Basic fibroblast growth factor forms new trabeculae that physically connect with pre-existing trabeculae, and this new bone is maintained with an anti-resorptive agent and enhanced with an anabolic agent in an osteopenic rat model.

Osteoporosis is a disease of excess bone fragility that results from both the loss of bone mass and trabecular bone microarchitecture, thereby creating a very fragile skeleton. The purpose of this study was to determine whether treatment of ovariectomized (OVX) osteopenic rats with basic fibroblast growth factor (bFGF) would stimulate the production of new trabeculae, and whether the newly formed trabeculae would make physical connections with the pre-existing trabeculae after prolonged estrogen deficiency. Six-month-old Sprague Dawley rats were OVXed or sham-operated and were left untreated until day 60 post-OVX. A high resolution microscopic scan (XTM) of the right proximal tibia was performed on groups 1 and 2 on day 1 post-OVX, and was repeated in all animals on day 60 post-OVX. At day 60 groups 1 and 2 were treated with vehicle and groups 3 to 6 were injected with bFGF 200 microg/kg/d intravenously for 15 days. At day 82, all animals obtained another in vivo XTM scan of the right tibia; then group 4 were treated with 17B estradiol 10 microg/kg/3x a week, group 5 were treated with hPTH (1-34) at 80 microg/kg/d for 35 days, group 6 were sacrificed, and groups 1 and 2 were treated with vehicle injections for 35 days. At day 110, all remaining animals were sacrificed, and repeat ex vivo XTM scans of the right proximal tibia were performed. Trabecular bone structural variables-including trabecular bone volume, connectivity, number, and thickness-were obtained from all XTM scans. Biochemical markers of bone turnover were also obtained 24 hours before each XTM scan (osteocalcin and deoxypyridinoline), and analyzed by ELISA. Animals OVXed and treated with vehicle had decreased trabecular bone volume, connectivity and number compared to sham-operated animals at both day 60 and day 110. Animals treated with bFGF from day 60-75 post-OVX had evidence of new trabeculae that physically connected with pre-existing trabeculae and also of increased trabecular bone volume seven days after the injections were discontinued. Biochemical markers of bone formation had a small and insignificant increase over baseline levels during the bFGF injections. Bone resorption markers were significantly reduced during the injection period, but returned to baseline levels after the injections were stopped. In addition, we also demonstrated that these newly formed trabecular connections could be maintained or added to with either estrogen or hPTH (1-34) treatments. Thirty-five days after ending the bFGF treatment, trabecular bone volume and connectivity was 25-80% higher in the estrogen and hPTH (1-34) treated animals compared to the untreated animals ( p<0.01). These results support continued development of bFGF as a potential treatment for severely osteoporotic individuals.

Ethnic differences in N-glucuronidation of nicotine and cotinine.

We previously reported that the metabolism of cotinine, the proximate metabolite of nicotine, is significantly slower in black than in white cigarette smokers. To understand why the metabolism of nicotine and cotinine might differ between blacks and whites, we studied the pattern of nicotine metabolism in blacks and whites. One hundred eight healthy smokers (51 blacks and 57 whites), of similar age, gender distribution, and smoking history, received an i.v. infusion of deuterium-labeled nicotine and cotinine. The clearance of cotinine, the fractional conversion of nicotine to cotinine, and the metabolic clearance of nicotine to cotinine were significantly lower in blacks than in whites. Blacks excreted significantly less nicotine as nicotine-N-glucuronide and less cotinine as cotinine-N-glucuronide than whites, but there was no difference in the excretion of 3'-hydroxycotinine-O-glucuronide. Nicotine and cotinine glucuronidation appeared to be polymorphic, with evidence of slow and fast N-glucuronide formers among blacks but was unimodal with fast conjugators only among whites. Other findings of note included the demonstration of a significant correlation between the distribution volumes of nicotine and cotinine with lean body mass: there was a smaller distribution volume and a shorter half-life for cotinine in women than in men and a smaller volume of distribution of cotinine in blacks than in whites. We conclude that the metabolism of cotinine is slower in blacks than in whites because of both slower oxidative metabolism of nicotine to cotinine (presumably via cytochrome P-450 2A6) and slower N-glucuronidation. Ethnic differences in the metabolism of other drugs undergoing N-glucuronidation should be studied.

Improved trauma care after reorganisation: a retrospective analysis.

OBJECTIVE: To shorten the time to make a diagnosis and to begin definitive treatment of severely injured patients, thereby improving their medical care. DESIGN: Retrospective analysis. SETTING: Teaching hospital, Sweden. SUBJECTS: 61 patients who had sustained high-energy injuries, including head injury which required surgical intervention, and fracture of the femoral shaft before (1987-1988 n = 23) and after (1991-1993 n = 38) the reorganisation. INTERVENTION: Trauma care was reorganised during the year 1989-1990 and the concept of early multidisiplinary treatment with the general surgeon as trauma-leader was adopted. MAIN OUTCOME MEASURES: The time required to make a diagnosis and begin definitive treatment as well as the assessment of medical care taking account of the patient's general condition and other injuries. RESULT: The immediate medical care was classified as delayed or inappropriate in 9 of 23 patients before, and in 2 of 38 patients after, the reorganisation (p = 0.001). The time needed to make a diagnosis was less than 4 hours in all cases. The time needed to start definitive treatment of head injuries was less than four hours in 9 of 12 patients before, and in 18 of 21 patients after the reorganisation. The internal fixation of femoral fractures was started within four hours in 2 of 11 femoral fractures before, compared with 12 of 17, after the reorganisation. CONCLUSION: The time to beginning definitive treatment of severe injuries was shorter after the reorganisation, as a result of early participation of members of the trauma team.

Electrophysiologic effects of adenosine in patients with supraventricular tachycardia.

BACKGROUND: We correlated the electrophysiologic (EP) effects of adenosine with tachycardia mechanisms in patients with supraventricular tachycardias (SVT). METHODS AND RESULTS: Adenosine was administered to 229 patients with SVTs during EP study: atrioventricular (AV) reentry (AVRT; n=59), typical atrioventricular node reentry (AVNRT; n=82), atypical AVNRT (n=13), permanent junctional reciprocating tachycardia (PJRT; n=12), atrial tachycardia (AT; n=53), and inappropriate sinus tachycardia (IST; n=10). There was no difference in incidence of tachycardia termination at the AV node in AVRT (85%) versus AVNRT (86%) after adenosine, but patients with AVRT showed increases in the ventriculoatrial (VA) intervals (13%) compared with typical AVNRT (0%), P<0.005. Changes in atrial, AV, or VA intervals after adenosine did not predict the mode of termination of long R-P tachycardias. For patients with AT, there was no correlation with location of the atrial focus and adenosine response. AV block after adenosine was only observed in AT patients (27%) or IST (30%). Patients with IST showed atrial cycle length increases after adenosine (P<0.05) with little change in activation sequence. The incidence of atrial fibrillation after adenosine was higher for those with AVRT (15%) compared with typical AVNRT (0%) P<0.001, or atypical AVNRT (0%) but similar to those with AT (11%) and PJRT (17%). CONCLUSIONS: The EP response to adenosine proved of limited value to identify the location of AT or SVT mechanisms. Features favoring AT were the presence of AV block or marked shortening of atrial cycle length before tachycardia suppression. Atrial fibrillation was more common after adenosine in patients with AVRT, PJRT, or AT. Patients with IST showed increases in cycle length with little change in atrial activation sequence after adenosine.

Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial.

Corticosteroid-induced osteoporosis is the most common secondary cause of osteoporosis. We conducted a 12-mo, randomized clinical trial of human parathyroid hormone 1-34 (hPTH 1-34) in postmenopausal women (mean age was 63 yr) with osteoporosis who were taking corticosteroids and hormone replacement therapy. Response to the treatment was assessed with bone mineral density (BMD) measurements of the lumbar spine by quantitative computed tomography (QCT); BMD measurements of the lumbar spine, hip, and forearm by dual-energy x-ray absorptiometry (DXA); and biochemical markers of bone turnover. The mean (+/-SE) changes in BMD of the lumbar spine by QCT and DXA in the PTH group were 35+/-5.5% and 11+/-1.4%, respectively, compared with a relatively small change of 1.7+/-1.8% and 0+/-0.9% in the estrogen-only group. The differences in mean percentage between the groups at 1 yr were 33.5% for the lumbar spine by QCT (P < 0.001) and 9.8% for the lumbar spine by DXA (P < 0.001). The changes in the hip and forearm were not significantly different between or within the groups. During the first 3 mo of PTH treatment, markers of bone formation increased to nearly 150%, whereas markers of bone resorption increased only 100%, suggesting an early uncoupling of bone turnover in favor of formation. These results suggest that parathyroid hormone dramatically increases bone mass in the central skeleton of postmenopausal women with corticosteroid- induced osteoporosis who are taking hormone replacement.

Acute changes in trabecular bone connectivity and osteoclast activity in the ovariectomized rat in vivo.

Estrogen deficiency results in a loss of trabecular bone mass and structure that leads to an increased incidence of osteoporotic fractures. The purpose of this study was to determine the time course for trabecular structure deterioration and changes in bone turnover just after ovariectomy in the rat. Six-month-old female virgin Sprague-Dawley rats had their right proximal tibia scanned by X-ray tomographic microscopy (XTM) at baseline (day 0). Animals were then randomized into two groups, and in each group 9 were sham-operated and 11 were ovariectomized and had repeat XTM scans on days 5, 13, 29, and 42 postovariectomy in group 1 and on days 8, 13, 33, and 50 postovariectomy in group 2. Urine was collected for deoxypyridinoline (DPD) cross-link measurements 24 h before each XTM scan and analyzed by ELISA. Trabecular bone structural variables and bone turnover endpoints were calculated from XTM data and standard histomorphometry. Trabecular connectivity decreased 27% by days 5 and 8 postovariectomy (p < 0.01) and continued to decrease up to day 50 postovariectomy (p < 0.01). The trabecular bone volume decreased 25% by 8 days postovariectomy (p < 0.01), and it continued to decrease through day 50. DPD cross-link excretion had increased 37% on day 13 (p < 0.01) and by over 100% of baseline by day 50 postovariectomy. Trabecular bone connectivity and volume deteriorate rapidly while DPD cross-link excretion increased more slowly in acute estrogen deficiency. These data suggest that if an agent is to preserve fully trabecular bone structure, it must be instituted very early in the estrogen-deficient state. They also suggest that a lag time exists before DPD excretion properly mirrors newly induced conditions of high bone turnover in this rat model.

Outcome for hospitalized patients with fever and neutropenia who are infected with the human immunodeficiency virus.

We conducted a retrospective cohort study to evaluate the occurrence of bacteremia and associated mortality among hospitalized patients who were seropositive for the human immunodeficiency virus (HIV) and who developed fever and neutropenia following antineoplastic chemotherapy or for other reasons. Review of medical records revealed 224 episodes in 142 patients. Of these episodes, 57% occurred following antineoplastic chemotherapy, and 43% occurred under other circumstances. Members of the chemotherapy group had significantly less-advanced HIV disease, a lower mean absolute-neutrophil-count nadir, and a shorter duration of hospitalization. There was no difference between the two groups in the frequency of bacteremia or mortality due to all causes when they were compared by multivariate analysis. Statistically significant univariate and multivariate predictors of bacteremia included sepsis syndrome and concurrent infection. Predictors of mortality included sepsis syndrome, concurrent infection, bacteremia, and antimicrobial therapy. This study suggests that the cause of neutropenia in HIV-seropositive patients is not a predictor of the outcome of fever and neutropenic episodes. Instead, clinical presentation and concomitant illnesses have a greater impact on outcome for a patient.

Transfusion significantly increases the risk for infection after splenic injury.

OBJECTIVES: To determine if splenectomy results in an increased risk for perioperative infection when analyzed against splenic repair and to identify factors associated with perioperative infection, respiratory complication, and admission to the intensive care unit following surgery for splenic trauma. DESIGN: Data were collected retrospectively from hospital records and analyzed using stepwise multiple logistic regression. SETTING: San Francisco (Calif) General Hospital, an urban level 1 trauma center. PATIENTS: All patients (n = 252) undergoing operation for traumatic splenic injury at San Francisco General Hospital from 1984 through 1990. Patients who died within 24 hours of presentation were excluded from the study. MAIN OUTCOME MEASURES: Perioperative infection, respiratory complications, and admission to the intensive care unit. RESULTS: Infection rates and the types of organisms yielded in cultures were similar between patients who underwent splenectomy and repair. Gram-negative and gram-positive organisms were found in equal numbers, and in no group did encapsulated organisms predominate. Splenectomy had no independent impact on any of the three outcome measures. Total blood transfusion was found to be the only independently significant variable associated with perioperative infection and respiratory complication. Total blood transfusion of more than 2 U and Injury Severity Score of greater than 25 were independently significantly associated with admission to the intensive care unit. CONCLUSIONS: The choice between splenectomy and splenic repair does not affect the risk for perioperative infection following injury, whereas blood transfusion significantly increases the risk for perioperative infection, respiratory complication, and admission to the intensive care unit.

Sialosyl-Tn. A novel mucin antigen associated with prognosis in colorectal cancer patients.

Colon cancers typically produce mucin. However, it is not known whether tumor mucin plays a biological role in cancer cell behavior. To address this issue, the expression of a mucin-associated antigen, sialosyl-Tn, was examined by immunohistochemical study in 128 primary colorectal carcinoma specimens from 137 patients who underwent curative surgical resection. Antigen expression was correlated with disease-free and overall 5-year survival. Sialosyl-Tn antigen expression occurred in 112 (87.5%) tumors, and was independent of age, gender, tumor location, Dukes' stage, depth of invasion, degree of differentiation, and ploidy status. Survival at 5 years for patients with sialosyl-Tn-negative versus sialosyl-Tn-positive tumors was 100% versus 73% (P less than 0.05) and disease-free survival was 94% versus 73%, respectively (P = 0.12). Although more advanced Dukes' stage, deeper invasion, and aneuploidy were all associated with poorer overall 5-year survival, antigen-negative tumors within each of these groups had much better prognoses than antigen-positive tumors. Multivariate regression analysis revealed that tumor ploidy (P less than 0.001) and sialosyl-Tn expression (P less than 0.05) were the two variables of most importance for predicting both disease-free and overall survival. The authors conclude that sialosyl-Tn expression is an independent predictor of poor prognosis in colon cancer, and therefore suggest that qualitative mucin alterations may reflect important differences in the biological behavior of these neoplasms.

Electrophysiologic effects of cigarette smoking in patients with and without chronic beta-blocker therapy.

After refraining from smoking for at least 8 hours, 22 adult male habitual smokers underwent baseline electrophysiologic study including atrial and ventricular burst pacing and programmed premature stimulation with single extrastimuli. After smoking 2 of their usual brand of cigarettes in rapid succession, the electrophysiologic protocol was repeated. Nicotine, catecholamine and carbon monoxide concentrations all increased significantly. Smoking increased heart rate and improved atrioventricular conduction in the 13 patients receiving chronic beta-blocker therapy (mostly for angina pectoris); increases in heart rate and improvement in atrioventricular conduction were not different statistically from those seen in patients not receiving beta-blocker therapy, suggesting the possibility of a direct effect of nicotine or other components of tobacco smoke. Ventricular refractoriness was not altered and atrial and ventricular arrhythmias were not increased by smoking. Persistent sympathomimetic actions of cigarette smoking may explain in part the failure of beta-blocking drugs to reduce cardiac mortality risk in smokers after myocardial infarction.

Coronary artery bypass graft patency: noninvasive evaluation with MR imaging.

A noninvasive means of determining coronary artery bypass graft (CABG) patency in symptomatic patients would be an important clinical asset. The accuracy of magnetic resonance (MR) imaging was evaluated for this purpose. Multiphasic electrocardiographically gated MR imaging examinations were performed in 25 patients with a total of 72 grafts. Transverse images of the heart at ten anatomic levels were obtained at five or six phases of the cardiac cycle. The MR images were read blindly to determine CABG patency versus occlusion, and these results were compared with those of coronary angiography performed within 2 months before the MR imaging. MR imaging correctly disclosed 43 patent grafts and 13 occluded grafts (predictive accuracy, 78%). Patency and occlusion were incorrectly diagnosed from MR imaging findings in five and four CABGs, respectively. CABG status could not be determined in seven (10%) grafts because the grafts were visualized at only one anatomic level. Thus, the accuracy of a definitive MR imaging evaluation was 91% (43 of 47 grafts) for patency determination and 72% (13 of 18 grafts) for occlusion determination. MR imaging appears to be a useful method for the noninvasive evaluation of CABGs.

Prognostic value of infranodal conduction time in patients with chronic bundle branch block.

His bundle recordings were obtained in 121 patients with chronic bundle branch block and the patients were followed for a mean period of 18 months. Seventy-nine patients had an infranodal conduction time (H-Q) less than 70 msec while 42 had H-Q greater than or equal to 70 msec. There was no significant difference in mean age, smoking history, diabetes, syncope, dizziness, blood pressure, and serum cholesterol or triglyceride levels between the two groups. There was a significantly greater incidence of progresssion to second degree or third degree atrioventricular block (9/42, 21%), and of severe congestive heart failure (16/42, 38%) in patients with H-Q greater than or equal to 70 compared with those with H-Q less than 70 (1/79, 1.3%; and 13/79, 16%, respectively). The risk of sudden death was significantly greater only in the group with H-Q greater than or equal to 70 and severe congestive heart failure. There was no correlation between the presence of first degree atrioventricular block and/or any particular type of bundle branch block pattern with sudden death and/or progression to second degree or third degree atrioventricular block. Analysis of the surface electrocardiogram is only of limited value in predicting high risk patients with chronic bundle branch block. Electrophysiologic studies are of greatest value in patients with bundle branch block with transient neurologic symptoms in whom no cause for the symptoms is evident.