Apoptosis and macrophage-mediated deletion of precursor B cells in the bone marrow of E mu-myc transgenic mice

Transgenic mice expressing the c-myc proto-oncogene under the control of the Ig heavy chain enhancer (E mu-myc) all eventually develop clonal pre-B- or B-cell tumors. The preneoplastic period is characterized by increased polyclonal proliferation of pro-B and pre-B cells in the bone marrow (BM) associated with a reduced number of B cells, suggesting a high degree of B-cell loss. To examine the mechanisms of this cell loss, we have identified B220+ B-lineage cells within the BM of pretumorous E mu-myc transgenic mice by in vivo radiolabeling and electron microscope radioautography. Large mitotic B220(+)-labeled cells form prominent clusters in the extravascular compartment of the BM. Some B220+ small lymphocytes, as well as large lymphoid cells, enter BM sinusoids. However, in addition, large numbers of B220+ cells exhibit nuclear chromatin condensation, fragmentation, and other morphologic features characteristic of apoptotic cell death. Propidium iodide staining and flow cytometry of BM cells from pretumorous E mu- myc transgenic mice, as well as agarose gel electrophoresis of DNA, confirm extensive apoptosis. Many B220+ apoptotic cells are closely associated with the extensive processes of prominent macrophages that contain numerous B220+ apoptotic bodies and complex lysosomal systems. These results suggest that the constitutive expression of c-myc oncogene in BM B-lineage cells, which increases the proliferation of precursor B cells, also leads to increased apoptotic cell death and rapid elimination by resident macrophages. Further mutations may be needed to block these protective mechanisms and permit surviving c-myc- dysregulated cells to leave the BM and to initiate tumorigenesis.     

Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C-->T, is present at an unexpectedly high frequency in the general population, as was the case for 625G-->A, together conferring susceptibility to ethylmalonic aciduria

We have shown previously that a variant allele of the short-chain acyl- CoA dehydrogenase ( SCAD ) gene, 625G-->A, is present in homozygous form in 7% of control individuals and in 60% of 135 patients with elevated urinary excretion of ethylmalonic acid (EMA). We have now characterized three disease-causing mutations (confirmed by lack of enzyme activity after expression in COS-7 cells) and a new susceptibility variant in the SCAD gene of two patients with SCAD deficiency, and investigated their frequency in patients with elevated EMA excretion. The first SCAD-deficient patient was a compound heterozygote for two mutations, 274G-->T and 529T-->C. These mutations were not present in 98 normal control alleles, but the 529T-->C mutation was found in one allele among 133 patients with elevated EMA excretion. The second patient carried a 1147C-->T mutation and the 625G- ->A polymorphism in one allele, and a single point mutation, 511C-->T, in the other. The 1147C-->T mutation was not present in 98 normal alleles, but was detected in three alleles of 133 patients with elevated EMA excretion, consistently as a 625A-1147T allele. On the other hand, the 511C-->T mutation was present in 13 of 130 and 15 of 67 625G alleles, respectively, of normal controls and patients with elevated EMA excretion, and was never associated with the 625A variant allele. This over-representation of the haplotype 511T-625G among the common 625G alleles in patients compared with controls was significant ( P < 0.02), suggesting that the allele 511T-625G-like 511C-625A- confers susceptibility to ethylmalonic aciduria. Expression of the variant R147W SCAD protein, encoded by the 511T-625G allele, in COS-7 cells showed 45% activity at 37 degrees C in comparison with the wild- type protein, comparable levels of activity at 26 degrees C, and 13% activity when incubated at 41 degrees C. This temperature profile is different from that observed for the variant G185S SCAD protein, encoded by the 511C-625A allele, where higher than normal activity was found at 26 and 37 degrees C, and 58% activity was present at 41 degrees C. These results corroborate the notion that the 511C-625A variant allele is one of the possible underlying causes of ethylmalonic aciduria, and suggest that the 511C-->T mutation represents a second susceptibility variation in the SCAD gene. We conclude that ethylmalonic aciduria, a commonly detected biochemical phenotype, is a complex multifactorial/polygenic condition where, in addition to the emerging role of SCAD susceptibility alleles, other genetic and environmental factors are involved.      

The spine: changes in T2 relaxation times from disuse

Magnetic resonance imaging of the spine was performed in six healthy male volunteers before and after 5 weeks of continuous bed rest. Imaging studies consisted of a single 1-cm sagittal section obtained with a spin-echo technique through the center of the spinal column. The T2s of the lumbar vertebral body and nucleus pulposus and the area of the latter were measured. In both vertebrae and disks, there was a significant decrease in T2 after bed rest. The nucleus pulposus also decreased in size with bed rest. The decrease in relaxation time of the lumbar vertebrae could be explained by the replacement of hematopoietic marrow by fatty marrow, a known consequence of paralytic immobilization. The decreases in size and T2 of the disks probably represent loss of water. The significance of these changes to the mechanical integrity of these structures after immobilization or space flight is not known but will depend in part on whether changes are progressive with increasing length of immobilization and on the rate and extent that they are reversed after reambulation. These results indicate that relaxation times can be altered by simple disuse, which often accompanies the underlying disease.     

Critical analysis of radiologist-patient interaction

A critical incident interview technique was used to identify features of radiologist-patient interactions considered effective and ineffective by patients. During structured interviews with 35 radiology patients and five patients' parents, three general categories of physician behavior were described: attention to patient comfort, explanation of procedure and results, and interpersonal sensitivity. The findings indicated that patients are sensitive to physicians' interpersonal styles and that they want physicians to explain procedures and results in an understandable manner and to monitor their well-being during procedures. The sample size of the study is small; thus further confirmation is needed. However, the implications for training residents and practicing radiologists in these behaviors are important in the current competitive medical milieu.     

Screening tests for blood donors presumed to have transmitted the acquired immunodeficiency syndrome

We investigated 18 sets of blood donors from 12 to 50 months after they donated blood to recipients who subsequently developed the acquired immunodeficiency syndrome (AIDS). Within each donor set, only one donor was suspected of having transmitted the disease (ie, member of an AIDS risk group). The other donors (n = 189) were not risk group members and served as controls. A number of laboratory tests distinguished suspected from nonsuspected donors, including determination of T helper/T suppressor cell ratio, antibody to hepatitis B core antigen, and immune complexes, but none of these was as sensitive and specific as tests for antibody to the human retrovirus, HTLV-III/LAV.     

SYSTOLIC MURMURS IN APPARENTLY HEALTHY INDIVIDUALS

Presence of a systolic murmur is not always indicative of organic heart disease or abnormality, especially so in asymptomatic individuals. We studied 210 young adults (192 males, 18 females) of the age group 16 to 23 years with systolic murmurs to evaluate the utility of noninvasive tests in ascertaining the presence or absence of heart disease. Each case was categorized after clinical evaluation and again after noninvasive investigations (chest radiogram, 12 lead ECG, and echocardiography) into 3 groups. Based on clinical evaluation alone, 190 (90.5%) cases had no evidence of heart disease (group A), 16 (7.6%) cases had definite heart disease (group C) and in 4 (1.9%) cases the presence of heart disease could not be ruled out definitely (group B). The recategorization after investigations did not alter the initial diagnosis in any of the subjects from groups A and C (98.1%). Two cases from group B (0.95%) changed groups whereas in the remaining 2 cases (0.95%) from group B no definite conclusions could be reached even after echocardiography.KEY WORDS: Heart disease, Heart murmurs, Echocardiography, Diagnosis     

Carcinoma breast metastatic to the hand and the foot

Metastases to the peripheral bones of the extremities are rare. Such lesions are often diagnosed as inflammatory or infective in nature. We present a report of a case of simultaneous involvement of the peripheral bones of the extremities – the talus and the thumb of the left hand – with a brief review of pathophysiology and management.     

Effect of 0.5 mm larger donor corneal size on intraocular pressure following penetrating keratoplasty

Background

Glaucoma can develop after penetrating keratoplasty resulting in irreversible loss of vision. The incidence of post-penetrating keratoplasty glaucoma varies from 31% in the early postoperative period to 29% after three months. Various factors are responsible for the rise of intraocular pressure (IOP). This study was carried out to evaluate the effect of 0.5 mm larger donor corneal size on IOP following penetrating keratoplasty.

Methods

Patients were divided into two groups: group I was phakic and group II consisted of aphakic and pseudophakic patients. The same surgical technique was used for obtaining and suturing the donor graft. The viscoelastics and the postoperative regime also remained the same in all cases. IOP was measured by the rebound tonometer.

Results

The incidence of postoperative raised IOP in the first seven days in the phakic group was found to range from 16 mmHg to 25 mmHg and IOP in the aphakic/pseudophakic group ranged from 16 mmHg to 42 mmHg. The IOP in the phakic group after three weeks of surgery was around 12.3 mmHg and that in the pseudophakic/aphakic group was 14.8 mmHg-16.2 mmHg. In aphakic patients, IOP was controlled in the first six months with eyedrops Timolol 0.5% and tablet acetazolamide which was given only for short periods. IOP settled to <12 mmHg with timolol 0.5% after six months. In the pseudophakic patients, IOP became normal by six months. These were inclusive of patients who had undergone anterior reconstruction and/or vitrectomy.

Conclusion

The study proves that keeping the donor corneal size 0.5 mm larger does not affect IOP and that aphakia itself is a factor responsible for rise of IOP due to anterior chamber angle compression.