Terminal acute myelogenous leukemia in a patient with congenital agranulocytosis

Congenital agranulocytosis terminating in acute myelogenous leukemia has been previously reported in only two cases of adolescent males. We describe the clinical and laboratory features of a 13-year-old male with congenital agranulocytosis, treated with G-CSF with initial good neutrophil response, who subsequently developed acute myeloid leukemia. This rare complication may define a preleukemic subset of patients for whom G-CSF therapy is ineffective. The diagnostic challenges of this case are presented.     

Normalization of the blood lactate profile in athletes

The power output-blood lactate or velocity-blood lactate relationship, the lactate "profile", is a widely used method for the evaluation of athletes. Recent observations have suggested a shift in the blood lactate profile when athletes are fatigued, as at training camps. This study was designed to determine whether the blood lactate profile could be corrected for progressive muscle glycogen depletion by normalizing for the peak exercise blood lactate concentration. Ten well-trained subjects performed incremental cycle ergometer exercise followed by supramaximal exercise (Wingate test) following 3 days of usual and 3 days of heavier than usual training. Following heavier than usual training, blood lactate accumulation was reduced during submaximal exercise such that the power output associated with a lactate concentration of 4 mM was significantly increased (3.08 vs 3.51 W/kg). The maximal blood lactate concentration was also reduced (14.8 vs 12.7 mM) although average supramaximal power output was unchanged (9.03 vs 8.92 W/kg). When the submaximal blood lactate concentrations were normalized for the maximal blood lactate concentration, there were no significant differences in the power output associated with 20% (2.6 vs 2.7 W/kg), 25% (3.1 vs 3.2 W/kg), or 30% (3.3 vs 3.5 W/kg) of maximal lactate. The results suggest that normalization based on peak exercise blood lactate may be a useful strategy for circumventing one of the primary practical barriers to the use of the blood lactate profile in athletes.     

"Crack smoke" is a respirable aerosol of cocaine base

The smoking of cocaine base [corrected] ("crack") has emerged as a significant substance abuse problem. A detailed characterization of cocaine smoke is a prerequisite for studies of its pharmacokinetics, abuse potential and toxicity. Model pipes were used to generate cocaine smoke analogous to that inhaled by human "crack" abusers. Using procedures to minimize pyrolysis, cocaine base smoke was determined to be 93.5% cocaine particles with the remainder being cocaine vapor. The average particle size generated from all model pipes was 2.3 mu which is small enough to ensure deposition into the alveolar region of the human lung. Although this particle size is eminently respirable [corrected] by primates, a much smaller fraction will reach the alveolar region of rodents. Special generating procedures would therefore be required to expose rodents to meaningful doses of airborne cocaine that mimic the rapid absorption achieved by "crack" smokers.     

Effect of lipopolysaccharide and lipid A on mouse liver pyruvate kinase activity.

Several investigators have reported lipid A as the biologically active unit in the lipopolysaccharide (LPS) molecule. To determine if lipid A was responsible for the reported increases in pyruvate kinase, mice were injected with endotoxin from Salmonella typhimurium SR-11, the Re mutant of Salmonella minnesota R 595, and lipid A-bovine serum albumin conjugate. The livers were homogenized and the activity of pyruvate kinase was measured. Similar increases in enzyme were obtained with all three preparations. These data imply that the lipid portion of the LPS molecule was responsible for alterations in host enzyme activity. To further determine if the lipid portion was the active unit, a lipid-degraded endotoxin (endotoxoid) prepared by potassium methylate treatment was inoculated into mice. An initial increase in liver pyruvate kinase activity was observed with all preparations. The marked increase observed at 16 h with the native product and lipid A conjugate was not obtained with the endotoxoid. These experiments extend and confirm previous observations that lipid A is responsible for the effects associated with LPS. Animals tolerant to endotoxin from S. typhimurium SR-11 were challenged with endotoxin from the Re mutant. A significant increase in pyruvate kinase activity was not obtained, suggesting that anti-O antibodies are not important in the development of tolerance.     

Effects of estrogen replacement on the progression of coronary-artery atherosclerosis

BACKGROUND: Heart disease is a major cause of illness and death in women. To understand better the role of estrogen in the treatment and prevention of heart disease, more information is needed about its effects on coronary atherosclerosis and the extent to which concomitant progestin therapy may modify these effects. METHODS: We randomly assigned a total of 309 women with angiographically verified coronary disease to receive 0.625 mg of conjugated estrogen per day, 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate per day, or placebo. The women were followed for a mean (+/-SD) of 3.2+/-0.6 years. Base-line and follow-up coronary angiograms were analyzed by quantitative coronary angiography. RESULTS: Estrogen and estrogen plus medroxyprogesterone acetate produced significant reductions in low-density lipoprotein cholesterol levels (9.4 percent and 16.5 percent, respectively) and significant increases in high-density lipoprotein cholesterol levels (18.8 percent and 14.2 percent, respectively); however, neither treatment altered the progression of coronary atherosclerosis. After adjustment for measurements at base line, the mean (+/-SE) minimal coronary-artery diameters at follow-up were 1.87+/-0.02 mm, 1.84+/-0.02 mm, and 1.87+/-0.02 mm in women assigned to estrogen, estrogen plus medroxyprogesterone acetate, and placebo, respectively. The differences between the values for the two active-treatment groups and the value for the placebo group were not significant. Analyses of several secondary angiographic outcomes and subgroups of women produced similar results. The rates of clinical cardiovascular events were also similar among the treatment groups. CONCLUSIONS: Neither estrogen alone nor estrogen plus medroxyprogesterone acetate affected the progression of coronary atherosclerosis in women with established disease. These results suggest that such women should not use estrogen replacement with an expectation of cardiovascular benefit.     

Identification of two point mutations and a one base deletion in exon 19 of the dystrophin gene by heteroduplex formation

Two thirds of the Duchenne muscular dystrophy population haveeither gene deletions or duplications. The nondeletion/duplicationcases are most likely the result of point mutations or smalldeletions and duplications that cannot be easily identifiedby current strategies. The major obstacle in identifying smallmutations is due to the large size of the dystrophin gene. Weselectively screened 5 DMD exons containing CpG dinucleotidesin 110 DMD patients without detectable deletions or duplications.Nonsenses mutations are frequently due to a C- to -T transitionwithin a CG dinucleotide pair. To screen for the nonsense mutations,we used the heteroduplex method. Utilizing this approach, weidentified 2 different nonsense mutations and a single basedeletion all occurring in exon 19. This is the first reportof a clustering of small mutations in the the dystrophin gene.     

Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.      

X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase

X-linked liver glycogenosis type II (XLG II) is a recently described X- linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.      

Review of Technology: Planning for the Development of Telesonography

Teleradiology allows contemporaneous interpretation of imaging exams performed at some distance from the interpreting radiologist. The transmitted images are usually static. However, there is benefit to real-time review of full-motion ultrasound (US) exams as they are performed. Telesonography is transmission of full-motion sonographic data to a remote site. We hypothesize that US exams, read after having been compressed utilizing Motion Picture Experts Group version 4 (MPEG-4) compression scheme, transmitted over the Internet as streaming multimedia, decompressed, and displayed, are equivalent in diagnostic accuracy to reading the examinations locally. MPEG-4 uses variable compression on each image frame to achieve a constant output bit rate. With less compression, the bit rate rises, and the only way the encoder can contain bit rate within the set bandwidth is by lowering frame rate or reducing image quality. We review the relevant technologies and industry standard components that will enable low-cost telesonography.