The antiandrogenic effects of delta 1-testolactone (Teslac) in vivo in rats and in vitro in human cultured fibroblasts, rat mammary carcinoma cells, and rat prostate cytosol.

The antiandrogenic properties of delta 1-testolactone (17 alpha-oxa-D-homo-1,4-androstane-3,17-dione; Teslac) were investigated in vivo and in vitro. Teslac (75 mg/day for 7 days) inhibited the rise in ventral prostate weight induced by testosterone (T) (P less than 0.001), dihydrotestosterone (DHT) (P less than 0.05), and a combination of T plus 17 beta-estradiol (E2) (P less than 0.01) in immature castrate rats. Similar effects were seen on the seminal vesicles after T and T plus E2 (P less than 0.001). Teslac also decreased prostate and seminal vesicle weights in intact immature rats. The effects of Teslac were dose and time dependent. Teslac did not change the concentration of serum T or DHT. However, Teslac inhibited DHT binding to the androgen receptor (Ki = 2.5 +/- 0.8 X 10(-7) M) in cytosol of the rat prostate. Teslac also inhibited DHT binding to the androgen receptor in cultured human prepuce fibroblasts and cultured rat mammary tumor cells (Ki = 1.9 +/- 0.3 X 10(-5) M). The results indicate that Teslac, in addition to its antiaromatase activity, is an antiandrogen by virtue of its interaction with the androgen receptor.

Inhaled nitric oxide prevents left ventricular impairment during endotoxemia.

We evaluated the effect of long-term inhalation of nitric oxide (NO) on cardiac contractility after endotoxemia by using the end-systolic elastance of the left ventricle (LV) as a load-independent contractility index. Chronic instrumentation in 12 pigs included implantation of two pairs of endocardial dimension transducers to measure LV volume and a micromanometer to measure LV pressure. One week later, the animals were divided into a control group (n = 6) or a NO group (n = 6). All animals received intravenous Escherichia coli endotoxin (10 micrograms. kg-1. h-1) and equivalent lactated Ringer solution. NO inhalation (20 parts/million) was begun 30 min after the initiation of endotoxemia and was continued for 24 h. In both groups, tachycardia, pulmonary hypertension, and systemic hyperdynamic changes were noted. The end-systolic elastance in the control group was significantly decreased beyond 7 h. NO inhalation maintained the end-systolic elastance at baseline levels and prevented its impairment. These findings indicate that NO exerts a protective effect on LV contractility in this model of endotoxemia.

New modes of mechanical ventilation.

Mechanical ventilation is required by surgical patients for a number of different reasons. The methods available to ventilate patients have increased in the last few years. Some of these techniques have proved helpful, while a few remain investigational searching for an application. Surgeons dealing with critically ill patients must remain current with alternative methods of ventilation.

Multiple, giant fibroadenoma.

Multiple, giant fibroadenomas are histologic and clinical variants of "juvenile" or "giant" fibroadenomas. These tumors are rare and occur mainly in adolescent and young adult black females. The individual lesions are well encapsulated with a histologic pattern primarily of the "juvenile" type, although cases of the "adult" type have been reported. A high incidence of recurrence is noted upon local excision, although this may decrease as the patient becomes older. Management options include local excision with reconstruction, reduction mammoplasty, and simple mastectomy with reconstruction. A case is described of this condition with review of the literature.

Prospective outcome analysis of a protocol for the surgical and rehabilitative management of burns to the hands.

Treatment protocols for the management of burned hands are essential for integrating team efforts and achieving optimal functional results. Standard protocols are especially useful during mass casualty incidents, when the admission of multiple patients with large burns and/or associated injuries may reduce the priority usually accorded the hands. We prospectively evaluated a surgical and rehabilitative treatment protocol for burned hands during a mass casualty incident, after which 43 burn patients with 82 burned hands were admitted to one burn center. Soft-tissue management was individualized to achieve, if possible, wound closure within 14 days, and included the use of topical antimicrobials, cutaneous debridement and/or tangential excision, biologic dressings, and split-thickness autografts. Range of motion therapy was based on daily measurement of active motion of the metacarpophalangealjoints. Static splinting alternating with continuous passive motion every 4 hours was utilized for sedated patients. Continuous passive motion alternating with active ranging and night splinting was utilized for metacarpophalangeal flexion <70 degrees. Active ranging and progressive resistance was utilized for metacarpophalangeal flexion > or =70 degrees. Sixty-four hands required excision and grafting, with 89 percent having at least one autografting procedure completed by postburn day 16. Total active motion of the hands treated averaged 220.6 degrees on discharge and 229.9 degrees at 3 months after injury. Mean hand grip strength was 60.8 pounds at discharge and 66.0 pounds at 3 months after injury. Adherence to a standard hand burn protocol resulted in timely wound coverage and recovery of hand function for a large group of patients treated at a single burn facility after a mass casualty incident.

Clinical trials of a biosynthetic temporary skin replacement, Dermagraft-Transitional Covering, compared with cryopreserved human cadaver skin for temporary coverage of excised burn wounds.

Human cadaver allograft skin (HCAS) is widely used for covering excised burn wounds when limited available skin donor sites or the overall patient condition does not permit immediate grafting with autologous skin. However, recurring problems are associated with HCAS including limited supply, variable quality, ultimate immune rejection, and the potential for bacterial and viral disease transmission. These problems speak for the need for development of a dependable substitute for HCAS. We evaluated the ability of a biosynthetic analogue of human skin to temporarily close excised burn wounds in humans. Dermagraft-TC (Advanced Tissue Sciences, Inc.) (DG-TC) is composed of human neonatal fibroblasts cultured on a synthetic dressing (Biobrane; Dow Hickam, Inc.) that consists of nylon mesh fabric covered with a thin layer of silicone rubber membrane, which provides an epidermal "barrier." The material is stored frozen and thawed immediately before use. DG-TC is semitransparent, thus facilitating continuous observation of the underlying wound surface. Burn wounds in 10 patients (mean age 33.5 years, mean burn size 39.9% total body surface area) were surgically excised. Two variants of the DG-TC skin analogs were tested: a material that was cryopreserved to maintain fibroblast viability (DG-TC Red) and a material that was frozen without efforts to maintain fibroblast viability (DG-TC Blue). A control site on each patient received cryopreserved HCAS. Each study site was approximately 1% total body surface area. When clinically indicated, patients were returned to the operating room where the skin replacements were removed, the wound bed was evaluated and prepared for grafting, and the wounds were closed with meshed split-thickness autograft skin. The results showed that adherence to the wound and subsequent autograft "take" were excellent with both DG-TC variants and were at least equivalent to HCAS. No evidence of immune rejection of DG-TC was seen, whereas in four patients evidence of epidermal sloughing/rejection was noted in the HCAS control sites, which limited persistence of those grafts on the wound. Further clinical trials with this skin analogue are in progress.

Pressure-controlled ventilation for the long-range aeromedical transport of patients with burns.

Pressure-controlled ventilation is used to treat smoke inhalation injury to achieve adequate oxygenation and ventilation at lower peak inspiratory pressures. A portable pressure-controlled time-cycled transport ventilator permits this modality to be used in the field. We have examined the safety and efficacy of this ventilator for aeromedical transfer of thermally injured patients. Burn flight teams transported 146 intubated patients with thermal injury to the U.S. Army Burn Center with this system. The average extent of burn injury was 40.45% total body surface area with an average full-thickness injury of 25.29% total body surface area. The transport ventilator was used for 57 rotary wing and 89 fixed wing missions. The study group was transported a total of 86,889 miles without in-flight morbidity, mortality, or failure of ventilation. Arterial blood gas analysis at conclusion of flight demonstrated an arterial pH > or = 7.35 in 85% of the patients, an arterial partial pressure of carbon dioxide < or = 45 torr in 97%, and an arterial partial pressure of oxygen > or = 70 torr in 99%. Pressure-controlled ventilation performed by an experienced transport team with this ventilator is safe and effective for the long-range aeromedical transfer of intubated patients with burns.

Computer-assisted evaluation of hand and arm function after thermal injury.

Comprehensive care of the burned upper extremity requires accurate and complete evaluation of function, including two-point discrimination, active and passive range of motion, and grip strength. These evaluations, when performed serially during a course of therapy, are time-consuming and manpower-intensive. We tested the utility and accuracy of a commercially available computer-assisted impairment evaluation system when used to automate and standardize measurement of upper-extremity function. The function of 80 upper extremities was evaluated with both the conventional and the computer-assisted methods. The time required to perform a complete examination with each method was recorded, and measurements of grip strength and total active motion made with both methods were compared. Complete upper-extremity evaluation required an average of 20.3 minutes with the computer-assisted method, compared to 62.9 minutes with conventional means. Measurements of extremity function with computer-assisted and conventional methods had correlation coefficients of 0.984 for grip strength and 0.996 for total active motion. The computer-assisted impairment evaluation system was found to be a useful and accurate adjunct in the acute and rehabilitative management of burned upper extremities.

Current management of purpura fulminans: a multicenter study.

Seven burn centers performed a 10-yr retrospective chart review of patients diagnosed with purpura fulminans. Patient demographics, etiology, presentation, medical and surgical treatment, and outcome were reviewed. A total of 70 patients were identified. Mean patient age was 13 yr. Neisseria meningitidis was the most common etiologic agent in infants and adolescents whereas Streptococcus commonly afflicted the adult population. Acute management consisted of antibiotic administration, volume resuscitation, ventilatory and inotropic support, with occasional use of corticosteroids (38%) and protein C replacement (9%). Full-thickness skin and soft-tissue necrosis was extensive, requiring skin grafting and amputations in 90% of the patients. One fourth of the patients required amputations of all extremities. Fasciotomies when performed early appeared to limit the level of amputation in 6 of 14 patients. Therefore, fasciotomies during the initial management of these patients may reduce the depth of soft-tissue involvement and the extent of amputations.

A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century.

Toxic epidermal necrolysis (TEN) is a potentially fatal disorder that involves large areas of skin desquamation. Patients with TEN are often referred to burn centers for expert wound management and comprehensive care. The purpose of this study was to define the presenting characteristics and treatment of TEN before and after admission to regional burn centers and to evaluate the efficacy of burn center treatment for this disorder. A retrospective multicenter chart review was completed for patients admitted with TEN to 15 burn centers from 1995 to 2000. Charts were reviewed for patient characteristics, non-burn hospital and burn center treatment, and outcome. A total of 199 patients were admitted. Patients had a mean age of 47 years, mean 67.7% total body surface area skin slough, and mean Acute Physiology and Chronic Health Evaluation (APACHE II) score of 10. Sixty-four patients died, for a mortality rate of 32%. Mortality increased to 51% for patients transferred to a burn center more than one week after onset of disease. Burn centers and non-burn hospitals differed in their use of enteral nutrition (70 vs 12%, respectively, P < 0.05), prophylactic antibiotics (22 vs 37.9%, P < 0.05), corticosteroid use (22 vs 51%, P < 0.05), and wound management. Age, body surface area involvement, APACHE II score, complications, and parenteral nutrition before transfer correlated with increased mortality. The treatment of TEN differs markedly between burn centers and non-burn centers. Early transport to a burn unit is warranted to improve patient outcome.

Training quality job interviews with adults with developmental disabilities.

Supported work models of vocational integration have increased the employability of individuals with developmental disabilities. Interview questions most frequently used and corresponding responses considered most beneficial to job applicants were derived from an empirical analysis of the "hiring community" and served as a basis for the development of the verbal job interview skills training package evaluated in this research. Dependent measures were objective, behavioral indices of the quality of job interview responses. One-to-one training by a direct training staff, job coach, and a trained behavior analyst resulted in improved responding by all subjects as indicated in a multiple baseline design across interview questions. Improved quality in responding to questions generalized to variations in interview questions, to a novel interviewer, and in an in vivo interview situation. Finally, global measures of social validity support the value of the quality-of-response training.

Measuring adherence in a community-based elderly population.

OBJECTIVE: To examine the reliability and validity of the Medication Adherence Individual Review-Screening Tool (MedAdhIR-ST) for assessing medication adherence in a community-dwelling elderly population. DESIGN: A prospective, observational pilot study comparing the reliability and validity of the MedAdhIR-ST and the Medication Adherence Questionnaire (MAQ). SETTING: Independent senior-housing apartments and senior centers in Wake County, North Carolina. PARTICIPANTS: Eligible subjects included individuals 60 years of age or older who were living in the community and managing their own medication regimens. INTERVENTIONS: Each subject was asked to participate in two assessment visits, two weeks (+/- 3 days) apart, in which the questions of the MedAdhIR-ST and MAQ were administered. MAIN OUTCOME MEASURE: Medication adherence. RESULTS: Both tools showed moderate-to-high test/retest reliability in the study population (correlation coefficient of 0.632 for MAQ, and 0.699 for MedAdhIR-ST), and moderate internal consistency (Cronbach's a of 0.551 and 0.584, respectively). Moderate concordance in the ability to assess adherence was observed between MedAdhIR-ST and MAQ (positive correlation coefficient of 0.450). When compared with refill records, MedAdhIR-ST was slightly more sensitive (67% vs. 43%) and specific (60% vs. 50%) for detecting adherence and nonadherence, respectively, compared with MAQ. Exploratory factor analysis indicated that MedAdhIR-ST is multidimensional. CONCLUSION: MedAdhIR-ST appears to be a reliable and valid tool for screening nonadherence in a community-dwelling elderly population.

Peritoneal lavage in the diagnosis of acute surgical abdomen following thermal injury.

Intraperitoneal sepsis is difficult to diagnose in thermally injured patients. We reviewed the use of diagnostic peritoneal lavage (DPL) in burn patients suspected of having intraperitoneal infection. Seventeen patients were identified in whom celiotomy, autopsy, or complete recovery could be used to validate the lavage results. A lavage was considered positive if there were greater than 500 white blood cells per mm3 or if microorganisms were present on Gram stain. Six patients had a positive DPL and 11 patients had a negative DPL. There were six true positive, no false positive, ten true negative, and one false negative studies resulting in a sensitivity of 0.86, specificity of 1.00, and diagnostic accuracy of 94%. No complications related to the DPL occurred. This procedure is safe and will rapidly and reliably discriminate between patients needing urgent celiotomy and those requiring further investigation to identify a source of sepsis.

Incidence of bacteremia after burn wound manipulation in the early postburn period.

BACKGROUND: Transient bacteremia associated with burn wound manipulation is considered a frequent occurrence and is commonly cited as an indication for perioperative antibiotic prophylaxis in burn patients. METHODS: In a prospective clinical setting, blood cultures (BC) were obtained from 19 burn patients at the following intervals: 30 minutes before wound cleansing (WC) or wound excision (WE), 30 minutes after the start of WC or WE, hourly until procedure completion, and 1 hour after completion. Burn wound biopsy for histologic grading and microbial culture was performed after the first BC. RESULTS: Twenty-two WC and 20 WE episodes were evaluated by 67 and 76 BC sets, respectively. Patients had a mean age of 42.8 years and mean burn size of 50% of the body surface area. Three WC episodes (13.6%) and four WE procedures (20.0%) were associated with postprocedure bacteremia. Two patients had both preprocedure and postprocedure bacteremia later attributed to nonburn wound infections. Excluding these cases, the bacteremia rate was 12.5% (9.5% from WC and 15% from WE). Wound biopsy culture and histologic analysis did not predict the occurrence of bacteremia. CONCLUSION: Current therapy is associated with a lesser incidence of burn wound manipulation-induced bacteremia than reported in prior series. The discordance between wound biopsy and BC results, the absence of positive histology, and the similarity of bacteremia occurrence rates with WC and WE confirm the effectiveness of current techniques of microbial control in burn wounds and question the need for perioperative antibiotic therapy in patients with burns involving less than 40% of the total body surface during the first 10 postburn days.

Factors contributing to delayed extremity amputation in burn patients.

BACKGROUND: Previous series of traumatic amputations have noted that delay in amputation results in prolonged hospital stay and delayed rehabilitation. A series of major extremity amputations after burn injury was analyzed to identify the frequency of delayed amputation and to identify factors resulting in the delay. METHODS: Chart review of burn admissions between January of 1991 and December of 1995. RESULTS: Twenty-eight patients underwent a total of 44 major extremity amputations. Thirty-five amputations in 22 patients were performed by postburn day 16 (mean 4.3). Nine amputations in six patients were delayed beyond postburn day 26 (mean, 48.3). Delayed amputations occurred in the subgroups of deep thermal burns with extensive necrosis and thermal burns complicated by infections. Early amputation was associated with a 13.6% mortality rate, delayed amputation with a 50% mortality rate. CONCLUSION: There is a bimodal distribution of time to amputation determined by mechanism of injury, severity of burn, and infectious complications. Earlier identification of nonsalvageable limbs may decrease infectious complications and improve the chances of patient survival.

A comparison of the cerebral and cardiovascular effects of complete resuscitation with isotonic and hypertonic saline, hetastarch, and whole blood following hemorrhage.

Hemorrhagic shock and closed head injury often accompany severe trauma. Hypertonic saline may be beneficial in these patients, but few have examined its properties when sufficient volume is infused to achieve sustained resuscitation. Solutions of 6% NaCl (HS), 0.9% NaCl (NS), 6% hetastarch (HE), and whole blood (WB) were used to resuscitate swine in hemorrhagic shock (MAP less than 30 mm Hg). The endpoint of resuscitation was normal oxygen delivery (DO2). Measurements of intracranial pressure (ICP), cerebral perfusion pressure (CPP), and intracranial elastance (ICE) were made in the absence and presence of an epidural mass, created by inflating an epidural balloon. HS resuscitation resulted in a lower ICP [5 +/- 1 versus 9 +/- 2 (HE), 17 +/- 3 (NS), and 10 +/- 3 (WB) mm Hg; p = 0.016], and normalization of CPP throughout resuscitation. Animals resuscitated with NS had a lower CPP by the end of resuscitation [CPP = 45 +/- 4 for NS group, versus 63 +/- 4 (HE), 66 +/- 4 (HS), and 63 +/- 5 (WB) mm Hg; p = 0.009]. ICE fell markedly in the HS group, [a decrease of 12 +/- 2 vs. a rise of 5 +/- 3 (HE), 2 +/- 3 (NS), and 6 +/- 3 (WB) mm Hg/ml; p = 0.0005]. This improvement was even more dramatic in the presence of an epidural mass [a fall of 21 +/- 3 vs. no change (HE, WB) and a rise of 4 +/- 3 (NS) mm Hg/ml; p = 0.0005]. For hemorrhage accompanied by severe head injury, resuscitation with HS may benefit victims by decreasing ICP and diminishing the effects of an intracranial mass.

Properitoneal synthetic mesh repair of recurrent inguinal hernias.

Safe reconstruction of the inguinal floor is the goal of any operation for repair of groin herniation. Operating in the properitoneal space avoids dissection of the scarred cord, and the incidence of testicular complications is markedly lowered. This study reports our experience with placing synthetic mesh between the peritoneum and the deficient inguinal floor for the repair of recurrent hernias of the groin area. During a five year period, 84 men underwent repair of 100 recurrent inguinal hernias using the properitoneal approach. Fifty-four patients had repair of a unilateral recurrent hernia, 16 had repair of a bilateral recurrent hernia and 14 had repair of both a recurrent hernia and a contralateral primary hernia. Postoperative complications occurred in six patients. No testicular complications were observed. Postoperative follow-up study ranged from six months to five years. There were only three recurrent hernias after this repair. All occurred within the first six months postoperatively. The properitoneal approach for repair of recurrent groin hernias using prosthetic mesh safely creates a new "fascia transversalis" with a low rate of recurrence and effectively eliminates testicular complications.

Chemical burns.

In chemical skin injuries, reduction of the time of exposure to the causative agent and recognition of systemic toxicity are necessary to lessen the severity of the insult, reduce morbidity, and maximize survival. During a 17-year period (1969 through 1985), 87 (2.1%) of the 4,212 burned patients admitted to the U.S. Army Institute of Surgical Research sustained chemical burns. Twelve of 87 patients died (13.8%). White phosphorous, the most common causative agent, produced cutaneous injury in 49 patients. Acids (13 patients), alkalies (ten patients), and organic solvents (five patients) were the other common causes of injury. Initial treatment consisted of water lavage. Later wound management was carried out with topical antibiotic therapy and excision and grafting as necessary. Systemic toxicity due to phenol, nitrate, and formate absorption occurred, as did acute tubular necrosis following copper sulfate treatment of white phosphorus burns. Inhalation injury occurred in five patients. A decrease in hospital stay for chemically injured patients was observed. To minimize chemical injury, clothing should be removed promptly and water lavage begun. Systemic toxicity and inhalation injury are rare but often severe and increase mortality.

Glucocorticoid and Fas ligand induced mucosal lymphocyte apoptosis after burn injury.

BACKGROUND: The purpose of this study was to examine the effects of a steam burn injury on apoptosis in gut-associated lymphoid tissue and to determine whether endogenous glucocorticoid and Fas ligand signaling were involved in this process. METHODS: Histologic analysis, in situ deoxynucleotidyl transferase dUTP nick-end labeling staining and annexin V and 7-amino-actinomycin-D flow cytometry of lymphocyte populations were evaluated in intraepithelial lymphocytes and Peyer's patch. Additional mice were pretreated with a glucocorticoid receptor antagonist (mifepristone) before the steam burn. Similarly, C3H/HeJ-FasL(gld) mice lacking functional Fas ligand were also studied. RESULTS: Apoptosis was significantly increased in intraepithelial lymphocytes and Peyer's patch after the burn injury. Mifepristone pretreatment significantly reduced apoptosis in both T- and B-cell populations in intraepithelial lymphocytes after the burn injury. In contrast, the increased apoptosis seen in B-cells from Peyer's patch was not seen in C3H/HeJFasL(gld) mice, whereas the increased apoptosis in CD8+ T-cells was unaffected. CONCLUSION: Both corticosteroids and FasL contribute to the apoptosis in gut-associated lymphoid tissues early after burn injury.

Glucocorticoid-induced, caspase-dependent organ apoptosis early after burn injury.

Immune suppression and increased apoptotic loss of circulating lymphocytes have been reported after burn injury. However, little is known about the underlying mechanisms responsible for the increased apoptosis of lymphoid and parenchymal cells in solid organs and the role played by inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL), as well as by glucocorticoids. To evaluate the role of endogenously produced glucocorticoids and FasL, mice subjected to a 20% steam burn were pretreated with a glucocorticoid receptor antagonist (mifepristone) or a neutralizing murine Fas fusion protein. Three and twenty-four hours after burn injury, histological analysis, caspase-3 activity, and in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and phenotyping of lymphocyte populations for apoptosis were evaluated. Burn injury increased the number of apoptotic cells and caspase-3 activity in thymus and spleen, but not in other solid organs. Increased apoptosis was seen in several T and B cell populations from both thymus and spleen. Mifepristone pretreatment significantly reduced the apoptosis and caspase-3 activity after burn injury, whereas blocking FasL activity had only minimal effects. We conclude that corticosteroids, and not FasL, are primarily responsible for the increased caspase-3 activity and apoptosis in thymus and spleen cell populations early after burn injury.