Immune Basis for Cimetidine-Induced Pancytopenia

We report a case of a female patient with chronic myelogenous leukemia who presented, 8 yr after initial diagnosis, with pancytopenia, encephalopathy, and myalgia. The tentative diagnosis was accelerated phase of chronic myelogenous leukemia. However, because the patient had been treated with cimetidine for 7 months we first omitted this drug. When cimetidine was stopped, bone marrow recovered, and myalgia and encephalopathy subsided. Immunological studies showed stimulation of the patient's lymphocyte blastogenesis by cimetidine and a marked increase in the proportion of cytotoxic/suppressor T lymphocytes after incubation of peripheral blood lymphocytes with cimetidine for 6 days. These findings indicate a role for cell-mediated immunity in the pathogenesis of cimetidine-induced pancytopenia in this patient.     

A familial lymphoproliferative disorder presenting with primary pulmonary manifestations.

A familial lymphoproliferative disorder presented in three male siblings with primary pulmonary involvement manifested as either lymphoid interstitial pneumonia or an angiodestructive polymorphous infiltrate morphologically resembling lymphomatoid granulomatosis. The polymorphous infiltrate consisted chiefly of mature T-cells with a few B-cells and plasma cells, and gene rearrangement studies failed to show clonality. Epstein-Barr virus, frequently associated with proliferative lesions in males in the X-linked lymphoproliferative syndrome, was not demonstrated in any of the pulmonary lesions. An HLA haplotype shared among the affected siblings was A1, B8, DR4. The unusual clinical presentation plus the lack of involvement by EBV in the pulmonary lesions suggests that this is a previously undescribed familial lymphoproliferative disorder.     

Dynamic tracking of human hematopoietic stem cell engraftment using in vivo bioluminescence imaging

The standard approach to assess hematopoietic stem cell (HSC) engraftment in experimental bone marrow transplantation models relies on detection of donor hematopoietic cells in host bone marrow following death; this approach provides data from only a single time point after transplantation for each animal. In vivo bioluminescence imaging was therefore explored as a method to gain a dynamic, longitudinal profile of human HSC engraftment in a living xenogeneic model. Luciferase expression using a lentiviral vector allowed detection of distinctly different patterns of engraftment kinetics from human CD34+ and CD34+CD38- populations in the marrow NOD/SCID/beta 2mnull mice. Imaging showed an early peak (day 13) of engraftment from CD34+ cells followed by a rapid decline in signal. Engraftment from the more primitive CD34+CD38- population was relatively delayed but by day 36 increased to significantly higher levels than those from CD34+ cells (P <.05). Signal intensity from CD34+CD38-engrafted mice continued to increase during more than 100 days of analysis. Flow cytometry analysis of bone marrow from mice after death demonstrated that levels of 1% donor cell engraftment could be readily detected by bioluminescence imaging; higher engraftment levels corresponded to higher image signal intensity. In vivo bioluminescence imaging provides a novel method to track the dynamics of engraftment of human HSC and progenitors in vivo.     

Methylation of foreign DNA sequences in eukaryotic cells.

The herpesvirus thymidine kinase gene has been used to introduce foreign DNA sequences into mouse L cells by DNA-mediated gene transfer. These inserted genes were then assayed for methylation at the specific sequence C-C-G-G by using the restriction enzyme isoschizomers Hpa II and Msp I. Despite the fact that 70% of the cellular C-C-G-G sites are methylated, herpesvirus sequences, plasmid DNA, and growth hormone gene DNA were found to remain unmethylated in 90% of the clones that contain these genes. DNA that had been methylated in vitro with Hpa II methylase was also inserted into L cells. The presence of this modification in the vector DNA did not, however, guarantee that these sequences remained methylated in the recipient clones. Only 10% of all transformed clones were found to contain methylated C-C-G-G sequences in the vector DNA, and these modifications were stable for 25-50 generations. Hha I and Mbo I were used to probe for methyl groups at these restriction sites, but none of the inserted sequences acquired these modifications. These results are discussed in relation to various models put forth to explain the process of methylation in eukaryotic cells.     

Use of plain radiography to screen for cervical spine injuries.

STUDY OBJECTIVE: Standard radiographic screening may fail to reveal any evidence of injury in some patients with spinal injury. The purposes of this investigation were to document the efficacy of standard radiographic views and to categorize the frequencies and types of injuries missed on plain radiographic screening of the cervical spine. METHODS: All patients with blunt trauma selected for radiographic cervical spine imaging at 21 participating institutions underwent a standard 3-view series (cross-table lateral, anteroposterior, and odontoid views), as well as any other imaging deemed necessary by their physicians. Injuries detected with screening radiography were then compared with final injury status for each patient, as determined by review of all radiographic studies. RESULTS: The study enrolled 34,069 patients with blunt trauma, including 818 patients (2.40% of all patients; 95% confidence interval [CI] 2.40% to 2.40%) having a total of 1,496 distinct cervical spine injuries. Plain radiographs revealed 932 injuries in 498 patients (1.46% of all patients; 95% CI 1.46% to 1.46%) but missed 564 injuries in 320 patients (0.94% of all patients; 95% CI 0.94% to 0.94%). The majority of missed injuries (436 injuries in 237 patients [representing 0.80% of all patients]; 95% CI 0.80% to 0.80%) occurred in cases in which plain radiographs were interpreted as abnormal (but not diagnostic of injury) or inadequate. However, 23 patients (0.07% of all patients; 95% CI 0.05% to 0.09%) had 35 injuries (including 3 potentially unstable injuries) that were not visualized on adequate plain film imaging. These patients represent 2.81% (95% CI 1.89% to 3.63%) of all injured patients with blunt trauma undergoing radiographic evaluation. CONCLUSION: Standard 3-view imaging provides reliable screening for most patients with blunt trauma. However, on rare occasions, such imaging may fail to detect significant unstable injuries. In addition, it is difficult to obtain adequate plain radiographic imaging in a substantial minority of patients.     

An unusual complication of missed appendicitis

A case of necrotizing fasciitis complicating missed appendicitis with perforation and abscess formation in a 63-year-old diabetic is presented. The case emphasizes the importance of thorough, conservative evaluation and management in elderly diabetic patients. The ED management of patients with necrotizing fasciitis is also briefly reviewed.     

The Elder Patient with Suspected Acute Coronary Syndromes in the Emergency Department

Objectives To describe the evaluation and outcomes of elder patients with suspected acute coronary syndromes (ACS) presenting to the emergency department (ED). Methods This was a post hoc analysis of the Internet Tracking Registry for Acute Coronary Syndromes (i^?trACS) registry, which had 17,713 ED visits for suspected ACS. First visits from the United States with nonmissing patient demographics, 12‐lead electrocardiogram results, and clinical history were included in the analysis. Those who used cocaine or amphetamines or left the ED against medical advice were excluded. Elder was defined as age 75 years or older. ACS was defined by 30‐day revascularization, Diagnosis‐related Group codes, or death within 30 days with positive cardiac biomarkers at index hospitalization. Multivariable logistic regression analyses were performed to determine the association between being elder and 1) 30‐day all‐cause mortality, 2) ACS, 3) diagnostic tests ordered, and 4) disposition. Multivariable logistic regression was also performed to determine which clinical variables were associated with ACS in elder and nonelder patients. Results A total of 10,126 patients with suspected ACS presenting to the ED were analyzed. For patients presenting to the ED, being elder was independently associated with ACS and all‐cause 30‐day mortality, with adjusted odds ratios of 1.8 (95% confidence interval [CI] = 1.5 to 2.2) and 2.6 (95% CI = 1.6 to 4.3), respectively. Elder patients were more likely to be admitted to the hospital (adjusted odds ratio, 2.2; 95% CI = 1.8 to 2.6), but there were no differences in the rates of cardiac catheterization and noninvasive stress cardiac imaging. Different clinical variables were associated with ACS in elder and nonelder patients. Chest pain as chief complaint, typical chest pain, and previous history of coronary artery disease were significantly associated with ACS in nonelder patients but were not associated with ACS in elder patients. Male gender and left arm pain were associated with ACS in both elder and nonelder patients. Conclusions Elder patients who present to the ED with suspected ACS represent a population at high risk for ACS and 30‐day mortality. Elders are more likely to be admitted to the hospital, but despite an increased risk for adverse events, they have similar odds of receiving a diagnostic test, such as stress cardiac imaging or cardiac catheterization, compared with nonelder patients. Different clinical variables are associated with ACS, and clinical prediction rules utilizing presenting symptoms should consider the effect modification of age.