ventilator days, pneumonia, acute respiratory distress syndrome, or death differed significantly between groups. CONCLUSIONS: Although children and adults differ in regard to injury mechanism, their overall injury severity, associated injuries, and outcomes are quite similar. Thus, contrary to previous reports, children do not have a more favorable outcome after PC.

Simplified insertion of a transpyloric feeding tube.

Placement of a transpyloric feeding tube is a common procedure done through a previous gastrostomy site. Conventional fluoroscopic and endoscopic methods can be tedious because of the difficulty in cannulating the pylorus. Described here is a simplified method to place a transpyloric feeding tube under fluoroscopy.

Airborne bacteria and viruses.

Coughing, sneezing, talking, bed-making, turning pages of books, etc. all generate microbial aerosols which are carried and dispersed by air movements. Inhalation of these particles may cause allergic responses but whether or not infectious disease ensues depends in part on the viability and infectivity of the inhaled microbes and their landing sites. Desiccation is experienced by all airborne microbes; gram-negative bacteria and lipid-containing viruses demonstrate phase changes in their outer phospholipid bilayer membranes owing to concomitant changes in water content and/or temperature. These changes most likely lead to cross-linking reactions of associated protein moieties principally at mid to high relative humidity (RH). For lipid-free viruses these reactions of their surface protein moieties occur most rapidly at low RH. Radiation, oxygen, ozone and its reaction products and various pollutants also decrease viability and infectivity through chemical, physical and biological modification to phospholipid, protein and nucleic acid moieties. The extent of damage and the degree of repair together with the efficacy of host defence mechanisms largely controls whether the causative microbes take hold and spread disease via the airborne route. At least indoors, where desiccation is the predominant stress, the general reversibility of membrane-phase changes by vapour-phase rehydration when coupled with efficacious microbial enzymatic repair mechanisms under genetic control, virtually ensures the spread of disease by the aerobiological pathway.

Poisoning mortality, 1985-1995.

Poisoning was reported as the underlying cause of death for 18,549 people in the United States in 1995 and was ranked as the third leading cause of injury mortality, following deaths from motor vehicle traffic injuries and firearm injuries. Poisoning was the leading cause of injury death for people ages 35 to 44 years. Poisoning death rates were higher in 1995 than in any previous year since at least 1979. From 1990 to 1995, the age-adjusted rate of death from poisoning increased 25%; all of the increase was associated with drugs. About three-fourths of poisoning deaths (77%) in 1995 were caused by drugs. The age-adjusted rate of drug-related poisoning deaths for males (7.2 per 100,000) in 1995 was more than twice that for females (3.0 per 100,000). From 1985 to 1995, poisoning death rates for males ages 35-54 years nearly doubled to 20.4 per 100,000, and the drug-related poisoning death rate for males ages 35-54 years nearly tripled, reaching 16.1 per 100,000. From 1990 to 1995, death rates associated with opiates and cocaine more than doubled among males ages 35-54 years. The numbers of opiate and cocaine poisoning deaths for 1995 more than doubled when all multiple cause of death codes were examined instead of only the underlying cause of death codes.

10 years after NHANES I: report of initial followup, 1982-84.

The NHANES I Epidemiologic Followup Study (NHEFS) was jointly initiated by the National Center for Health Statistics and the National Institute on Aging in collaboration with other National Institutes of Health and Public Health Service agencies. The goal of NHEFS is to examine the relationship of baseline clinical, nutritional, and behavioral factors assessed in the first National Health and Nutrition Examination Survey (NHANES I-1971-75) to subsequent morbidity and mortality. Data collection for the initial phase of followup took place between 1982 and 1984 and included tracing of all NHANES I participants, determining their vital status, conducting in-depth interviews with surviving participants or with proxies for those who were deceased or incapacitated, conducting selected physical measurements, obtaining facility records for stays in hospitals or nursing homes that occurred during the period of followup, and obtaining death certificates for decedents. Ninety-three percent of the original cohort was successfully traced. Interviews were conducted for 93 percent of traced, surviving participants and 84 percent of traced, surviving participants and 84 percent of traced, deceased subjects. Physical measurements were obtained for approximately 95 percent of surviving, interviewed subjects. Death certificates are available for more than 95 percent of the decedents, and 18,136 facility records were received for 6,477 subjects.

10 years after NHANES I: mortality experience at initial followup, 1982-84.

The NHANES I Epidemiologic Followup Study (NHEFS) was initiated jointly by the National Center for Health Statistics and the National Institute on Aging in collaboration with other National Institutes of Health and Public Health Service agencies. The goal of NHEFS is to examine the relationship of baseline clinical, nutritional, and behavioral factors assessed in the first National Health and Nutrition Examination Survey (NHANES I-1971-75) to subsequent morbidity and mortality. Tracing for the initial followup began in 1981 and ended in 1984. This article compares the mortality experience of the NHEFS cohort with survival probabilities and cause-of-death distributions derived from U.S. vital statistics data. The analysis was done for 28 age-race-sex specific subgroups. The survival of each group of the NHEFS cohort corresponds quite closely to that expected on the basis of the U.S. life table survival probabilities. Mortality differentials by age, race, and sex are also quite similar between NHEFS and U.S. vital statistics. In addition, the cause-of-death distributions among NHEFS participants are quite similar to those expected based on national vital statistics. Thus, there do not seem to be any serious biases in the mortality data. The NHEFS, therefore, provides a unique resource for assessing the effects of baseline sociodemographic, health, and nutritional factors on future mortality in a large, heterogeneous sample that is representative of the nation's population.

Staging and surgery for lung cancer.

Surgery for lung cancer has evolved dramatically over the years. Although 5-year survival for patients with lung cancer remains low, new surgical techniques have increased survival rates for different stages of lung cancer. The article reviews the stages of lung cancer, the different surgical techniques used to treat lung cancer, and the complications of those surgical techniques.