Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia.

Pseudoachondroplasia (PSACH) is a well characterized dwarfing condition mapping to chromosome 19p12-13.1. Cartilage oligomeric matrix protein (COMP), a cartilage specific protein, maps to the same location within a contig that spans the PSACH locus. Using single strand conformation polymorphism (SSCP) analysis and nucleotide sequencing we have identified COMP mutations in eight familial and isolated PSACH cases. All mutations involve either a single base-pair change or a three base-pair deletion in exon 17B. Six mutations delete or change a well conserved aspartic acid residue within the calcium-binding type 3 repeats. These results demonstrate that mutations in the COMP gene cause pseudochondroplasia.

Clarifying domains of internalizing psychopathology using neurophysiology.

Current initiatives such as the National Institute of Mental Health's Research Domain Criteria project aim to reorganize classification of mental disorders along neurobiological lines. Here, we describe how consideration of findings from psychiatric research employing two physiological measures with distinct neural substrates--the startle blink reflex and the error-related negativity (ERN)--can help to clarify relations among disorders entailing salient anxiety or depressive symptomatology. Specifically, findings across various studies and reviews reveal distinct patterns of association for both the startle blink reflex and the ERN with three key domains of psychopathology: (1) Fear (or phobic) disorders (distinguished by increased startle to unpleasant stimuli, but normal-range ERN). (2) Non-phobic anxiety disorders and negative affect (associated with increased ERN, increased startle across all types of emotional stimuli and increased baseline startle) and, more tentatively (3) Major depression (for which patterns of response for both startle and ERN appear to vary, as a function of severity and distinct symptomatology). Findings from this review point to distinct neurobiological indicators of key psychopathology domains that have been previously demarcated using personality and diagnostic data. Notably, these indicators exhibit more specificity in their relations with these three domains than has been seen in quantitative-dimensional models. Implications of these findings are discussed.

Implementation of active injury management (AIM) in youth with acute concussion: A randomized controlled trial.

BACKGROUND: Nearly 2 million youth seek acute medical care following concussion in the U.S. each year. Current standard of care recommends rest for the first 48 h after a concussion. However, research suggests that prolonged rest may lengthen recovery time especially for patients with certain risk profiles. Research indicates that physical activity and behavioral management interventions (sleep, stress management) may enhance recovery. To date, there is limited empirical evidence to inform acute (<72 h) concussion recommendations for physical activity and behavioral management in adolescents. OBJECTIVE: To determine the effectiveness of physical activity and behavioral management for acute concussion in adolescents and young adults, and to evaluate the role of patient characteristics on treatment response. METHODS: This multicenter prospective randomized controlled trial will determine which combination of physical activity and behavioral management is most effective for patients 11-24 years old who present to the emergency department or concussion clinic within 72 h of injury. Participants are randomized into: 1) rest, 2) physical activity, 3) mobile health application (mHealth) behavioral management, or 4) physical activity and mHealth app conditions. Assessments at enrollment, 3-5 days, 14 days, 1 month, and 2 months include: concussion symptoms, balance, vestibular-ocular and cognitive assessments, quality of life, and recovery time. Somatic symptoms and other risk factors are evaluated at enrollment. Compliance with treatment and symptoms are assessed daily using actigraph and daily self-report. The primary study outcome is symptoms at 14 days. CONCLUSION: Prescribed physical activity and behavioral management may improve outcomes in youth following acute concussion.

Obstetric morbidity associated with amniotic sheets.

OBJECTIVE: The objective of this study was to determine whether amniotic sheets are associated with an increase in obstetric and neonatal morbidity. METHODS: Using a cohort study design, we identified all women with amniotic sheets, detected by a second-trimester ultrasound examination at a university hospital over a 6-year period. All women who received an ultrasound examination during that time, without a diagnosis of amniotic sheets, were also identified, and two women from among this group were randomly selected as controls for each case. Maternal and neonatal data were abstracted from the medical records, and maternal and neonatal morbidity were compared between the two groups. RESULTS: One hundred and twenty-two women with pregnancies with a diagnosis of amniotic sheets were identified and compared to 244 women with pregnancies without a diagnosis of amniotic sheets. Composite obstetric morbidity was higher in women with amniotic sheets: 21.3% vs. 8.2% (relative risk (RR) 2.6; 95% CI, 1.5-4.5). Additionally, in women with amniotic sheets, neonates were more likely to be born with a birth weight of < 2500 g (RR 3.3; 95% CI, 1.8-6.4) and were more likely to be admitted to the neonatal intensive care unit (RR 2.3; 95% CI, 1.3-4.3). There were no perinatal deaths observed in either group. CONCLUSION: Amniotic sheets are associated with an increase in adverse obstetric outcomes.

Artificial kidneys and clearance calculations.

Clearance of solutes by artificial kidneys can be calculated using plasma flow and solute concentration, whole blood flow and plasma solute concentration, and midpoint of dialysis blood or plasma solute concentration and total amount of solute removed. Using these methods, the clearance of procainamide (PA) and N-acetylprocainamide (NAPA) was determined in 4 patients. In all but one case clearances using total amount recovered were greater than clearances using whole blood flow and plasma concentration. Without exception, clearance determined using amount recovered was substantially greater than clearance using plasma flow and plasma levels, suggesting that both PA and NAPA are removed not only from plasma but also from red blood cells. In vitro clearance of PA, NAPA, quinidine, and phenobarbital by 11 clinically available artificial kidneys and an XAD-4 hemoperfusion column was determined and differences were found.

Predictors of total parenteral nutrition-induced lipogenesis.

OBJECTIVE: To evaluate the incidence and cause of parenteral nutrition-induced lipogenesis. DESIGN: Retrospective patient review. SETTING: A 40-bed predominantly surgical ICU. PATIENTS: One hundred forty patients receiving central venous nutrition and mechanical ventilatory support. INTERVENTIONS: Indirect calorimetry was used to determine patient's measured energy expenditure (MEE) and respiratory quotient (RQ). Additionally total caloric intake (TCAL), glucose infusion rate, basal energy expenditure (BEE), estimated stress factor, and calculated energy expenditure (CEE) were assessed in each patient. MEASUREMENTS AND MAIN RESULTS: Net fat synthesis was found as RQs exceeded 1 in 47 percent of patients. Statistically significant differences in oxygen consumption, CO2 production, measured energy expenditure, total and carbohydrate caloric intake, and glucose infusion rate were found between groups of patients with an RQ < or = or > 1. Seventy-three percent of patients with glucose infusion rates > 4 mg/kg-min had RQs > 1. CONCLUSIONS: Net fat synthesis was found in a surprisingly large number of critically ill patients receiving central venous nutrition. Many of these patients received carbohydrate calories in excess of their measured energy expenditure, even though it appeared that they needed this level of caloric intake by clinical assessment. The high carbohydrate total parenteral nutrition (TPN) solutions with lipids provided only for prevention of essential fatty acid depletion resulted in an unacceptably high incidence of fat synthesis. The results suggest that caloric intake may be optimized in critically ill patients using indirect calorimetry. When calorimetry is not available, a total caloric intake of up to 140 percent of the BEE with glucose infusion rates not exceeding 4 mg/kg-min and fats providing 40 to 60 percent of calories will meet the energy requirements of most critically ill patients without forcing the RQ > 1.

Errors in estimating energy expenditure in critically ill surgical patients.

Thirty-one critically ill surgical patients were receiving central parenteral nutrition. All were intubated, and 29 were receiving mechanical ventilatory support. Nutritional and metabolic data were recorded at the time of indirect calorimetry. Measured energy expenditure (MEE) was compared with predictions of basal energy expenditure (BEE) and calculated energy expenditure, defined as the product of BEE and a stress factor estimated by the nutrition support service to account for severity of illness and activity. The MEE was significantly greater than the BEE and significantly less than the calculated energy expenditure. The estimated stress factor was significantly greater than the actual MEE/BEE ratio, and the correlation between these values was poor. Clinical assessment may overestimate energy expenditure in critically ill patients because of the apparent degree of illness used to determine the stress factor. Bedside indirect calorimetry may be useful to assess more accurately energy expenditure and optimize nutritional support.

Physiologic effects of steep positioning in the surgical intensive care unit.

Ten hemodynamically stable patients requiring mechanical ventilation for radiographically symmetric acute lung disease were studied during steep lateral positioning and continuous rotation in a Roto Rest kinetic treatment bed. There were no significant hemodynamic or ventilatory differences among the four positions (supine, right side down, left side down, and rotating). In four patients, arterial oxygen pressure (PaO2) decreased 16% to 49% in the lateral position when compared with the supine position. Continuous rotation restored the PaO2 toward the supine value in each patient. In six patients, PaO2 increased 11% to 35% during lateral positioning. In five of the six patients, the increase in PaO2 differed between sides, suggesting asymmetric lung disease. Continuous rotation did not significantly alter the PaO2 from the supine values in these patients. Adverse effects on oxygenation caused by positional changes may be reversed by continuous rotation using the Roto Rest kinetic bed.

Preload assessment in trauma patients during large-volume shock resuscitation.

OBJECTIVES: To evaluate the utility of the right ventricular end-diastolic volume index (RVEDVI) as a method of preload assessment in trauma patients during large-volume shock resuscitation, and to compare the RVEDVI with the pulmonary artery occlusion pressure (PAOP) as a predictor of preload in this patient population. DESIGN: Retrospective study of a consecutive series of 46 trauma patients, admitted between June 1, 1992, and June 1, 1993, who received a volumetric oximetry pulmonary artery catheter and greater than 10 L of fluid in 24 hours. SETTINGS: University level 1 trauma center. MAIN OUTCOME MEASURES: Correlations of the RVEDVI and PAOP with the cardiac index (CI) during the defined study period. RESULTS: Three hundred fourteen measurements of the RVEDVI, PAOP, CI, and other hemodynamic variables were evaluated. Patients received a mean +/- SD of 22.1 +/- 13.3 L of blood and fluid during the 24 hours. The RVEDVI correlated better (P < .001) with the CI (r = 0.39) than did the PAOP (R = 0.05). Furthermore, there was a better correlation (P < .04) between the RVEDVI and CI when the RVEDVI was 130 mL/m2 or less (r = 0.54) than when it was greater than 130 mL/m2 (r = 0.30). CONCLUSIONS: The RVEDVI is a better predictor of preload than the PAOP in trauma patients during large-volume shock resuscitation. When the RVEDVI is 130 mL/m2 or less, volume administration will likely increase the CI.

2-Hydroxydesipramine and desipramine plasma levels: how are they related to antidepressant response?

Thirty-six outpatients aged 20 to 51 with RDC primary major depressive disorder (MDD) completed a 5-week trial of desipramine following a week of single-blind placebo. Five had a past history of hypomanic disorder. For all but one patient, daily dosage at bedtime was constant for the final 4 weeks, with a mean (S.D.) of 168.1 (46.5) mg. Plasma samples drawn at the three final weekly visits were assayed by high-performance liquid chromatography for 2-hydroxydesipramine (2-OH-DMI) and desipramine. Mean (S.D.) plasma levels were 59.8 (30.0) ng/ml for 2-OH-DMI and 142.9 (138.6) ng/ml for desipramine. Thirteen patients (36%) had a final 17-item Hamilton depression rating < and = 6 and were classified as responders. According to receiver operating characteristics analysis, patients with plasma 2-OH-DMI levels > and = 58 and < 92 ng/ml had a greater likelihood of responding than those with lower or higher levels (p = 0.005, Fisher's exact test), while patients with plasma desipramine levels > and = 64 ng/ml were more likely to respond than those with lower levels (p = 0.032, Fisher's exact test). Results using an alternate response criterion were similar. These findings suggest that in desipramine-treated outpatients with primary MDD the relationship between therapeutic response and plasma levels is curvilinear for 2-OH-DMI and linear for desipramine.

Fibrinolytic agents inhibit platelet adhesion onto collagen type I-coated surfaces at high blood flow conditions.

The effect of fibrinolytic agents on platelet adhesion onto insolubilized collagen type I was evaluated. Normal human whole blood samples were incubated with agents and perfused over collagen-coated surfaces in a parallel-plate flow chamber. Platelet adhesion and aggregation were analyzed by video microscopy and image processing. When blood was perfused at 1500/s, both streptokinase and urokinase, each at 500 U/ml, caused a significantly less normalized platelet deposition, compared with controls. At 480/s, platelet deposition was not different between controls and test samples. Inhibition of platelet deposition at high flow rates was partly due to inhibition of platelet adhesion. Both ristocetin- and ADP-induced platelet aggregation were inhibited in test samples. The agents caused proteolytic degradation of plasma fibrinogen, but no degradation of platelet glycoproteins Ib and IIb-IIIa (GPIb and GPIIb-IIIa) and of plasma von Willebrand factor in test samples prior to perfusion. Post-perfusion von Willebrand factor degradation was not found. Plasmin may cause functional changes to plasma proteins and/or platelet receptors, altering their adhesive properties under flow. At high shear, fibrinogen degradation products may interfere with GPIIb-IIIa binding to insolubilized von Willebrand factor, leading to decreased platelet adhesion. Inhibition of platelet adhesion by thrombolytic agents could help maintain vessel patency after recanalization in stenosed arteries. Publishers.

High-inflation pressure and positive end-expiratory pressure. Injurious to the lung? No.

Survival rates in ARDS with conventional ventilation using high oxygen fractions and low PEEP levels have been reported to be less than 10%. In three prospective evaluations of ARDS in the 1980s, mortality rates remained greater than 60%. Early studies using high-level PEEP therapy in severe ARDS by Douglas, Downs, Kirby, and Civetta showed improved survival rates with ranges between 60% and 80%. In 1979 Gallagher reviewed 59 patients with ARDS who were treated with PEEP greater than 15 cm H2O titrated to improve FRC by achieving an intrapulmonary shunt fraction of 15%. The overall survival was 65%, with only 5% of the patients dying secondary to respiratory failure. In the more recent study by Miller in trauma patients and later by DiRusso in a variety of surgical patients, the overall mortality rate for those patients receiving PEEP greater than 15 cm H2O was 20% to 30%. Of the 14 patients who died, only seven (10% of the total) succumbed to respiratory failure. The remaining patients died from the primary underlying disease with normal oxygenation or after significant weaning from high PEEP levels. By using a goal-oriented approach to the management of patients with severe ARDS, we have found that high-level PEEP therapy was effective in lowering the intrapulmonary shunt and improving the SaO2 at acceptable levels of inspired oxygen. All of these patients were ventilated with traditional high tidal volumes (10 to 15 mL/kg) and therefore exhibited high peak inspiratory airway pressures. This support method did not seem to cause lung injury or an excessive amount of barotrauma in these patients, but in fact, was associated with a lower mortality rate (30%) than reported in other studies of patients with lesser degrees of lung oxygenation dysfunction and extrapulmonary organ system dysfunction. Currently available information indicates that increases in mean airway pressure (induced with PEEP or other modes of ventilatory support to restore losses in FRC that occur during ARDS) and limiting exposure to toxic concentrations of oxygen minimize ventilator-induced secondary lung injury and maximize chances for survival. Arbitrary limitations of peak inspiratory or end-expiratory airway pressure or mandatory tidal volume in patients with severe ARDS seem to be unfounded. Failure to achieve adequate physiologic end-points in these patients may increase morbidity and mortality rates.

The new pulmonary arterial catheters. Right ventricular ejection fraction and continuous cardiac output.

The flow-directed pulmonary artery catheter is the mainstay of hemodynamic monitoring in critically ill and injured patients. During its 25-year history, the catheter has been modified to measure mixed venous oxygen saturation, right ventricular ejection fraction, and recently, continual thermodilution cardiac output. The clinical application of the new generations of pulmonary artery catheters is reviewed in this article.

Continuous monitoring of mixed venous oxygen saturation during aortofemoral bypass grafting.

Measurement of mixed venous oxygen saturation (SvO2) may be helpful in the care of critically ill patients. Serial determinations of SvO2 give an index of the relationship between oxygen delivery and tissue oxygen consumption. Continuous monitoring of SvO2 is now readily available with the Shaw Oximetrix pulmonary artery catheter (Oximetrix Inc., Mountain View, CA). This system has provided useful information in the high risk cardiac surgery patient. Continuous monitoring of mixed venous saturation may be helpful in high risk or critically ill general and peripheral vascular surgery patients both in the intensive care unit and in the operating room. The following clinical report is presented to illustrate the usefulness of continuous SvO2 monitoring in a high risk vascular surgery patient.

Evaluation of acute mental status change in the nonhead injured trauma patient.

Acute mental status change in the first 24 hours after trauma is uncommon in nonhead injured patients who initially present with a normal sensorium. Although arterial hypoxemia is the classic etiology for such a mental status change, three less common etiologies should always be considered: cerebral fat embolism, blunt carotid artery injury, and vertebrobasilar artery thrombosis. Prompt diagnosis and appropriate treatment can significantly improve patient morbidity and mortality. Three nonhead injured trauma patients are described illustrating cerebral fat embolism, blunt carotid artery injury, and vertebrobasilar artery thrombosis as causes of acute mental status change. Each patient initially presented with a clear sensorium, but subsequently developed neurological deficits within 24 hours after admission. All had a normal admission CT scan of the head. MRI or conventional arteriography was diagnostic in each case. Any patient who is initially lucid and subsequently develops a neurological deficit, or a patient whose neurological status does not correlate with brain CT findings should undergo immediate evaluation for possible cerebral fat embolism or cervical vessel injury. An algorithm for management of nonhead injured trauma patients with acute mental status deterioration is presented.

Ingested endotracheal tube in an adult following intubation attempt for head injury.

General surgeons are often consulted for assistance in the management of ingested foreign bodies. Deglutition of an endotracheal tube is an unusual complication of airway management. In these cases, the artificial airway is "lost" when it becomes lodged deep into the esophagus. Endoscopic extraction has been described as therapeutic. We report a case in which prehospital endotracheal intubation attempt for the management of closed head injury resulted in a swallowed endotracheal tube. The tube remained undetected until radiographs were performed for a second unrelated traumatic event 2 years later. Endoscopic extraction was unsuccessful, due to rigidity of the tube. Surgical extraction via gastrotomy was uneventful. Surgeons involved in trauma and other emergency settings should be aware of this complication and options in management.

Personality change in head trauma: a validity study of the Neuropsychology Behavior and Affect Profile.

This study represents the first attempt to cross validate and report on the Neuropsychology Behavior and Affect Profile (NBAP) using closed head injury (CHI) participants. The NBAP is designed to measure emotional functioning before and following a brain event. Two CHI samples, differing primarily by method of ascertainment, were compared to a group of normal controls. Results provided support for concurrent and predictive validity of the NBAP across both CHI samples. Significantly higher levels of postinjury emotional functioning in clinic-referred CHI patients compared to CHI individuals not seeking treatment (strictly research participants) was demonstrated. A surprising finding was that pre-injury emotional levels of clinic-referred subjects were rated as less severe than that of controls. Based on this finding, the possibility of a gradient effect was discussed in which raters appeared to place selectively greater weight on current condition, while simultaneously making premorbid levels less severe than they really were. Results were discussed in the context of study limitations and directions for further research.

Clinical and research implications of revising psychological tests.

This article integrates those of other contributors to this special section, "Methods and Implications of Revising Assessment Instruments," to underscore important conceptual factors to consider when undertaking test revisions. These considerations include determination of when test measures have become sufficiently understood to be incorporated in a test revision, cohort effects, revision of administration formats and test instructions, and comparisons of performance levels across test versions. The discussion of these factors also takes into consideration clinical practice and educational implications of making a transition to revised test versions.

Handling and culture of bovine embryos: survey of media used by 26 embryo transfer companies in the USA.

Embryo transfer has evolved from a few highly centralized clinics to a widespread number of clinics offering both clinic and on-the-farm services. Practitioners in the field have made very few changes in the handling and culture of embryos. A short review of general handling techniques, plus a survey of media used by 26 companies in the USA, is presented here. Currently, phosphate-bufferend saline (PBS) plus two other commercially available media (EMCARE and ViGro) are used by these companies. Fourteen different combinations of these products were reported and only 11 of the 26 consistently used the same medium for flushing, culture and freezing.

Estrus synchronization with an oral progestogen prior to superovulation of postpartum beef cows.

Ovarian follicular dynamics and steroid secretion patterns were monitored in postpartum beef cows that were synchronized for estrus with melengestrol acetate (MGA) or prostaglandin F(2alpha) (PGF) prior to superovulation. Twenty-four muhiparous Angus cows were stratified by number of days postpartum to an MGA or PGF treatment prior to superovulation. Cows in the MGA group were fed 0.5 mg MGA/d for 14 d in a grain carrier. Superstitnulatory treatments began 14 d after withdrawal of MGA from feed or 11 d after administering a single injection of 500 microg cloprostenol (PGF). Supersthnulatory treatments (FSH) were administered twice daily in decreasing doses (7.5, 5, 5, 2.5 mg) over 4 d. Sixty and 72 h after initiating the superstimulatory treatments, all cows were treated with 750 microg and 500 microg PGF, respectively Cows were inseminated at 0, 12, and 24 h from the onset of standing estrus with semen from 2 proven sires. Cows within treatment were inseminated with 1, 2 and 1 (single) or 2, 4 and 2 units (double) of semen at the designated insemination times. Blood sampling and transrectal ultrasonography of ovaries were performed daily beginning 2 d prior to the initiation of FSH treatment and were continued through embryo recovery. Ovaries were examined daily to determine the number and size of follicles. Plasma samples were analyzed for progesterone and estradiol. Follicles were counted and categorized based on a 5 to 9 mm range or >/= 10 mm. At the end of superovulatory treatment there were more (P /= 10 mm among cows that were estrus synchronized with MGA (75 +/- 1.2) than with PGF (3.9 +/- 1.2) These differences were reflected in higher (P