Ethical issues in developing pharmacogenetic research partnerships with American Indigenous communities.

Pharmacogenetic research offers the potential to improve the safety and efficacy of drug prescribing. Assuring that the benefits of this research reach indigenous and other medically underserved people is an important justice concern. First, however, a legacy of mistrust, derived from traditional research practices that disempower communities, must be overcome. Linking pharmacogenetic research to collaborative, power-sharing research partnerships provides a valuable opportunity to develop new and positive precedents for genetic research in indigenous communities.

Computed tomography assessment of lung volume changes after bronchial valve treatment.

The aim of the present study was to correlate clinical outcome measures following treatment with bronchial valves with regional lung volume. Computed tomography (CT) scan data from 57 subjects with severe emphysema were obtained from nine North American clinical trial sites. IBV(R) Valves (Spiration, Inc., Redmond, WA, USA) were placed to occlude segmental and subsegmental bronchi in right and left upper lobes using a flexible bronchoscope. Subjects completed a St George's Respiratory Questionnaire (SGRQ), pulmonary function test (PFT) and exercise capacity test. CT scans were analysed at baseline and at 1, 3 or 6 months after treatment to measure total and lobar lung density, volume and mass. Total lung volumes measured using CT were strongly correlated with PFT and did not change with treatment. However, the treated upper lobes significantly decreased in volume in 88% of the observations, by mean+/-sd 335+/-444 mL, or a decrease of 10.2% in the 6 month data. The untreated lobes had an 11.6% increase in volume. Changes in regional lung volume were associated with clinically meaningful improvements in SGRQ (-8.95+/-16.22), but not clinically meaningful PFT changes. The significant health status improvements reported by subjects following bilateral bronchial valve treatment are associated with regional lung volume changes and interlobar shift measured using computed tomography.

High tumor grade in salivary gland mucoepidermoid carcinomas and loss of expression of transforming growth factor beta receptor type II.

BACKGROUND: Mucoepidermoid carcinoma (MEC) of salivary glands is a malignant, locally aggressive neoplasm with metastatic potential. The clinical course is usually dependent on histology; however, low-grade carcinomas can result in metastases and tumor-related death. Transforming growth factor beta1 (TGF-beta1) is a potent cytokine that affects growth inhibition of various cells and stimulates extracellular matrix production and angiogenesis. Loss of TGF-beta receptor type II (TGF-beta RII) expression has been related to resistance of TGF-beta1-mediated growth control and tumor progression. In this study, we correlate MEC tumor grade with expression of TGF-beta1 and TGF-beta RII. DESIGN: Immunohistochemical staining was performed on 16 MEC specimens for activated forms of TGF-beta1 and TGF-beta RII. The percentage of cells in which staining yielded positive findings for activated TGF-beta1 and TGF-beta RII was correlated with tumor grade. RESULTS: Activated TGF-beta1 was detected in 16 specimens (100%) of MEC and showed strong positive and diffuse staining. Predominately cytoplasmic staining of TGF-beta1 was seen in salivary gland ducts, stroma, and endothelial cells. There was an inverse correlation between tumor grade and loss of expression of TGF-beta RII. All low-grade MEC tumors yielded positive staining results, whereas only one case of intermediate-grade MEC had TGF-beta RII expression. No high-grade MEC showed TGF-beta RII expression. CONCLUSIONS: Loss of expression of TGF-beta RII correlates with tumor grade. The localization of activated TGF-beta1 within neoplastic epithelium, tumor-associated stroma, and endothelium suggests that it might play a role in the stromal proliferation and/or angiogenesis associated with MEC.

Transforming growth factor and neutralizing antibodies in subglottic stenosis.

Transforming growth factor beta 1 (TGF-beta1), which is implicated in the pathogenesis of fibrotic diseases such as interstitial fibrosis, may be associated with subglottic stenosis. To study this hypothesis, we measured TGF-beta1 expression sequentially in 28 rats after posterior cricoid injury, using both standard immunohistochemistry and reverse transcriptase-polymerase chain reaction. In addition, an osmotic pump infused TGF-beta1 in 18 rats, normal saline solution in 9 rats, and neutralizing antibodies in 9 rats. Specimens were stained for fibronectin and procollagen at 1, 7, and 21 days and underwent optical density analysis. In the injured airway, TGF-beta1 expression peaked at 1 day and returned to baseline by 21 days. The TGF-beta1 infusion led to an increase in the expression of extracellular matrix proteins relative to controls. In contrast, neutralizing antibodies led to a decrease in extracellular matrix protein expression. These findings suggest that TGF-beta1 may possibly play a role in the pathogenesis of subglottic stenosis.

Immunolocalization of erythropoietin and erythropoietin receptor in vestibular schwannoma.

Vestibular schwannomas constitute approximately 6% of intracranial tumors. Apart from the association with neurofibromatosis-2 (NF-2), where a defect in chromosome 22 has been identified, the pathogenesis of sporadic vestibular schwannomas is largely unknown. Very few studies have explored the role of neurotrophic growth factors in vestibular schwannoma. The objective of this study is to evaluate for the presence and pattern of EPO and EPO-R expression within vestibular schwannomas. Our hypothesis that erythropoietin (EPO) and erythropoietin receptor (EPO-R) were expressed in vestibular schwannomas was based on a recent report of rapid growth of a vestibular schwannoma in a patient undergoing preoperative EPO treatment. Using immunohistochemistry, we have demonstrated that both EPO and EPO-R are expressed in a majority of these tumors.

Immunolocalization of activated transforming growth factor beta1 in juvenile nasopharyngeal angiofibroma.

BACKGROUND: Juvenile nasopharyngeal angiofibroma (JNA) is a histologically benign, locally aggressive neoplasm of the nasopharynx that exclusively affects male adolescents. It is known to be sensitive to androgens, but there are likely intermediary cytokines and/or growth factors that mediate aggressive stromal cell proliferation and angiogenesis. Transforming growth factor beta1 (TGF-beta1) is a polypeptide that is secreted in an inactive form, cleaved to produce an active form, and then deactivated in the tissues. It activates fibroblast proliferation and is known to induce angiogenesis. OBJECTIVES: To evaluate the presence of activated TGF-beta1 within the stroma of JNA specimens and to quantify the percentage of JNA specimens expressing the active growth factor. DESIGN: Immunohistochemical analysis was performed on 19 specimens of JNA using a unique antibody that identifies only the activated form of TGF-beta1. The percentage of cells staining positively for activated TGF-beta1 was determined semiquantitatively by visual methods. RESULTS: Of 19 cases stained, all 19 (100%) showed strong positive staining (2 cases with 33%-66% of cells staining and 17 with 66%-100% of cells staining). Activated TGF-beta1 was identified in stromal cell nuclei and cytoplasm and in the endothelium of the capillaries within all specimens of JNA. CONCLUSIONS: The localization of activated TGF-beta1 to the fibroblasts and endothelial cells within JNA tumors suggests that TGF-beta1 may play a role in the stromal cell proliferation and angiogenesis associated with JNA. Additional receptor studies and more quantitative methods of analysis are needed to further define the role of TGF-beta1 in the pathogenesis of JNA.

Computed tomography--guided needle biopsy of head and neck lesions.

OBJECTIVE: To evaluate the diagnostic efficacy of computed tomography (CT)-guided needle biopsies of head and neck lesions. DESIGN: All CT-guided needle biopsies of head and neck lesions performed between September 1994 and February 1999 were included. Cytopathologic and histologic records, along with patient clinical records, were reviewed. SETTING: A tertiary care medical center. PATIENTS: Patients referred for evaluation of lesions inaccessible to routine methods of needle biopsy. RESULTS: Thirty-seven patients underwent 42 CT-guided biopsies. There were included 12 lesions in or adjacent to the skull base and 9 lesions around the pharyngoesophageal or laryngotracheal complex; the other lesions were located in the deep lobe of the parotid gland (n = 7), deep neck area (n = 12), and thyroid gland (n = 2). Diagnostic cytologic biopsy specimens were obtained in 38 (91%) of 42 needle biopsy procedures. The results were supported histologically and/or clinically in 36 cases (95%). Eighteen patients underwent open surgical procedures. Histologic confirmation was found in 86% of cases. Nineteen patients (51%) avoided an open surgical procedure: 11 with benign disease and 8 with recurrent malignancy. There were no false-positive or false-negative results, and no complications were identified. CONCLUSIONS: Computed tomography-guided needle biopsy is a safe and reliable minimally invasive technique for the diagnosis of poorly accessible or deep-seated lesions of the head and neck. Diagnostic needle biopsies allow improved preoperative planning and patient counseling in surgical patients and avoidance of open surgical procedures in patients with benign disease or recurrent malignant neoplasms.

Analysis of low-speed rotational atherectomy for the reduction of platelet aggregation.

Platelet activation is an important determinant of acute outcomes of percutaneous intervention. The objective of this study was to assess the effect of rotational atherectomy on platelet activation in an in vitro model. Freshly collected heparinized porcine blood was exposed to a 2.0-mm Rotablator burr rotating at one of three speeds: 180,000, 140,000, or 0 rpm. The specimens were analyzed immediately for concentration and size of platelet aggregates and plasma-free hemoglobin. There were significantly more platelet aggregates of >20-microm diameter at higher speeds (7,434+/-2,193 at 180,000, vs. 2,269+/-627 at 140,000, vs. 633+/-258 aggregates/ml at 0 rpm; P < 0.001). Plasma-free hemoglobin, a simple measure of cell damage, decreased with decreasing rotational speed (429+/-168 mg/dl at 180,000, vs. 88+/-44 mg/dl at 140,000, vs. 9+/-9 mg/dl at 0 rpm; P < 0.0001). In vitro, platelet activation decreases with decreasing burr speed, suggesting that the use of the Rotablator system at its minimum approved speed (140,000 rpm) could prove clinically beneficial.

Transdermal clonidine as an adjunct to enalapril: an evaluation of efficacy and patient compliance.

This four-center, 20-week, open-label study evaluated transdermal clonidine as an adjunct to enalapril 10 mg daily and demonstrated patterns of compliance. Seventy-four mildly to moderately hypertensive patients (mean seated blood pressure, 150/101 mm Hg) received enalapril 10 mg once daily as initial monotherapy. In 66 patients, the seated diastolic blood pressure remained greater than or equal to 90 mm Hg at the trough blood levels of enalapril. Transdermal clonidine (3.5 cm2, 7.0 cm2, or 10.5 cm2, equivalent to 0.1 mg, 0.2 mg, and 0.3 mg clonidine/day, respectively) then was added as needed to achieve blood pressure control. Forty-eight patients achieved diastolic blood pressures less than 90 mm Hg on concomitant therapy; 44 patients completed 8 weeks of maintenance dosing with a mean blood pressure of 134/85 mm Hg. Oral compliance, as measured by an electronic device that was actuated each time the medication vial was opened, varied from 48 to 140%. Compliance with the transdermal clonidine regimen was excellent; the patch was worn as directed during 96% of the patient-weeks of therapy. The authors conclude that blood pressure can be controlled by a combination of transdermal clonidine and enalapril in patients that do not adequately respond to enalapril monotherapy. Patients poorly complying with oral regimens may be candidates for a trial of transdermal clonidine monotherapy.

Treatment of traumatic rupture of the thoracic aorta. A 15-year experience.

Traumatic rupture of the thoracic aorta is increasing in incidence and remains a highly lethal injury. The morbidity associated with this injury also remains high. We retrospectively reviewed the records of all patients admitted to our emergency department with ruptured thoracic aortas during a 15-year period to determine the reason for this persistently high morbidity and mortality and to identify any factors that might improve the outcome. We found that patients who are in unstable condition on arrival in the emergency department or who become unstable before reaching the operating room are not likely to survive. Patients who are injured in automobile accidents have a greater chance of survival than do those injured in motorcycle accidents or car-pedestrian accidents. Patients who are in hemodynamically stable condition after aortic injury survive only if diagnosis and treatment are prompt. Major complications of repair following thoracic aortic injury relate primarily to the length of cross-clamp time, and every effort should be devoted to keeping the cross-clamp time less than 30 minutes.

Esophagobronchial fistula and mediastinal tuberculosis.

A 59-year-old man was seen with what preoperatively was thought to be an acquired esophagobronchial fistula secondary to an old burned-out infection with tuberculosis. At operation the gross and microscopic findings were most compatible with a congenital H-shaped esophagobronchial fistula. However, cultures of calcified lymph nodes grew Mycobacterium tuberculosis. The need for culturing calcified tissue to assure proper treatment is emphasized.

Indications for placement of drains in the splenic fossa.

Drainage of the splenic fossa has for years remained a controversial issue. A large potential space exists in the left hypochondrium following splenectomy. Proponents of the use of drainage maintain that drainage is safe, efficacious in removal of blood, serum, and pancreatic enzymes, and carries little, if any, risk of subsequent infectious morbidity. Critics of the use of drainage cite the heretofore reported high incidence of subphrenic abscess formation in those patients in whom drains are placed as the reason for abandoning routine or therapeutic drainage of the splenic fossa.

Comparative anatomy and histochemistry of human and canine latissimus dorsi muscle.

Gross and histologic studies of human and canine latissimus dorsi muscle were carried out to identify anatomic and histochemical properties that may be relevant to its use as a resource muscle, particularly for heart reconstruction. In both human and canine latissimus dorsi, three distinct muscle segments were observed, differing in direction of fibers, fiber characteristics, thickness, and blood supply. The entire canine latissimus dorsi could also be separated into superficial and deep layers, whereas only the anterolateral segment of human latissimus dorsi was separated further by the neurovascular bundle. Histochemical studies suggested significant differences between the ratios of fast to slow fibers in the superior and anterolateral segments of human muscle. Variation in size, weight, and shape within and between subjects demonstrates a need for careful evaluation of the potential resource muscle.

Validity of 3-methylhistidine excretion as an indicator of skeletal muscle protein breakdown in humans.

The urinary excretion of 3-methylhistidine (3MEH) in humans and animals has been used as a biologic marker for skeletal muscle protein breakdown. In rats, it has been recently suggested that there is a significant contribution of 3MEH in urine from the gastrointestinal tract due to the rapid turnover of protein in that tissue. To evaluate this point in humans, six patients with short bowel were evaluated. They were placed on three-day meat-free diets while 24-hour urine collections were obtained. The mean +/- SEM 3MEH in the short-bowel group was 3.27 +/- 0.34 mumol/kg/d and the mean +/- SEM molar ratio of 3MEH to creatinine was 0.0212 +/- 0.0012. These data were not significantly different from the control group at 95% confidence level. The results suggest that the contribution of the small intestine appears to be negligible, therefore urinary 3MEH should continue to be a valid index of skeletal muscle breakdown in man.

The significance of colloid osmotic pressure during induced hypothermia.

Colloid osmotic pressure (COP) during hypothermia with and without total circulatory arrest was evaluated in 20 adult mongrel dogs (average body weight = 18.6 kg). All animals were surface-cooled to 20 degrees C (rectal temperature) under halothane-diethyl ether azeotrope anesthesia and divided into 4 equal groups. In Groups I (non-arrest) and II (60 minute-arrest) 10% low molecular weight dextran (LMWD; 1 gm/kg = 10 ml/kg) was administered during cooling. Physiological saline (10 ml/kg) was given in Groups III (non-arrest) and IV (60 minute-arrest) during cooling. COP in LMWD groups increased significantly during cooling and was consistently higher than it was in the saline groups during rewarming. There were no significant differences in heart rate (HR), mean arterial pressure (MAP), central venous (CVP) and pulmonary artery wedge pressures (PAW) between the 4 groups during cooling. The increase in hematocrit (Hct) in animals that received saline was significant at the end of cooling and during rewarming. Hct was not significantly changed in Group I throughout the procedure, whereas in Group II (60 minute-arrest) it increased significantly during rewarming despite the administration of LMWD. Rewarming time in Group II was significantly shorter than in Group IV (144.2 +/- 9.6 min vs 193.2 +/- 32.6 min, respectively). We conclude that the administration of LMWD effectively reduces hemoconcentration and is also beneficial for maintaining better peripheral circulation.

Whole body protection during three hours of total circulatory arrest: an experimental study.

Survival following 3 hr of total circulatory arrest under profound hypothermic conditions was explored in 19 adult mongrel dogs. Thermoregulatory management included combined surface/perfusion hypothermia and azeotrope anesthesia in 95% O2/5% CO2. All animals were resuscitated and survived for at least 12 hr. During the last seven trials (Group II) the following principles were applied: uniform whole-body cooling where differences between rectal, esophageal, and pharyngeal temperatures averaged less than 1 degree C, induction of circulatory arrest at approximately 3 degrees C, constant lung inflation (10-12 cm H2O between 20 degrees C cooling and 20 degrees C rewarming, including the 3-hr arrest period) and ventilation assistance with positive end-expiratory pressure (4 cm H2O) after 20 degrees C rewarming, intraoperative maintenance of colloid osmotic pressure (COP) above 11 mm Hg, replacement of the cooling perfusate with a colloid-rich rewarming prime (COP = 15 mm Hg) and restoration of hemostasis with fresh whole blood transfusions. The application of these principles resulted in the long-term survival of five animals with four survivors displaying no clinically detectable neurological abnormalities. However, two animals developed optic impairment and one animal died from intusseption on the fourth postoperative day. Despite the improved results, it should also be noted that during pilot (Group I) studies (from which the aforementioned principles were derived) fatalities from complications attributed to systemic edema, central nervous system, or pulmonary or coagulation dysfunctions occurred in 9 out of 12 trials. We conclude that whole body protection following 3 hr of total circulatory arrest at a uniform temperature less than 5 degrees C can be successfully accomplished.

Patch closure of aortic annulus mycotic aneurysms.

Twenty-three patients with bacterial endocarditis and mycotic aneurysms of the aortic annulus were treated between 1978 and 1985. There were 18 men and 5 women ranging from 24 to 72 years old. All patients had congestive heart failure and positive blood cultures as a complication of the endocarditis and were in New York Heart Association (NYHA) Functional Class III or IV. The aneurysm complicated late prosthetic valve endocarditis in 7 patients and native valve endocarditis in 16. The most common infecting organisms were streptococci (12 patients) and staphylococci (7 patients). The noncoronary sinus was the most frequent site for aneurysm formation. Following debridement of the abscess cavity, the orifice of the aneurysm was closed with a patch of Dacron in 20 patients and autologous pericardium in 3. A prosthetic valve (18 bioprosthetic and 5 mechanical) was secured to the noninfected portion of the native annulus and to the patch at the level of annulus. There were 3 deaths, 1 perioperative and 2 late, each without evidence of residual infection or aortic insufficiency. There are 20 late survivors (87%). After a mean follow-up of 1 year, all patients are in NYHA Functional Class I. Patch closure of mycotic aneurysms involving the aortic annulus permits aggressive debridement of the abscess cavity and affords closure of the orifice without tension. The prosthetic valve can be seated at the level of the native annulus, thus avoiding complicated reconstructive procedures of the aortic root and coronary arteries. This technique is an effective alternative in selected cases of mycotic aneurysms involving the aortic annulus.

Simplified technique for pericardial patch of the right ventricular outflow tract.

Pericardial patching to enlarge the right ventricular outflow tract is often required in congenital cardiac surgery in lesions such as tetralogy of Fallot, pulmonary atresia, pulmonary stenosis, and pulmonary artery repair following removal of a palliative pulmonary artery band. A method of simplifying the attachment of the pericardial patch onto the right ventricular outflow tract is described.

Blood anesthetic levels during surface-induced deep hypothermia under halothane-diethyl ether azeotrope anesthesia.

Blood anesthetic concentration and clinical indicators related to anesthetic management during surface-induced deep hypothermia were determined in seven adult mongrel dogs. The azeotrope of halothane and diethyl ether was assayed by gas chromatography. Blood concentration of halothane ranged from a pre-cooling control of 0.74 vol % to 0.11 vol % at 20 degrees C rewarming; ether ranged from 0.06 vol % at 20 degrees C rewarming to 0.22 vol % at 35 degrees C rewarming. Administration of anesthetic was reduced during cooling because of the spontaneous decrease in mean arterial pressure and heart rate. After elective circulatory arrest was induced, anesthetic was not required until after cardiac resuscitation at about 22 degrees C rewarming. Initial clinical signs indicating a need to increase administration of anesthetic included spontaneous respiration and an increase in mean arterial pressure. Blood azeotrope concentration was significantly lower during rewarming than at comparable temperatures during cooling. We conclude that blood concentration of halothane and ether changes as a function of body temperature and that anesthetic demand may be diminished following total circulatory arrest.