The Acute Toxicity of Inhaled Beryllium Metal in Rats

The Acute Toxicity of Inhaled Beryllium Metal in Rats. HALEY,P. J., FINCH, G. L., HOOVER, M. D., AND CUDDIHY, R. G. (1990).Fundam. Appl. Toxicol. 15, 767–778. We exposed rats onceby nose only for 50 min to a mean concentration of 800 µg/m³of beryllium metal (initial lung burden, 625 µg) to characterizethe acute toxic effects within the lung. Histological changeswithin the lung and enzyme changes within bronchoalveolar lavage(BAL) fluid were evaluated at 3, 7, 10, 14, 31, 59, 115, and171 days postexposure (dpe). Beryllium metal-exposed rats developedacute, necrotizing, hemorrhagic, exudative pneumonitis and intraalveolarfibrosis that peaked at 14 dpe. By 31 dpe, inflammatory lesionswere replaced by minimal interstitial and intraalveolar fibrosis.Necrotizing inflammation was observed again at 59 dpe whichprogressed to chronic-active inflammation by 115 dpe. This inflammationworsened progressively, as did alveolar macrophage and epithelialhyperplasia, becoming severe at 171 dpe. Low numbers of diffuselydistributed lymphocytes were also present but they were notassociated with granulomas as is observed in beryllium-induceddisease in man. Throughout the experiment, total numbers ofcells were elevated within the BAL samples due primarily toincreased numbers of neutrophils. Lymphocytes were not elevatedin BAL samples collected from beryllium-exposed rats at anytime after exposure. Lactate dehydrogenase (LDH), ß-glucuronidase,and protein levels were elevated in BAL fluid from 3 through14 dpe but returned to near normal levels by 31 dpe. LDH increasedonce again at 59 dpe and remained elevated at 171 dpe. ß-Glucuronidaseand protein levels were slightly, but not significantly, elevatedfrom 31 through 171 dpe. Results indicate that inhalation ofberyllium metal by rats results in severe, acute chemical pneumonitisthat is followed by a quiescent period of minimal inflammationand mild fibrosis. Progressive, chronic-active, fibrosing pneumonitisis observed later. Chronic beryllium lung disease of man isan immunologically mediated granulomatous lung disease, whereasberyllium-induced lung lesions in rats appear to be due to directchemical toxicity and foreign-body-type reactions.     

Malignant Sustained Ventricular Tachyarrhythmias in Women:

Implantable Defibrillators in Women. Clinical rhythm, heart disease, ejection fraction, defibrillation threshold, recurrent arrhythmias, and mortality were compared in 268 consecutive recipients (213 men and 55 women) of their first implantable cardioverter defibrillator for life-threatening ventricular tachycardia or fibrillation. Women were younger than men, less likely to have structural heart disease, and more likely to have clinical ventricular fibrillation, a higher ejection fraction, and a lower defibrillation threshold. Complications of defibrillator placement were similar in both sexes. Unadjusted survival tended to be higher in women than in men (97% vs 90%, respectively, at 2 years, P = 0.08), largely due to fewer deaths from noncardiac causes or cardiac causes other than arrhythmia (P = 0.04). Women also tended to be at lower, albeit still substantial, risk for recurrent arrhythmias during follow-up (37% vs 52% in men at 2 years, P = 0.11). After adjustment for baseline differences, overall survival, arrhythmia death-free survival, nouarrhythmia death-free survival, and frequency of recurrent arrhythmias were not found to be gender related. Despite their apparent "lower risk" status on initial presentation, women remained at substantial risk for recurrent arrhythmias. This underscores the need to avoid being unduly biased by the "appearance" of health in managing women with malignant arrhythmias. That survival and other clinical endpoints were all ultimately independent of gender emphasizes the importance of other clinical variables in assessing risk from ventricular tachyarrhythmias.     

Phase II trial of imatinib mesylate in recurrent, biomarker positive, ovarian cancer (Southwest Oncology Group Protocol S0211)

Platinum-resistant ovarian cancer continues to be a difficult therapeutic problem. Clearly, molecularly targeted agents should be evaluated in this patient population. Patients were eligible for this phase II study with stage III or IV ovarian cancer, whose tumor expressed Kit (CD117) or platelet-derived growth factor receptor (PDGFR) and with relapse of measurable disease within 6 months of completing frontline, platinum- and taxane-based chemotherapy. Patients were treated daily with 400 mg of imatinib mesylate orally. It was assumed that the agent would be of no further interest if the population response rate was less than 10%. A two-stage design was used for patient accrual. A total of 34 patients were registered to the study. Of these, 15 were found to be ineligible or not evaluable (8 because their tumor samples were negative for both DC117 and PDGFR). Of 19 evaluable patients, 2 (11%) tested positively for c-Kit and 17 (89%) tested positively for PDGFR. There were no objective responders. Thirteen patients (68%) had increasing disease or symptomatic deterioration, and six (32%) went off protocol during the first month due to adverse events. Median progression-free survival was 2 months (95% CI 1-3 months) and median overall survival was 10 months (95% CI 6-18 months). Eleven percent of patients experienced grade 4 hematologic/metabolic toxicity and 37% experienced grade 3 nonhematologic toxicity. We conclude that imatinib mesylate as a single agent does not appear to have useful clinical activity in c-Kit and/or PDGFR positive, recurrent ovarian cancer in heavily pretreated patients with ovarian cancer.     

Hereditary Long QT Syndrome Associated with Cardiac Conduction System Disease

This report describes the cardiac conduction abnormalities, detected by invasive electrophysiological study, in two identical siblings with symptomatic congenital long QT syndrome. Both patients had evidence of intra-Hisian conduction delay in response to programmed atrial stimulation and pacing induced infranodal block was seen in one of the two patients. The response of the observed conduction delay to autonomic interventions is described. The observed electrophysiologic abnormalities are consistent with previously reported pathological findings and document the association of functional conduction system disease with congenital QT prolongation.     

Radiofrequency Catheter Ablation of the Atrioventricular Junction by a Supravalvular Noncoronary Aortic Cusp Approach

Radiofrequency catheter ablation of the atrioventricular janction is usually achieved from either the right or left atrioventricular junction. We describe a new approach in which the atrioventricular junction was successfully ablated from the supravalvular region of the noncoronary cusp of the aortic valve in an unusual patient in whom conventional approaches were unsuccessful.     

Clinical Results with Electrophysiologist-Implanted Cardioverter-Defibrillators

With the advent of nonthoracotomy leads and smaller devices. implantation techniques for implantable cardioverters defibrillators (ICDs) have been simplified. We reviewed the outcome of pectoral ICD implantation by electrophysiologists in 51 consecutive patients, 47 males and 4 females, mean age 60 ± 12 years, presenting with aborted sudden cardiac death (14) and drug refractory hypotensive ventricular tachycardia (37). Patients were implanted with either the PCD Jewel^TM 7219D (37) or 72197C (14) Medtronic pectoral ICDs. The mean operative time was 98 ± 31 minutes. There was no operative mortality. Complications occurred in 2 (4%) patients: right ventricular lead dislodgement requiring lead repositioning occurred in 1 patient, and 1 patient treated with anticoagulants, who had received a subcutaneous patch lead, developed a hematoma not requiring surgical reintervention. The mean defibrillation threshold was 18.6 ± 5.5 J, but was significantly lower for the 7219C(14.1 ± 5.0 J) compared to the 7219D (20.6 ± 4.4J) device, P = 0.0001. A two-lead system consisting of a right ventricular electrode (RVA) and a superior vena caval lead (SVC) was utilized in 29, RVA/SVC-subcutaneous patch in 5 and active can in 17 patients, Patients were discharged after 4.3 ± 3 days. The procedure time was significantly shorter for the 7219C device (79.7 ± 18.9 vs 105.2 ± 32.8 minutes., P = 0.0035]. Over the fallow-up period of 8 ± 5 (range 1–20] months, 26% patients received appropriate therapy (95% antitachycardia pacing, 5% shock). Concomitant antiarrhythmic therapy was utilized in 41% of patients. Ninety-eight percent of patients are alive. One patient died of congestive heart failure. Clinical results with electrophysiologist-implanted pectoral ICDs demonstrate lou morbidity and no operative mortality in this clinical series and lower DFTs and shorter procedure times may be achieved with 7219C (active can) device.     

Clinicopathological correlates of CD56 expression in multiple myeloma: a unique entity?

Summary. Prior studies have suggested that loss of plasma cell CD 5 6 expression in multiple myeloma defines a unique patient subset and that CD56 expression reliably discriminates between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). We conducted a study of 68 untreated patients with MM from a single institution to define the clinicopathological correlates of CD56 expression. We find CD56 expression in 55% of MM. Lack of CD56 expression does not define a unique clinicopathological or prognostic entity in MM. Strong CD 5 6 expression can also be found in MGUS and does not help to distinguish from MM.